Frontiers in Neuroscience: understanding the brain

1. Frontiers in Neuroscience: understanding the brain

2. 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

3. Neuron with axon, dendrites & synapses

6. 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 ..

7. Glutamate Receptors A. Ligand gated ion channel, “Ionotropic”, NMDA AMPA Kainate B. “metabotropic”, mGluR GPCR 8 types

8. 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)

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

11. 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

12. 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

13. Neural Plasticity Plasticity of connections Synaptic number & efficacy Use-dependent Cellular plasticity Neurogenesis Adult neural stem cells

14. 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

15. Growth of pyramidal cell dendritic arbour Mature Immature

16. 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

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

18. 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)

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

20. Signalling pathways underlying synaptic plasticity Kotaleski JH and Blackwell KT Nature Reviews Neuroscience 11 (Apr 2010) 239

21. 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

22. Epigenetics & modification of chromatin structure Epigenetic modifications

23. Nature 447(2007)178 Picower Institute @ MIT

24. Sources of Neural Stem Cells • Embryonic • Adult peripheral tissues • Adult Brain • Induced pleuripotent cells

25. 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

26. Origin and migration of stem cells in situ Gage, FH: Science 287(2000)1433 Dentate gyrus

27. 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

28. 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

29. Motor recovery after stroke Good recoverers Healthy controls 2 weeks 6 months Carey et al, 2006 Left

30. Brain Networks

31. Optical probes and reporters AXON DENDRITE Scanziani & Hausser Nature 461(2009)930

32. Optogenetics – controlling the brain with light

33. Optogenetics in the Mouse

34. Clarity

39. Mirror Neuron System

41. 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

42. Florey: Research Divisions Neuroimaging Cognitive Neuroscience Mental Health Stroke Epilepsy Neurodegeneration Systems Neurophysiology Neuropeptides Brain Development & Regeneration Multiple Sclerosis

43. Florey Platforms • Platforms: • Neuroimaging • Stemcore – Stem Cells Australia • Advanced microscopy • Histology • Behavioral animal models • Neuroscience Trials Australia

44. 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

45. 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

46. 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

47. 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

49. 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)

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