Neuroembryology as a Process of Pattern Formation

Neuroembryology as a Process of Pattern Formation
1. The Development of Brains
2. A Self-Organization Perspective on the Development of the Nervous
System
3. Pattern Formation and Self-Organization
A. Cellular Slime Molds
4. Rules of Pattern Formation in Brains
A. Migration
B. Differentiation
C. Connectivity
D. Selective Survival
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1. The Development of Brains
Today, I want to focus on how the brain develops as a complex process of pattern
formation resulting in large part from self-organization.
For development, self-organization is a process by which components (e.g., cells)
interact in relatively simple ways to create complicated patterns of organization
and structure.
Key features of self-organization are that
1) The parts themselves do not have a “blue print” or “instruction book” for
how they should organize themselves with respect to other parts.
2) There is no overall controlling element directing the organization.
3) Instead, complex patterns can emerge from local interactions with other cells
and physicochemical properties of their substrate and context.
2. A Self-Organization Perspective on the Development of the Nervous
System
There are many questions that can be asked about how such a complex system
such as a brain emerges during development:
1) How are all of the neurons generated from a single-celled embryo (i.e.
zygote)?
2) How do a neural cells “know” what type they are to become?
3) How do neurons end up in the correct spatial location in the brain?
4) How do specific connections form among neurons?
5) How can we get this incredible complexity from so few genes?
All of these questions and many more have been addressed since the early 1800s
and today they are still one of the more active areas of study of the nervous
systems of animals.
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3. Pattern Formation and Self-Organization
A. Cellular slime molds
Video: Aggregation Close up, Aggregation, Slug, Fruiting Body
Figure 1. Dictyostelium discoideum (a cellular slime mold) grows as free-living amoebae in litter and feed on
bacteria. When food supplies are exhausted, they undergo a complex developmental cycle in which 10,00050,000 amoebae aggregate to form a multicellular fruiting body. Dictyostelium is a very interesting system for
looking at biological pattern formation and inter cellular interactions. The aggregation of individual Dictyostelium
amoebae occurs by chemotaxic responses to periodic cAMP signals. When starvation sets in, a small percentage
of amoebae start producing periodic pulses of cAMP (note that this does not require specialized pulsing amoebae,
but only that a few randomly start pulsing). These pulses are amplified and spread to surrounding amoebae.
Individual amoebae move chemotaxically towards increasing cAMP concentrations. Waves of migrating
amoebae are seen as expanding spirals or concentric rings. As the amoebae continue to aggregate, they form
streams and collect in a mound. In the mound, the amoebae differentiate into two distinct cell types: prestalk
and prespore, which later will form the stalk and spore head, respectively. The prestalk cells locate in the tip on
top of the mound, which elongates, topples over and forms the slug. As a slug , individual amoebae behave as a
single organism. The slug stage enables cellular slime moulds to migrate towards the surface of the litter to
disperse their spores. The key point is that process is mediated by local interactions between amoebae. The
proximate causal interactions between cells are cAMP signals sent and released by amoebae. There is no “blue
print” or hierarchical control of this process, it is self-organizing.
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B. Embryonic Development and Induction
The first step in embryonic development involves the fertilized egg dividing into
many cells called blastomeres around a central cavity called the blastocoel. The
structure itself is the blastocyst.
Figure 2.The first step in embryonic development involves the fertilized egg dividing into many cells
called blastomeres around a central cavity called the blastocoel. The structure itself is the blastocyst.
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The second step is gastrulation in which the blastomeres begin to move and
reorganize forming an invagination that results in three different tissue layers (i.e.,
the germ tissue layers):
Figure 3. Gastrulation
Ectoderm (outer layer; these cells give rise to the nervous system and skin),
Mesoderm (middle layer; these cells give rise to the muscle, skeleton, connective
tissue, and cardiovascular and urogenital systems), and
Endoderm (inner layer; these cells give rise to the gut and other internal organs)
During the third step (developmental stage), neurulation occurs in which a
groove forms along the anterior-posterior axis of the ectoderm (on the we page
there is a link to a movie that illustrates this process).
Ectodermal cell on either side of this neural groove thicken and form the neural
plate, which lies on the dorsal (top) surface of the developing embryo.
As the embryo develops, the folds of the neural plate meet and cover the groove,
forming the neural tube from which will emerge the brain and the spinal cord of
the central nervous system.
During neural tube formation, some cells break away from the neural plate and
move just above the top of the neural tube, forming the neural crest, which will
eventually give rise to spinal and autonomic ganglia.
Cell proliferation begins at this point along the neural tube resulting in distinct
specializations along the rostral-caudal axis. Cell proliferation gives rise to
specific brain divisions: prosencephalon, mesencephelon, and
rhombencephelon. These three structures eventually become the cerebral
hemispheres, the midbrain, and the brain stem, respectively.
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Figure 4. Regional specification of the developing brain. (A) Early in gestation the neural tube becomes
subdivided into the prosencephalon (at the anterior end of the embryo), mesencephalon, and
rhombencephalon. The spinal cord differentiates from the more posterior region of the neural tube. The
initial bending of the neural tube at its anterior end leads to a cane shape. Below is a longitudinal section
of the neural tube at this stage, showing the position of the major brain regions. (B) Further development
distinguishes the telencephalon and diencephalon from the prosencephalon; two other subdivisions—the
metencephalon and myelencephalon—derive from the rhombencephalon. These subregions give rise to
the rudiments of the major functional subdivisions of the brain, while the spaces they enclose eventually
form the ventricles of the mature brain. Below is a longitudinal section of the embryo at the
developmental stage shown in (B). (C) The fetal brain and spinal cord are clearly differentiated by the
end of the second trimester.!Several major subdivisions, including the cerebral cortex and cerebellum,
are clearly seen from the lateral surfaces.
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4. Principles of Pattern Formation in Brains
A. Migration
After cell division (mitosis), cells that become neurons are in many respects like
the amoebae we just talked about. These cells call neuroblasts lack many of the
characteristics of mature neurons, such as the shape of the cell body, and dendritic
and axonal branches.
To fully develop as specific types of neurons, they must first migrate and
aggregate at various locations in the developing brain. Indeed, some cells must
migrate many millimeters.
Like the amoebae, the migrating neuroblasts extend part themselves in one
direction and pull the rest of the cell in that direction.
As with Dictyostelium amoebae, local physical and chemotaxic interactions
among neuroblasts and substrate are critical. But, these interactions among
migrating cells with each other and with their substrate are not as well understood
as in Dictyostelium.
The case of radial glial (video 2) cells is often cited as one mechanism by which
migrating cells move to specific locations.
Many waves of migrating cells move up these “rope” ladders.
In order for proper development to occur, earlier migrating cells must get off at the
right place or pile ups can occur.
Failure to do so can lead to sever developmental abnormalities in development
such as "reeler" and "staggerer" mice.
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Figure 5. Neuroblast migrating along radial glial scaffolding.
Is there anything that seems incomplete about this account of cell migration?
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B. Differentiation
Fate: In embryology refers to the final outcome or location of a cell during
development. It does not mean predetermined. It is a useful descriptive term for
talking about how a cell comes to have a specific location and phenotype.
Figure 6. Differentiation of cortical neurons.
After the amoebae like neuroblasts reach a destination in the developing nervous
system they begin to differentiate, which means that a variety of factors interact to
generate a cell with a specific phenotype, including interactions with other cells,
chemical and electrical synaptic activity.
For example, the peripheral autonomic nervous system is divided into sympathetic
and parasympathetic ganglia, which are mostly adrenergic and cholinergic
respectively. These two types of neurons depend on different neurotransmitters:
Adrenergic depend on norepinephrine and cholinergic on actycholine. Which
neurotransmitter they use is determined late in differentiation and depends on
context.
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C. Connectivity
Just as the amoebae like neuroblasts must migrate to regions of the developing
brain, the essence of functioning brains are the patterns of connections formed by
the axons and dendrites of developing neurons.
Axons and dendrites move towards targets as neurites. The growth cone (video
2) is at the tip of neurites and it responds to cues and interactions with its local
environment. In much the same way as migrating cells.
Nerve growth factor (NGF) can guide the direction of the neural growth cone just
as cAMP guides the movement of Dictyostelium amoebae.
Neurites move by finger-like extensions from the growth cones, which adhere to
the substrate and drag the neurite along.
Just as with neural selectivity and death, dendrites can be increased or decreased
by the gradients of NGF surrounding a cell.
Figure 7. Neural growth cones.
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D. Selective Survival
Figure 8. After new neurons are generated (a), the different patterns of input activity
(red and blue arrows), which are associated with different information related to the
animal's experience, activate different subsets of new neurons (b, c). Then, the activated
new neurons are selected for survival (d, e). Thus, the resulting new circuits are
selectively determined by input activity and represent the information associated with the
input activity.
During neural development, too many neurons typically begin to differentiate and
attempt to establish connections to target areas. Through processes that are not
well understood, competitive interactions arise for trophic factors (substances
released by target or other cells that promote growth). Those that win out establish
connections and those that do not die.
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