Department of Neuroscience and Pharmacology

Department of Neuroscience and Pharmacology
Annual Report 2012
Mission statement
It is our mission to seek explanations
of how minds make molecules and
molecules make sense, and to impart
these explanations to students of medicine, human biology, odontology and
other health-related disciplines, and
the general public, in order to promote
general understanding of the brain and
the body, and to benefit the health and
prosperity of humankind.
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Annual Report 2012
Table of Contents
Preface 4
Staff and Organization
8
Laboratories 13
PhD Theses
57
Publications 58
Financial Overview
67
Preface
The Department of Neuroscience and Pharmacology
(DNP) was a novelty at the University of Copenhagen
as well as in Denmark as a whole when it was founded
in 2007. Researchers at other conventional teaching
departments voluntarily elected to join the new entity,
in connection with a total restructuring of the Faculty
of Health Sciences, now known as the Faculty of Health
and Medical Sciences. The restructuring meant that
teaching departments were reshuffled and new research
departments created in their place. The teaching would
now be a Faculty task, while research would be managed in research departments and in externally funded
but temporary centers of excellence. In the case of
the DNP, the researchers came from erstwhile classical
departments such as physiology, anatomy, biochemistry,
and pharmacology, as well as from more specialized
departments such as the Protein Laboratory and the
Institute of Eye Pathology, which all ceased to exist as
independent units when the DNP was formed.
Research Themes
The integration of these diverse traditions and research
methods became a major task of the new department.
The research was subsumed under the deliberately
equivocal motto “Minds Make Molecules, Molecules
Make Sense”, which at one level encompasses the roles
of mind, molecules, and sense in the generation of
conscious brain functions, and at another level describes
the roles of researchers in the discovery and evaluation
of new drugs that benefit living creatures. The efforts
of the department are seen as moving from the purest
molecular pharmacology via neuropsychopharmacol4
Annual Report 2012
ogy to an understanding of signaling among neuronal
networks and its roles in the execution of conscious and
unconscious motor acts by animals and humans. The
three themes that define the work of the department
are reflected in the department’s motto. The concepts
of minds, molecules, and sense seamlessly tie together
the activities of the department. The themes include the
study of minds that make and release molecules in the
brain, and the molecules that make sense of the world
that minds depend on.
First, minds make molecules by means of synthesis and
release of transmitters and modulators, as evidenced in
this department by the operation of ion channels, the
fusion machinery that is active during exocytosis, the
phasic and tonic release of neuromodulators such as
dopamine, and the interactions of neurotransmitters,
neuropeptides and growth factor receptors with synaptic
cell adhesion molecules, , which are key agents in the
interpretation of molecular cues in the brain and determinants of synaptic plasticity. How mindsets accomplish
these mechanical acts is of course one of two ultimate
mysteries of conscious life.
Second, molecules make sense by specific interaction
with receptors and transporters, as described by the 7TM
toggle model and the dopamine transporter sites, and by
the mechanism of gain modulation of synaptic input, including the modulation of synaptic input to retinal granule cells. The mechanisms are not only mechanical but
also topographic as shown by the possible effects of differences of membrane shape. The way molecules make
sense of the world can now be shown in cells grown on
nanowires. These essentially mechanical interactions are
of course easier to conceive of than the mechanical effects of minds and hence they occupy a major part of the
attention of the department’s researchers.
Third, the sense provided by molecular interactions
evidently makes up our minds, by means of plastic processes during development, maturation, and aging, as
exemplified by the cobblestone domains of ionic currents
that appear to define neurons during development, and
the serotonergic modulation of spike initiation of central
fatigue. The genetics of retinal and olfactory circuits
affect development as modeled by drosophila eyes,
and the genetics of mood seem to contribute to major
depression. The sense of ghrelin regulates appetite, and
the sense of other molecules affects food intake, light
responsive ganglion cells that regulate circadian rhythms
and the contents of minds in blindness and blindsight.
Plasticity also influences the work of motor-neurons after
spinal cord injury.
The way sense makes minds is the second ultimate
mystery of conscious life. Energy turnover as measured
by oxygen consumption may be responsible for the
phase transition from unconscious to conscious sensation by actively inducing the molecular transformations
that enable conscious integration. Neuroglobins and
uncoupling proteins are possible regulators of this transition. How molecular transformations make minds is
unknown and remains our ultimate challenge.
Department Structure
At the last count, the DNP had 335 associated researchers and staff members, working in nine designated labo-
Albert Gjedde
ratories and one administrative unit. Of the 335 members, 29 are tenured professors and associate professors,
and 46 are so-called junior scientists in tenure-track or
temporary appointments. The department is also host to
114 Master and Graduate students, as well as 97 guest
researchers from many places around the world. The
technical and administrative staff now numbers 42 individuals, which is comparatively low by Danish standards.
The research is distributed among the nine laboratories
of the department, ranging from the Molecular Pharmacology Laboratory, via the Molecular Neuropharmacology and Genetics Laboratory, the Neuropsychiatry
Laboratory, and the Protein Laboratory, to the Neuronal
Signaling Laboratory, the Cellular and Systems Neurobiology Laboratory, known as the CSNlab, the Motor
Control Laboratory, and the Brain Research and Integrative Neuroscience Laboratory, abbreviated BRAINlab. The
Annual Report 2012
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1
2
3
4
5
Eye Pathology Laboratory has a special status as the only
laboratory with routine clinical tasks in the service of eye
surgery. Typically a laboratory has three tenured scientists, 5 non-tenured researchers, 11 guest researchers, 13
students, and 4 technicians. Thus, each laboratory has
about 36 members, usually divided into three collaborating research groups, a size identified in many studies as
ideal for breakthrough research.
In all the laboratories, researchers do animal work,
and in four of the laboratories they also study humans
in health or disease. Each laboratory is headed by an
elected Coordinator, and the coordinators form the
department’s Coordination Committee together with the
management team, the latter composed of the Department Manager, and the incumbents of the Chair and the
three Vice Chairs for neurobiology and pharmacology
research and teaching, respectively.
All members of the DNP congregate at an annual
two-day meeting away from home where the research
and the affairs of the department are reviewed. Each
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Annual Report 2012
member group, senior faculty, junior faculty, students
and technical-administrative staff, has a forum, which
contributes to the annual meeting with criticism and
strategic suggestions. At the latest annual meeting in
January 2013 the members reviewed the approximately
150 peer-reviewed full papers published by the department in 2012, including one publication in Nature
Communication, three publications in PNAS, one paper
in Biological Psychiatry, and one paper in PLoS Biology.
Productivity
The productivity of the department in the three areas
of effort, teaching, research, and outreach, is measurable in several ways. In all three areas, the efforts make
an impact, and an impact can be gauged by appropriate means. In teaching, the impact is felt in terms of
students’ performance at exams. Unfortunately, the
performance is determined only as the percentage of
students that pass the exams and complete their education, rather than the grades in relation to students’
abilities. It is the sad truth here that the efforts change
to match the measures, rather than improve in relation
to an objective standard. Thus, the challenge is to make
students pass, rather than to make sure that they match
the objective standards.
The same trend is evident in the research area, in which
efforts now are influenced by the bibliometric measures
that are used to gauge research productivity. Thus we
encounter Hirsch index massage and citation optimization, both from researchers and from journals, which ask
authors of submitted papers whether they can include
more citations of papers published in that journal. Yet,
the fact is that Hirsch indices depend on age of authors
and number of published papers per author, rather than
mainly on the quality of the authorship and the science.
Finally, the impact of outreach is extremely uncertain and
random, subject to forces that have very little relation to
academic values, as recent scandals have revealed. It is
not known to which extent the impact of outreach can
reliably by determined, beyond the fifteen minutes of
fame that we are all entitled to enjoy. In this context, the
impact of the department’s research is the main concern.
A department of the present size has multiple
themes, as outlines above, with differently sized national
and international networks that affect citation rates. This
is an important perspective when evaluators compare
the bibliometric indices of different researchers and
groups at the department. The observation that Hindices depend primarily on age and number of papers
is confirmed by this department, as shown in Figure 1,
which covers tenured researchers at the department,
associate professors in light gray and full professors in
dark gray. The graph confirms the well-know observation
that average H-indices of generally reputable scientists in
the life-sciences average unity, relative to age minus 30
of the author. Thus, indices above the line of slope = 1
are above average and indices below that line are below
average.
H-indices also vary as a function of number of papers
published, but the ratio of H-index relative to the number
of papers declines rapidly. A scientist may publish numerous extremely highly cited papers as lone author, or as
co-author, but he or she cannot exceed the H index
that corresponds to the number of papers, regardless of
success. In Figure 2, the Nobel laureate indicated by the
black dot had neither the highest number of papers nor
the highest H index. Figure 2 is not based on departmental statistics but is culled from a separate academic environment to enlarge the range of publications numbers.
The department’s subdivisions of laboratories can
be graded in terms of average age-corrected H-indices,
calculated as Hirsch/(Age-30), and the grades likewise
differ from average much above unity to averages much
below, as shown in Figure 3. This distribution is likely
to be tied to success in grant applications as shown in
Figure 4, in which the laboratories’ current (May 2013)
grant totals are listed with the same laboratory references. While success in grantmanship is not guaranteed
for the highest age corrected H-index averages, a low H
index average almost invariably is associated with poor
application success, as shown in Figure 5. Thus, a major
task of the department consists in improving the application success rate by raising the H index averages.
Annual Report 2012
The Annual Report 2012 is an expansion of a financial
statement that the Department of Neuroscience and
Pharmacology (also known as INF) is obliged to make
every year. The plan to demonstrate that we put funds to
very good use is a new initiative which is still evolving.
We place the report on our homepage and you can print
out copies for extracurricular reading. If you find errors,
see problems, and have comments, please let us know.
You will benefit next year’s report that way. Whatever
it is that you are happy or unhappy about in the report,
it is actually important additional evidence that minds
do make molecules that do make sense that does make
minds.
Albert Gjedde
Annual Report 2012
7
Staff and ­
organization
The Department of Neuroscience and Pharmacology (INF)
is the first department of Neuroscience at the University
of Copenhagen, and the creation of the Department reflects the global interest in research in neuroscience. The
Department is spread out over several buildings at the
Panum Institute under the Faculty of Health and Medical
Sciences (SUND). The Eye Pathology and Neuropsychiatry laboratories are both situated at Rigshospitalet, the
Bionanotechnology and Nanomedicine Laboratory at the
H.C. Ørsted Institute, and the rest of the laboratories
are situated in the Panum Institute. INF was created in
connection with organizational restructuring at SUND on
the 1st of January, 2007, and the Department consists
of research groups from almost all previous departments
at the Faculty. The Anthropological Laboratory and two
research groups from the Department of Exercise and
Sport Science were previously in Building 33.3, which is
now occupied by the Department. There are 9 laboratories, 2 clusters, and 1 research school affiliated with the
Department.
Management team
• Head of Department, Albert Gjedde
• Deputy Head of Department for instruction
in Neuroscience, Henrik Jahnsen
• Deputy Head of Department for instruction
in Pharmacology, Mette Rosenkilde
• Deputy Head of Department for research
in Pharmacology, Thue W. Schwartz
• Department Administrator, Tine Olsen
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Annual Report 2012
Adjunct Professors
Hansen, Anker Jon
Keiding, Susanne
Wong, Dean Foster
Senior Faculty
Berezin, Vladimir
Berg, Rune
Bock, Elisabeth Marianne
Eriksen, Tine Alkjær
Gether, Ulrik
Gjedde, Albert
Hay-Schmidt, Anders
Heegaard, Steffen
Holst, Birgitte
Hounsgaard, Jørn Dybdahl
Hultborn, Hans
Jahnsen, Henrik
Kjærulff, Ole
Larsen, Jytte Overgaard
Lauritzen, Martin Johannes
Løland, Claus Juul
Mellerup, Erling Thyge
Midtgaard, Jens
Møller, Morten
Olsen, Niels Vidiendal
Perrier, Jean-Francois
Plenge, Per Krener
Prause, Jan Ulrik
Rekling, Jens
Rosenkilde, Mette Marie
Schwartz, Thue Walter
Simonsen, Erik Bruun
Sørensen, Jakob Balslev
Walmod, Peter Schledermann
Woldbye, David
Junior Faculty
Antoku, Yasuko
Barkat, Tania Rinaldi
Benned-Jensen, Tau
Boni, Louise Juhl
Christiansen, Søren Hoffman Oliviera
Dreyer, Jakob K.K.
Elbrønd-Bek, Heidi
Eriksen, Jacob
Frandsen, Aase
Gesslein, Bodil
Gotfryd, Kamil
Jensen, Dorte Marie Skytt
Jørgensen, Trine Nygaard
Klementjev, Boris
Kolko, Miriam
Kolkova, Katya
Korchounova, Irina
Kubiak, Xavier
Kucharz, Krzysztof
Kupers, Ronny Clement Florent
Madsen, Kenneth Lindegaard
Mathiesen, Claus
Meehan, Claire
Moldovan, Mihai
Nielsen, Janne
Noraberg, Jens
Pallesen, Karen Johanne
Pankratova, Stanislava
Petersen, Peter Christian
Pinheiro, Paulo
Ptito, Maurice
Rasmussen, Peter
Rasmussen, Søren Gøgsig Faarup
Rath, Martin Fredensborg
Rickhag, Mattias
Roland, Per Ebbe
Rose, Nadia Cherouati
Rovsing, Louise
Spiess, Katja
Stecina, Katinka
Sørensen, Gunnar
Vafaee Seyedi, Manoucher
Walter, Alexander
Weikop, Pia
Wierda, Keimpe
Student Body
Andreassen, Thorvald Faurschou
Anjum, Uswa
Arfelt, Kristine Niss
Billesbølle, Christian Bache
Blok, Julie Elgaard
Bonde, Lars Holtse
Broberg, Christoffer
Cakmak, Ishak
Carlsen, Eva Maria Meier
Christensen, Rasmus Kordt
Christensen, Louise Videbæk
Christensen, Peter Møller
Christiansen, Martin Sandau
Da Silva, Mari-Ann
Dietz, Lene Thea
Dmytriyeva, Oksana
Egeskov-Madsen, Anuska La Rosa
Engelstoft, Maja Storm
Federspiel, Frederik
Gjørlund, Michelle Denise
Graae, Anne-Sofie
Guld, Asger Toke
Guzulaitis, Robertas
Gøtzsche, Casper Rene
Hansen, Naja Liv
Herlo, Rasmus
Herly, Mikkel
Herskind, Anna
Holm-Hansen, Signe
Jansen, Anna Mai
Jensen, Ann-Sofie Mølleskov
Jensen, Nanna Hovelsø
Jensen, Kristian Høj Reveles
Jensen, Sara Stilling
Jessen, Sanne Barsballe
Johansen, Annette
Johnsen, Cecilie Hundahl
Kamstrup, Kristian Møgeltoft
Karlsen, Anna Kirstine Schou
Karlsen, Morten Lundin
Khennouf, Lila
Koblauch, Henrik
Krüger, Dinna B
Larsen, Ann-Cathrine
Annual Report 2012
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Li, Dana
Lind, Barbara Lykke
Lind, Jonna
Lund, Viktor Karlovich
Løbner, Laura Louise Nalubega Flei
Madsen, Christian Medom
Mathiesen, Signe
Meiadi, Amani
Mortensen, Kristian Nygaard
Munch, Anders Sonne
Müller, Felix
Møller, Anne Cathrine Laustrup
Navntoft, Charlotte
Nielsen, Maiken
Nielsen, Morten Unger
Nikanorov, Andrey
Nordgaard, Julie Caroe
Pedersen, Anna-Kathrine
Pedersen, Ellis
Petersen, Anders Victor
Petersen, Pernille Emilie
Ponsaing, Laura Graves
Raffalt, Peter
Rahbek, Mette
Rahbek-Clemmensen, Troels
Raida, Zindy
Rasmussen, Ida Søndergaard
Rasmussen, Peter Kristian
Regnell, Christine
Ren, Liqun
Roed, Sara Nørklit
Rohde, Kristian
Rosberg, Mette Romer
Rostgaard, Nina
Rummel, Pia
Schjoldager, Janne
Sichlau, Rasmus
Skjolding, Anders Dæhli
Sparre-Ulrich, Alexander
Steen, Anne Marie Førrisdahl
Stender, Johan
Staalsø, Jonathan Myrup
Sukiasyan, Natalya
Tawfik, Sassam
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Annual Report 2012
Toft, Trine
Toft-Kehler, Anne Katrine
Tran, Thuy Linh
Vestergaard, Mikkel
Vestmar, Marie Aare
Vouorenpää, Anne Elina
Waller, Katja Linda
Willumsen, Alex
Zhang, Yifan
Zhang, Chenying
Aachmann-Andersen, Niels Jacob
Midtgaard, Tinne
Olsen, Tine
Pedersen, Steen
Petersen, Anne-Marie Nordvig
Pihl, Maria Bergkvist
Rosenquist, Lone
Simons, Mette
Simonsen, Inger Smith
Thøgersen, Randi
Wolder, Merete Louise
Øberg, Christina Louis
Technical and Administrative
Personnel
Astrup, Thomas
Banke, Linda
Bennike, Bente Guldhammer
Broberg, Anne Mette E.L.
Brændstrup, Charlotte Taul
Clausen, Pernille Krøl
Czerny, Donna Grazyna
Elsman, Pia Hother
Engel, Lis
Feiberg, Pia S.K.
Gjedde, Albert
Grøndahl, Lillian
Hansen, Birgit Heine
Hansen, Lasse
Iversen, Henrik Lykke
Jonassen, Anna Sofie Holm
Jung, Anita Gabrielle
Khadim, Nabeela
Kimer, Tina
Korsgaard, Elisa
Kaas, Anette Dencker
Larsen, Olav
Lotfi, Mojdeh
Lønstrup, Michael
Madsen, Ole. S. Lindegaard
Madsen, Lene Nordby
Matzke, Christian
Meinertz, Dorthe
Mellergaard, Tine Thorup
Michler, Lars
External Associate Professors
Sander, Mikael
Worck, Rene
Guest Researchers
Ambartsumian, Noona
Bergersen, Linda Hildegaard
Christensen, Marie Deen
Fink-Jensen, Anders
Fordsmann, Jonas Christoffer
Gagnon, Lea
Grogorian, Mariam
Jensen, Peter Koch
Klingelhöfer, Jörg
Krarup, Christian
Loukanidine, Evgueni
Nahimi, Adjmal
Owczarek, Sylwia
Rubenstein, Amit
Soroka, Vladyslav
Steiness, Eva
Thomsen, Kirsten
von Lüttichau, Hans Rudolf
Weber, Jens
Winding, Ole
Laboratories with
interdisciplinary staff
Names with * are staff members with
appointments outside INF
Jens Bo Nielsen's group
from Department of Exercise and
Sport Sciences – Panum Institute
Andersen, Henrik
Arbonés, Dida Rodriguez
Bonnevie*, Veronika
Causse*, Lisbeth
Christensen*, Mark Schram
Christiansen*, Lasse
Choi*, Julia
Geertsen*, Svend Sparre
Hansen, Marie Stjerne
Henriksen, Lene
Johansen, Stefan
Karabanov, Anke
Lehnhoff, Janna
Li*, Xi
Lorentzen*, Jacob
Lundbye-Jensen*, Jesper
Nielsen*, Jens Bo
Nissen*, Ulla Vig
Petersen*, Nicolas
Pingel, Jessica
Pull, Marc Roig, Junior Faculty
Rosenbaum*, Anina
Willerslev-Olsen*, Maria
Schou*, Louise
Skriver, Kasper
Wiencke*, Jacob
Zhang, Mengliang
Annual Report 2012
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Annual Report 2012
Laboratories in 2o12
Brain Research and Integrative Neuroscience Laboratory
Cellular and Systems Neurobiology Laboratory
Eye Pathology Laboratory
Molecular Neuropharmacology and Genetics Laboratory
Molecular Pharmacology Laboratory
Motor Control Laboratory
Neuronal Signaling Laboratory
Neuropsychiatry Laboratory
Protein Laboratory
Read more online at inf.ku.dk/english/research/labs
Annual Report 2012
13
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Annual Report 2012
Brain Research and Integrative
­Neuroscience Laboratory
Research at the BRAINlab is aimed at understanding
normal, pathological and adaptive brain functioning,
both at the molecular and systems level, thereby using a
wide variety of techniques and approaches. Research at
the BRAINlab covers different themes, and encompasses
studies related to brain plasticity and sensory functioning, consciousness research, cortical dynamics of visual
perception, brain energy turnover and the neuropathological mechanisms of eye diseases. The BRAINlab is
physically spread out over 3 sites (18-1, 24-3 and Symbion Science Park, Østerbro). The plan is to relocate the
Symbion labs back to Panum (33-3) during spring 2013.
Research teams within BRAINlab
1. Cross-modal plasticity following sensory deprivation (Kupers-Ptito research group)
In our laboratory, we study cross-modal plasticity following the loss of a sensory input such as vision (blindness)
or audition (deafness). We thereby use a combination of
psychophysics, brain imaging techniques and transcranial
magnetic stimulation in order to study the presence of
compensatory plasticity and its underlying neural correlates. Do blind and deaf subjects compensate for their
loss of vision by developing supranormal abilities in one
of the remaining sensory domains? If so, what is the role
of the occipital cortex in this compensatory plasticity?
Lately, we have examined changes in olfactory, gustatory
and thermal processing in congenitally blind subjects.
We use in-vivo brain imaging methods to study the
effects of sensory deprivation on the reorganization
of the cortex. Our studies have shown that congeni-
tally blind subjects show significant reductions in grey
and white matter, not only along all the structures of
the visual system but also in non-visual areas. Using
diffusion-weighted magnetic resonance imaging (DWI),
we are currently investigating changes in the microstructural integrity of the major fiber tracts that connect the
visual cortex with other parts of the brain. We have now
also started collecting data in subjects suffering from
congenitally and acquired deafness in order to compare
plasticity-related changes in the brain following two different forms of sensory loss.
One of the functions of the photoreceptors in the eyes
is to provide light input to the SCN in order to synchronize circadian rhythms to the solar light-dark cycle and
prevent free-running. Considering the central role of light
in entraining the circadian rhythm to a 24-h cycle, blind
subjects are prone to disturbances in circadian rhythms.
In collaboration with the Danish Center for Sleep Medicine, we are studying sleep patterns and dream and
dream content in congenitally and late blind subjects.
2. Cerebral correlates of pain perception (Kupers
research group)
We study the cerebral correlates of pain processing in
normal and pathological conditions. In collaboration
with the University of Brussels (Belgium), we are using
fMRI to study the mechanisms underlying the emotional
conditioning of pain in normal volunteers. Nociceptive
processing is not purely dictated by the sensory characteristics of the stimulus, but is the result of the interaction between the latter and the state of the nervous
system at that particular time.
Annual Report 2012
15
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16
Annual Report 2012
3. Primate Laboratory (Ptito endocannabinoid
research group)
The monkey laboratory is situated at the Behavioral
Sceicne Foundation of the island of Saint Kitts (West
Indies). We study the development and plasticity of the
visual system in normal and cortically lesioned animals,
using traditional anatomical and histological techniques
such as tracer injections, immunohistochemistry, gene
expression, etc. The ongoing projects concern
1 the expression, localization and functional role of
cannabinoid receptors in the visual system, from the
retina up to the visual cortex. Our data indicate that
the cannabinoid receptor CB1 is mainly expressed in
the foveal cones, CB2 in the Müller cells and GPR55
in the rods. We have proposed a model for the role
of each of these cannabinoid receptors in vision that
could explain the visual effects of cannabis consumption. Moreover, CB1 and CB2 were localized in the
optic nerve and dLGN;
2) the negative effects of fetal alcohol exposure on the
development of the retina and the ascending pathways to the cortex. Our preliminary results indicate
that the endocannabinoid receptor may contribure
to the deterious effects of alcohol on retinal development by interfering with axonal growth of ganglion
cells.
4. Glaucoma research (Kolko Eye research group)
Glaucoma is one of the leading causes of blindness
worldwide. Overall, glaucoma is defined by a progressive optic neuropathy characterized by the loss of retinal
ganglion cells (RGC). The Eye research group aims to
develop a strategy for glaucoma treatment directed
against the glia cells supporting RGC, the Müller cells.
Müller cells supply the RGC with essential nutrients and
signaling components and remove damaging neurotransmitters released from the RGC. The Eye research
group has set up a model of glaucoma focusing on the
Müller cells that will be used to investigate the functional
interaction between RGC and Müller cells, and elucidate
how glaucomatous stress effect the ability of Müller cells
to support RGC.
5. Cortical network dynamics. Visual neurophysiology (Roland research group)
The group of Per Roland tries to unravel the cortical
dynamics that lead to visual perception, using very fast
voltage sensitive dye imaging and multi-electrode recordings in rodents.
6. The Brain and Muscle Energy Group (Bergersen
research group)
Conducts research in the following areas: 1) Molecular
investigations of synaptic and glial function; 2) Transgenic mice models: Neuronal dysfunction caused by
mitochondria-specific damage after inducible expression
of a mutated mtDNA repair enzyme.; 3) lactate transport
in living cells in brain tissue, and ultrastructural localization of neurotransmitter receptors in myelin; 4) Epilepsy
in patients and rat models: changes in lactate transport;
5) ADHD animal model studies: neurotransmitter receptors; 6) DNA repair and dementia.
7. Molecular Neurobiology of Aging and Consciousness (MNAC) (Gjedde research group)
CPINE: infrastructure facility founded at the DNP on
the basis of a grant from the Ministry of Science. CPINE
hosts a 9.4 Tesla magnet for in-vivo and in-vitro animal
studies.
The group explores the rise and fall of human
consciousness as functions of brain energy metabolism
and neurotransmission during development, aging, and
neurodegeneration. In collaboration with the COMA research Unit, University of Liège (Belgium), MNAC studies
brain metabolism and cerebral functioning in patients in
the minimally conscious and persistent vegetative state.
The MNAC links the BRAINlab to the Center of Healthy
Aging at Copenhagen University, CFIN at Aarhus University, and CMBN at the University of Oslo.
Research techniques
• Brain imaging (PET, fMRI, DTI, DTT, H-MRS); Kinetic
modeling
• Psychophysics; Transcranial Magnetic Stimulation
(TMS)
• Neuro-anatomy animals (immunohistochemistry, stereology); Animal models of brain plasticity (monkey,
hamster)
Annual Report 2012
17
• Very fast voltage sensitive dye imaging. Multi-electrode recordings.
• Primary cell cultures/co-culture systems
• Cell lines, Molecular biology, Western blotting; Cell
death assays
• Combined patch-clamp electrophysiology and fluorescent pH imaging
• Transgenic mice models; DNA repair
Funding
• Lundbeck fondation
• FSS
• Harland Sanders Foundation
• VOS
• Faculty of Health Sciences
Collaborations – Domestic
• DIKU, University of Copenhagen (RK, AG)
• DRCMR, Hvidovre University Hospital (RK, MP)
• Danish Center for Sleep Medicine, Glostrup University Hospital (RK, MP)
• Niels Bohr Institute (PR)
• Center of Functionally Integrative Neuroscience
(CFIN), Aarhus University (AG, RK, MP)
Collaborations – International
• School of Optometry, University of Montreal, Qc,
Canada (RK, MP)
• COMA Science group, University of Liège, Belgium
(RK, AG)
• Cognitive and Affective Neuroscience Laboratory,
University of Tilburg, the Netherlands (RK)
• McGill University, Montreal, Qc, Canada (AG, MP, RK)
• Laboratory for Human Brain Dynamics, Nicosia,
Cyprus (RK)
• Behavioral Scienc e Foundation, Saint Kitts (MP)
• Dept. of Laboratory Medicine & Molecular Diagnostics, University of Pisa, Italy (RK, MP)
• Institute of Neuroscience, Université de Louvain,
Brussels, Belgium (RK)
• Neuroscience Center and Department of Ophthalmology, NO, USA (MK)
• University of Nice-Sophia Antipolis, France (MK)
• Department of Ophthalmology, University of Mainz,
Germany (MK)
18
Annual Report 2012
• University of Pompeo Fabra, Barcelona, Spain (PR)
• CNRS, Gif sur Yvette, France (PR)
• CNRS research for theoretical neuroscience, Marseille, France (PR)
• Department of Biophysics, Georgetown University,
Washington, USA (USA)
• University College London, UK (LHB)
• Yale University Medical School, New Haven, USA
(LHB)
• Rikshospitalet, Oslo, Norway (LHB)
• Centre for Molecular Biology and Neuroscience
(CMBN), University of Oslo (AG, LHB)
• Johns Hopkins University (JHU), Baltimore, US (AG)
BRAINlab 2012 Publications
1. Aanerud J, Borghammer P, Chakravarty MM, Vang K, Rodell AB,
Jonsdottir KY, Møller A, Ashkanian M, Vafaee MS, Iversen P, Johannsen P, Gjedde A. Brain energy metabolism and blood flow differences in healthy aging. J Cereb Blood Flow Metab. 2012;32:117787.
2. Bailey CJ, Sanganahalli BG, Herman P, Blumenfeld H, Gjedde A, Hyder F. Analysis of Time and Space Invariance of BOLD Responses in
the Rat Visual System. Cereb Cortex. 2013;23:210-22. doi: 10.1093/
cercor/bhs008.
3. Bergersen LH, Gjedde A. Is lactate a volume transmitter of metabolic
states of the brain? Front Neuroenergetics. 2012;4:5. doi: 10.3389/
fnene.2012.00005.
4. Borghammer P, Cumming P, Østergaard K, Gjedde A, Rodell A,
Bailey CJ, Vafaee MS. Cerebral oxygen metabolism in patients with
early Parkinson’s disease. J Neurol Sci. 2012;313:123-8.
5. Borghammer P, Hansen SB, Eggers C, Chakravarty M, Vang K,
Aanerud J, Hilker R, Heiss WD, Rodell A, Munk OL, Keator D, Gjedde
A. Glucose metabolism in small subcortical structures in Parkinson’s
disease. Acta Neurol Scand. 2012;125:303-10.
6. Bouskila J, Burke MW, Zabouri N, Casanova C, Ptito M, Bouchard
JF. Expression and localization of the cannabinoid receptor type 1
and the enzyme fatty acid amide hydrolase in the retina of vervet
monkeys. Neuroscience. 2012;202:117-30.
7. Burke MW, Kupers R, Ptito M. Adaptive neuroplastic responses
in early and late hemispherectomized monkeys. Neural Plasticity
2012;2012:852423.
8. Cheng C, Edin NF, Lauritzen KH, Aspmodal I, Christoffersen S, Jian
L, Rasmussen LJ, Pettersen EO, Xiaoqun G, Bergersen LH. Alterations
of monocarboxylate transporter densities during hypoxia in brain
and breast tumour cells. Cell Oncol (Dordr). 2012;35:217-27.
9. Desgent S, Ptito M. Cortical GABAergic interneurons in crossmodal plasticity following early blindness. Neural Plast. 2012;
2012:590725.
10. Dyrby TB, Søgaard LV, Hall MG, Ptito M, Alexander DC. Contrast and
stability of the axon diameter index from microstructure imaging
with diffusion MRI. Magn Reson Med. 2012 Sep 28.
11. Gagnon L, Schneider FC, Siebner HR, Paulson OB, Kupers R, Ptito
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
M. Activation of the hippocampal complex during tactile maze
solving in congenitally blind subjects. Neuropsychologia. 2012
Jun;50(7):1663-71.
Gejl M, Egefjord L, Lerche S, Vang K, Bibby BM, Holst JJ, Mengel
A, Møller N, Rungby J, Brock B, Gjedde A. Glucagon-like peptide-1
decreases intracerebral glucose content by activating hexokinase
and changing glucose clearance during hyperglycemia. Cereb Blood
Flow Metab. 2012;32:2146-52.
Gejl M, Søndergaard HM, Stecher C, Bibby BM, Møller N, Bøtker HE,
Hansen SB, Gjedde A, Rungby J, Brock B. Exenatide alters myocardial
glucose transport and uptake depending on insulin resistance and
increases myocardial blood flow in patients with type 2 diabetes. J
Clin Endocrinol Metab. 2012;97:E1165-9.
Kehler AK, Andersen C, Andreasen JR, Vohra R, Junker N, Poulsen
KA, Kolko M. Interaction between VEGF and calcium-independent
phospholipase A2 in proliferation and migration of retinal pigment
epithelium. Curr Eye Res. 2012;37:500-7.
Kupers R, Beaulieu-Lefebvre M, Schneider F, Paulson O, Siebner H,
Ptito M. Neural correlates of olfactory processing in congenital blindness. Neuropsychologia, 2011;49:2037-44.
Lauritzen F, Heuser K, de Lanerolle NC, Lee TS, Spencer DD, Kim JH,
Gjedde A, Eid T, Bergersen LH. Redistribution of monocarboxylate
transporter 2 on the surface of astrocytes in the human epileptogenic hippocampus. Glia. 2012;60:1172-81.
Linnet J, Mouridsen K, Peterson E, Møller A, Doudet DJ, Gjedde A.
Striatal dopamine release codes uncertainty in pathological gambling. Psychiatry Res. 2012;204:55-60.
Nahimi A, Høltzermann M, Landau AM, Simonsen M, Jakobsen
S, Alstrup AK, Vang K, Møller A, Wegener G, Gjedde A, Doudet
DJ. Serotonergic modulation of receptor occupancy in rats treated
with L-DOPA after unilateral 6-OHDA lesioning. J Neurochem.
2012;120:806-17.
Ormel L, Stensrud MJ, Bergersen LH, Gundersen V. VGLUT1 is
localized in astrocytic processes in several brain regions. Glia.
2012;60:229-38.
Perez EL, Lauritzen F, Wang Y, Lee TS, Kang D, Zaveri HP, Chaudhry
FA, Ottersen OP, Bergersen LH, Eid T. Evidence for astrocytes as a
potential source of the glutamate excess in temporal lobe epilepsy.
Neurobiol Dis. 2012;47:331-7.
Ptito M, Kupers R, Lomber S, Pietrini P. Sensory deprivation and brain
plasticity. Neural Plast. 2012;2012:810370.
Ptito M, Matteau I, Zhi Wang A, Paulson OB, Siebner HR, Kupers R.
Crossmodal recruitment of the ventral visual stream in congenital
blindness. Neural Plast. 2012;2012:304045.
Regnell CE, Hildrestrand GA, Sejersted Y, Medin T, Moldestad O, Rolseth V, Krokeide SZ, Suganthan R, Luna L, Bjøras M, Bergersen LH.
Hippocampal adult neurogenesis is maintained by Neil3-dependent
repair of oxidative DNA lesions in neural progenitor cells. Cell Rep.
2012;2:503-10.
Rinholm JE, Bergersen LH. Neuroscience: The wrap that feeds neurons: comment on Nature. 2012;487:443-8. Nature. 2012;487:4356.
Rodell AB, Aanerud J, Braendgaard H, Gjedde A. Low Residual CBF
Variability in Alzheimer’s Disease after Correction for CO(2) Effect.
Front Neuroenergetics. 2012;4:8. doi: 10.3389/fnene.2012.00008.
Schaefer K, Blankenburg F, Kupers R, Grüner JM, Law I, Lauritzen
M, Larsson HB. Negative BOLD signal changes in ipsilateral primary
somatosensory cortex are associated with perfusion decreases
and behavioral evidence for functional inhibition. Neuroimage.
2012;59:3119-27.
27. Tran MT, Arendt-Nielsen L, Kupers R, Elberling J. Multiple chemical
sensitivity: On the scent of central sensitization. Int J Hyg Environ
Health. 2012;50:1663-71.
28. Vafaee MS, Vang K, Bergersen LH, Gjedde A. Oxygen consumption
and blood flow coupling in human motor cortex during intense
finger tapping: implication for a role of lactate. J Cereb Blood Flow
Metab. 2012;32:1859-68.
29. Zhan C, Wang J, Kolko M. Diverse regulation of retinal pigment
epithelium phagocytosis of photoreceptor outer segments by
calcium-independent phospholipase A2 group VIA and secretory
phospholipase A2, group IB. Curr Eye Res. 2012;37:930-40.
Annual Report 2012
19
Breathind in a dish
Schematic illustration representing in A the localization of the principal cannabinoid receptors in the monkey
retina and in B a hypothetical function for CB2R. CB1R is localized in neural components and CB2R in glial
Figure
legend
Figure
legend
components (Müller cells). Color bars in the legend indicate the intensity of CB1R (green) and CB2R (magenta)
expressions. OS/IS, outer and inner segments of rods and cones; ONL, outer nuclear layer; OPL, outer plexiform
Respiratory
rhythm
is
studied
under
vitro
conditions.
Acutely
prepared
brainstem
layer; Respiratory
rhythm
is
studied
under
vitro
conditions.
Acutely
prepared
brains
INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer; C, cones; R, rods; H, horizontal
slices
continue
to
produce
a
breathing
rhythm
(left),
and
a
novel
organotypic
sl
slices
continue
to
produce
a
breathing
rhythm
(left),
and
a
novel
organotypic
cells; B,
bipolar cells; A, amacrine cells; G, retinal ganglion cells; M, Müller cells. *From Bouskila et al., 2012).
culture
preparation
(right)
comprised
of
a
brainstem
slice
and
two
slices
from
t
culture
preparation
(right)
comprised
of
a
brainstem
slice
and
two
slices
fro
cerebellum
also
produce
regular
rhythm
patterns
in
particular
respiratory‐relate
cerebellum
also
produce
regular
rhythm
patterns
in
particular
respiratory‐rel
areas
(red,
blue
circles).
areas
(red,
blue
circles).
20
Annual Report 2012
Cellular and Systems
Neurobiology Laboratory
The aim of the Laboratory is to understand how single
cells and small assemblies of neurons contribute to
brain function. A variety of electrophysiological and
optical techniques are used to study living neurons in
functional in vitro preparations of nervous tissue. We
seek to answer fundamental questions such as: How do
the spatiotemporal properties of dendrites and single
neurons affect synaptic processing in sensory and motor
networks? What neural microcircuit mechanisms are
involved in sensory representation and in the generation
of motor patterns? How do developmental processes
specify functional microcircuits? The Laboratory consists
of two groups: The Jens C. Rekling and Henrik Jahnsen
group, and Jens Midtgaard’s sensory physiology group.
The overall aims are pursued in a number of specific
projects:
1. Respiratory rhythmogenesis: En-block brainstem and
slice preparations from newborn mice are used to
study the cellular and system properties of respiratory
neurons with the aim of understanding how breathing rhythm is generated.
2. Neuronal domains: Slice and whole-mount preparations from newborn mice are used to study coordinated calcium activity in neighboring groups of
neurons with the aim of understanding early devel-
opmental specification of neural function.
3. Processing of proprioceptive sensory information
and cerebellar function: Slice preparations from
the inferior olive from newborn mice are used to
study spontaneous coordinated activity in clusters of
inferior olive neurons with the aim of understanding early olivocerebellar development and function.
The internal processing in the cerebellar cortex is
analyzed in the intact cerebellum. Of particular focus
is the inner workings of mossy fibers, and the Golgi
cell inhibitory control of the mossy fiber-granule cell
synapse in the input layer of the cerebellar cortex.
4. Sensory cortical function: the olfactory system serves
as a model for central representation and processing of external sensory information. The function of
the olfactory bulb and olfactory cortex is analyzed in
intact vertebrate preparations in vitro. Of particular
interest is the function of dendrites and early inhibitory filtering in sensory processing.
Cellular and Systems Neurobiology Laboratory
2012 Publications
1. Rekling J.C., Jensen K.H., Jahnsen H. (2012).Spontaneous cluster activity in the inferior olivary nucleus in brainstem slices from postnatal
mice. J Physiol April 2012 590 (7) 1547-1562.
2. Gabbiani, F., Midtgaard, J. Neural Information Processing. October
2012. eLS (c) 2012. John Wiley & Sons, Ltd.
Annual Report 2012
21
Eye Pathology
Laboratory
The Eye Pathology Institute is a sub-specialized pathology laboratory, which for more than 100 years, has
performed ophthalmic pathology service to the health
system of Denmark. In addition ophthalmic pathology
service is given to veterinary ophthalmologists and the
ZOO. The specimens collected from these sources form
part of our scientific material. Main topics are: basal
patho-mechanisms of eye disease and eye pathology
techniques. Among the actual focus areas are: Intra ocular cancers (malignant uveal melanoma, retinoblastoma
and metastases) prevalence and genetic deviations; lacrimal gland tumours and ophthalmic region lymphomas;
their epidemiology, morphology and genetic aberrations.
Also conjunctival and other mucosal, pre malignant and
malignant melanocytic tumors are under study. Animal
models for human eye diseases have been developed.
The actual animal study involves comparison of snake
spectacles and human contact lenses..
Research Techniques
• Electron microscopy
• Gene profiling and mRNA analysis
• Immunohistochemistry
• In situ hybridization
• Light-, fluorescence- and con-focal microscopy
• Paraffin and frozen histo-pathological techniques
Financing
• I & E Jensens Mindelegat
• Kræften Bekæmpelse
• Synoptikfonden
• Velux Fonden
22
Annual Report 2012
• Værn om Synet
• Øjenfonden
Collaborations
• Cancer Centre, Sahlgrenska, Gothenburg, Sweden
• Clinical ophthalmological departments and departments of genetics and pathology in
• Denmark. Copenhagen ZOO
• Ophthalmic Oncology Centre, Liverpool, United
­Kingdom
8.
9.
10.
11.
Eye Pathology Laboratory 2012 Publications
1. Bagger M, Prause JU, Heegaard S, Urbak SF, Degn T, Kiilgaard JF.
Late onset retinoblastoma presenting with vitreous haemorrhage.
Open Ophthalmol J. 2012;6:23-5.
2. Bechtold D, Hove HD, Prause JU, Heegaard S, Toft PB. Plexiform
neurofibroma of the eye region occurring in patients without neurofibromatosis type 1. Ophthal Plast Reconstr Surg. 2012;28:413-5.
3. Christiansen AT, Kiilgaard J, Smith M, Ejstrup R, Wnek GE, Prause
JU, Young MJ, Klassen H, Kaplan H, la Cour M. The influence
of brightness on functional assessment by mfERG: A study on
scaffolds used in retinal cell transplantation in pigs. Stem Cell Int
2012;ID263264:7pages.
4. Christiansen AT, Tao SL, Smith M, Wnek GE, Prause JU, Young MJ,
Klassen H, Kaplan HJ, la Cour M, Kiilgaard JF. Subretinal implantation of electrospun, short nanowire and smooth poly (_-caprolactone) (PCL) scaffolds to the subretinal space of porcine eyes. Stem
Cell Int 2012; ID 454295: 8 pages.
5. Ejstrup R, la Cour M, Heegaard S, Kiilgaard JF. Toxicity profiles of
subretinal indocyanine green, Brilliant Blue G, and triamcinolone
acetonide: a comparative study. Graefes Arch Clin Exp Ophthalmol
2012;250:669-77.
6. Ejstrup R, la Cour M, Kyhn MV, Heegaard S, Kiilgaard JF. Effect of
glial cell line-derived neurotrophic factor on retinal function after
experimental branch retinal vein occlusion. Invest Ophthalmol Vis Sci
2012;14:53:6207-13.
7. Hamoudi H, Rudnick JC, Prause JU, Tauscher K, Breithaupt A, Teifke
JP, Heegaard S. Anterior segment dysgenesis (Peters’ anomaly) in
12.
13.
14.
15.
16.
17.
18.
19.
two snow leopard (Panthera uncia) cubs. Vet Ophthalmol. 2012 Dec
6. doi: 10.1111/vop.12017. [Epub ahead of print]
Kiilgaard JF, Scherfig E, Prause JU, Cour laM. Transplantation of
amniotic membrane to the subretinal space in pigs. . Stem Cell Int
2012;ID716968:5 pages.
Klauber S, Jensen PK, Prause JU, Kessing SV. Surgical treatment of
iris and ciliartis boby melanoma: follow-up of a 25-year-series of
patients. Acta Ophthalmol 2012;90:122-7.
Molvaer RK, Andreasen A, Heegaard S, Thomsen JS, Hjortdal J,
Urbak SF, Nielsen K. Interactive 3D computer model of the human corneolimbal region: crypts, projections and stem cells. Acta
Ophthalmol. 2012 Jun 8. doi: 10.1111/j.1755-3768.2012.02446.x.
[Epub ahead of print]
Rasmussen ML, Ekholm O, Prause JU, Toft PB. Quality of life of eye
amputated patients. Acta Ophthalmol. 2012;90:435-40.
Rasmussen PK, Ralfkiaer E, Prause JU, Sjö LD, Toft PB, Siersma VD,
Heegaard S. Diffuse large B-cell lymphoma of the ocular adnexal
region: A nation-based study. Acta Ophthalmol. 2012 May 2. doi:
10.1111/j.1755-3768.2011.02337.x.
Svahn TF, Heegaard S, Prause JU, Toft PB. A Circum-Corneal Conjunctival Nevus in a Child. Orbit. 2012;31:177-8.
Tran TL, Bek T, Holm L, la Cour M, Nielsen S, Prause JU, Rojek A,
Hamann S, Heegaard S. Aquaporins 6-12 in the human eye. Acta
Ophthalmol Scand 2012. Epub ahead of print.
Toft, PB, Rasmussen, MLR, and Prause, JU. One-Stage ExplantImplant Procedure of Exposed Hydroxyapatite Orbital Implants. Acta
Ophthalmol. 2012;90:210-4.
von Holstein SL, Fehr A, Therkildsen MH, Heegaard S, Stenman G.
CRTC1-MAMl2 fusion gene in mucoepidermoid carcinoma of the
lacrimal gland. Oncology Report 2012;27(5):1413-6.
von Holstein SL, Therkildsen MH, Prause JU, Stenman G, Siersma
VD, Heegaard S. Lacrimal gland lesions in Denmark between 1974
and 2007. Acta Ophthalmologica. 2012 Apr 4. Epub ahead of print
von Holstein SL, Coupland SE, Briscoe D, Le Tourneau C, Heegaard
S. Epithelial tumours of the lacrimal gland: a clinical, histopathological, surgical and oncological survey. Acta Ophthalmologica. 2012
Apr 4. Epub ahead of print
Wadt K, Choi J, Chung JY, Kiilgaard J, Heegaard S, Drzewiecki
KT, Trent JM, Hewitt SM, Hayward NK, Gerdes AM, Brown KM. A
cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma. Pigment Cell Melanoma Res.
2012;25:815-8.
Annual Report 2012
23
24
Annual Report 2012
Molecular Neuropharmacology
and Genetics Laboratory
Molecular Neuropharmacology Group counts 25-30
people including 2 Associate Professors, 2 Assistant
Professor, 6 post docs, 12 PhD students, 2 Research Assistant, a number of Master’s students and 6 technicians.
The group is separated into four integrated research
teams with focus on i) cellular biology and genetics of
neurotransmitter transporters/receptors (headed by Ulrik
Gether and Trine Jørgensen), ii) molecular pharmacology
and structure of neurotransmitter transporters (headed
by Associate Professor Claus J. Løland), and iii) cellular
‘scaffolding’ processes in the CNS (headed by Kenneth
L. Madsen). In addition to the already establish four
group Søren Gøgsig Faarup Rasmussen started in 2011
to establish his lab (Sørensen lab), which research focus
on understanding the structural basis for the functional
properties of G-protein coupled receptors (GPCRs) and
neurotransmitter transporters.
The overall purpose of our research is to achieve insight
into molecular, cellular and genetic processes responsible
for synaptic signal transmission and how these processes can be modulated by drugs. We have main focus
on the presynaptic transporters for the biogenic amine
transmitters, dopamine, norepinephrine and serotonin.
These transporters belong to the family of Neurotrans
mitter:Sodium:Symporters (NSS) and tightly control the
availability of the biogenic amines in the synaptic cleft.
The transporters are targets for pharmaceuticals used
against depression, anxiety disorders and ADHD as well
as for drugs of abuse such as cocaine and amphetamine.
In addition, we have a major interest in ‘scaffolding’
proteins such as e.g.PICK1 that via specific protein-pro-
tein interactions and protein-lipid interactions organize
neurotransmitter transporters and receptors into desired
cellular microdomains and multiprotein signaling complexes.
In our research we employ a broad spectrum of in vitro
and in vivo techniques ranging from advanced biophysical techniques to genetic mouse models. In particular,
the group has strong expertise in structural and pharmacological analyses of neurotransmitter receptors and
transporters, expression and purification of membrane
proteins and scaffolding proteins, characterization of
protein-proteins interactions, fluorescence spectroscopy,
knock-in and knock-out mouse models and advanced
bioimaging techniques.
Research Techniques
Mutagenesis, PCR, expression in mammalian cell lines
and Xenopus laevis oocytes, pharmacological assays
(uptake assays, radioligand binding assays, scintillation
proximity binding [SPA] assays), bacterial expression
and purification of membrane proteins and scaffolding
proteins, protein-protein binding assays (fluorescence
polarization assays, co-immunoprecipitations, FRET),
site-directed fluorescence labeling, fluorescence spectroscopy, confocal fluorescence microscopy (including
live imaging), biochemical assay (SDS-PAGE and Western
blotting; biotinylation assays), generation of genetic
mouse models (knock-ins).
The research of the Rasmussen lab is focused on
understanding the structural basis for the functional
properties of G-protein coupled receptors (GPCRs) and
Annual Report 2012
25
neurotransmitter transporters by use of various chemical
tools, fluorescence spectroscopy, and crystallography.
Techniques include expression, purification and stabilization of GPCRs in detergent solution, various assays
to determine expression and functionality (radioligand
binding, fluorescence spectroscopy & microscopy, in vitro
G protein coupling assays, SDS-PAGE & Western blot
analysis), generating and characterizing conformational
antibodies (reconstitution of GPCRs in liposomes, ELISA
assays, radioligand binding, fluorescence spectroscopy,
size-exclusion chromatography), and crystallization
setups (in detergent solution, lipid bicelles, and lipidic
mesophases).
Funding Sources
• Danish Research Councils
• Lundbeck Foundation
• Lundbeck Foundation Junior Group Leader Fellowship
• National Institute of Drug Abuse U.S.A., University
of Copenhagen (Program of Excellence), EU and the
Novo Nordic Foundation
• UNIK Synthetic Biology
Collaborators – Domestic
• Birgitte Holst, INF
• David Woldbye, INF
• Dimitrios Stamou, Department of Chemistry, The
Nano-Science centre
• Fleming Poulsen, NAT
• Jakob Balslev Sørensen, INF
• Kristian Strømgaard, FARMA
• Lise Arleth, LIFE
• Nikos Hatzakis, Department of Chemistry, The NanoScience centre
• Ole Kjærulff, INF
• Protein Science Center, SUND
Collaborators – International
• Amy Newman, NIDA, Baltimore
• Aurelio Galli, Vanderbilt University
• Brian Kobilka, Stanford University
• Gregers Rom Andersen, Aarhus University
• Harald Sitte, University of Vienna
• Harel Weinstein, Cornell University
26
Annual Report 2012
•
•
•
•
•
•
•
•
•
•
Jan Steyaert, Vrije University Brussels
Jonathan Javitch, Columbia University
Jonathan Katz, NIDA, Baltimore
KaYoung Chung, Sungkyunkwan University
Lynette Daws, University of Texas
Pil Seok Chae, Hanyang University
Rick Huganir, Johns Hopkins University
Roger Sunahara, University of Michigan, Ann Arbor
Sam Gellman, University of Michigan
William Weis, Stanford University
Molecular Neuropharmacology and Genetics Lab
2012 Publications
1. Ammendrup-Johnsen, I, Thorsen TS, Gether U and Madsen KL:
“Serine 77 in the PDZ Domain of PICK1 Is a Protein Kinase C alpha
Phosphorylation Site Regulated by Lipid Membrane Binding” Biochemistry (2012): 51.2 P.586-596.
2. Bröer S and Gether U: “The solute carrier 6 family of transporters”
British Journal of Pharmacology (2012): 167.2 p. 256-278
3. Chae PS, Rasmussen SGF, Rana R, Gotfryd K, Kruse AC, Manglik A,
Cho KH, Nurva S, Gether U, Guan L, Loland CJ, Byrne B, Kobilka BK
and Gellman SH: “A new Class of Amphiphiles Bearing Rigid Hydrophobic Groups for Solubilization of Membrane Proteins” Chemistry
A European Journal (2012): 18.31. p. 9485-9490
4. Chae PS, Rana RR, Gotfryd K, Rasmussen SG, Kruse AC, Cho KH,
Capaldi S, Carlsson E, Kobilka B, Loland CJ, Gether U, Banerjee S,
Byrne B, Lee JK and Gellman SH: “Glucose-Neopentyl Glycol (GNG)
amphiphiles for membrane protein study”Chem Commun (Camb)
(2012): Nov 19
5. Koefoed P, Woldbye DPD, Hansen TV, Eplov LF, Christiansen SH,
Mors O, Kessing LV, Werge, Kaipio K, Pesonen U, Fahmy T, Mellerup
E, Jakobsen KD, Hansen ES, Knudsen GM, Bukh JD, Bock C, Lindberg C, Kristensen AS, Dam H, Nordentoft M, Als TD, Wang AG,
Gether U, Rehfeld JF and Bolwig TG: “Association of the leucine-7
to proline-7 variation in the signal sequence of neuropeptide Y with
major depression” Acta Neuropsychiatricia (2012): 24.2 P.81-90
6. Knorr U, Sondergaard MHG, Koefoed P, Jorgensen A, FaurholtJepsen M, Vinberg M, Gether U and Kessing LV: “Increased whole
blood brain-derived neurotrophic factor in healthy individuals with
a family history of affective disorder: a case-control study” Biopolar
Disorders (2012): 14.SI.1 p.94-94. 5th Biennial Conference of the
International-Society-for-Bipolar-Disorders
7. Knorr U, Vinberg M, Mortensen EL, Winkel P, Gluud C, Wetterslev
J, Gether U and Kessing LV:”Effect of Chronic Escitalopram versus
Placebo on Personality Traits in Healthy First-Degree Relatives of
Patients with Depression: A Randomized Trial” Plos One (2012): 7.2
8. Loland CJ, Mereu M, Okunola OM, Cao J, Prisinzano TE, Kopajtic T, Shi L, Katz JL, Tanda G and Newman AH: “R-Modafinil
(Armoda­finil): “A unique dopamine uptake inhibitor and potential
medication for psychostimulant abuse” Biological Psychiatry (2012):
72(5):405-413
9. Madsen KL, Thorsen TS, Rahbek-Clemmensen T, Eriksen J and
Gether, U: “Protein Interacting with C Kinase 1 (PICK1) Reduces
Reinsertion Rates of Interaction Partners Sorted to Rab11-dependent
10.
11.
12.
13.
Slow Recycling Pathway” Journal of Biological Chemistry (2012):
287.15 p.12293-12308
Plenge P, Shi L, Beuming T, Te J, Newman AH, Weinstein H, Gether
U and Loland CJ: “Steric Hindrance Mutagenesis in the Conserved
Extracellular Vestibule Impedes Allosteric Binding of Antidepressants
to the Serotonin Transporter” Journal of Biological Chemistry (2012)
28747:39316-2
Simmons KJ, Gotfryd K, Billesbølle CB, Loland CJ, Gether U, Fishwick
CW and Johnson AP: “A virtual high-throughput screening approach to the discovery of novel inhibitors of the bacterial leucine
transporter, LeuT” Molecular Membrane Biology (2012): Epub, Aug
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Sørensen G, Weikop M, Dencker D, Loland CJ, Bengtsen CH, Petersen JH, Fink-Jensen A, Wörtwein G and Woldbye DP: “Neuropeptide Y Y5 receptor antagonism attenuates cocaine-induced effects in
mice” Psychopharmacology (Berl) (2012): 222(4):565-577
Zocher M., Zhang C., Rasmussen S.G.F., Kobilka B.K and Müller
D.J: “Cholesterol increases the kinetic, energetic, and mechanical
stability of the human _2 adrenergic receptor”. Proc. Natl. Acad. Sci.
USA. (2012) 109:3463-72
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Annual Report 2012
Molecular Pharmacology Laboratory
Laboratory for Molecular Pharmacology consists
of three independent groups headed by Birgitte
Holst, Mette M Rosenkilde and Thue W Schwartz.
The common research theme for the three groups
is the relationship between structure and function of 7TM (seven transmembrane segment), G
protein-coupled receptors. The structure-function
relationship is studied in close collaboration with
computational chemistry groups – in particular Professor Thomas Frimurer and his group – and various
medicinal chemistry groups in academia and in the
biotech and pharmaceutical industry. Pharmacological concepts from the invtro studies are carried
over into the in vivo pharmacological setting and
probed in various animal models.
Common technologies:
Molecular Pharmacology technology – Basic molecular biology technologies especially heterologous
eukaryotic expression systems and site directed mutagenesis, binding assays and multiple signal transduction
systems as well as basic biochemical technologies such
as , for example Western blot analysis, QPCR technology
for testing gene expression etc. Isolation and functional
characterization of pancreatic islets, adipocytes, lymphocytes etc. from animals e.g. transgenic animals.
Group of Birgitte Holst
Molecular Pharmacology – One main focus area
constitute in vitro structure and function studies of
7TM G protein coupled receptors involved in metabolic
homeostasis and glucose metabolism. This includes the
molecular basis for ligand recognition, potency and
efficacy and phenomena such as constitutive receptor
activity, allosteric ligand function, and signal transduction
pathway biased signaling etc. The molecular pharmacology is closely integrated with computational chemistry
(Thomas Frimurer at CPR, SUND), with medicinal chemistry (Annette Beck-Sickinger, Leipzig University), with cell
biology (Nick Holliday, University of Nottingham, UK) and
currently being integrated with biophysic methods (Tom
Sakmar, Rockefeller University). We are mainly focusing
on following metabolic 7TM receptors as model systems:
Ghrelin receptor, GPR39, melanocortin receptors, neurotensin receptors and melatonin receptors
In vivo Metabolic Receptology – We are currently
focusing on hormones (ghrelin, PYY etc.) and receptors
involved in the gut brain communication axis controlling food intake and energy expenditure. In particular
the interaction with the homeostatic appetite regulating
center in hypothalamus but also interaction with the
central reward systems (with David Woldbye, INF, SUND,
KU), control of the endocrine pancreas (ghrelin R, GPR39
etc.) and in adipocyte metabolism – pt. focusing on 7TM
receptors in the control of lipolysis (especially GPR39,
adrenoceptors, GPR81 and GPR109A) is important. We
are using and establishing various forms of transgenic
animal models (for example with Jeff Zigmann, South
Western Medical School, Dallas, USA) as well as testing in vivo novel pharmacological tool compounds to
determine the metabolic function of 7TM receptors. An
important part of the in vivo studies are integrating and
probing knowledge from basic molecular pharmacology
Annual Report 2012
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(see above) with in vivo endocrinology and pharmacology. One example is to probe the physiological, in
vivo importance of the constitutive receptor activities
originally discovered in the ghrelin receptor system by
novel inverse agonists and transgenic models including
adenovirus models. Another example is to probe the in
vivo importance of biased agonists that are characterized
by selectively coupling only a few of the possible signaling pathways. Several biased agonist has been developed for the ghrelin receptor and our group are currently
characterizing the physiological role of these agonists
compared to un-biased agonists.
Metabolic characterization of the orphan ghrelin receptor family member, GPR39 in the function of pancreatic beta-cells, adipocytes constitute another important
research area.
brown fat homeostasis and fat accumulation
4) Kristian Helin and Karl Agger – importance of histone
demethylases for energy homeostasis and fat accumulation
5) Anders Hay Smith – The importance of Neuroglobulin for body weigth and energy homoestasis.6)
Bente Klarlund, Pernille Højlund and Klaus – FSTL3
electroporation and effect on energy homeostasis.
7) Axel Kornerup and Britt T. Christensen 8) Thomas
Mandrup Poulsen and Jacob Bondo Hansen – importance of the Fe transporter for beta cell function.
Rodent Metabolic Phenotyping Center – BH has
founded and is head of “Rodent Metabolic Phenotyping Center”, an in vivo laboratory or core facility at
SUND specialized in testing metabolic functions of mice
and rats, which is being used for a variety of rodent
models of especially obesity and diabetes as well as for
testing the metabolic phenotype of various transgenic
mouse models and the effects of hormones, drugs,
drug candidates and pharmacological tool compounds.
The equipment and capabilities at the center includes:
1) TSE calometry test systems – i.e. cages to measure
food intake, energy expenditure (CO2 production, O2
consumption etc.), locomoter activity done under variable temperature 2) MRI scanner for measuring body
composition and composition of tissue samples, biopsies
etc 3) Specialized cages for studies of food intake in real
time in rats and mice and “chipped”, group-housed
mice and 4) Intellicages – specialized cages for measuring animal behavior, i.e. especially reward, food intake
related behavior.
Collaborative projects:
1) Gether and Kjærulff lab INF – probe the metabolic
importance to the intracellular protein PICK1 for
secretion of peptide hormones.
2) Harald Hansen lab “old FARMA” – Study the regulation of lipid metabolites important for energy homeostasis and food intake
3) Lars Bo Nielsen – Study of ApoM for energy and
Group of Mette M Rosenkilde – Basic pharmacology
within the area of 7TM receptors
Molecular Pharmacology – Structure-function studies
of 7TM G protein coupled receptors within in particular
the immune system (cytokine and lipid receptors) and
the endocrine system (incretin, neuropeptide, melanocortin, melatonin, lipid and orphan receptors). This includes
the molecular basis for ligand recognition and receptor
activation, action of allosteric and orthosteric agonists,
antagonists, super- and inverse agonists. Identification
of novel compounds by site-directed drug discovery
methods and chemogenomics. Description of signalling
phenomenons such as constitutive activity, functional
selectivity (biased activity) and receptor cross-talk. The
molecular pharmacology is closely integrated with
computational chemistry (Thomas Frimurer at CBMC,
SUND, David Gloriam at Department of Drug Design and
Pharmacology, SUND, and Jon Våbenø at Tromsø University) with medicinal chemistry (Harald Severin Hansen at
Department of Drug Design and Pharmacology, SUND,
Trond Ulven at University of Southern Denmark, SDU
and Bengt Erik at Bergen University University) with
nanotechnology for probing receptor-ligand interaction (in collaboration with Gertrud Hjortø, Department
of Micro- and Nanotechnology, DTU) with cell biology
and virology (Nikolaj Kulahin at Novo, Denmark, Sten
Seier Poulsen at BMI, SUND, Thomas N. Kledal, National
Veterinary Virology Institute, DTU, Anette Mankerts and
Annual Report 2012
SeaHorse equipment – For testing the in vitro and ex
vivo basic metabolism of cells (cell lines, isolated adipocytes, muscle cells, hepatocytes, pancreatic islets etc.)
as well as isolated mitochondria.
Bernhard Ehlers, both at Robert Koch Institute, Berlin,
and Andreas Sailer at Novartis, Switcherland) and are
currently being integrated with various virus-expression
systems and development of virus-model systems for the
in vivo studies, in particular with respect to in vivo and in
situ signalling properties, of wildtype and mutated 7TM
receptors (see below).
In vivo Metabolic Receptology – We are mainly
focusing on incretin hormones (GIP, GLP1), GLP2,
neuropeptides (NPY, PYY a.o.), lipid receptors (GPR119
a.o.) as well as orphan receptors of putative impact for
metabolic control (GPR26 a.o.), and use in vivo human
tests, and rodent in- and ex vivo experiments. The testing
in healthy humans, obese and type 1/2 diabetes mellitus
takes place in collaboration with Filip Knop and Tina
Vilsbøll, Department of Internal Medicine (Diabetologisk Forskningsenhed), Gentofte Hospital, and with the
Jens Juul Holst laboratory, BMI, SUND. The rodent test
systems are designed and conducted in collaboration
with the Jens Juul Holst laboratory, BMI, SUND. The in
vivo studies also include test of novel tool compounds in
human and rodents.
In vivo Immune Receptology – We are in particular
interested in understanding every pharmacology-related
aspect of the virus-exploited 7TM receptors. These
includes the virus-induced 7TM receptors, such the
chemokine receptor EBI1 (or CCR7) and the oxysterol
receptor EBI2 (or GPR183), and the virus-encoded
7TM receptors, such as the ORF74-family encoded by
rhadinviruses, the BILF1-family encoded by lymphocryptoviruses, and the US28, US27, UL33 and UL78 encoded
by human cytomegalovirus (and rodent homologs in
the case of UL33 and UL78). The in vivo tests related to
EBI2 involves cell-type specific overexpression of human
EBI2 in mice, EBI2 knock out models combined with
strategies for T-cell depletion (in collaboration with Peter
J. Holst, Department of International Health, Immunology and Microbiology, SUND, Allan Randrup and Jan
Pravsgaard Christensen, Lab. For Experimental Virology,
SUND). Furthermore, we are establishing various forms
of transgenic animal models for the virus-encoded
receptors (for example with Helen Farrell and Nick Davis
Poynter, Queensland University) and for virus-encoded
ligands for endogenous receptors (Anette Mankertz,
Robert Kock Institute, Berlin), in addition to testing in
vivo novel pharmacological tool compounds (in collaboration with Andreas Sailer, Novartis, Switzerland and
Rob Jepras, GSK, Stevenage, London) and to determine
the immune-regulating and virus-implicated functions of
7TM receptors. An important part of the in vivo rodent
studies is to integrate and probe knowledge from basic
molecular pharmacology (see above) with in vivo immunology, virology and pharmacology. For example probing
the immunological, in vivo importance of the constitutive
receptor activities (a common phenotypic trait of many
virus-exploited 7TM receptors) by novel inverse agonists/
antagonists and transgenic models using adeno- and
retrovirus models.
Group of Thue W Schwartz
Molecular Pharmacology – Structure and function
studies of 7TM G protein coupled receptors as described above using especially metabolic 7TM receptors
as model systems (Ghrelin receptor, GPR39, GPR119,
TGR5, GPR41/43, GPR40, GPR120, the GIP R etc.) are
closely integrated with computational chemistry (Thomas Frimurer at CPR & CMBR, SUND), with medicinal
chemistry (Annette Beck-Sickinger, Leipzig University,
Trond Ulven, Syddansk University, and Rob Jones Arena
Pharmaceuticals, San Diego), with cell biology (Nick
Holliday, University of Nottingham, UK) and are currently
also being integrated with biophysics based on AMBER
mutation suppression technology for incorporation
of unnatural amino acids in eukaryotic cell lines (Tom
Sakmar, Rockefeller University and B. Holst Lab, INF,
KU). Structure and function of adhesion 7TM receptors
(for example GPR56, 64, 112 and 116) is a major new
focus area which also includes basic protein chemistry
related to expression of receptor domains for use as
pharmacological tools, for structural characterization and
identification of binding partners (with Matts Wikstrøm
CPR, KU).
Site directed “drug discovery” – that is, a package of
technologies to exploit knowledge about 7TM receptor structure and function to discover and design novel
ligands, i.e. pharmacological tool compounds and drug
lead compounds through probing of iterative series of
Annual Report 2012
31
target-customized mini-libraries of small molecule compounds selected by means of computational chemistry
(with Thomas Frimurer at CPR, SUND); testing of small
molecule and peptide ligands in the in vitro, ex vivo and
in vivo setting through various drug delivery systems
(with B. Holst Lab, INF, SUND).
Functional Genomics – Characterization of the in vitro
and in vivo functional consequences of genetic variants
of especially 7TM receptors and associated proteins
especially involved in metabolism (with Oluf B. Pedersen
and Torben Hansen, CBMR, SUND, KU & Sadaf Farooqi,
Univ Cambridge, UK).
Enteroendocrinology – Characterization of the molecular pharmacology (e.g. 7TM receptor, chemo-sensor
and adhesion 7TM repertoire as well as adaptor protein
and signalling protein repertoire) and cell biology (e.g.
functional interplay of receptors and associated proteins
in signaltransductosomes and the control of the cellular
development and differentiation of enteroendocrine cells
from crypt stem cells, miRNA expression and function)
of enteroendocrine cells and their interplay with and
control of neighbouring enterocytes and nerves – being
part of the gut-brain axis. A major focus is on establishing and exploiting reporter mice expressing, for example
variants of GFP/RFP under the expressional control of
“promoters” for a) gut hormones, b) grains (secretory
granule proteins) and c) potential 7TM chemosensors
combined with immunohistochemistry, FACS purification, LC-MS proteomic analysis (with Jesper V.Olsen,
CPR, SUND, KU) and for example epigenetic analysis
(with Nils Tommerup, IMMI, SUND, KU). These analytical
studies are deeply integrated with an array of functional
studies in various ex vivo and in vivo models using, for
example novel transgenic animal models and pharmacological tool compounds (with JJ Holst Lab B BMI/CBM
and B.Holst Lab and Rodent Metabolic Phenotyping Centre, CBMR, SUND). The lab has a number of national and
international collaborations including – through CBMR
– International research Alliances with South Western
Medical School (Jeff Zigman Lab) and Gothenburg
University, Wallenberg Laboratories (Fredrik Bäckhed
Lab) and collaborations with biotech and pharmaceutical
industries including with Merck Research Laboratories
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Annual Report 2012
(Rahway, New Jersey) and Arena Pharmaceuticals (San
Diego, CA).
Special techniques
Custom made dedicated QPCR arrays for, for example
murine, and human 7TM receptors (the largest family of
membrane proteins and drug targets) for adaptor and
scaffolding proteins (under development)
Cell sorting: /- MoFlo XDP / Asterios – analytical and in
particular preparative cell sorting
Immunohistochemistry: establishing a comprehensive
library of antibodies against gut peptides, 7TM receptors
and associated proteins.
Funding
• FSS, Medical Research Council, Denmark
• NovoNordisk Fonden Center for Basic Metabolic
Research
• Novonordisk Fonden
• Hørslev Fonden
• Lundbeck Fonden
• Fru Chastine og AP-Møller Fonden
• EU
• SUND, PhD stipends for some of my PhD students
• Other small national foundations
• Merck – international alliance
Molecular Pharmacology Laboratory
Publications 2012
1. Bellmann-Sickert K, Elling CE, Madsen AN, Little PB, Lundgren K,
Gerlach LO, Bergmann R, Holst B, Schwartz TW, Beck-Sickinger AG.
Long-acting lipidated analogue of human pancreatic polypeptide is
slowly released into circulation. J Med Chem. 2011;54:2658-67
2. Ben-Baruch A, Burkhardt AM, Combadiere C, Farber JM, Graham
GJ, Horuk R, Locati M, Luster A, Matsushima K, Murphy PM, Nomiyama H, Power CA, Proudfoot AEI, Rosenkilde MM, Sparre-Ulrich
AH, Thelen M, Yoshie O, and Zlotnik A (alphabetic author list).
IUPHAR nomenclature committee. International Union of Pharmacology Nomenclature XXIIV. Update on the Extended Family of
Chemokine Receptors (NC-IUPHAR). Pharmacological Reviews, 2012
[in press]
3. Benned-Jensen T, Mokrosinski J, and Rosenkilde MM. The E92K
melanocortin 1 receptor mutant induces cAMP production and arrestin recruitment but not ERK activity indicating biased constitutive
signaling. PLoS One. 2011;6:e24644
4. Benned-Jensen T, Norn C, Laurent S, Madsen CM, Larsen HM, Arfelt
KN, Wolf RM, Frimurer TM, Sailer AW, Rosenkilde MM. Molecular
Characterization of Oxysterol Binding to the Epstein-Barr Virusinduced Receptor 2 (GPR183). J Biol Chem. 2012;287:35470-83
Annual Report 2012
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5. Benned-Jensen T, Smethurst C, Page KR, Sivertsen B, Blanchard AD,
Jepras R, Rosenkilde MM. Ligand modulation of EBI2 – Identification of a potent and efficacious inverse agonist. J Biol Chem.
2011;286:29292-302
6. Clemmensen C, Madsen AN, Smajilovic S, Holst B, Bräuner-Osborne
H. L-Arginine improves multiple physiological parameters in mice
exposed to diet-induced metabolic disturbances. Amino Acids.
2011;43:1265-75
7. Egerod KL, Engelstoft MS, Grunddal KV, Nøhr MK, Secher A, Sakata
I, Pedersen J, Windeløv JA, Füchtbauer EM, Olsen J, Sundler F,
Christensen JP, Wierup N, Ol-sen JV, Holst JJ, Zigman JM, Poulsen SS,
Schwartz TW. A Major Lineage of Enteroen-docrine Cells Coexpress
CCK, Secretin, GIP, GLP-1, PYY, and Neurotensin but Not Somatostatin. Endocrinology, 2012,153: 5782-95
8. Egerod KL, Jin C, Petersen PS, Wierup N, Sundler F, Holst B,
Schwartz TW. _-Cell Specific Overexpression of GPR39 Protects
against Streptozotocin-Induced Hyperglycemia. Int J Endocrinol.
2011;2011:401258
9. Els S, Schild E, Petersen PS, Kilian TM, Mokrosinski J, Frimurer TM,
Chollet C, Schwartz TW, Holst B, Beck-Sickinger AG. An aromatic
region to induce a switch between agonism and inverse agonism at
the ghrelin receptor. J Med Chem. 2012;55:7437-49
10. Farrell HE, Abraham AM, Cardin RD, Sparre-Ulrich AH, Rosenkilde
MM, Spiess K, Jensen TH, Kledal TN, Davis-Poynter N. Partial Functional Complementation Between Human and Mouse Cytomegalovirus Chemokine Receptor Homologues. Virology. 2011;85:6091-5
11. Hansen HS, Rosenkilde MM, Holst JJ, Schwartz TW. Endogenous
agonist for GPR119 as a fat sensor. Pharmacol Sci Rev. 2012;33:37481
12. Hansen HS, Rosenkilde MM, Holst JJ, Schwartz TW. GPR119 as a fat
sensor. Trends Pharmacol Sci., 2012, 33:374-81 .
13. Hansen JB, Tonnesen MF, Madsen AN, Hagedorn PH, Friberg J,
Grunnet LG, Heller RS, Nielsen AØ, Størling J, Baeyens L, Anker-Kitai
L, Qvortrup K, Bouwens L, Efrat S, Aalund M, Andrews NC, Billestrup N, Karlsen AE, Holst B, Pociot F, Mandrup-Poulsen T. Divalent
metal transporter 1 regulates iron-mediated ROS and pancreatic _
cell fate in response to cytokines. Cell Metab. 2012;16:449-61
14. Hansen KB, Rosenkilde MM, Knop FK, Wellner N, Diep TA, Rehfeldt
JF, Andersen UB, Holst JJ, Hansen HS. 2-Oleoylglycerol is a GPR119
agonist and signals GLP-1 release in humans. J Clin Endocrinol
Metabol. 2011;96:E1409-17
15. Heppner KM, Chaudhary N, Müller TD, Kirchner H, Habegger
KM, Ottaway N, Smiley DL, Dimarchi R, Hofmann SM, Woods SC,
Sivertsen B, Holst B, Pfluger PT, Perez-Tilve D, Tschöp MH. Acylation
Type Determines Ghrelin’s Effects on Energy Homeostasis in Rodents
Endocrinology. 2012;153:4687-95
16. Jensen AM, Sparre-Ulrick AH, Davis-Poynter N, Rosenkilde MM.
Structural Diversity in Conserved Regions Like the DRY-Motif among
Viral 7TM Receptors-A Consequence of Evolutionary Pressure? Adv
Virol. 2012;231813 (15 pages)
17. Jensen PC, Thiele S, Elder A, Kolbeck R, Gosh S, Frimurer TM,
Rosenkilde MM. Reversed binding of a small molecule ligand in
homologous chemokine receptors – differential role of extracellular
loop 2. Br J Pharmacol. 2012;166:258-75
18. Kissow H, Hartmann B, Holst JJ, Hare KJ, Hansen LS, Rosenkilde
MM, Poulsen SS. Glucagon-like peptide-1 (GLP-1) receptor agonists
or DPP-4 inhibition do not accelerate neoplasia in carcinogen treated
mice. Reg Pept. 2012;179:91-100
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Annual Report 2012
19. Mokrosi_ski J, Frimurer TM, Sivertsen B, Schwartz TW, Holst B.
Modulation of constitutive activity and signaling bias of the ghrelin
receptor by conformational constraint in the second extracellular
loop. J Biol Chem. 2012;287:33488-502
20. Mungalpara J, Thiele S, Eriksen Ø, Eksteen J, Rosenkilde MM,
Våbenø J. Rational Design of conformationally Constrained Cyclopentapeptide CXCR4 Antagonists. J Med Chem. 2012;55:1028791
21. Møller CL, Raun K, Jacobsen ML, Pedersen TA, Holst B, CondeFrieboes KW, Wulff BS. Characterization of murine melanocortin
receptors mediating adipocyte lipolysis and examination of signalling
pathways involved. Mol Cell Endocrinol. 2011;341: 9-17
22. Nørregaard K, Benned-Jensen T, Rosenkilde MM. EBI2, GPR17 and
GPR18 – structural and functional similarities. Curr Top Med Chem
Rev. 2011;11:618-28
23. Pedersen SL, Bhatia VK, Jurt S, Paulsson JF, Pedersen MH, Jorgensen
R, Holst B, Stamou D, Vrang N, Zerbe O, Jensen KJ. Improving
membrane binding as a design strategy for amphipathic peptide
hormones: 2-helix variants of PYY3-36. J Pept Sci. 2012;18:579-87
24. Petersen PS, Jin C, Madsen AN, Rasmussen M, Kuhre R, Egerod KL,
Nielsen LB, Schwartz TW, Holst B. Deficiency of the GPR39 receptor
is associated with obesity and altered adipocyte metabolism. FASEB
J. 2011;25:3803-14
25. Rummel PC, Arfelt KN, Baumann L, Jenkins T, Thiele S, Luttichau
HR, Johnsen A, Pease J, Ghosh S, Elder A, Kolbeck R, Rosenkilde
MM. Molecular requirements for CCR8 receptor inhibition – Probedependent allosteric interactions. Br J Pharmacol. 2012;167:1206-17
26. Sivertsen B, Lang M, Frimurer TM, Holliday ND, Bach A, Els S, Engelstoft MS, Petersen PS, Schwartz TW, Beck-Sickinger AG, Holst B.
Unique interaction pattern of a functionally biased ghrelin receptor
agonist. J Biol Chem. 2011;286:20845-60
27. Steen A, Rosenkilde MM. Molecular Pharmacology of CXCR4 Inhibition. Invited Review. Book chapter. Novel Developments in Stem Cell
Mobilization. Editors: Fruehauf S and Calandra G. Chapter 2:23-35
(2012)
28. Thiele S, Malmgaard-Clausen M, Engel-Andreasen, J, Steen A,
Rummel PC, Nielsen M, Gloriam D, Frimurer T, Ulven T, Rosenkilde MM. Modulation in selectivity and allosteric properties of
small-molecule ligands for CC-chemokine receptors. J Med Chem.
2012;55:8164_77
29. Thiele S, Steen A, Jensen PC, Mokrosinski J, Frimurer TN, Rosenkilde MM. Allosteric and orthosteric sites in the CC-chemokine
receptor CCR5 – a chimeric receptor approach. J Biol Chem.
2011;286:37543-54
30. Torekov SS, Ma L, Grarup N, Hartmann B, Hainerová IA, Kielgast U,
Kissow H, Rosenkilde MM, Lebl J, Witte DR, Jørgensen T, Sandbaek
A, Lauritzen T, Madsen OD, Wang J, Linneberg A, Madsbad S, Holst
JJ, Hansen T, Pedersen OB. Homozygous carriers of the G-allele
of rs4664447 of the glucagon gene (GCG) are characterized by
decreased fasting and stimulated levels of insulin, glucagon and
GLP-1GLP2, GCG. Diabetologia. 2011;54:2820-31
31. Ugleholdt R, Pedersen J, Füchtbauer -M, Kissow HL, Nytofte N,
Poulsen SS, Rosenkilde MM, Seino Y, Thams PG, Holst PJ, Holst JJ.
Adipocyte Glucose-dependent Insulinotropic Polypeptide receptor
restores high fat diet induced body weight gain in mice. J Biol
Chem. 2011;286:44632-45
32. Valentin Hansen L, Holst B, Frimurer TM, Schwartz TW. PheVI:09
(Phe6.44) as a sliding micro-switch in 7TM G protein coupled recep-
tor activation. J Biol Chem. 2012;287:43516-26
33. Wellner N, Tsuboi K, Madsen AN, Holst B, Diep TA, Nakao M, Tokumura A, Burns MP, Deutsch DG, Ueda N, Hansen H. Studies on the
anorectic effect of N_acylphosphatidylethanolamine and phosphatidylethanolamine in mice. Biochim Biophys Acta. 2011;1811:508-12
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Annual Report 2012
Motor Control Laboratory
The research group is unique nationally and internationally by combining expertise and knowledge from neuroscience, health research and sport sciences, which is
also reflected in the dual association of the group to INF/
Health Faculty and IFI/Science Faculty. The group thus utilizes inspiration and knowledge from both the neuroscientific/health and sport science/exercise research areas to
address central research questions of interest within the
two fields The research group originates from research
on spinal cord neural circuitries and spinal motoneurones, which still remains a major focus area, but the
group has gradually extended its field of interest first to
an understanding of the corticospinal control of human
movement and then more broadly to an understanding
of the basis of voluntary movement. Many of the present
research questions thus relate to how movements are
generated at a cortical level and how we consciously
perceive our movements. The contribution of unconscious (reflex) contributions to voluntary (conscious)
movements, however remain a fundamental interest.
In addition, the group are interested in quantify human
movement and understand how the body and anatomical structures are loaded in dynamic situations. Methods
that involve biomechanical and computational musculoskeletal modeling are applied for these purposes.
Through inspiration from sport sciences the group has
also over the past 10 years developed a keen interest in
understanding the neural basis of motor learning and the
field of neuroplasticity has consequently become one of
the most important focus areas for the research in the
group. The group attempts to understand how different
levels of the nervous system interact and contribute to
the gradual improvement of motor performance during
learning.Through this work, the research group has
obtained considerable knowledge, which may also be
used for rehabilitation following brain and spinal cord
injury. The group has consequently for some years aimed
to utilize this knowledge in practically-oriented clinical
rehabilitation projects. For this purpose, we established
´Center for Research in Spasticity and Neurorehabilitation´
in 2006. Through this center, we have now established
close collaboration with the neurological departments
and rehabilitation clinics at the major hospitals in the
Copenhagen area and we have a number of ongoing
projects with them. Most importantly we have established
a very close collaboration with The Helene Elsass Center,
which is a private center for training of children with
cerebral palsy. Research in cerebral palsy has consequently
become another of our main research interests and we
are striving – together with The Helene Elsass Center – to
create an active and stimulating research environment for
young researchers interested in cerebral palsy.
Mihai Moldovan & Christian Krarup (Nervegroup)
Current research at the Nervelab includes: Investigation
of the membrane dysfunction in P0 mutant peripheral
axons (a model of Charcot-Marie-Tooth disease) with
particular interest in the link between the ectopically
expressed NaV1.8 channels and conduction failure
that could provide a new therapeutic target investigation of the peripheral motor axon dysfunction in the
SOD1G127X mouse (a model for amyotrophic lateral
sclerosis) the link between impulse conduction and
neuronal degeneration (Na+ mediated axonal degeneraAnnual Report 2012
37
tion) in various mouse models of peripheral neuropathies
impaired axonal degeneration and regeneration in the
presence of mutant Schwann cells deficient of the myelin
protein P0 the neuroprotective effect of S100A4 peptide
mimetics with particular emphasis of nerve regeneration
an peripheral neuropathy
Research Techniques
In animals:
• 2-photon microscopy
• Behavioral animal studies
• Immunohistochemistry
• In vivo and in vitro extra- and intracellular microelectrode recordings in mice, rats and cats.
• PCR
In humans:
• Biomechanical movement analysis
• Eelectroencephalography (EEG)
• Functional Magnetic Resonance Imaging (fMRI)
• Kinematic movement analysis
• Peripheral nerve stimulation
• Transcranial magnetic stimulation (TMS)
Mihai Moldovan & Christian Krarup (Nervelab):
we investigate the function of mouse peripheral motor
axons by combining in vivo “threshold-tracking” nerve
excitability techniques with classical conduction studies,
behavioral methods (Rotor-rod and walking-track analysis), histological quantification of myelinated axons and
gene expression studies.
Financing
• Aase og Ejnar Danielsens Fond
• A. P. Møller og Hustru Chastine Mc-Kinney Møllers
Fond
• Danish Medical Research Council
• The Danish Council for Independent Research | Humanities
• Foundation for Research in Neurology
• International Foundation for Research in Paraplegia
• Jytte and Kaj Dahlboms fond
• Kulturministeriets Udvalg for Idrætsforskning
• Ludvig and Sara Elsass Foundation
• Lundbeck Foundation
38
Annual Report 2012
•
•
•
•
•
Novo Nordisk Foundation
Scleroseforeningen
Sofus Carl Emil & Olga Doris Friis Legat
Team Danmark
Whittaker Foundation
Collaborations – Domestic
• Bente Kiens, Department of Exercise and Sport Sciences, University of Copenhagen, Denmark
• Charlotte Jakobsen, DTU, Denmark
• Fin Biering-Sørensen, Spinal Cord Injury Unit, Rigshospitalet, Denmark
• Finn C. Nielsen, Department of Clinical Biochemistry,
Rigshospitalet, University of
• Copenhagen
• Hartwig Siebner, MR-Department, Hvidovre Hospital,
Denmark
• Thomas Sinkjær, Aalborg University, Denmark
• Jorge Quevedo, Department of Physiology, Biophysics
and Neurosciences, CINVESTAV, Mexico City, México
Collaborations – International
• Bernard Conway, University of Strathclyde, Glasgow,
United Kingdom
• Carolynn Patten, University of Florida, USA
• Center of Excellence in Neuroscience, Carol Davila
University of Medicine and Pharmacy, Bucharest,
Romania (Mihai Moldovan)
• Dave McCrea, Department of Physiology, University
of Manitoba, Winnipeg, Canada
• John N. Wood, Molecular Nociception Group, University College London, United Kingdom
• John Rothwell, Movement and balance unit, Queen
sq. London, United Kingdom
• Johnathan Cole, Southamton University, UK
• Jorge Quevedo, Department of Physiology, Biophysics
and Neurosciences, CINVESTAV, Mexico City, México
• Laurent Bouyer, Lavall University, Quebec, Canada
• Ole Kiehn, Mammalian Locomotor Laboratory,
Karolinska Institute, Department of Neuroscience,
Stockholm, Sweden
• Rob Brownstone; Departments of Neurobiology and
Neurosurgery, Dalhousie University, Halifax, Canada
• Rock Levinson, University of Colorado School of
Medicine, Denver, CO, USA
• Roger Madison RD, Department of Surgery, Duke
University Medical Center, Durham, NC, USA
• Rudolf Martin, Neurology, Developmental Neurobiology, University of Würzburg, Germany
• Simon Farmer, University College London, UK
• Simon Gandevia, Prince of Wales Medical Institute,
Sydney, Australia
• Xiangyu Kong, Medical University in Chengde, China
Motor Control Laboratory 2012 Publications
1. Alkjaer T, Wieland MR, Andersen MS, Simonsen EB, Rasmussen J.
Computational modeling of a forward lunge: towards a better understanding of the function of the cruciate ligaments. J Anat. 2012
Dec;221(6):590-7.
2. Alkjær T, Raffalt P, Petersen NC, Simonsen EB. Movement behavior
of high-heeled walking: how does the nervous system control
the ankle joint during an unstable walking condition? PLoS One.
2012;7(5):e37390.
3. Alkjær T, Simonsen EB, Magnusson SP, Dyhre-Poulsen P, Aagaard P.
Antagonist muscle moment is increased in ACL deficient subjects
during maximal dynamic knee extension. Knee. 2012 Oct;19(5):6339.
4. Butler JE, Petersen NC, Herbert RD, Gandevia SC, Taylor JL. Origin
of the low-level EMG during the silent period following transcranial
magnetic stimulation. Clin Neurophysiol. 2012 Jul;123(7):1409-14
5. Barthélemy D, Alain S, Grey MJ, Nielsen JB, Bouyer LJ. Rapid changes
in corticospinal excitability during force field adaptation of human
walking. Exp Brain Res. 2012 Mar;217(1):99-115.
6. Enríquez Denton M, Wienecke J, Zhang M, Hultborn H, Kirkwood
PA. Voltage-dependent amplification of synaptic inputs in respiratory
motoneurones. J Physiol. 2012 Jul 1;590(Pt 13):3067-90.
7. Herz DM, Christensen MS, Reck C, Florin E, Barbe MT, Stahlhut C,
Pauls KA, Tittgemeyer M, Siebner HR, Timmermann L. Task-specific
modulation of effective connectivity during two simple unimanual
motor tasks: a 122-channel EEG study. Neuroimage. 2012 Feb
15;59(4):3187-93.
8. Joseph C, Buga AM, Vintilescu R, Balseanu AT, Moldovan M, Junker
H, Walker L, Lotze M, Popa-Wagner A. Prolonged gaseous hypothermia prevents the upregulation of phagocytosis-specific protein
annexin 1 and causes low-amplitude EEG activity in the aged rat
brain after cerebral ischemia. J Cereb Blood Flow Metab. 2012
Aug;32(8):1632-42.
9. Juul-Kristensen B, Hansen H, Simonsen EB, Alkjær T, Kristensen
JH, Jensen BR, Remvig L. Knee function in 10-year-old children
and adults with Generalised Joint Hypermobility. Knee. 2012
Dec;19(6):773-8.
10. Koblauch H, Heilskov-Hansen T, Alkjær T, Simonsen EB, Henriksen
M. The Effect of Foot Progression Angle on Knee Joint Compression
Force during Walking. J Appl Biomech. 2012 Aug 22.
11. Krarup C, Moldovan M. Reappraising I(h:) do myelinated motor and
sensory axons of human peripheral nerves operate at different resting membrane potentials? J Physiol. 2012 Apr 1;590(Pt 7):1515-6.
12. Leukel C, Lundbye-Jensen J, Christensen MS, Gollhofer A, Nielsen
JB, Taube W. Subconscious visual cues during movement execution
allow correct online choice reactions. PLoS One. 2012;7(9).
13. Lorentzen J, Nielsen D, Holm K, Baagøe S, Grey MJ, Nielsen JB.
Neural tension technique is no different from random passive movements in reducing spasticity in patients with traumatic brain injury.
Disabil Rehabil. 2012;34(23):1978-85
14. Lorentzen, J , Grey, MJ , Geertsen, SS , Biering-Sørensen, F , Brunton, K, Gorassini, M& Nielsen, JB 2012, ‘ Assessment of a portable
device for the quantitative measurement of ankle joint stiffness
in spastic individuals ‘ Clinical Neurophysiology , vol 123, nr. 7, s.
1371-1382.
15. Lorentzen J, Willerslev-Olsen M, Crone C, Sinkjær T, Nielsen JB.
[New knowledge of spasticity and its treatment]. Ugeskr Laeger.
2012 Feb 27;174(9):569-73.
16. Lundell H, Barthelemy D, Biering-Sørensen F, Cohen-Adad J, Nielsen
JB, Dyrby TB. Fast diffusion tensor imaging and tractography of the
whole cervical spinal cord using point spread function corrected
echo planar imaging. Magn Reson Med. 2013 Jan;69(1):144-9.
17. Meehan CF, Grondahl L, Nielsen JB, Hultborn H. Fictive locomotion
in the adult decerebrate and spinal mouse in vivo. J Physiol. 2012
Jan 15;590(Pt 2):289-300
18. Moldovan M, Alvarez S, Pinchenko V, Marklund S, Graffmo KS,
Krarup C. Nerve excitability changes related to axonal degeneration in amyotrophic lateral sclerosis: Insights from the transgenic
SOD1(G127X) mouse model. Exp Neurol. 2012 Jan;233(1):408-20.
19. Petersen TH, Willerslev-Olsen M, Conway BA, Nielsen JB. The motor cortex drives the muscles during walking in human subjects. J
Physiol. 2012 May 1;590(Pt 10):2443-52.
20. Ritterband-Rosenbaum A, Christensen MS, Nielsen JB. Twenty weeks
of computer-training improves sense of agency in children with spastic cerebral palsy. Res Dev Disabil. 2012 Jul-Aug;33(4):1227-34.
21. Roig M, Skriver K, Lundbye-Jensen J, Kiens B, Nielsen JB. A single
bout of exercise improves motor memory. PLoS One. 2012;7(9)
22. Simonsen EB, Alkjær T. The variability problem of normal human
walking. Med Eng Phys. 2012 Mar;34(2):219-24.
23. Simonsen EB, Tegner H, Alkjær T, Larsen PK, Kristensen JH, Jensen
BR, Remvig L, Juul-Kristensen B. Gait analysis of adults with
generalised joint hypermobility. Clin Biomech (Bristol, Avon). 2012
Jul;27(6):573-7.
24. Simonsen EB, Alkjær T, Raffalt PC. Reflex response and control of
the human soleus and gastrocnemius muscles during walking and
running at increasing velocity. Exp Brain Res. 2012 Jun;219(2):16374
25. Simonsen EB, Svendsen MB, Nørreslet A, Baldvinsson HK, HeilskovHansen T, Larsen PK, Alkjær T, Henriksen M. Walking on high heels
changes muscle activity and the dynamics of human walking significantly. J Appl Biomech. 2012 Feb;28(1):20-8.
26. Simonsen EB, Cappelen KL, Skorini R_, Larsen PK, Alkjær T, DyhrePoulsen P. Explanations pertaining to the hip joint flexor moment
during the stance phase of human walking. J Appl Biomech. 2012
Nov;28(5):542-50.
27. Zhang M, Hultborn H, Sukiasyan N, The distribution of calcium
channel Cav1.3 in the central nervous system and its functions in
relation to motor control. Ed Mark R. Figgins; Nova Science Publishers, 2012; pp 1-48
Annual Report 2012
39
40
Annual Report 2012
Neuronal Signaling Laboratory
Research in the laboratory is directed towards understanding signaling processes in the nervous system at all
levels of organization, ranging from the molecular level
(for instance molecules involved in the release of transmitters), over the cellular level (for instance plasticity,
regulation or integration of synaptic signals), up to the
systems level (communication in networks of neurons, or
between neurons and astrocytes; the relation between
functional activity, regional metabolism and blood flow).
The research also includes studies of aging and disease
models.
Research Techniques
The research groups use a multitude of techniques:
• GMO, viral expression, knock-out mice
• advanced optical methods, 2-photon microscopy, Ca
imaging
• electrophysiology: field potentials, unit recordings, sharp electrodes, patch, iontophoresis
• Preparations: cell culture, acute slices from mice and
turtles. Integrated carapace spinal cord preparation
from turtles. Everything in vivo in mice and rats
• immunohistochemistry
• intracellular recordings of a single neuron embedded
in an active network (brain or spinal cord
• microiontophoresis
• pharmacology
• recordings of brain blood flow and oxygen metabolism
• simultaneous multi-unit recording (~50 neurons)
from spinal motor network activity
• mathematical modeling, simulations, signal analysis
Financing
• Agnes og Poul Friis Fond
• Antidoping Danmark
• Nordea Fonden via Center for Healthy Aging
• Det frie forskningsråd for sygdom og sundhed
• Det frie forskningsråd for sygdom og sundhed,
Sapere Aude
• Faculty of Health Sciences, University of Copenhagen
(stipends for PhD students)
• International Association for the Study of Pain
• Leducq Foundation
• Lundbeck Foundation
• Lundbeck Foundation Center for Neurovascular Signaling
• Lundbeck Foundation Center for Biomembranes in
Nanomedicin
• Novo Nordisk Foundation
• Owensenske Fond
• Sofus Carl Emil Friis Fond
• SYNSYS, Large Integrating Project, EU-FP7
Collaborating research Centers
Martin Lauritzen and the TransNeuro Group are
members of Center for Healthy Aging, Lundbeck
Foundation Center for Neurovascular Signaling, and
the Leducq Transatlantic Network of Excellence.
Jakob Sørensen and Neurosecretion Group are members of Attention to Dopamine: From Psychological
Functions to Molecular Mechanism, UCPH Excellence
Programme for Interdisciplinary Research (2016 Funds)
Rune Berg, Per Roland, Jørn Hounsgaard and Jakob
Dreyer are members of Dynamical Systems InterdiscipliAnnual Report 2012
41
nary Network, UCPH Excellence Programme for Interdisciplinary Research (2016 Funds)
Collaborations
• Aidas Alaburda, Department of Biochemistry & Biophysics, Vilnius University, Lithuania
• Alex Brazhe, Department of Biophysics, Faculty of
Biology, Moscow State University, RussiaAlastair
Buchan, Oxford University, United Kingdom
• Brian MacVicar, University of British Colombia,
Canada
• David Attwell, University College, London, United
Kingdom
• Eric Newman, University of Minnesota, MN, USA
• Gytis Svirskis, Laboratory of Neurophysiology, Kaunas
University, Lithuania
• Jorgina Satrústegui, Universidad Autónoma de Madrid, Spain
• Karin Lykke Hartmann, Aarhus University, Denmark
• Kimmo Jensen, Aarhus University, Denmark
• Laboratory of Prof. S. Gandevia, Prince of Wales
Medical Research Institute, Australia
• Manfred Lindau, Cornell University, Ithaca, NY, USA
• Matthijs Verhage, Freie Universität, Amsterdam,
Netherlands
• N. Schmidt, Department of Biomedicine, University of
Copenhagen
• Nils Brose, Max-Planck-Institut für experimentelle
Medizin, Göttingen, Germany
• Bente Pakkenberg, Research Laboratory for Stereology and Neuroscience BBH
• Rodolfo Delgado-Lezama. CINVESTAV Mexico,
Mexico
• Raul Russo, IIBCE, Montevideo, Uruguay
• Richard Exley, University of Oxford, United Kingdom
• Serge Charpak, University of Paris, France
• Stephanie Cragg, University of Oxford, United Kingdom
• Susanne Ditlevsen, Matematisk Institut, Københavns
Universitet
• Ulla Vig Nissen, Afdeling for Rygmarvsskader, Glostrup Hospital
• Yosef Yarom, Life Science Institute, Hebrew University
of Jerusalem, Israel
42
Annual Report 2012
Neuronal Signaling Laboratory 2012 Publications
1. Guzulaitis R, Hounsgaard J, Alaburda A. Inhibition of motoneurons
during the cutaneous silent period in the spinal cord of the turtle.
Exp Brain Res. 2012; 220(1):23-28.
2. Hounsgaard J, Häusser M. Probing the functional properties of
mammalian dendrites (R. Llinas and M.Sugimori, J. Physiology, 1980,
305:197-213). Cerebellum. 2012; 11(3):609-11.
3. Kolind J, Hounsgaard J, Berg RW. Opposing Effects of Intrinsic Conductance and Correlated Synaptic Input on V-Fluctuations during
Network Activity.Front Comput Neurosci. 2012; 6:40.
4. Lauritzen M, Dirnagl U. Celebrating the 30th anniversary of our
journal. J Cereb Blood Flow Metab. 2012; 32(7):1097.
5. Lauritzen M, Mathiesen C, Schaefer K, Thomsen KJ. Neuronal
inhibition and excitation, and the dichotomic control of brain
hemodynamic and oxygen responses. Neuroimage. 2012 Aug
15;62(2):1040-50.
6. Mohrmann R, Sørensen JB. SNARE requirements en route to exocytosis: from many to few. J Mol Neurosci.; 2012; 48(2):387-94.
7. Schäfer K, Blankenburg F, Kupers R, Grüner JM, Law I, Lauritzen M,
Larsson HB. Negative BOLD signal changes in ipsilateral primary
somatosensory cortex are associated with perfusion decreases and
behavioral evidence for functional inhibition. Neuroimage. 2012 Feb
15;59(4):3119-27.
Annual Report 2012
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44
Annual Report 2012
Neuropsychiatry Laboratory
The Laboratory of Neuropsychiatry is situated at the Department of Psychiatry at Rigshospitalet. Research areas
include clinical and experimental studies of the biological
basis for psychiatric and neurodegenerative disorders as
well as drug addiction. Other main research areas are
anaestesiology, cerebral vascular function and metabolism, erythopoietin, hypoxia, high altitude and exercise
physiology, and perioperative neuroprotection.
A steering group consisting of Anders Fink-Jensen,
Gitta Wörtwein, Pernille Koefoed and Bente Bennike
heads the laboratory. Secretary is Anne-Mette Broberg.
Gitta Wörtwein’s, Pia Weikop’s and Anders
­Fink-Jensen’s groups
• Anders Fink-Jensen, professor, DM Sci.
• Gitta Wörtwein, associate professor, PhD
• Pia Weikop, associate professor, PhD
• Gunnar Sørensen, PhD, post-doc.
• Ditte Dencker, PhD, post-doc
• Tom Bolwig, professor emeritus
• Anders Jørgensen, PhD student
• Bente Bennike, TAP
• Birgit Hansen, TAP
• Pernille Clausen, TAP
• Pernille Herrestedt Hansen, M.Sc. student
• Katrine Maigaard, medical student
• Kristin Forsberg, medical student
• Nadia Aalling, medical student
Main Research areas
Neurobiological mechanism underlying drug abuse,
psychosis and affective disorders using transgenic mouse
models and the microdialysis technique in order to investigate the neurobiological functions of receptor subtypes
and transporters. In addition, a number of behavioural
tests in combination with in vitro-techniques are applied
in order to investigate the neurobiological mechanisms
underlying various disease models of symptoms of psychosis, drug addiction, stress, depression and anxiety.
Niels Vidiendal Olsen’s group
Main Research areas
Anaestesiology, cerebral vascular function and metabolism, erythopoietin, hypoxia, high altitude and exercise
physiology, and perioperative neuroprotection.
Pernille Koefoed’s group
• Erling Mellerup, associate professor
• Pernille Koefoed, associate professor
• Bente Bennike, TAP
Main Research areas
Our mean focus is on the genetics of psychiatric disorders, especially on the genetics of bipolar disorder. Bipolar disorder (BD) is a spectrum of psychiatric conditions
characterized by severe mood fluctuations ranging from
extreme elation, or mania, to severe depression usually
accompanied by disturbances in behaviour. We have so
far focused on genes where the proteins are involved in
generation of action potentials. We work with combinations of SNP genotypes and clinical data using software
develop in collaboration with GenoKey ApS. The software is Array-based technology of geometrical representation of logic, a method used for modelling, analysis,
Annual Report 2012
45
and real-time deduction of complex combinational
systems. It is new to use this progrem in calculating combinations of SNP and/or other values in associated with
disease. Our work on bipolar disorder gave four clusters
of patients specific combinations, and recent preliminary
results show different clinical phenotypes of the patients
in the different clusters. We are currently working on using this method on other datasets as a proof of concept.
We also work on exploiding new genes associated with
psychiatric genetics.
Financing
• A. P. Møller and Hustru Chastine Mc-Kinney Møllers
Foundation
• Carlsberg Foundation
• Danielsens Foundation
• The Danish National Psychiatric Research Foundation
• Ivan Nielsen Foundation
• Lundbeck Foundation
• The Toyota-Foundation
• Novo Nordisk Foundation
• Wørzners Mindelegat
Methods
• Addiction related behavioural tests in rats and mice
(acute and chronic self-administration (cocaine, food,
sugar, alcohol etc.), conditoned place preference,
withdrawl tests, sensitization, reinstatement, etc.)
• Anxiety and depression tests in rats and mice (elevate
plus-maze, open field, social interaction, light dark
transition, Porsolt swim test, tail suspension, anhedonia/sacharin preference, etc.)
• Cognitive tests in rats and mice (Morris water maze,
T-maze, Novel object recognition, Novel place
• recognition, juvenile recogniton, etc.)
• ECS in rats and mice
• ELISA, RIA
• Experimental studies in normal human subjects and
clinical studies in patient groups
• High troughput Fast Real Time PCR, qRT-PCR
• Histology
• Hot plate test, rotarod, locomotor activity cages
• HPLC with electrochemical, fluorescens and UV
detection
• Immunohistochemistry, in situ hybridization, receptor
46
Annual Report 2012
autoradiography
• Microdialysis in freely moving rats and mice
• Stress models in mice and rats (restraint, social isolation, maternal deprivation, etc.)
Collaborations – Domestic
• Lars Vedel Kessing, Martin Balslev Jørgensen, Ida
Hageman, Henrik Dam, Klaus Munkholm, Maj Vinberg, Ulla Knorr, Mia Greisen Søndergaard; Psychiatric Centre Copenhagen, Department O, Rigshospitalet, Copenhagen University Hospital
• Bente Pakkenberg, Research Laboratory for Stereology and Neuroscience, Bispebjerg
• University Hospital
• Ulrik Gether, Molecular Neuropharmacology Group,
INF
• David Woldbye, Protein Laboratory, INF
• Birgitte Holst, Molecular Pharmacology Group, INF
• Gert Lykke Moeller, GenoKey ApS, ScionDTU
• Gregers Wegener, Center of Psychiatric Research,
University of Aarhus, Risskov, Denmark
• Ole Mors, Center of Psychiatric Research, University
of Aarhus, Risskov, Denmark
• Thomas Werge, Danish Psychiatric Biobank, Center
of Psychiatry, Sct. Hans Hospital,
• Roskilde, Copenhagen University Hospital, Denmark
Collaborations – International
• Alexandra Mathé, Karolinske Institute, Sweden
• Anders Bjørklund, Wallenberg Neuroscience Center,
Lund University, Sweden
• Barak Caine and Morgane Thomsen, Alcohol and
Drug Abuse Research Center,
• McLean Hospital / Harvard Medical School, USA
• Bjarne Ersboell and Murat Kulahci, DTU Data Analysis, Department of Informatics
• and Mathematical Modelling, Danish Technical University, Lyngby, Denmark
• Jürgen Wess, Molecular Signaling Section, National
Institutes of Health, USA
• Ole A. Andreassen, Department of Psychiatry, Oslo
University Hospital and Institute of
• Psychiatry, University of Oslo
• Åsa Petersén, Department of Experimental Medical
Science, Lund University, Sweden
Laboratory of Neuropsychiatry is part of:
• Danisk Psychiatric Biobank (DPB
• Panic Disorder International Consortium (PAN*I*C)
with PI Professor DM Francis McMahon
• National Institute of Mental Health, NIH, Bethesda,
USA
• Scandinavian Collaboration of Psychiatric Etiology
(SCOPE)
Neuropsychiatry Laboratory 2012 Publications
1. Dencker, Ditte; Weikop, Pia; Sørensen, Gunnar; Woldbye, David P
D; Wörtwein, Gitta; Wess, Jürgen; Fink-Jensen, Anders. An allosteric
enhancer of M(4) muscarinic acetylcholine receptor function inhibits
behavioral and neurochemical effects of cocaine. Psychopharmacology, Vol. 224, Nr. 2, 2012, s. 277-87.
2. Jorgensen, A., Maigaard, K., Wörtwein, G., Hageman, I., Henriksen,
T., Weimann, A., Møller, P., Loft, S., Hau, J., Poulsen, H. E. &
Jorgensen, M. B. Chronic restraint stress in rats causes sustained increase in urinary corticosterone excretion without affecting cerebral
or systemic oxidatively generated DNA/RNA damage. Progress in
Neuro-Psychopharmacology & Biological Psychiatry. 40C, 2012, s.
30-37.
3. Gøtzsche, Casper René; Nikitidou, Litsa; Sørensen, Andreas T;
Olesen, Mikkel V; Sørensen, Gunnar; Christiansen, Søren H O;
Ängehagen, Mikael; Woldbye, David P D; Kokaia, Merab. Combined
gene overexpression of neuropeptide Y and its receptor Y5 in the
hippocampus suppresses seizures. Neurobiology of Disease, Vol. 45,
Nr. 1, 2012, s. 288-96.
4. Mellerup, Erling; Andreassen, Ole; Bennike, Bente; Dam, Ole Henrik;
Durovic, Srdjan; Hansen, Thomas; Melle, Ingrid; Møller, Gert Lykke;
Mors, Ole; Koefoed, Pernille. Connection between Genetic and
Clinical Data in Bipolar Disorder. PLoS One, Vol. 7, Nr. 9, 2012, s.
e44623.
5. Maigaard, K., Hageman, I., Jørgensen, A., Jørgensen, M. B. &
Wörtwein, G. Electroconvulsive stimulations prevent chronic stressinduced increases in L-type calcium channel mRNAs in the hippocampus and basolateral amygdale. Neuroscience Letters. Supplement.
516, 1, 2012, s. 24-8.
6. Dyrvig, Mads; Hansen, Henrik H; Christiansen, Søren H; Woldbye,
David P D; Mikkelsen, Jens D; Lichota, Jacek. Epigenetic regulation
of Arc and c-Fos in the hippocampus after acute electroconvulsive
stimulation in the rat. Brain Research Bulletin, Vol. 88, Nr. 5, 2012, s.
507-13.
7. Jørgensen, A., Law, I., Nielsen, S. & Jørgensen, M. B. Fluorodeoxyglucose positron emission tomography in juvenile systemic lupus
erythematosus with psychiatric manifestations: relation to psychopathology and treatment response in two cases. Rheumatology. 51, 1,
2012, s. 193-5.
8. Mellerup, Erling; Møller, Gert Lykke; Koefoed, Pernille. Genetics of
complex diseases : variations on a theme. Medical Hypotheses, Vol.
78, Nr. 6, 2012, s. 732-4.
9. Bolwig, Tom G. Historical aspects of Danish psychiatry. Nordic Journal of Psychiatry. Supplement, Vol. 66 Suppl 1, 2012, s. 5-13.
10. Gøtzche CR, Nikitidou L, Sørensen AT, Olesen MV, Sørensen G,
Christiansen SH, Ängehagen M, Woldbye DPD, Kokaia M. Ligand-
11.
12.
13.
14.
15.
16.
17.
18.
19.
receptor combination gene therapy for epilepsy: seizure suppression
by hippocampal overexpression of neuropeptide Y and its receptor
Y5. Neurobiol. Dis. 2012; 45:288-96.
Sørensen, Gunnar; Woldbye, David P D. Mice lacking neuropeptide
Y show increased sensitivity to cocaine. Synapse (New York), Vol. 66,
Nr. 9, 2012, s. 840-3.
Dencker, Ditte; Thomsen, Morgane; Wörtwein, Gitta; Weikop, Pia;
Cui, Yinghong; Jeon, Jongrye; Wess, Jürgen; Fink-Jensen, Anders.
Muscarinic Acetylcholine Receptor Subtypes as Potential Drug
Targets for the Treatment of Schizophrenia, Drug Abuse and Parkinson’s Disease. A C S Chemical Neuroscience, Vol. 3, Nr. 2, 2012, s.
80-89.
Sørensen, Gunnar; Jensen, Morten; Weikop, Pia; Dencker, Ditte;
Christiansen, Søren H; Loland, Claus Juul; Bengtsen, Cecilie Hee;
Petersen, Jørgen Holm; Fink-Jensen, Anders; Wörtwein, Gitta; Woldbye, David P D. Neuropeptide Y Y5 receptor antagonism attenuates
cocaine-induced effects in mice. Psychopharmacology, Vol. 222, Nr.
4, 2012, s. 565-77.
Licht, Cecilie L; Christoffersen, Maria; Okholm, Mads; Damgaard,
Laerke; Fink-Jensen, Anders; Knudsen, Gitte M; Erritzoe, David.
Simultaneous polysubstance use among Danish 3,4-methylenedioxymethamphetamine and hallucinogen users : combination patterns and proposed biological bases. Human Psychopharmacology:
Clinical and Experimental, Vol. 27, Nr. 4, 2012, s. 352-63.
Fink-Jensen, Anders. Skift af antipsykotika er ofte nødvendigt og
ikke ganske ukompliceret. Ugeskrift for Laeger, Vol. 174, Nr. 5,
2012, s. 262.
Hasselbalch, Jacob; Knorr, U; Hasselbalch, S G; Gade, Ann Aaen;
Kessing, L V. The cumulative load of depressive illness is associated
with cognitive function in the remitted state of unipolar depressive
disorder. European Psychiatry, 2012
Sass, Amdi; Wörtwein, Gitta. The effect of subchronic fluoxetine
treatment on learning and memory in adolescent rats. Behavioural
Brain Research, Vol. 228, Nr. 1, 2012, s. 169-75.
Dencker D, Weikop P, Sørensen G, Woldbye DPD, Wörtwein G, Wess
J, Fink-Jensen A. The M4 muscarinic acetylcholine receptor plays a
critical role in the behavioural and biochemical effects of cocaine
Psychopharmacol. 2012;224:277-87.
Hjaeresen, M-L., Hageman, I., Wortwein, G. & Jørgensen, M. B.
Time course and duration of changes in Kv7.2 and Kv11.1 mRNA
expression in the hippocampus and piriform cortex following electroconvulsive stimulations. 2012 I : Brain Stimulation. 5, 1, s. 55-60.
Annual Report 2012
47
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Annual Report 2012
Protein Laboratory
Main Research Areas
Elucidation of the role of synaptic cell adhesion
molecules in learning and memory under neurodegenerative conditions.
During the last decade by means of nuclear magnetic
resonance (NMR) spectroscopy and X-ray crystallography,
the structures of modules constituting the ectodomain
of several synaptic cell adhesion molecules have been
determined. The list includes the neural cell adhesion
molecule (NCAM), the olfactory cell adhesion molecule
(OCAM), and synaptic cell adhesion molecules such as
neuroplastin and nectin-1. The mechanisms of NCAMmediated cell adhesion and FGF-receptor activation have
been elucidated at the atomic level. We have also discovered that the synaptic cell adhesion molecules, neuroplastin and nectin-1, in neurons use the FGF-receptor for
signaling in that way inducing neuronal differentiation
and survival. Based on structural studies and molecular
modeling, a number of low molecular weight mimetics
of these cell adhesion molecules has been developed
and used as pharmacological tools to study the role of
these molecules in synaptic mechanisms of learning and
memory in vitro and in vivo. Our current research also is
focusing on the role of the novel synaptic cell adhesion
molecule, neurexin and neuroligin, in neuroregeneration and plasticity in relation to Alzheimer’s disease (AD)
pathology.
Development of growth factor receptor agonists
with neuroprotective and memory enhancing
propertie.
We have used the structural and molecular modeling
approaches to design mimetics/agonists of a number of
growth and neurotrophic factors including FGF2, glial
cell line-derived neurotrophic factor (GDNF), artemin,
brain-derived neurotrophic factor (BDNF), cilliary neurotrophic factor (CNTF) and erythropoietin. Some of these
agonists have been demonstrated to induce neuronal
differentiation, promote survival and increase presynaptic
function in vitro and in vivo and to display neuroprotective and memory enhancing properties in vivo.
Development of antagonists of ErbB receptors
inhibiting glioma cell growth in vitro and in vivo.
The epidermal growth factor family of receptor tyrosine
kinases (ErbBs) play essential roles in tumorigenesis and
cancer disease progression, and therefore has become
an attractive target for structure-based drug design. We
have recently developed a number of peptide-based
antagonists of the ErbB receptors inhibiting receptor
activation and glioma cell migration in vitro.
Development of mouse models to study the role of
brain microenvironment-derived factors in glioma
genesis and intracranial metastases
Malignant brain tumors remain a serious clinical problem
today. These tumors can be subdivided in (i) primary
tumors that originate directly from brain cells and (ii)
secondary tumors – that originate from other organs
forming intra-cranial metastases. Unlike other cancers,
Annual Report 2012
49
current clinical approaches, targeting brain neoplasia,
have failed and there is a desperate need for more effective therapies.
The Neuro-Oncology Group (NOG), which was
recently established at the INF, is studying the cross-talk
between tumor cells and components of the tumor
microenvironment by utilizing a variety of methods, including genetically engineered mouse models1-3. These
studies have identified cellular component and factors
of the tumor microenvironment which are drivers of
tumor progression and metastasis4,5. Targeting one of
these factors, the pro-metastatic and pro-inflammatory
S100A4 protein by an antibody-base therapy, substantially inhibited metastasis formation in a spontaneous
and an induced tumor mouse model6.
To explore whether there are similar mechanism and
factors of the brain tumor microenvironment involved
in glioma and intracranial metastasis formation, we will
develop new mouse models of spontaneous glioma
(pS100A4-SV40Tag) and brain metastasis (astrocyte
“education”). Gene-expression profiling of mouse
astrocytes activated by conditioned media from glioma
and carcinoma cells metastatic to the brain will be used
to identify potential therapeutic targets. The S100A4
protein, which is upregulated in astrocytes surrounding
glioma lesions and brain metastasis of breast cancer, will
be targeted by neutralizing antibodies or peptides in
order to prevent disease progression.
Function of Neuropeptide Y.
Using adeno-associated viral vectors, over expression of
functional neuropeptide Y Y2 receptors was induced in
the hippocampus of rats. This treatment was found to
be associated with significant seizure-suppressant effect
in two temporal lobe epilepsy models: kindling and
kainate-induced seizures. This supports the concept that
gene therapy with overexpression of antiepileptic transgenes could be a potential future treatment for epilepsy.
Studying the neuropeptide Y (NPY) system in repeated
episodes of alcohol withdrawal, prominent changes
in the expression of NPY and its receptors Y1, Y2, and
Y5. These changes could be importantly involved in the
process by which repeated withdrawal episodes lead to
the worsening of alcohol withdrawal symptoms (e.g.
seizures) and dependence.
50
Annual Report 2012
Investigations of molecular clocks in the brain and
the neuroanatomical structures involved in the
generation and regulation of circadian rhythms.
We have during 2012 shown the presence of a peripheral clock in the neocortex and cerebellum of the Sprague
Dawley rat. This was done by in situ hybridization,
immunohistochemistry and qRT-PCR demonstrating the
presence of all core clock genes in both brain structures.
The expression is located in neurons and the mRNA
levels exhibit an oscillating nature with peaks delayed
as compared to the expression of by same genes in the
master clock in the suprachiasmatic nucleus. Lesion of
the suprachiasmatic nucleus abolished the cortical and
cerebellar rhythms showing that these peripheral clocks
are dependent on the master clock. We are at the moment investigating the hormonal factors, which may be
involved in the master clock’s regulation of the cortical
and cerebellar clock genes.
We have performed a detailed mapping of the
vasopressinergic neurons in the mouse hypothalamus
including the accessory magnocellular nuclei by in situ
hybridization. We have further investigated, whether the
vasopressin expression in these nuclei showed a diurnal
rhythm. The suprachiasmatic nucleus was the only structure exhibiting a light-independent endogenous diurnal
rhythm in vasopressin levels.
A major target area of the optic-circadian system is
the pineal gland. We have investigated the location and
developmental expression of several transcription factors
in the rat pineal gland and retina. We are now studying
the influence of the homeobox genes Rax and Crx on
morphology and activation of key phototransduction
elements in the mature pinealocytes and photoreceptor
cells of the retina. We have in a pineal culture system
by adenoviral transduction of constructs encoding short
hairpin RNAs or full-length transcripts been able to show
that the transcription factors Rax and Crx are involved in
transcriptional regulation of the rate-limiting enzyme in
daily melatonin synthesis, arylalkylamine N-acetyltransferase, in the rat pineal gland.
We have in collaboration with the Novo Nordic Metabolic Center in a transgenic mouse shown the presence
of a receptor for short chain fatty acids (FFAR3) to be
present in autonomic and somatic ganglia with either
afferents or efferents to the gut.
Stereological investigations.
It has been shown that motor nerves regenerates faster
and/or more complete than do sensory nerves following
a nerve crush lesion. Finally, a new stereological method
has been developed to quantify cell volume in arbitrarily
rotated sections. Ongoing projects:
• Quantitative evaluation of nerve degeneration and
regeneration following crush lesion in sensory and
motor nerves and the effects of beta-methasone on
both processes.
• Quantitative evaluation of PGP 9.5 positive fibres in
small salivary glands in aging humans.
• Quantitative evaluation of hippocampus in neonatal
guinea pigs following maternal C-vitamine deficiency.
• Quantitative evaluation of visceral fat cells and
inflammatory cells following longterm intake of fat
diet.
• Quantitative evaluation of collagen fibrils in patellar
tendon and Achilles tendon following various experimental and natural metabolic and life style situations.
• Quantitative evaluation of experimental osteomyelitic
lesions for comparison with the detection ability in
various scanning techniques.
Neuronal tracings.
Neural tracing in rats (and pigs), especially serotonergic,
and projections involved in regulation of central autonomic functions, sleep-wake cycling and anxiety/stress
characterisation of the neural pathways that contains
neuroglobin or cytoglobin.
Neuroanatomy and evolution of the nervous system.
Neural tracing in rats, mice (and pigs) are used for characterization of serotonergic, neuroglobin and cytoglobin
containing central pathways. Especially projections
involved in regulation of central autonomic functions,
sleep-wake cycling and anxiety/stress are investigated.
The in vivo function of neuroglobin and cytoglobin
are investigated in transgenic mice models, by using
behavioral, neuroanatomical and micro array techniques.
The anatomical localization of these globins in the brain
is studied in several species including human.
Development of neurotransmitter systems and chemi-
cally defined neuronal populations are investigated, by
use of immunohistochemical methods, in several invertebrates and vertebrates in order to elucidate the evolution of these systems, and to use these neurochemically
defined systems for reconstruction of the phylogeny of
the animal kingdom.
Research Techniques
• animal models
• behavioural models
• cloning and production of recombinant proteins
• cloning of neural genes
• computer-assisted fluorescence microscopy and image analysis
• confocal microscopy
• cultures of primary neurons
• cultures of pinealocytes
• electron microscopy
• experimental animal research lab.
• gene cloning
• GMO lab.
• histology lab.
• human models
• immunohistochemistry
• in situ hybridization
• in situ hybridization, receptor autoradiography, functional receptor binding (35S-GTPgS)
• in vitro cell cultures
• isotope lab.
• KO-mice
• light and electron microscopy
• neuroanatomy
• neuronal in vivo tracings
• northern blots
• protein purification (FPLC)
• qRT-PCR
• stereological quantification of tissue sections
(CAST-grid stereology system)
• surface plasmon resonance (BIACORE 2000)
• transgene mice
• viral vector in vivo gene therapy
• western blots
• microarray data analysaia
• promoter analysis
Annual Report 2012
51
Financing
• Augustinusfonden
• Dagmar Marshalfonden
• The Carlsberg Foundation
• The Danish Medical Research Council
• The Danish Research Foundation
• Hørslevfonden
• Lundbeck Foundation
• National Councils for Natural and Medical Sciences
• Novo Nordisk Foundation
• Programme of Excellence
• Proof-of-concept Foundation of the University of
Copenhagen
• Scleroseforeningen
• Simon Fougner Hartmann’s Family Foundation
Collaborations – Domestic
• Prof. Niels Tommerup, Department of Cellular and
Molecular Medicine, Faculty of Health and Medical
Sciences,, University of Copenhagen
• Prof. Thue W.Schwartz , Novo Nordisk Center for
Basic Metabolic Research, University of Copenhagen
• Prof. Jan Fahrenkrug, Department of Clinical Medicine, Bispebjerg Hospital, University of Copenhagen
• A. Nygaard Madsen, B. Holst, D. Woldbye, Molecular
Pharmacology Laboratory and Protein Laboratory, INF
• A. Redsted Rasmussen, School of Conservation,
Royal Danish Academy of Fine Arts, Copenhagen
• Anders Fink-Jensen, Assoc. Prof. Gitta Wörtwein and
Pia Weikop, Ph.D., Laboratory of Neuropsychiatry ,
INF and Rigshospitalet
• D. Klærke, Faculty of Life Sciences, University of
Copenhagen
• Gregers Wegener, Aarhus University
• J. Damsgaard Mikkelsen, Rigshospitalet
• J. Hannibal, Bispebjerg Hospital
• J. Nyengaard, Aarhus University
• J. Olesen, Glostrup Hospital
• L. Friis-Hansen, Rigshospitalet
• Morten La Cour, Glostrup Hospital
• Thomas N Sager, Ph.D., H. Lundbeck A/S
• Ulrik Gether, Molecular Neuropharmacology and
Genetics Laboratory, INF
• Lars Pinborg, Epilepsiklinikken, Rigshospitalet
52
Annual Report 2012
• Carsten Thomsen, Diagnostisk Radiologisk Klinik,
Rigshospitalet
• Anne Sabers, Epilepsiklinikken N8501, Rigshospitalet
• Troels Kjær, Klinisk Neurofysiologisk afdeling 3062,
Rigshospitalet
• Bo Jespersen, Neurokirurgisk Klinik Afsnit 2092,
Rigshospitalet
• Birthe Kragelund, SbiN Laboratory, Biologisk Institut,
SUND
• Anne Marie Lynge Pedersen, KU
• Jens Lykkesfeldt, KU
• Michael Kjaer, KU
• Ole Lerberg Nielsen, KU
• Hanne Mikkelsen, KU
Collaborations – International
• Ana Paula Silva, University of Coimbra, Portugal
• Anthony K. Ho, Medical Sciences Building, University
of Alberta, Edmonton, Alberta, Canada
• CNRS Paris, France
• Prof. Paul Pevét, Neurobiologie des fonctions rythmiques et saisonnieres, University of Strasbourg,
Strasbourg, France
• Ass. prof. Estela M. Muñoz, National University of
Cuyo, Mendoza, Argentina
• Dalhousie University, Canada C. Lowry, Boulder, USA
• Davic C. Klein, Section on Neuroendocrinology,
Program in Developmental Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute
of Child Health and Human Development, National
Institutes of Health, Bethesda, MD, USA
• Deniz Kirik, Wallenberg Neuroscience Center, Lund
University, Sweden
• Professor Carmen Sandi, École Polytechnique de
Lausanne, EPFL, Switzerland
• Eric Grouzmann, Pharm.D., Ph.D., FAMH Clinical
Chemistry Centre Hospitalier Universitaire Vaudois,
Lausanne, Switzerland
• Francisco Ambrosio, , University of Coimbra, Portugal
• Joao O. Malva, Institute of Biochemistry, University of
Coimbra, Portugal
• Medizinische Hochschule Hannover, MHH, Germany
• Merab Kokaia, Wallenberg Neuroscience Center,
Lund University, Sweden
Annual Report 2012
53
• Professor Michael Stewart, Open University, United
Kingdom
• Professor Dominique Muller, University of Geneve,
Switzerland
• Trinity College, Dublin, Ireland
• University College London, United Kingdom
• Professor Alexander Zharkovsky, University of Tartu,
Estonia
• University of Tasmania, Australia
• Karl Erik Kahnberg, Gøteborg Universitet
• Ziad Barghash, Gøteborg Universitet
• Universität Tübingen, Germany
• Wallenberg Neuroscience Center, Lund University,
Sweden
9.
10.
11.
12.
Protein Laboratory 2012 Publications
1. Amrutkar DV, Ploug KB, Hay-Schmidt A, Porreca F, Olesen J, JansenOlesen I. mRNA expression of 5-hydroxytryptamine 1B, 1D, and 1F
receptors and their role in controlling the release of calcitonin generelated peptide in the rat trigemi-novascular system. Pain. 2012;
153:830-8.
2. Bojesen KB, Clausen O, Rohde K, Christensen C, Zhang L, Li S, Kohler L, Nielbo S, Nielsen J, Gjorlund MD, Poulsen FM, Bock E, Berezin
V. Nec-tin-1 binds and signals through the fibro-blast growth factor
receptor. J Biol Chem. 2012, 287:37420-37433.
3. Bonde, J.P., Hansen, J., Kolstad, H., Mikkelsen, S., Olsen, J., Blask,
D., Harma, M., Kjuus, H., Koning, H.J.De, Olsen, J., Møller, M.,
Schernhammer, E., Stevens, R..G., Åkerstedt, T.: “Work at night
and breast cancer: Report on evidence-based options for preventive
actions”. Scand.J. Work Env.Health, 2012, 38(4):380-90.
4. Coon SL, Munson PJ, Cherukuri PF, Sug-den D, Rath MF, Møller M,
Clokie SJ, Fu C, Olanich ME, Rangel Z, Werner T; NISC Comparative
Sequencing Program, Mullikin JC, Klein DC. Circadian changes in
long noncoding RNAs in the pineal gland. Proc Natl Acad Sci U S A.
2012;109(33):13319-24.
5. Dencker D, Weikop P, Sørensen G, Woldbye DP, Wörtwein G, Wess
J, Fink-Jensen A. An allosteric enhancer of M(4) muscarinic acetylcholine receptor function inhibits behavioral and neurochemical
effects of cocaine. Psychopharmacology, 2012, 224 (2), 277-87.
6. Dmytriyeva O, Pankratova S, Owczarek S, Sonn K, Soroka V, Ridley
CM, Marsolais A, Lopez-Hoyos M, Ambartsumian N, Lukanidin E,
Bock E, Berezin V, Kiryushko D. The metastasis-promoting S100A4
protein confers neuroprotection in brain injury. Nat Commun., 2012.
13:31197.
7. Enevoldsen MN, Kochoyan A, Jurgenson M, Jaako K, Dmytriyeva O,
Walmod PS, Nielsen JD, Nielsen J, Li S, Korshunova I, Klementiev B,
Novikova T, Zharkovsky A, Berezin V, Bock E. Neuroprotective and
memory enhancing properties of a dual agonist of the FGF receptor
and NCAM. Neurobiol Dis. 2012, 48:533-545.
8. Erhardt A, Akula N, Schumacher J, Czamara D, Karbalai N, MüllerMyh-sok B, Mors O, Borglum A, Kristensen AS, Woldbye DP,
Koefoed P, Eriksson E, Maron E, Metspalu A, Nurnberger J, Philibert
RA, Kennedy J, Domschke K, Reif A, Deckert J, Otowa T, Kawamura
54
Annual Report 2012
13.
14.
15.
16.
17.
18.
19.
20.
21.
Y, Kaiya H, Okazaki Y, Tanii H, Tokunaga K, Sasaki T, Ioannidis JP, McMahon FJ, Binder EB. Replica-tion and meta-analysis of TMEM132D
gene variants in panic disorder. Transl Psychiatry. 2012;.2:e156.
Gjørlund, MD, Nielsen J, Pankratova S, Li S, Korshunova I, Bock E,
Berezin V: Neuroligin-1 induces neurite outgrowth through interaction with neurexin-1_ and activation of fibroblast growth factor
recep-tor-1. FASEB J, 2012, 26:4174-4186.
Gonçalves J, Baptista S, Olesen MV, Fon-tes-Ribeiro C, Malva JO,
Woldbye DP, Silva AP. Methamphetamine-induced changes in the
mice hippocampal neuropeptide Y sys-tem: implications for memory
impairment. J Neurochem. 2012;123:1041-53..
Gregersen N, Dahl HA, Buttenschøn HN, Nyegaard M, Hedemand A,
Als TD, Wang AG, Joensen S, Woldbye DPD, Koefoed P, Kristensen
AS, Kruse TA, Børglum A, Mors O Genome-wide study of panic
disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene. Eur J Hum Genetics 2012;20:84-90.
Gøtzsche, Casper René; Nikitidou, Litsa; Sørensen, Andreas T;
Olesen, Mikkel V; Sørensen, Gunnar; Christiansen, Søren H O;
Ängehagen, Mikael; Woldbye, David P D; Kokaia, Merab. Combined
gene overexpression of neuropeptide Y and its receptor Y5 in the
hippocampus suppresses seizures. Neurobiology of Disease, 2012,
45(1), 288-96.
Hundahl CA, Fahrenkrug J, Hay-Schmidt A, Georg B, Faltoft B, Hannibal J. Circadian behaviour in neuroglobin deficient mice. PLoS One.
2012; 7(4):e34462.
Hundahl CA, Fahrenkrug J, Luuk H, Hay-Schmidt A, Hannibal J.
Restricted expres-sion of Neuroglobin in the mouse retina and
co-localization with Melanopsin and Tyrosine Hydroxylase. Biochem
Biophys Res Commun. 2012;425(1):100-6.
Hundahl CA, Kelsen J, Hay-Schmidt A. Neuroglobin and Cytoglobin expres-sion in the human brain. Brain Struct Funct. 2012;
218(2):603-9.
Klingelhöfer J, Grum-Schwensen,B., Beck, M., Petersen Knudsen,R.,
Grigorian,M., Lukanidin,E., Ambartsumian, N. Anti-S100A4 antibody
suppresses metastasis formation by blocking stroma cell invasion,
Neoplasia, 2012,14,1260-1268.
Knafo S, Venero C, Sánchez-Puelles C, Pereda-Peréz I, Franco A,
Sandi C, Suárez LM, Solís JM, Alonso- Nanclares L, Martín ED,
Merino- Serrais P, Borcel E, Li S, Chen Y, Gonzalez-Soriano J, Berezin
V, Bock E, Defelipe J, Esteban JA. Facilitation of AMPA receptor synaptic delivery as a molecular mechanism for cognitive enhancement.
PLoS Biol. 2012 10 (2):e1001262.
Koefoed P, Woldbye DPD, Hansen TV, Eplov LF, Christiansen SH,
Mors O, Kessing LV, Werge, Kaipio K, Pesonen U, Fahmy T, Mellerup
E, Jakobsen KD, Hansen ES, Knudsen GM, Bukh JD, Bock C, Lindberg C, Kristensen AS, Dam H, Nordentoft M, Als TD, Wang AG,
Gether U, Rehfeld JF and Bolwig TG: “Association of the leucine-7
to proline-7 variation in the signal sequence of neuropeptide Y with
major depression” Acta Neuropsychiatricia , 2012: 24 (2); 81-90.
Lukanidin E, Sleeman JP. Building the niche: the role of the S100 proteins in metastatic growth. Semin Cancer Biol. 2012, 22, 216-25.
Olesen MV, Christiansen SH, Gøtzsche CR, Holst B, Kokaia M, Woldbye DP. Y5 neuropeptide Y receptor overexpression in mice neither
affects anxiety- and depression-like behaviours nor seizures but
confers moderate hyperactivity. Neuropeptides. 2012 Apr;46(2):719.
Olesen MV, Christiansen SH, Gøtzsche CR, Woldbye DPD. Neuropeptide Y Y1 receptor hippocampal overexpression via viral vectors is
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
associated with moderate anxiolytic-like and proconvulsant effects in
mice. J Neurosci Res, 2012, 90:498-507
Owczarek S, Berezin V. Neuroplastin: Cell adhesion molecule and
signaling receptor. Int J Biochem Cell Biol. 2012, 44:1-5.
Pankratova S, Gu B, Kiryushko D, Korshunova I, Køhler LB, Rathje
M, Bock E, Berezin V. A new agonist of the erythropoietin receptor,
Epobis, induces neurite outgrowth and promotes neuronal survival. J
Neurochem. 2012, 121:915-923.
Pingel J, Fredberg U, Qvortrup K, Larsen JO, Scherling P, Heinemeier
KM, Kjaer M, Langberg H. Local biochemical and morphological
changes in humjan Achilles tendinopathy: A case con-trol study.
BMC Musculoskelet Disord. 2012, 13, 53.
Raida Z, Hundahl CA, Kelsen J, Nyengaard JR, Hay-Schmidt A. Reduced infarct size in neuroglobin-null mice after experimental stroke
in vivo. Exp Transl Stroke Med. 2012 Aug 20;4 (1):15.
Raida Z, Reimets R, Hay-Schmidt A, Hundahl CA. Effect of permanent
middle cerebral artery occlusion on Cytoglobin ex-pression in the
mouse brain. Biochem Biophys Res Commun. 2012;424(2):274-8.
Ramachandran R, Bhatt DK, Ploug KB, Olesen J, Jansen-Olesen I,
Hay-Schmidt A, Gupta S. A naturalistic glyceryl trinitrate infusion
migraine model in the rat. Cephalalgia. 2012,32(1):73-84.
Rath MF, Rohde K, Møller M. Circadian Oscillations of Molecular
Clock Com-ponents in the Cerebellar Cortex of the Rat. Chronobiol
Int., 2012; 29(10):1289-99.
Sørensen G, Weikop M, Dencker D, Loland CJ, Bengtsen CH, Petersen JH, Fink-Jensen A, Wörtwein G, Woldbye DP. Neuropeptide Y
Y5 re-ceptor antagonism attenuates cocaine-induced effects in mice.
Psychopharmacology . 2012; 222(4):565-577.
Sørensen G, Woldbye DP. Mice lacking neuropeptide Y show
increased sensitivity to cocaine. Synapse, 2012, 66(9); 840-3.
Winther M, Berezin V, Walmod PS. NCAM2/OCAM/RNCAM: Cell
adhesion molecule with a role in neuronal compartmentalization. Int
J Biochem Cell Biol. 2012, 44:441-446.
Annual Report 2012
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56
Annual Report 2012
PhD theses in 2012
Hansen, Jonas Tind
Project: Molekylære faktorer for G proteinuafhængig
Angiotensin II Type 1 receptoraktivering
Hansen, Louise Valentin
Project: Mikro-kontakter i den globale aktiverings­
mekanisme for 7TM receptorer
Hasseldam, Henrik
Project: Udvikling og behandling af Eksperimentel Autoimmun Encephalomyelitis ved brug af cannabinoider
herunder hypotermi
Jørgensen, Anders
Project: Oxidatively generated DNA/RNA damage in
psychological stress states.
Kongerslev, Mickey Toftkjær
Project: Personlighedsforstyrrelse hos unge: En under­
søgelse af sammenhænge mellem psykopati, mentalisering og voldelig kriminalitet hos unge kriminelle, samt
udvikling og undersøgelse af de psykometriske egen­
skaber ved Millon Adolescent Clinical Inventory
Mokrosinski, Jacek
Project: Site-directed tethering in 7TM receptors in
exploring ligand-binding site interactions, activation
mechanism and drug discovery
Møller, Thor Christian
Project: Development of a functional screening platform
for PDZ domain interactions
Mønsted, Christina Labarrera
Project: Sensorisk inhibition i et dendrodendritisk
netværk
Petersen, Pia Steen
Project: karaktyerisering af GPR39 receptorens funktionelle rolle i fedtvæv og den endokrine pancreas – et
nyt lægemiddel taget
Thiele, Stefanie
Project: Activation Mechanism of Chemokine ReceptorsInsights gained from Ligand Coupling and Metal Ion
Site-Studies
Annual Report 2012
57
Publications 2012
1. Alkjær T, Raffalt P, Petersen NC, Simonsen EB. Movement Behavior
of High-Heeled Walking: How Does the Nervous System Control the
Ankle Joint during an Unstable Walking Condition? PLoS One. 2012
;7(5):e37390.
2. Alkjær T, Simonsen EB, Magnusson SP, Dyhre-Poulsen P, Aagaard P.
Antagonist muscle moment is increased in ACL deficient subjects
during maximal dynamic knee extension. Knee. 2012 Oct;19(5):6339.
3. Alkjaer T, Wieland MR, Andersen MS, Simonsen EB, Rasmussen J.
Computational modeling of a forward lunge: towards a better understanding of the function of the cruciate ligaments. J Anat. 2012
Dec;221(6):590-7.
4. Ammendrup-Johnsen, I, Thorsen TS, Gether U and Madsen KL:
“Serine 77 in the PDZ Domain of PICK1 Is a Protein Kinase C alpha
Phosphorylation Site Regulated by Lipid Membrane Binding” Biochemistry (2012): 51.2 P.586-596.
5. Amrutkar DV, Ploug KB, Hay-Schmidt A, Porreca F, Olesen J, JansenOlesen I. mRNA expression of 5-hydroxytryptamine 1B, 1D, and 1F
receptors and their role in controlling the release of calcitonin generelated peptide in the rat trigemi-novascular system. Pain. 2012;
153:830-8.
6. Andersen B, Felding UA, Krarup C. Increased probability of
repetitive spi-nal motoneuron activation by transcra-nial magnetic
stimulation after muscle fatigue in healthy subjects. J Appl Physiol.
2012;112(5):832-40.
7. Araç D, Aust G, Calebiro D, Engel FB, Formstone C, Goffinet A,
Hamann J, Kittel RJ, Liebscher I, Lin HH, Monk KR, Petrenko A, Piao
X, Prömel S, Schiöth HB, Schwartz TW, Stacey M, Ushka-ryov YA,
Wobus M, Wolfrum U, Xu L, Langenhan T. Dissecting sig-naling and
functions of adhesion G protein-coupled receptors. Ann N Y Acad
Sci. 2012 Dec;1276:1-25
8. Bagger M, Prause JU, Heegard S, Urbak SF, Degn T, Kiilgaard JF. Late
onset retinoblastoma presenting with vitreous haemorrhage. Open
Ophthalmol J. 2012;6:23-5.
9. Ben-Baruch A, Burkhardt AM, Combadiere C, Farber JM, Graham GJ,
Horuk R, Locati M, Luster A, Matsushima K, Murphy PM, Nomiyama
H, Power CA, Proudfoot AEI, Rosenkilde MM, Sparre-Ulrich AH,
Thelen M, Yoshie O, and Zlotnik A (alphabetic author list). IUPHAR
nomenclature committee. International Union of Pharmacology
Nomenclature XXIIV. Update on the Extended Family of Chemokine
Receptors (NC-IUPHAR). Pharmacological Reviews, 2012 [in press]
58
Annual Report 2012
10. Bailey CJ, Sanganahalli BG, Her-man P, Blumenfeld, H, Gjedde A,
Hyder F: Analysis of Time and Space Invariance of BOLD Respons-es
in the Rat Visual System. Cereb. Cortex, 2013, 23(1), 210-22.
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in corticospinal excitability during force field adaptation of human
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102.Kunding AH, Mortensen MW, Christensen SM, Bhatia VK, Makarov
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103.Kupers R, Beaulieu-Lefebvre M, Schneider F, Paulson O, Siebner H,
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104.Kaalund SS, Riise J, Broberg B, Fabricius K, Karlsen AS, Secher
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105.Lauritzen M, Dirnagl U. Celebrating the 30th anniversary of our
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108.Leukel C, Lundbye-Jensen J, Christen-sen MS, Gollhofer A, Nielsen
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109.Licht, Cecilie L; Christoffersen, Maria; Okholm, Mads; Damgaard,
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110.Linnet J, Mouridsen K, Peterson E, Møller A, Doudet DJ, Gjedde A.
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112.Lorentzen J, Nielsen D, Holm K, Baagøe S, Grey MJ, Nielsen JB.
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Annual Report 2012
63
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147.Rasmussen PK, Ralfkiaer E, Prause JU, Sjö LD, Toft PB, Siersma VD,
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148.Rath MF, Rohde K, Møller M. Circadi-an Oscillations of Molecular
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149.Regnell CE, Hildrestrand GA, Sejer-sted Y, Medin T, Moldestad O,
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LH. Hippocampal Adult Neurogenesis Is Maintained by Neil3-Dependent Repair of Oxidative DNA Lesions in Neural Progenitor Cells.
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150.Roig M, Skriver K, Lundbye-Jensen J, Kiens B, Nielsen JB. A single
bout of exercise improves motor memory. PLoS One. 2012;7(9).
151.Rinholm JE, Bergersen LH.: Neuroscience: The wrap that feeds
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152.Ritterband-Rosenbaum A, Christensen MS, Nielsen JB. Twenty weeks
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153.Rekling JC, Jensen KH, Jahnsen H. Spontaneous cluster activity in
the infe-rior olivary nucleus in brainstem slices from postnatal mice. J
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154.Rodell AB, Aanerud J, Braendgaard H, Gjedde A. Low Residual CBF
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155.Roig M, Skriver K, Lundbye-Jensen J, Kiens B, Nielsen JB. A single
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64
Annual Report 2012
156.Rummel PC, Arfelt KN, Baumann L, Jenkins TJ, Johnsen A, Pease J,
Ghosh S, Kolbeck R, Rosenkilde MM. Molecular requirements for
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157.Sass, Amdi; Wörtwein, Gitta. The effect of subchronic fluoxetine
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158.Schaefer K, Blankenburg F, Kupers R, Grüner JM, Law I, Lauritzen
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159.Simmons KJ, Gotfryd K, Billesbølle CB, Loland CJ, Gether U, Fishwick
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160.Simonsen EB, Cappelen KL, Skorini R_, Larsen PK, Alkjær T, DyhrePoulsen P. Explanations pertaining to the hip joint flexor moment
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Nov;28(5):542-50.
161.Simonsen EB, Alkjær T. The variability problem of normal human
walking. Med Eng Phys. 2012 Mar;34(2):219-24.
162.Simonsen EB, Alkjær T, Raffalt PC. Reflex response and control of
the human soleus and gastrocnemi-us muscles during walking and
running at increasing velocity. Exp Brain Res. 2012 Jun;219(2):16374.
163.Simonsen EB, Cappelen KL, Skorini R, Larsen PK, Alkjær T, DyhrePoulsen P.Explanations to the Hip Joint Flexor Mo-ment During the
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164.Simonsen EB, Svendsen MB, Nørreslet A, Baldvinsson HK, HeilskovHansen T, Larsen PK, Alkjær T, Henriksen M. Walking on high heels
changes muscle activity and the dynamics of human walking significantly. J Appl Biomech. 2012 Feb;28(1):20-8.
165.Simonsen EB, Tegner H, Alkjær T, Larsen PK, Kristensen JH, Jensen
BR, Remvig L, Juul-Kristensen B. Gait analysis of adults with
generalised joint hypermobility. Clin Biomech (Bristol, Avon). 2012
Jul;27(6):573-7.
166.Sivertsen B, Lang M, Frimurer TM, Holliday ND, Bach A, Els S, Engelstoft MS, Petersen PS, Schwartz TW, Beck-Sickinger AG, Holst B.
Unique interaction pattern of a functionally biased ghrelin receptor
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167.Steen A, Rosenkilde MM. Molecular Pharmacology of CXCR4 Inhibition. Invited Review. Book chapter. Novel Developments in Stem Cell
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168.Svahn TF, Heegaard S, Prause JU, Toft PB. A circum-corneal conjunctival nevus in a child. Orbit. 2012;31(3):177-8.
169.Sørensen, Gunnar; Jensen, Morten; Weikop, Pia; Dencker, Ditte;
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170.Sørensen G, Weikop M, Dencker D, Loland CJ, Bengtsen CH, Petersen JH, Fink-Jensen A, Wörtwein G, Woldbye DP. Neuropeptide Y
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171.Sørensen G, Woldbye DP. Mice lacking neuropeptide Y show
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172.Thiele S, Malmgaard-Clausen M, En-gel-Andreasen J, Steen A, Rummel PC, Nielsen MC, Gloriam DE, Fri-murer TM, Ulven T, Rosenkilde MM. Modulation in Selectivity and Allosteric Properties of
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174.Torekov SS, Ma L, Grarup N, Hartmann B, Hainerová IA, Kielgast U,
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JJ, Hansen T, Pedersen OB. Homozygous carriers of the G-allele
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177.Toft, PB, Rasmussen, MLR, and Prause, JU. One-Stage ExplantImplant Procedure of Exposed Hydroxyapatite Orbital Implants. Acta
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178.Ugleholdt R, Pedersen J, Füchtbauer -M, Kissow HL, Nytofte N,
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180.Valentin-Hansen L, Groenen M, Nygaard R, Frimurer TM, Holliday
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Annual Report 2012
65
66
Annual Report 2012
Finances 2012
Total financial overview
Income, salaries and
operational costs, mio DKK
Departments operate with two main accounts, covering
internal and external funds, known respectively as VT10
and VT50. There are other funds, covered by other VT
numbers, such as sale of services, for example, which are
not relevant to the department in the current repertory
of activities.
In 2012, the total turnover of internal funds (VT10)
reached 40.5 Million DKK, of which 36.8 Million DKK are
salaries and 13.2 Million DKK are other costs. In 2012,
the total turnover of external funds (VT50) increased to
69.6 Million DKK, of which 30.6 Million DKK are salaries
and 39.0 Million DKK are other costs. Compared to
2011, this is an increase of 3,6 Million DKK.
Thus, the total turnover of the department in 2012
was 110,1 Million DKK, which vere financed partly by
funds – 9.5 Million – accumulated prior to 2012.
Table 1
VT 10 Internally financed
2012
2011
Income
Salaries
Operational costs
40.5
-36.8
-13.2
52.0
-38.1
-8.9
-9.5
5.0
VT 50 Externally financed
2012
2011
Income
Salaries
Operational costs
69.6
-30.6
-39.0
66.0
-31.5
-34.6
0.0
0.0
-9.5
5.0
Total
Total
Grand total
Overview (VT10), DKK
Transfer
Transfer
primo 2012
Net 2012
ultimo 2012
Reassignment
Non-assigned funds
Assigned funds
Total VT30
Total department
Table 2
Corrected
transfer
ultimo 2012
6,425,082
8,825,070
35,031
-5,640,004
-3,804,667
-78,565
785,078
5,020,403
-43,534
-3,542,007
3,542,007
-2,756,929
8,562,410
-43,534
15,285,183
-9,523,236
5,761,947
5,761,947
Annual Report 2012
67
Income
Basic grant
In 2012, departments of the Faculty of Health and
Medical Sciences received a basic grant composed of a
teaching grant and a research grant. The research grant
is allocated on the basis of a key established in 2007.
The Eye Pathology laboratory is separately funded by the
Home Office.
The teaching grant is allocated on the basis of a distribution determined in 2009, which meant that the teaching grant depends on the actual educational activities
within certain types of classroom and confrontational
teaching. The teaching grant consists of a preliminary
award and later clearing of cross-departmental teaching.
The tenured researcher salaries totaled 17.5 M
DKKmio.DKK Teaching duties in general are designed
to match approximately 50% of the work of tenured
researchers, to be covered from the teaching grant. Yet,
the teaching grant of 6.5 Million DKK covered less than
required for the teaching duties of tenured staff, with a
shortfall of almost 2.3 Million DKK.
To the teaching budget of 2012, the department
delivered 9,059 hours (UAT) of teaching, representing
5.1 Million DKK, including operations and laboratory and
computer services. In addition, the department delivered
2 Million DKK worth of teaching to other departments.
From 2008, overhead revenues reverted 100% to
departments, whereas previously only 25% reverted.
Overhead helps cover indirect costs such as facilities,
heating, electricity, cleaning, building maintenance, and
management. However, overhead is released only when
actual expenditure is incurred on external grants with
overhead.
The Faculty of Health and Medical Sciences paid a
bonus of DKK 100,000 to the department for the appointment in 2011 of a woman as professor.
Two researchers were compensated for course management with a total of DKK 226,885.
68
Annual Report 2012
Other income
Special grants were awarded to teach laboratory interns
and a workshop student as a supplement to the operational expenses. Teaching at the Science Faculty of lecturers at this department gave a bonus of DKK 727,902.
Tuition fees transferred by error to the department in
2011 were offset in the 2012 financial statement.
In 2010, the University revised the guidelines for
financial management, which among other changes
meant that inactive grant accounts and grant accounts
with overdraft in VT50 were closed and surplus transferred to the VT10 departmental funds. This is reflected
in the substantial deficit in VT50 accounts in association
with transfer of project accounts to VT10 accounts.
Other income came from employee payments for
massage system, compensation for salary outlays associated with collaborative agreement with Hvidovre Hospital and disbursements of pensions associated with UNIK
centers, and laboratory payments for the recruitment of
electronics mechanic Ronny Tim Holm.
Income (VT10), DKK
Table 3
Research Grant
Funds for strategic development
Eye Pathology Appropriation
Teaching Grant
Teaching Clearance
Overhead
Female professor
Star grant
Compensation for course management
18,909,125
3,216,744
2,100,000
5,208,028
1,371,142
5,957,951
100,000
4,535,00
226,885
Basic Grant total
41,624,875
Student grants
Deficit VT50 transferred to VT10
Other income
23,722
-1,354,787
231,770
Other total
-1,099,295
Total Revenue
40,525,580
Expenses
Salaries
Salary expenditure from internal funds totaled DKK
36,793,152. Below are descriptions for each main group.
Annual wage negotiations amounted to 1% of payroll
including pension contributions. Social contributions as
ER, AES, and flex jobs are not included as payroll types
but as operational expenses.
Researchers
• Professor Jakob Balslev Sørensen applied for an advertised associate professorship in neuroscience with
deadline 15 August 2007 and was appointed professor 1 January 2009 through funding from the Lundbeck Foundation for 5 years. He took leave from the
associate professor position and used the released
funds in the same period to employ postdoctoral
fellow Keimep Wierda and technician Anne-Marie N.
Petersen.
• Professor Elisabeth Bock decided to reduce working
hours to 15 from 1 of May 2012.
• Professor Martin Lauritzen was released one day a
week from Glostrup Hospital from 1 August 2011 for
2 years.
• Professor Per Ebbe Roland was extended by one year
from 1 February 2012, paid from his own overhead
funds.
• Associate Professor Birgitte Holst was appointed
professor 1 year from 1 March 2012.
• Associate Professor Steffen Heegaard was appointed
as clinical professor for 5 years from 1 May 2011
with service at Glostrup Hospital.
• Associate Professor Erling Mellerup extended his
100% leave with 1 additional year from 1 September
2012.
• Associate Professor Karen Martinez and Professor
Dimitrios Stamou transferred appointments to the
Science faculty on 1 January 2012.
• Associate Professor Pernille Koefoed was extended 6
months from 1 February 2012.
Salaries (VT10), DKK
Operating expenses (VT10), DKK
Table 4
Researchers
Parttime researchers (D-VIP)
Technicians (FU-TAP)
Parttime Technicians (DTAP-FU)
Administrative (ADM-TAP)
Parttime Administrative (D-TAP)
22,503,357
124,980
9,274,178
223,654
4,635,141
31,843
Total
36,793,152
Travel
Materials
Equipment
Other costs
Total
Table 5
2,619,744
7,117,334
2,193,641
1,246,381
13,177,099
Annual Report 2012
69
• Associate Professor Per Plenge chose to reduce working hours to 30% from April 1, 2012.
• Associate Professor Aase Frandsen was extended 1
August 2012 for 6 months.
• Ten employees were appointed on wage subsidies in
2012 in BRAINlab, Neuropharm Lab, Protein lab and
Molpharm lab.
• Two Associate Professor / Assistant Professor positions in pharmacology were announced with deadline 16 April 2012
• One position as professor MSO in Molecular and
Metabolic Pharmacology was advertised with a deadline in September 2012.
Part-time researchers
• Two teaching assistants and three guest teachers
contributed to teaching of, respectively, heart/vascular, kidney, diuretics, prostate, heart disease, and one
teaching assistant was employed for biomechanical
teaching.
Administrative and technical personnel
• Laboratory and purchasing coordinator Lis Hansen
resigned at the end of 2012.
• PA Charlotte Elliott resigned 31 July 2012.
70
Annual Report 2012
• PA Christina Louis Øberg was appointed 1 August
2012.
• Budget Officer Annie Wendell resigned June 30,
2012
• Budget Consultant Thomas Astrup joined the department 1 October 2012, shared between INF and ICMM.
• Medical secretary Lis Engel was employed at the Eye
Pathology lab March 15, 2012.
• Medical secretary Pia Feilberg was employed at the
Eye Pathology lab (20 hours/week) 15 March 2012.
• Workshop apprentice Ronny Holm completed his
term 31 August and was subsequently employed for
three months.
• Technician Anne-Marie Petersen was transferred to
ordinary funds (VT10) 1 July 2012.
• Technician Nabeela Khadim at Neuropharm laboratory went on maternity leave in 2012 and Technician
Jytte Rasmussen was hired as replacement.
• Technician Merete Wolder from the Eye Pathology
Laboratory went on maternity leave on 21 January
2012, and technician Maria Pihl was hired for one
year 1 April 2012 as replacement.
Part-time technicians
• Two student assistants were employed to handle
gowns and glassware.
Shared Items
This list refers to the common product list of items
covered by the department. The list is available at the department website. The list from 2011 has been extended
with coffee/tea, glassware, Fruit Scheme, office furniture
and water (milliQ). In addition, in 2012 the department
covered the following items:
• Massage scheme from January to October
• Costs of catering services
• Kitchen, microwave, coffee maker and fridge for
33.3 Section A
• Painting radiators at 33.3 Section A
• Office couch
• 7 PCs
• curtains for 18.1 and 24.2
• blinds for bathrooms at 33.3
• Furniture for BRAINlab at Symbion
• Height adjustable tables for medical secretaries at
Eye path Lab
• Desks, tables and other furniture for 24.2 in connection with relocation
• Removal of electronic door lock at 33.3
• Renovation and new tables for room 18.6.56
• Mail distribution center at 33.3
• Termination of landline telephones
• Contributions to Culture Night event
• INF Annual Meeting at Borupgaard February 2-3
• Machine shop agreement with BMI department
• INF newsletter
• Distinguished Seminars
• Catering for meetings of KoM, ILVILIA, LSU, LAMU,
ADM, Faculty, Annual Meeting
Employees at INF participated in the following development programs and courses:
VIP
• Animal Training
• Pedagogical training of assistant professors
• Introductory course on glial biology
• Danish course
TAP
• Diploma in Management
• How to write a competitive grant for
EU Framework 7
• Service English and academic terminology for
­technical and administrative staff
• University of Copenhagen mail and calendar
• English speaking and writing courses
• Technical training
• CS network group
• ITIL project
• Conflict management
• Mindfullness
Financial result of the year 2012
The department left the financial year 2012 with a net
shortfall of DKK 5,640,004 (VT10 non-assigned funds).
Annual Report 2012
71
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Annual Report 2012
Annual Report 2012 © Department of Neuroscience and Pharmacology, University of Copenhagen, 2013.
Graphic design: Signs & Wonders. Photo: Jørgen Nielsen. Cover illustration: Glucose metabolism at rest in a normal sighted (upper 2 rows) and a congenitally blind (lower 2 rows) subject, shown on mid-sagittal brain sections. Note the increased metabolism in the occipital cortex of the blind subject.
Annual Report 2012
73
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