Changing Brain

7/23/2019 Changing Brain

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The Changing Brain :Construction of neural circuits

By : Sapur

Roll no : 1

3rd year, In

School of


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Two central features of neural circuits must be established after

generated and have migrated to their final positions :

1. Nerve cells in different regions must be linked together via axon pathways.

2. Orderly synaptic connections must be made among appropriate pre- and post-syna


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The Axonal Growth Cone

The directed growth of axons and the recognition of synaptic targets is mediated by aat the tip of each growing axon called the growth cone.

It detects and respond to signalling molecules that:

Identify correct pathways.

Prohibit incorrect trajectories.

Ultimately facilitate functional synaptic partnerships.


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Central features of axonal growth :

The energy and power of growing axons reflect the cellular properties of the growth

When moving along an established pathway pioneered by other axons, growth conessimple in shape.

In contrast, when a growing axon first extends in a new direction the growth cone flaextends numerous filopodia, actively searching for appropriate cues to direct subseq

These changes of growth cone shape at decision points have been observed in botperipheral and central nervous system.


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LamellapodiumFilopodia

A growth co

sensory gang

for actin (red)

Actin predomi

extensions of t

Tubulin is pred

extending intof the growth

Globular acti

incorporated

leading edge

response to at

Repulsive cue

and retrogra

towards th

Organized m

the cytoskelet


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Signals Involved in Axon Guidance

(A)Extracellular matrix

multiple integrin recep

(B)Homophilic, Ca2+

-inadhesion molecules (CA

(C) Ca2+-dependent

(Cadherins)

(D) The netrin/slit fa

repulsive secreted sign

(E)Semaphorins(primeither be bound to the

Receptors (plexins an

on growth cones.

(F)Ephrins,which can

membrane-associated,

receptors, which ar

kinases.


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The importance of adhesive interaction

axon growth and guidance. Consequences of mutations in genes encoding cell surface adhesion molecules includ

human developmental or neurological disorders like:

X-linked hydrocephalus.

MASA (an acronym for mental retardation, aphasia, shuffling gait, and adducted thumbs)

Kalmans syndrome (which compromises reproductive and chemosensory function).

X-linked spastic paraplegia.

These mutations can also lead to the absence of the corpus callosum and of the corttract.


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Diffusible Signals for Axon Guidance:

Chemo-attraction and Repulsion There are two types of tropic molecules (Target-derived signals) involved in axonal gu

Tropic moleculeswhich guide growing axons toward a source and,

Trophic moleculeswhich supportthe survival and growth of neurons and their processeappropriate target has been contacted.

Guiding tropic molecules can be chemo-attractants or chemo-repellants.

The best-characterized class of chemo-attractant molecules is the netrins.

The netrins themselves have high homology to extracellular matrix molecules like lamsome cases may actually interact with the extracellular matrix to influence directed a


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Chemorepellant molecules

Two broad classes of chemorepellent molecules have been described:

NoGos : Associated with central nervous system myelin. Their receptors are evidimportant after injury to the adult brain, where they inhibit axon growth at regiodamage.

Apart from NoGos, some protein components of the myelin sheath, including myelialso can be chemorepulsive for growing axons.

Semaphorins : Chemorepellents active during neural development.


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An Example of molecular Axon guidance s

Chemotropic moleculesdeveloping spinal cord.

(A) Commissural neurons s

the ventral region of

including the floorplate.

(B) Opposing activities of

the ventral midline of the s

This molecular guidance

that the axons cross

appropriate levels of the

remain on the correct sid

their targets.


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Summary of growth cone responsesrange of cues available in the environm

Attractant cues, either secreted or

surface, can guide a growth cone to a

domain, or help maintain growing

bundles, or fascicles.

The relative availability of difmolecules can influence the speed o

growing axon.


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Formation of Topographic Maps

In the somatic sensory, visual, and motor systems, neuronal connections are arrangeneighbouring points in the periphery are represented at similarly adjacent locations iappropriate regions of the central nervous system.

In other systems (e.g., the auditory and olfactory systems), there are also orderly repof various stimulus attributes like frequency or receptor identity.

How do growing axons distribute themselves with such fidelity within target regions in

The answer was given by Roger Sperry in the form of chemo-affinity hypothesis, based work in the visual system of frogs and goldfish.


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U

DU

D

U

D

Optic nerve is surgically interrupted.

Eye is rotated by 180 degrees.

Axons are allowed to regenerate.Optical

tectum

Retina

Optical

tectum


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Some point to be noted :

The behavior of growing axons suggested that thereare gradients of cell surface molecules to whichgrowing axons respond to establish a basictopographic map.

Positive interactions : Due to increased adhesion ofthe growth cones to the substrate.

Repulsive interactions with inappropriate regions

tend to collapse the growth cones. RAGS (repulsive axon guidance signal) / ephrin-A5is

a likely candidate for negative guidance.


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Selective Synapse Formation :

Many of the adhesion molecules that participate in axon guidance contribute to thand stabilization of a synaptic site on target cells, as well as to the ability of a grrecognize specific sites as optimal.

Ephrins have been suggested to contribute to this process, as have cadherins. Indiversity of ligands and receptors makes these adhesion molecule families attractive

At the neuromuscular junction, a molecule called agrin is initiates some of the eventhe formation of a fully functional synapse.


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An intriguing parallel in Drosophila !

The gene for the cell adhesion molecule DSCAM (fly ortholog of the mammaliandocell adhesion molecule) has approximately 38,000 isoforms based upon the numbethe gene and predicted splicing.

In the fly, DSCAM is expressed at synaptic sites in the developing nervous system. It iswhether or not individual splice isoforms are differentially expressed at distinct showever, if this is the case, the genomic diversity may contribute to synaptic diversity.

While the mammalian orthologue of DSCAM does not show a similar diversity, somethe protocadherin family.


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Potential molecular mediators of synapse identity. (A) Organization of the DSCAM gene inDrosophila. Eac

exon regions (4, 6, 9, and 17) has several alternative splice variants, and different combinations of these fo

potential 37,000 isoforms of the DSCAM protein that can be expressed at distinct synaptic sites in the flys d

system. (B) Similar variability of multiple alternative exons is seen in the mammalian gene for -protocadher


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Thank you.

Changing Brain

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