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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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Neuroscience recent advances
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



Neurotransmitter classes
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
Glutamate Receptors

A. Ligand gated ion channel, “Ionotropic”,

NMDA

AMPA

Kainate

B. “metabotropic”, mGluR GPCR

8 types


Serotonin receptors
Serotonin Receptors

Thirteen distinct human subtypes

5-HT1-7

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 function

“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
Neural Plasticity function

Plasticity of connections

Synaptic number & efficacy

Use-dependent

Cellular plasticity

Neurogenesis

Adult neural stem cells


Neural darwinism
Neural Darwinism function

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



Memory synaptic plasticity ltp
Memory, Synaptic Plasticity, LTP function

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
Synaptic Plasticity function

Numbers of synapses

Synaptic efficacy

Presynaptic, modulation of neurotransmitter release

Postsynaptic modulation of receptors and signalling pathways

Use-dependent


Persistent neuronal activity causes: function

Changes in synaptic strength

Increase in synapse number

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

AXON

DENDRITE

Matus (2001)


Long Term Potentiation (LTP) function

.

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


Signalling pathways underlying synaptic plasticity function

Kotaleski JH and Blackwell KT

Nature Reviews Neuroscience 11 (Apr 2010) 239


Epigenetics function

  • 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 function

Epigenetic modifications


Nature 447(2007)178 functionPicower Institute @ MIT


Sources of neural stem cells
Sources of Neural Stem Cells function

  • Embryonic

  • Adult peripheral tissues

  • Adult Brain

  • Induced pleuripotent cells


Induced pluripotent stem cells
Induced Pluripotent Stem Cells function

  • 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 functionin situ

Gage, FH: Science 287(2000)1433

Dentate gyrus


Neural growth factors neurogenesis
Neural Growth functionFactors,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
BDNF and Depression function

Antidepressant

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 function

Good recoverers

Healthy

controls

2 weeks

6 months

Carey et al, 2006

Left


Brain Networks function


Optical probes and reporters function

AXON

DENDRITE

Scanziani & Hausser Nature 461(2009)930




Clarity function



The florey institutes for neuroscience and mental health
The Florey Institutes for Neuroscience and Mental Health function

  • Amalgamation of 4 Institutes:

    • HFI, NSRI, BRI, MHRI

  • Staff 550, 120 students

  • Four campuses:

    • Parkville, Austin, West Parkville,

    • RMH ( MBC )

  • Ten divisions

  • Platforms


Florey research divisions
Florey: Research Divisions function

Neuroimaging

Cognitive Neuroscience

Mental Health

Stroke

Epilepsy

Neurodegeneration

Systems Neurophysiology

Neuropeptides

Brain Development & Regeneration

Multiple Sclerosis


Florey platforms
Florey Platforms function

  • Platforms:

  • Neuroimaging

  • Stemcore – Stem Cells Australia

  • Advanced microscopy

  • Histology

  • Behavioral animal models

  • Neuroscience Trials Australia


Conclusions 1
Conclusions 1 function

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
Conclusions function3

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
Conclusions 2 function

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


Conclusions
Conclusions function

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
Synapse Abnormalities & Developmental Brain Disorders function

  • 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
Neuroscience: Enabling Technologies neurons

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

Connectivity

optogenetics, CLARITY

Large scale modeling

mathematics, computer science & engineering


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