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Frontiers in Neuroscience: understanding the brain. Neuroscience: Recent Advances. Electrochemical basis of nervous transmission Neural Plasticity brain connections, neural stem cells Deciphering connectivity of the brain optogenetics , “Clarity”

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Frontiers in Neuroscience: understanding the brain

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Frontiers in Neuroscience: understanding the brain

Neuroscience: Recent Advances

  • Electrochemical basis of nervous transmission

  • Neural Plasticity

    • brain connections, neural stem cells

  • Deciphering connectivity of the brain

    • optogenetics, “Clarity”

  • Some recent discoveries from functional neuroimaging

    • face recognition, mirror neurons, default state network

Neuron with axon, dendrites & synapses

Neurotransmitter Classes

I. Amino acids

glutamate, aspartate, GABA, glycine

mmol/g, fast point to point transmission

II. Amines

ACh, DA, NA, 5-HT, Histamine

ug/g, neuromodulation

III. Peptides

eg CCK, ENK, SP, VIP, SOM, LHRH, DYN, AVP, NT, pmo/g, modulate I and II

IV. Other

CO, prostanoid, cannabinoid, purine ..

Glutamate Receptors

A. Ligand gated ion channel, “Ionotropic”,




B. “metabotropic”, mGluR GPCR

8 types

Serotonin Receptors

Thirteen distinct human subtypes


5-HT1A,B,D etc

GPCRs except 5-HT3 which is a ligand-gated ion channel

Further diversity of 5-HT2C from RNA editing

Modulate AC (5-HT1,4), increase IP3 (5-HT2), cation channel (5-HT3)

Presynaptic Proteins potentially involved in neurotransmitter release (after Jessell and Kandell (1993))

Phylogeny of proteins involved in synapse formation or function

Tamas J Ryan and Seth G.N. Grant

The origin and evolution of synapses

Nature Reviews Neuroscience 10(2009)761

The origin and evolution of synapses

“Many mammalian synaptic components existedbefore the appearance of synapses…..

synapse formationwould have evolved before other stages in neuraldevelopment including neuronal migration….

Tamas J Ryan and Seth G.N. Grant

Nature Reviews Neuroscience 10(2009)761

Neural Plasticity

Plasticity of connections

Synaptic number & efficacy


Cellular plasticity


Adult neural stem cells

Neural Darwinism

Nerve cells compete with each other to make connections

Major implications for brain development, learning and memory as well as for adaptation, recovery and repair after injury

Growth of pyramidal cell dendritic arbour



Memory, Synaptic Plasticity, LTP

Donald Hebb (1949) proposed that memory is encoded and stored in neural networks:

“When an axon of cell A is near enough to excite cell B

and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased”

TerjeLomo and Timothy Bliss working in the laboratory of Per Andersen in Norway

long-lasting potentiation (LTP) in rabbit hippocampus 1973

Synaptic Plasticity

Numbers of synapses

Synaptic efficacy

Presynaptic, modulation of neurotransmitter release

Postsynaptic modulation of receptors and signalling pathways


Persistent neuronal activity causes:

Changes in synaptic strength

Increase in synapse number

The number and strength of synapses is important for learning and memory



Matus (2001)

Long Term Potentiation (LTP)


Kandel, ER, JH Schwartz and TM Jessell (2000) Principles of Neural Science. New York: McGraw-Hill

Signalling pathways underlying synaptic plasticity

Kotaleski JH and Blackwell KT

Nature Reviews Neuroscience 11 (Apr 2010) 239


  • Alterations in gene expression that are self perpetuating in the absence of the original signal that caused them

  • Modification of chromatin structure

    • DNA methylation – cytosine in CpG dinucleotides

    • Histone modifications P, Me, Ac

      • eg promoters of Creb,Bdnf, c-Fos

    • Non-coding RNAs

Epigenetics & modification of chromatin structure

Epigenetic modifications

Nature 447(2007)178 Picower Institute @ MIT

Sources of Neural Stem Cells

  • Embryonic

  • Adult peripheral tissues

  • Adult Brain

  • Induced pleuripotent cells

Induced Pluripotent Stem Cells

  • Cells from adult tissue eg skin

  • Introduction of four genes

  • Conversion of cells to pluripotency

  • Potentially a new source for therapy

    Thompson et al; Yamanaka et al; 2007

Origin and migration of stem cells in situ

Gage, FH: Science 287(2000)1433

Dentate gyrus

Neural Growth Factors,Neurogenesis

Brain derived neurotrophic factor (BDNF):

Promotes survival of nerve cells

Regulates activity-dependent synaptic plasticity

Stimulates neurogenesis in adult brain

Reviewed by - Russo_Neustadt: SemClin Neuropsychiatry 8(2003)109

BDNF and Depression


Reduced in hippocampus, increased NAc in depression

Increased levels with antidepressants, physical exercise

Met/Val 66 mutation associated with altered stress response and depression

Reviewed by - Russo_Neustadt: SemClin Neuropsychiatry 8(2003)109

Motor recovery after stroke

Good recoverers



2 weeks

6 months

Carey et al, 2006


Brain Networks

Optical probes and reporters



Scanziani & Hausser Nature 461(2009)930

Optogenetics – controlling the brain with light

Optogenetics in the Mouse


Mirror Neuron System

The Florey Institutes for Neuroscience and Mental Health

  • Amalgamation of 4 Institutes:


  • Staff 550, 120 students

  • Four campuses:

    • Parkville, Austin, West Parkville,

    • RMH ( MBC )

  • Ten divisions

  • Platforms

Florey: Research Divisions


Cognitive Neuroscience

Mental Health




Systems Neurophysiology


Brain Development & Regeneration

Multiple Sclerosis

Florey Platforms

  • Platforms:

  • Neuroimaging

  • Stemcore – Stem Cells Australia

  • Advanced microscopy

  • Histology

  • Behavioral animal models

  • Neuroscience Trials Australia

Conclusions 1

The brain is much more plastic than previously believed

Genes acting through trophic and guidance factors determine the basic wiring pattern of the brain

During development initially there is an excess of neurons and synaptic connections

These are pruned by use-dependent mechanisms

Similar processes are invoked in recovery of function after injury

Conclusions 3

The molecular mechanisms of synaptic plasticity, memory and learning are being elucidated with remarkable speed owing to genomics, proteomics and systems biology approaches

Mutations affecting these processes underlie several neurodevelopmental disorders including Fragile X, Rett syndrome, Tuberose Sclerosis and Autism

Conclusions 2

Contrary to the dogma that the adult brain cannot repair itself, neural stem cells do exist in the adult brain and are capable of regenerating new nerve cells.

Understanding the molecular mechanisms of neurogenesis and synaptic plasticity holds the promise of greatly enhancing repair after injury or degeneration


Connectivity of the brain (“The connectome”) is dauntingly complex

However, the combination of optical techniques and with genetics enables analysis of neural pathways with specified neurochemistry, connectivity or function

This will lead to an explosion of knowledge of how the brain functions, including large scale computer modelling

Synapse Abnormalities & Developmental Brain Disorders

  • Fragile X Syndrome

    • Commest cause of mental retardation

    • Autism in 15-30%

    • Mutation decreases production of FMRP

    • Long spindly dendritic spines with impaired synaptic function

  • Rett Syndrome

    • MeCP2 critical role in regulating number of synapses

    • Deficiency of MeCP2 > defective synapses with mental retardation & autism

  • Tuberose Sclerosis

    • Mutations in TSC1 or TSC2

    • Autism & epilepsy, mental retardation, synapse

    • malformation

  • Autism

    • NeuroIligin family (NLG3 & NLG4) and interacting proteins (SHANK3)

Sources of trophic support for peripheral and central neurons

Target derived neuronal survival factors Squire et al, Acad Press 2003

Neuroscience: Enabling Technologies

Chemical basis of nervous transmission

proteomics, mass spectrometry, genomics, electrophysiology, molecular biology

Plasticity of synapses & connectivity

as above, behavior (learning & memory)

Neural stem cells

cell and developmental biology,

Cerebral localization

functional MRI, pathways in animal studies


optogenetics, CLARITY

Large scale modeling

mathematics, computer science & engineering

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