PLASTICIDAD A B A C

PLASTICIDAD
Capacidad de los circuitos neuronales de experimentar
modificaciones funcionales que se traducen en una diferencia en
el procesamiento de la información (relación Input  Output)
ANTES
input
A
DESPUES
output
B
input
A
output
C
PLASTICIDAD SINAPTICA
Cambios transitorios o permanentes en la eficacia de la transmisión sinaptica
subumbral
eficacia
sináptica
supra
+
Mecanismos involucrados en aprendizaje y memoria (hipocampo y corteza)
Inducción de potenciación sináptica
respuesta
Estímulo (baja frecuencia)
Tren de alta frecuencia (100 Hz x 1s)
Estímulo (baja frecuencia)
Hay un cambio de estado
La sinapsis "recuerda" que fue hiperestimulada
Modificación de circuitos por plasticidad sináptica
Input A
output B
Plasticidad sináptica
Input A
output C
La plasticidad sinaptica es uno de los mecanismos celulares
involucrados en memoria
+MK‐801
El LTP se bloquea mediante antagonistas del receptor de NMDA
La plasticidad sináptica produce cambios a nivel fisiológico y morfológico (anatómico)
Las sinapsis pueden potenciarse o deprimirse Nivel fisiológico cambios en las propiedades de la transmisión sináptica
Nivel anatómico cambios en la estructura de la conectividad neuronal
Modificación de circuitos neuronales por neurogénesis
Input A
output B
output D
ESTO OCURRE EN EL CEREBRO ADULTO
Early evidence on adult neurogenesis
Altman, 1962-1967: adult rats injected with 3H-thymidine to assess cell
proliferation in response to cerebral lesions.
Find labeled granule neurons in the dentate gyrus and olfactory bulb
Thymidine
analog
Altman; Science 1962
Kaplan and Hinds,1977: find 3H-thymidine in hippocampal and OB neurons
without lesion
Science, 1977
Nottebohm, 1983 -: neurogenesis in the adult canary
HVC high vocal center
Cerebral nucleus involved in song learning
Sexual dimorfism
Males sing many songs, complex songs, and
have a big HVC
Females sing few simple songs, small HVC
Male HVC size changes depending on the season
Females treated with testosterone display enlarged HVC and complex songs
Goldman and Nottebohm: changes in HVC size are due to neurogenesis or to increased
number of synaptic connections?
Female canaries injected with con 3H-thymidine
2 groups: with and w/o testosterone
RESULTS
All adult females show labeled HVC neurons
Testosterone increases cell proliferation and also survival of new neurons
There is a continuous production of new neurons, probably for functional replacement
Are labeled cells real neurons?
Patton & Nottebohm, 1983
-Canaries treated with H3-thymidine
-Electrophysiological recordings of several dozens of neurons in HVC in vivo
- Electrical activity in response to sounds
-HRP filling and colabeling
- Find new neurons with appropriate electrical properties: NEURONS BORN IN THE
ADULT BRAIN CAN PROCESS SENSORY INFORMATION
Science, 1992
Striatal cells isolated and grown in vitro
Capable of proliferation
May give rise to neurons and astrocytes in vitro
NSE
BrdU
NF-168
GFAP
GABA
Substance P
PNAS 1993
3H-thymidine
injection in adult rats
Subventricular cells dissociated and proliferated in culture
Give rise to labeled neurons and astrocytes
MAP2ab
J Neurosci 1993
PSA-NCAM in DG
Labels immature neurons
Colocalization of BrdU and PSA-NCAM: Young neurons born in the adult hippocampus
Electronic micrograph of immature neuron in the adult DG
Seki and Arai, 1993
Nature Medicine, 1998
Postmortem brains of adult patients that received BrdU for tumor diagnose
Neuronas BrdU+ en el Giro Dentado
Exp Neurol 1999
Progenitor cells from adult human brain generate neurons in vitro
Ultrastructural characterization of adult SVZ cells:
Type A: migrating neuronal precursors (PSA-NCAM, Tuj1, Nestin)
Type B: Astrocytic type (GFAP, Vimentin, Nestin)
Type C: Actively dividing cells
E: Ependymal cells (enpithelial separate SVZ from ventricle)
Doetsch & Alvarez Buylla 1997
Only GFAP+ type B cells and ependymal cells remain in the SVZ after ARAC treatment
GFAP immunogold
12 h after ARAC: type B cells (astrocytes) only
48 h after ARAC: type C cells
30 days after BrdU they find B cells:
C cells divide too fast and Brdu label gets diluted
A cells (neuroblasts) migrate away from SVZ
Retroviral infection of AP in mice expressing
the avian leukosis virus receptor (Tva R)
under the GFAP promoter
Infects GFAP+ cells undergoing mitosis
Cell progeny expresses AP
Demonstrates that GFAP cells generate OB
neurons
Current model of neurogenesis in the adult SVZ
Doetsch & Alvarez Buylla 1999
NEUROGENIC REGIONS OF THE ADULT MAMMALIAN BRAIN
Lateral Ventricles
Subventricular Zone (SVZ)
Dentate Gyrus of the Hippocampus
Subgranular Zone (SGZ)
OB
Ming & Song 2011
METHODS TO IDENTIFY ADULT-BORN NEURONS
IT MUST BE DETERMINED THAT A CELL: 1. WAS BORN IN THE ADULT BRAIN
2. IS A NEURON
BROMODEOXYURIDINE
RETROVIRUS
TRANSGENIC MICE
Ming and Song, 2005
NEUROGENIC REGIONS ARE PRIMARILY DETERMINED BY THE ENVIRONMENT RATHER
THAN THE NEURAL PROGENITOR CELLS (NPCs)
NPCs isolated from brain areas
can generate neurons
In vitro
Ex vivo
(grafting to neurogenic environments)
Specific lesions
Cortex (Magavi, 2000)
CA1 (Nakatomi, 2002)
Striatum (Arvidsson, 2002; Parent, 2002)
Lie et al., 2004
vs
Models for NPC potential: A. one progenitor type produces different neurons;
B. different progenitors for different neurons
Different types of OB interneurons subtypes produced postnatally
Viral targetting of NPCs from different areas of the ventricular wall
Cortical
Dorsal
Medial
Ventral
Eje AP:
i
ii
iii
iv
v
vi
Different types of interneurons subtypes produced postnatally
Different areas produce deep or superficial GCs
The pattern is maintained in adult animals
CalB+
CalR+
TH+
Determinants for neuronal phenotype are in the cells and not in the niche
CalB+
CalR+
TH+
BIOLOGICAL SIGNIFICANCE OF ADULT HIPPOCAMPAL NEUROGENESIS?
HIPPOCAMPAL FUNCTION
NEUROGENESIS
AND BEHAVIOR
• ADULT NEUROGENESIS HAS BEEN DESCRIBED FROM INVERTEBRATES TO HUMANS
• THE ADULT HIPPOCAMPUS PRODUCES A SUBSTANTIAL AMOUNT OF NEW NEURONS
• THE RATE OF NEUROGENESIS IS ALTERED BY PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS
• IMPAIRED ADULT NEUROGENESIS HAS CONSEQUENCES IN BEHAVIOR, LEARNING AND MEMORY
• NEW NEURONS ARE FUNCTIONAL
THE HIPPOCAMPUS IS INVOLVED IN LEARNING AND MEMORY
INVOLVED IN DECLARATIVE MEMORY (FACTS AND EVENTS), H.M.
CRITICAL ROLE IN SPATIAL MEMORY
HIGH DEGREE OF LONG-LASTING SYNAPTIC PLASTICITY (LTP/LTD)
SYNAPTIC PLASTICITY IS INVOLVED IN MEMORY-RELATED FUNCTIONS (increasing evidence)
THE MORRIS WATER MAZE: A PARADIGM FOR STUDYING SPATIAL LEARNING
RANDOM
NAVIGATION
USE OF
SPATIAL
CUES
MICE USE CONTEXTUAL CUES TO FIND THE PLATFORM. STORAGE OF PLATFORM/CUES RELATIONSHIPS
LEARNING IN THE HIDDEN PLATFORM PARADIGM IS IMPAIRED BY NMDAR BLOCKADE
control
DL-AP5 (blocks NMDAR)
TIME SWIMMING IN QUADRANT
MORRIS AND COLLEAGUES, 1986
KNOWN HIPPOCAMPAL MECHANISMS TO PROCESS SPATIAL INFORMATION
PLACE CELLS: SPACE CAN BE ENCODED IN THE FIRING PATTERN OF HIPPOCAMPAL NEURONS
RESPONSES RECORDED FROM 4
NEURONS DURING EXPLORATION OF A
LINEAR CAGE
RESPONSES RECORDED FROM 80
NEURONS DURING EXPLORATION OF A
SQUARE CAGE
FROM NAKAZAWA ET AL. 2004 (O’KEFFEE AND DOSTROVSKY ’70s, WILSON AND MCNAUGHTON 90´s)
THE RATE OF NEUROGENESIS IS REGULATED BY PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS
THE HIPPOCAMPUS OF A YOUNG ADULT RAT PRODUCES ABOUT 6% OF THE TOTAL NUMBER OF DENTATE
GRANULE CELLS PER MONTH
THIS RATE IS
INCREASED BY:
ENRICHED ENVIRONMENT, VOLUNTARY EXERCISE
LEARNING PARADIGMS
PATHOLOGICAL CONDITIONS: ISCHEMIA OR SEIZURES
… AND
DECREASED
BY:
AGING
STRESS, DEPRESSION
INFLAMMATION
enriched environment
running
NEUROGENESIS IS REGULATED BY PHYSIOLOGICAL CONDITIONS
housing BrdU injections
Time (days)
0
12
“1 day” group (assess proliferation)
1day
control
runner
enriched
4 wk
“4 wk” group (survival)
NeuN + BrdU
NEUROGENESIS IS REGULATED BY PHYSIOLOGICAL CONDITIONS
RUNNING INCREASAES PROLIFERATION OF PROGENITOR CELLS
ENRICHMENT INCREASES SURVIVAL OF NEW NEURONS
van Praag et al 1999
HIPPOCAMPUS-DEPENDENT TASKS CAN ACTIVATE ADULT-BORN NEURONS
BrdU injections
Exploration
remove brain
30 min later
5 months
6 mo rats
ARC: immediate early gene, expression induced by neuronal activity
NeuN
BrdU
Arc
Time (days)
IMPAIRED ADULT NEUROGENESIS PRODUCES BEHAVIORAL EFFECTS
Induction: Gancyclovir
TK facilitates incorporation of gancyclovir
into DNA during replication
Induction: Doxicyclin
Bax expression induces apoptosis
Induction: Tamoxifen
DTA expression induces apoptosis
Deng et al NRN 2010
PloS ONE 2008