Frontiers in Neuroscience: understanding the brain

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Frontiers in Neuroscience understanding the brain
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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

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Neuron with axon, dendrites synapses
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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 ..

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Glutamate Receptors

• A. Ligand gated ion channel, Ionotropic,
• NMDA
• AMPA
• Kainate
• B. metabotropic, mGluR GPCR
• 8 types

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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)

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Presynaptic Proteins potentially involved in
neurotransmitter release (after Jessell and
Kandell (1993))
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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
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The origin and evolution of synapses
Many mammalian synaptic components existed
before the appearance of synapses.. synapse
formation would have evolved before other stages
in neural development including neuronal
migration.
Tamas J Ryan and Seth G.N. Grant Nature Reviews
Neuroscience 10(2009)761
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Neural Plasticity

• Plasticity of connections
• Synaptic number efficacy
• Use-dependent
• Cellular plasticity
• Neurogenesis
• Adult neural stem cells

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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

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Growth of pyramidal cell dendritic arbour
Mature
Immature
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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
• Terje Lomo and Timothy Bliss working in the
  laboratory of Per Andersen in Norway
• long-lasting potentiation (LTP) in rabbit
  hippocampus 1973

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Synaptic Plasticity

• Numbers of synapses
• Synaptic efficacy
• Presynaptic, modulation of neurotransmitter
  release
• Postsynaptic modulation of receptors and
  signalling pathways
• Use-dependent

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

• Persistent neuronal activity causes
• Changes in synaptic strength
• Increase in synapse number

AXON
DENDRITE
Matus (2001)
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Long Term Potentiation (LTP)
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Kandel, ER, JH Schwartz and TM Jessell
(2000) Principles of Neural Science. New York
McGraw-Hill
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Signalling pathways underlying synaptic
plasticity
Kotaleski JH and Blackwell KT Nature Reviews
Neuroscience 11 (Apr 2010) 239
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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

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Epigenetic modifications
Epigenetics modification of chromatin structure
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Nature 447(2007)178 Picower Institute _at_ MIT
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Sources of Neural Stem Cells

• Embryonic
• Adult peripheral tissues
• Adult Brain
• Induced pleuripotent cells

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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

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Origin and migration of stem cells in situ Gage,
FH Science 287(2000)1433
Dentate gyrus
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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 Sem Clin
  Neuropsychiatry 8(2003)109

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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 Sem Clin
  Neuropsychiatry 8(2003)109

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Motor recovery after stroke
Good recoverers
Healthy controls
2 weeks
6 months
Carey et al, 2006
Left
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Brain Networks
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Optical probes and reporters
AXON
DENDRITE
Scanziani Hausser Nature 461(2009)930
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Optogenetics controlling the brain with light
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Optogenetics in the Mouse
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Clarity
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Mirror Neuron System
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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

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Florey Research Divisions
Neuroimaging Cognitive Neuroscience Mental
Health Stroke Epilepsy Neurodegeneration Systems
Neurophysiology Neuropeptides Brain Development
Regeneration Multiple Sclerosis
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Florey Platforms

• Platforms
• Neuroimaging
• Stemcore Stem Cells Australia
• Advanced microscopy
• Histology
• Behavioral animal models
• Neuroscience Trials Australia

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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

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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

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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

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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

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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 gt 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)

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Sources of trophic support for peripheral and
central neurons
Target derived neuronal survival factors Squire
et al, Acad Press 2003
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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