SynapticPlasticity2022.pptx

The presentation is for personal use only and must not be copied or used outside of BSMS Synaptic Plasticity In Learning & Memory Dr Natasha Sigala [email protected] Module 202 Neuroscience & Behaviour Outline How the brain encodes memories at different levels: • electrophysiological • molecu...

The presentation is for personal use only and must not be copied or used outside of BSMS Synaptic Plasticity In Learning & Memory Dr Natasha Sigala [email protected] Module 202 Neuroscience & Behaviour Outline How the brain encodes memories at different levels: • electrophysiological • molecular • structural Drugs that influence memory • alcohol • benzodiazepines • cholinergic drugs • cognitive enhancers Connectome, the map of neural connections in the brain Learning outcomes By the end of this lecture you should be able to: Explain how the brain encodes memories at an electrophysiological, molecular and structural level Describe Hebb’s rule and define what a cell assembly is Describe in detail LTP and LTD and their function Give examples of experimental evidence for the role of LTP in memory formation Describe drug effects on learning and memory Define what the connectome is 3 Types of Memory Explicit Implicit 4 How do we learn? Learning: the response of the brain to environmental events and involves adaptive changes in synaptic connectivity which will in turn alter behaviour. 5 Wiring / Synaptic Connections thalamus 6 7 8 9 10 Hebb’s rule “Let us assume that the persistence or repetition of a reverberatory activity (or "trace") tends to induce lasting cellular changes that add to its stability.… 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.” Donald Hebb, The Organization of Behavior, 1949 11 Rules of synaptic modification 1. Neurons that fire together wire together 2. Neurons that fire out of sync lose their link. Strengthening and weakening synaptic connections in the brain provide a means by which learning occurs and memories can be formed. Prof. Carla Shatz, Stanford University 12 Take a hippocampal neuron with inputs from: Cell A – sensory input for sight of rose Cell B – sensory input for smell of rose Cell C – sensory input for smell of onion Individually stimulation of the hippocampal neuron by any of these cells may be insufficient to create an EPSP great enough to fire an action potential 13 Take a hippocampal neuron with inputs from: Cell A – sensory input for sight of rose Cell B – sensory input for smell of rose Cell C – sensory input for smell of onion Individually stimulation of the hippocampal neuron by any of these cells may be insufficient to create an EPSP great enough to fire an action potential When A and B are activated together – on seeing and smelling the rose the coincident EPSPs may summate sufficiently to cause an action potential in the hippocampal neuron If this association is made repeatedly - the simultaneous firing of cells A and B onto the hippocampal neuron - those synapses will be strengthened (over the synapse from cell C which does not fire coincidently). The strengthening of the synapses of cell A and B will be sufficient that they will individually be able to elicit action potentials in the hippocampal neuron. ->The sight of a rose will become associated with the smell of a rose rather than the smell of an onion. Long term potentiation (LTP) mechanism underlying synaptic strengthening Hippocampus - shape and anatomy means pathways can be easily distinguished and recorded from electrophysiologically -LTP has now been studied in most other brain areas too Record from cells within the dentate gyrus: Subsequent perforant pathway stimulation results in increase in EPSP amplitude (size) High frequency electrical stimulation (HFS) of the perforant pathway (input) One HFS - LTP lasts hours Multiple HFS - LTP lasts days/months Timothy Bliss Terje Lømo 15 Long term potentiation (LTP) Temporal: Summation of inputs reaches a stimulus threshold that leads to the induction of LTP. e.g. Repetitive stimulation (HFS) Associative: simultaneous stimulation of a strong and weak pathway will induce LTP at both pathways. (Spatial summation) Coincidence detection “Cells that fire together wire together” Specific: LTP at one synapse is not propagated to adjacent synapses (input specific). 16 What’s happening at the synapse? Glutamate release onto inactive cell (membrane at resting potential) AMPA receptor activated to create EPSP NMDA receptor blocked by Mg2+ ion Depolarization from AMPA activation not sufficient to expel Mg2+ Glutamate release onto an active Cell (membrane depolarized) AMPA receptor activated Mg2+ block on NMDA receptor relieved Na+ through AMPA and NMDA channels Ca2+ through NMDA channel 17 What’s happening at the synapse? contd. Ca2+ entry through the NMDA receptor leads to activation of: •Protein kinase C •Calcium calmodulin-dependent protein kinase II (CaMKII) 1) phosphorylates existing AMPA receptors, increasing their effectiveness CaMKII 2) stimulates the insertion of new AMPA receptors into the membrane Before: Few AMPA receptors Small EPSPs After: More AMPA receptors working more effectively Larger EPSPs LTP 18 CaMKII - molecular switch - sustained activity after repolarization Ca2+ entry through the NMDA receptor leads to activation of Calcium calmodulin-dependent protein kinase II (CaMKII) CaMKII has autocatalytic activity - becomes phosphorylated When phosphorylated is constitutively active - no longer requires Ca2+ Maintains phosphorylation, insertion of AMPA receptors etc. after the depolarizing stimulus has receded Molecular switch which maintains increased excitability of neuron for minutes to hours 19 Presynaptic events in LTP Long term potentiation also involves presynaptic events Postsynaptic neuron can feed back to presynaptic neuron by retrograde neurotransmitter - Nitric Oxide (NO) Ca2+ through the NMDA channel activates Nitric oxide synthase NO diffuses from site of production and activates guanylyl cyclase in the presynaptic terminal Guanylyl cyclase produces the second messenger cGMP Signal transduction cascade leads to increased glutamate release from the synaptic button 20 Late phase LTP Protein synthesis required for long-lasting LTP (days, months) Protein synthesis inhibitors prevent the consolidation of long term memories and LTP Stages of memory formation Acquisition (training) Consolidation Recall (testing) Protein synthesis inhibitor injected just post-acquisition (training) inhibits recall - necessary for consolidation CREB - cAMP Response Element Binding protein activated by phosphorylation by a number of etc) kinases (PKA, CaMKII 21 Early vs late phase LTP (short vs long term events) Early phase LTP lasts a minute to an hour and can be explained by the actions of Ca2+ through the NMDA receptor and subsequent enhancement of AMPA receptor efficiency, presynaptic events etc. Late phase LTP lasts hours, days or months -requires new protein synthesis and can involve morphological changes and the establishment of new synapses Ca2+ activated signal transduction cascades: - activate new protein synthesis from dendritically localized mRNAs filter back to the cell body to stimulate new gene transcription (CREB -mediated), protein synthesis and recruitment of new proteins to the synapse 22 Always an opposite - Long Term Depression (LTD) Long Term Potentiation is created in slice preparations by High frequency stimulation (HFS: 100x 100Hz) Same players involved: NMDA dependant process AMPA receptors are de-phosphorylated and removed from the membrane prolonged low level rises in Ca2+ activate phosphatases rather than kinases EPSP amplitude Low frequency stimulation (LFS: 100x 1 Hz) actually causes the opposite and rather than getting an increase in EPSP amplitude on further stimulation you get a decrease HFS 23LFS LTP and LTD reflect bidirectional regulation of: 1. phosphorylation and 2. number of postsynaptic AMPA receptors 24 Do all these changes in synaptic activity really lead to learning? NMDA receptor activity in the hippocampus essential for both LTP and spatial learning AP5 - NMDA receptor antagonist -blocks hippocampal LTP blocks learning in the Morris Water Maze Richard Morris Normal rat First trial After multiple trials 25 Do all these changes in synaptic activity really lead to learning? NMDA receptor activity in the hippocampus essential for both LTP and spatial learning AP5 - NMDA receptor antagonist -blocks hippocampal LTP blocks learning in the Morris Water Maze Normal rat First trial After multiple trials Rat with AP5 infused into hippocampus 26 Studies on animals - relevance to humans? Human inferotemporal cortex removed during surgery maintained in vitro HFS - produced LTP LFS - produced LTD 27 Drug effects on learning and memory I Alcohol NMDA receptor antagonist (as well as other sites) Blackouts and amnesia caused by drinking directly blocking normal LTP processes? Alcohol disrupts hippocampal theta rhythms and disrupts short term memory. Chronic alcoholism and associated nutritional deficiency can result to Korsakoff syndrome or psychosis: loss of recent memory, and tendency to fabricate accounts of recent events (confabulation). 28 Drug effects on learning and memory II Benzodiazepines Indirect agonist of GABAA receptors: - binding increases the receptor affinity for GABA increase frequency of channel opening - anxiolytic and hypnotic drugs Side effect to anxiolytic and sedative properties: - anterograde amnesia 29 - Drug effects on learning and memory III Cholinergics / Anticholinergics Acetylcholine projections: Basal forebrain bundle: Medial septum to hippocampus Basal nucleus to cortex (from Bear, Connors & Paradiso 2nd ed) Septum to hippocampus projection regulates theta waves Scopolamine (muscarinic receptor antagonist) suppresses theta waves and impairs spatial learning 30 Drug effects on learning and memory IV Alzheimer’s disease Acetylcholinesterase inhibitors (e.g. physostigmine) Boost cholinergic function Improves memory impairments In a healthy brain? (from Bear, Connors & Paradiso 2nd ed) Controversial as to whether they improve memory May increase attention Most cognitive enhancing effects of both acetylcholinesterases and other cholinergic drugs, e.g. nicotine, seen in impaired subjects, i.e. Alzheimer’s patients, or in restoring performance of animals with lesions. 31 Other learning processes which use LTP or similar mechanism Activity dependent synaptogenesis (development) Motor learning - e.g. riding a bike - cerebellar 32 Prof. Sebastian Seung on the Connectome 33 Summary Cells that fire together wire together Long Term Potentiation - molecular mechanism for memory? early and late phases Cells that fire out of sync, lose their link - LTD Drugs that modulate memory Connectome 35 CREB, cAMP Response Element Binding protein, is involved in which aspect of memory and LTP formation? A. acquisition B. consolidation C. early phase LTP D. presynaptic events involved in LTP E. recall LTD involves A. High Frequency stimulation B. Activation of kinases C. Phosphorylation of AMPA receptors D. Insertion of new AMPA receptors E. Prolonged low level rises in Ca2+ concentration Reading Materials Bear, Connors & Paradiso: Chapters 23, 24, 25 Purves et al.: Chapters 8, 24 Kandel, Schwartz & Jessel: Chapter 63 38