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”

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Frontiers in neuroscience understanding the brain

Frontiers in Neuroscience: understanding the brain


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


Frontiers in neuroscience understanding the brain

Neuron with axon, dendrites & synapses


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)


Frontiers in neuroscience understanding the brain

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


Frontiers in neuroscience understanding the brain

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


Frontiers in neuroscience understanding the brain

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

Neural Plasticity

Plasticity of connections

Synaptic number & efficacy

Use-dependent

Cellular plasticity

Neurogenesis

Adult neural stem cells


Neural darwinism

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

Growth of pyramidal cell dendritic arbour

Mature

Immature


Memory synaptic plasticity ltp

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

Synaptic Plasticity

Numbers of synapses

Synaptic efficacy

Presynaptic, modulation of neurotransmitter release

Postsynaptic modulation of receptors and signalling pathways

Use-dependent


Frontiers in neuroscience understanding the brain

Persistent neuronal activity causes:

Changes in synaptic strength

Increase in synapse number

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

AXON

DENDRITE

Matus (2001)


Frontiers in neuroscience understanding the brain

Long Term Potentiation (LTP)

.

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


Frontiers in neuroscience understanding the brain

Signalling pathways underlying synaptic plasticity

Kotaleski JH and Blackwell KT

Nature Reviews Neuroscience 11 (Apr 2010) 239


Frontiers in neuroscience understanding the brain

Epigenetics

  • 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


Frontiers in neuroscience understanding the brain

Epigenetics & modification of chromatin structure

Epigenetic modifications


Frontiers in neuroscience understanding the brain

Nature 447(2007)178 Picower Institute @ MIT


Sources of neural stem cells

Sources of Neural Stem Cells

  • Embryonic

  • Adult peripheral tissues

  • Adult Brain

  • Induced pleuripotent cells


Induced pluripotent stem 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


Frontiers in neuroscience understanding the brain

Origin and migration of stem cells in situ

Gage, FH: Science 287(2000)1433

Dentate gyrus


Neural growth factors neurogenesis

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

BDNF and Depression

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


Frontiers in neuroscience understanding the brain

Motor recovery after stroke

Good recoverers

Healthy

controls

2 weeks

6 months

Carey et al, 2006

Left


Frontiers in neuroscience understanding the brain

Brain Networks


Frontiers in neuroscience understanding the brain

Optical probes and reporters

AXON

DENDRITE

Scanziani & Hausser Nature 461(2009)930


Frontiers in neuroscience understanding the brain

Optogenetics – controlling the brain with light


Frontiers in neuroscience understanding the brain

Optogenetics in the Mouse


Frontiers in neuroscience understanding the brain

Clarity


Frontiers in neuroscience understanding the brain

Mirror Neuron System


The florey institutes for neuroscience and mental health

The Florey Institutes for Neuroscience and Mental Health

  • 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

Neuroimaging

Cognitive Neuroscience

Mental Health

Stroke

Epilepsy

Neurodegeneration

Systems Neurophysiology

Neuropeptides

Brain Development & Regeneration

Multiple Sclerosis


Florey platforms

Florey Platforms

  • Platforms:

  • Neuroimaging

  • Stemcore – Stem Cells Australia

  • Advanced microscopy

  • Histology

  • Behavioral animal models

  • Neuroscience Trials Australia


Conclusions 1

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

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

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


Conclusions

Conclusions

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

  • 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)


Frontiers in neuroscience understanding the brain

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

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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