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1. Neuroplasticity Neurobiologie Les 3 1st Master BiomedischeWetenschappen Robrecht Raedt

2. Overview • Introduction • Synaptic plasticity • Short term plasticity • Learning and memory mechanisms • Short-term sensitization/long-term sensitization • Long-term potentiation • Long-term depression • Intrinsic neural plasticity • Homeostatic plasticity • Memory systems in the mammalian brain • Cortical Neuroplasticity • Neuroplasticity and neuro-prostheses • Deep brain stimulation

3. Introduction on neuroplasticity • Neuroplasticity= changes in activity and organization of the brain due to ‘experience’ • Changes: • Physiological • Anatomical • Previous dogma’s: • The brain is rigid • Plasticity is limited to the hippocampus • Plasticity is limited to development/childhood • All brain regions show some form of plasticity, even in adulthood

4. Synaptic plasticity • Changes in input-output relationship in neuronal networks due to changes in synaptic efficacy • Excitatory/inhibitory • Activity-dependent • Different time scales: milliseconds, hours, days • Short-term plasticity (msec-min) • Long-term plasticity (min-lifetime)

5. Short-term plasticity • Facilitation • Augmentation • Potentiation (post-tetanic) • Depression • - Form of plasticity depends on: • a. type of neuron • b. type of stimulation

6. Short-term plasticity • Mechanism: Repeatedneuronalactivity Changes in calcium-concentration Changes in neurotransmitter release (quanta) PRESYNAPTIC • - more: facilitation/augmentation/potentiation • less: depression

7. Short term depression • Vesicle depletion • No depression in low Ca2+ or high Mg2+ environment • High release probability and small pool

8. Short term depression * Inactivation Ca2+ channels * Mobilizationvesicles ↓ NT release ↓

9. Short term depression • Autoinhibition via stimulation of presynapticautoreceptors • Receptor desensitization

10. Short term potentiation Ca2+ Ca2+ Ca2+ Ca2+ Ca2+

11. Short term potentiation • Residual Ca2+ remaining in active zones after presynaptic activity • Summating with Ca2+ peak during subsequent action potentials at site triggering exocytosis • More distant facilitation sites (second messengers systems/kinases) • Potentiation: longer period after strong tetanus • Overloading of processes responsible for removing excess Ca2+ • Ca2+ extrusion pumps • Plasma membrane ATPaseand Na+- Ca2+exhange • Ca2+ uptake in organelles

12. Learning and memory • Long-term plasticity • Repeated synaptic activity → changes last for hours/days • Sensitization • Long-term potentiation • Long-term depression • Intrinsic synaptic plasticity • Homeostatic plasticity

13. Associative learning

14. Non-associative learning • Habituation : reduction in response to a stimulus • Dishabituation: restoration/recovery of a response due to presentation of another strong stimulus • Sensitization: enhancement of response due to presentation of a strong stimulus

15. Aplysia studies • Kandel: Nobel Prize in Physiology or Medicine in 2000 • Simple nervous system (few cells) • Accessible for detailed anatomical, biophysical, biochemical and molecular studies • Neurons and neural circuits that mediate behavior have been identified • Changes during learning have been identified • Memory mechanisms • Induction • Expression • Maintenance (consolidation)

16. Short-term sensitization • Heterosynaptic facilitation • Secundary messenger systems • Ion channel permeability • Phosporylation of synapsin (release of vesicles from pool) • Sensitization • Action potential is broader (inhibition of K-channels) • More transmitter is available

17. Long-term sensitization • 5HT → activation of cAMP/PKA cascade • induction of gene transcription! • translocation of PKA to nucleus • cAMP responsive element binding protein (CREB1) • Autoregulation of transcription (promotor binding - feedback) • 5HT → Tyrosine receptor kinase-like molecule (ApTrk) • MAPK: phosphorylation of CREB2 → derepression of CREB1

18. Long-term sensitization • ApCAM (Homologue of NCAM) • Downregulation (reduced synthesis, increased internalization) • Additional connections can be made by sensory neuron • AplysiaTolloid/BMP-like protein (ApTBL-1) • Zn2+ dependent protease • Activate TGF-βfamily (mimics 5HT effects) • Positive feedback loop • AplysiaUbiquitin hydrolase (ApUch) • Intracellular feedback loop • Increaseddegradation of regulatory unit of PKA

19. Long-term vs. short-term sensitization • Decreased duration of AP • Structural changes: neurite outgrowth • Increased high-affinity glutamate uptake • Nt. available for release • Nt. clearance (duration of EPSP/receptor desensitization) • Changes in postsynaptic cell

20. Associative learning in Aplysia

21. Associative learning in Aplysia • ‘Coincidence ‘ detection • Postsynaptic • Glutamate (delivered by presynaptic in response to CS) • Depolarization (induced by US, serotonin)

22. Vertebrate studies: LTP • More difficult to link synaptic plasticity with learning • Increase in synaptic strength • Induced by brief burst of spike activity in presynaptic afferents • Responsible for information storage in several brain regions, different animal models • No uniform mechanism for inducing LTP • Depending on experimental conditions

23. LTP at the CA3-CA1 synapse

24. LTP (E-LTP; L-LTP) • Mechanism: Repeatedactivation Glutamate,depolarization NMDA-receptorreleasesMg2+ • [Ca2+] ↑ ↑ AMPA-receptors ↑ and ionicconductance↑ Proteinsynthesis POSTSYNAPPTISCH ‘early ‘LTP (< 90 min) ‘late’ LTP (> 90 min)

25. LTP • Classical properties: • Cooperativity: probability of LTP, magnitude of change increases with number of stimulated afferents • Associativity: LTP only induced at weak input when associated with activity in strong input • Input specificity: Unstimulated weak pathway not facilitated after tetanus of strong pathway

26. Hebbian Mechanism • Donald Hebb (1949): ‘When an axon of cell A is near enough to excite a 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.’ • ‘Cells that fire together, wire together’ • Coincident activity in two synaptically coupled neurons increases the synaptic strength between them • Not all forms of LTP obey Hebb’s law: • e.g. Mossy fiber-CA3 synapse

27. LTP: mechanisms for induction, expression and maintenance • Multiple mechanisms for induction • Increased [Ca2+ ]I • AMPA and NMDA (Hebb) • Cooperativity: strong synaptic input necessary to depolarize membrane, AMPAR) • Associativity/input selectivity: weak input in itself does not relieve Mg2+ block • VGCC • Mechanisms for L-LTP highly conserved across species (cfrAplysia)

28. LTP expression • CA3-CA1 synapse: • (5) increase of functional AMPA • (4) P of AMPA receptor: increased conductance • (4) TARPs: AMPA receptor trafficking

29. LTP maintenance • E-LTP: phosphorylation of substate protein • L-LTP: alteration in gene expression • Transcription factors (fos, zif268) • Cytoskeletalproeins (arc) • Signal transduction molecules (CaMkinase II) • Critical time window (<2h) • Synapse specificity: tagging by kinase(s) • Positive feedback/re-activation of L-LTP mechanisms

30. Long term depression • Repeatedactivity(Hippocampus: 10 min, 1 Hz) • Depolarization • NMDA-receptorreleases Mg2+ • [Ca2+] ↑ • AMPA-receptordefosforylatie • internalisationAMPA-receptors • Learning mechanism in cerebellum (eye-blink reflex: decrease in synaptic strength in a postsynaptic inhibitory neuron) • Reversal of LTP • NMDA-dependent and – independent mechanisms POSTSYNAPPTISCH

32. LTP or LTD Dependson: • Brainregion/type of neuron • Increase in [Ca2+] • mild -> LTD (proteinphosphatase) • high-> LTP (protein kinase) • Characteristics of repeatedactivity • High frequencies-> LTP • Low frequencies (≤ 1Hz) -> LTD

33. Intrinsic neural plasticity • Changes in input-output relationship in neuronal networks due to changes in density or functional properties of voltage- gated ion channels • Probability that a cell fires in response to depolarization by EPSP • EPSP to spike coupling • Different between neural dendrites, soma and axons

34. Intrinsic neural plasticity

35. Intrinsic neural plasticity • Dendritic ion channels • Voltage attenuation of EPSPs, EPSP to AP • Voltage attenuation and filtering of back-propagating AP • STDP (spike-timing dependent plasticity) • Voltage gated Na+ and Ca2+ channels allow dendrites to generate own spikes (dendritic spikes)

36. Intrinsic neural plasticity • A type K+ current (IA current) • Active at membrane potentials lower than AP threshold • Activated by dendritic EPSP • EPSP attenuation • b-AP attenuation

37. Homeostatic plasticity • Allow neurons to sense how active they are are and to adjust their properties to maintain stable function • Stabilizes the activity of a neuron or neuronal circuit in the face of perturbations that alter excitability (e.g. changes in number of synapses) • Synaptic scaling • Regulation of intrinsic neuronal excitability • Regulation of synapse number • ‘Metaplasticity’

38. Synapticplasticity and instability

39. Synapticscaling • Blocking GABAergic transmission • Initial bursting of neurons • Firing rates become normal again • Transfection with inwardly rectifying potassium channel • Decreased firing rates • Recovery over time

40. Synaptic scaling

41. Regulation of intrinsic neuronal excitability

42. Regulation of synapse number

43. Metaplasticity

44. Learning and memory: brain systems

45. Learning and memory: brain systems • Severe amnesiafor recent events • Unablefor form new memories • Unaffected IQ score, no defectiveperception • Onlyretention of information ifactivelyrehearsed • Childhood memory relatively intact • Acquire new motor skills

46. Declarative (explicit) memory • episodic memory • personal events • semantic memory • learning new facts • Procedural (implicit) memory

47. Hippocampus • Hippocampus

48. Hippocampus • the subiculum • hippocampus = hippocampus proper = Ammon’shorn • dentategyrus • a thin band of cortex that lies on the upper surface of the parahippocampalgyrus. • an input centre and receives signals that are relayed to it via the enthorhinal cortex and its cells project to cells in the hippocampal formation.

49. dentate gyrus (1) cornu ammonis (2) Their three layered cortex is continuous below with the subiculum (3) which has four, five then six layers as it merges with the parahippocampal gyrus (4).

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