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Year 2 Medicine > Synaptic Plasticity in Learning and Memory > Flashcards

Synaptic Plasticity in Learning and Memory Flashcards

1
Q

Types of memory

  • … - declarative memory - facts, events
  • … - nondeclarative memory - classical conditioning e.g. procedural memory: skills,habits, skeletal musculature, emotional responses (Amygdala)
A
  • Explicit - declarative memory - facts, events
  • Implicit - nondeclarative memory - classical conditioning e.g. procedural memory: skills,habits, skeletal musculature, emotional responses (Amygdala)
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2
Q
  • Explicit - … memory - facts, events
  • Implicit - … memory - classical conditioning e.g. procedural memory: skills,habits, skeletal musculature, emotional responses (Amygdala)
A
  • Explicit - declarative memory - facts, events
  • Implicit - nondeclarative memory - classical conditioning e.g. procedural memory: skills,habits, skeletal musculature, emotional responses (Amygdala)
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3
Q

How do we learn?

  • Learning: the response of the brain to … events and involves … changes in … connectivity which will in turn alter …
A
  • Learning: the response of the brain to environmental events and involves adaptive changes in synaptic connectivity which will in turn alter behaviour
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4
Q

Wiring/Synaptic Connections

A
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5
Q

Donald Hebb Theory - 1949

  • Group of cells connected with each other - cell assembly
  • Neurons that … together … together
A
  • Group of cells connected with each other - cell assembly
  • Neurons that fire together wire together
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6
Q

Rules of synaptic modification

  • 1) Neurons that … together … together
  • 2) Neurons that fire out of … lose their …
  • Strengthening and weakening synaptic connections in the brain provide a means by which learning occurs and memories can be formed
A
  • 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
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7
Q

Rules of synaptic modification

  • 1) Neurons that fire together wire together
  • 2) Neurons that fire out of sync lose their link
  • … and … synaptic connections in the brain provide a means by which … occurs and … can be formed
A
  • 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
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8
Q

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 … - 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 … - the simultaneous firing of cells A and B onto the hippocampal neuron - those synapses will be … (over the synapse from cell C which does not fire coincidently)
  • The … 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 … with the smell of a rose rather than the smell of an onion
A
  • 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
    *
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9
Q

Long term potentiation (LTP)

What is it?

A
  • 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
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10
Q

Long term potentiation (LTP)

  • Mechanism underlying … …
  • … - shape and anatomy means pathways can be easily distinguished and recorded from electrophysiologically
    • LTP has now been studied in most other brain areas too
A
  • 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
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11
Q

LTP - mechanism underlying synaptic strengthening

  • … - 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 … gyrus: subsequent perforant pathway stimulation results in

  • High frequency electrical stimulation (HFS) of the perforant pathway (input)
    • One HFS - LTP lasts …
    • Multiple HFS - LTP lasts …/…
A

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

  • High frequency electrical stimulation (HFS) of the perforant pathway (input)
    • One HFS - LTP lasts hours
    • Multiple HFS - LTP lasts days/months
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12
Q

LTP

  • … - summation of inputs reaches a stimulus threshold that leads to the induction of LTP e.g. repetitive stimulation (HFS)
  • … - simultaneous stimulation of a strong and weak pathway will induce LTP at both pathways. (Spatial summation) coincidence detection “cells that fire together wire together”
  • … - LTP at one synapse is not propagated to adjacent synapses (input specific)
A
  • 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)
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13
Q

LTP

  • Temporal - summation of inputs reaches a stimulus threshold that leads to the induction of LTP e.g. … stimulation (HFS)
  • Associative - simultaneous stimulation of a strong and weak pathway will induce LTP at both pathways. (… summation) coincidence detection “cells that fire together wire together”
  • Specific - LTP at one synapse is not … to adjacent synapses (input specific)
A
  • 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)
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14
Q

What’s happening at the synapse? - learning and memory (LTP)

  • Glutamate release onto inactive cell (membrane at … …)
  • … receptor activated to create EPSP
  • NMDA receptor blocked by Mg2+ ion
  • Depolarization from … activation not sufficient to expel Mg2+
  • Glutamate release onto an active cell (membrane …)
  • … receptor activated
  • Mg2+ block on NMDA receptor relieved
  • Na+ through … and NMDA channels
  • Ca2+ through NMDA channel
A
  • 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
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15
Q

What’s happening at the synapse? - learning and memory (LTP)

  • … release onto inactive cell (membrane at resting potential)
  • AMPA receptor activated to create EPSP
  • … receptor blocked by Mg2+ ion
  • Depolarization from AMPA activation not sufficient to expel Mg2+
  • … release onto an active cell (membrane depolarized)
  • AMPA receptor activated
  • Mg2+ block on … receptor relieved
  • Na+ through AMPA and … channels
  • Ca2+ through … channel
A
  • 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
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16
Q

What’s happening at the synapse? - LTP Contd.

  • Ca2+ entry through the … receptor leads to activation of:
    • Protein kinase …
    • Calcium …-dependent protein kinase II (CAMKII)
  • Phosphorylase existing AMPA receptors, increasing their effectiveness
  • Stimulates the insertion of new … receptors into the membrane
A
  • Ca2+ entry through the NMDA receptor leads to activation of:
    • Protein kinase C
    • Calcium calmodulin-dependent protein kinase II (CAMKII)
  • Phosphorylase existing AMPA receptors, increasing their effectiveness
  • Stimulates the insertion of new AMPA receptors into the membrane
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17
Q
  • Before high frequency stimulation - few … receptors, small EPSPs
  • After - More … receptors working more effectively, larger EPSPs leading to …
A
  • Before high frequency stimulation - few AMPA receptors, small EPSPs
  • After - More AMPA receptors working more effectively, larger EPSPs leading to LTP
18
Q

CAMKII - molecular switch - sustained activity after repolarization

  • Ca2+ entry though the NMDA receptor leads to activation of calcium calmodulin-dependent protein kinase II (CaMKII)
  • CaMKII has autocatalytic activity - becomes …
  • When … is constitutively active - no longer requires Ca2+
  • Maintains …, insertion of AMPA receptors etc. after the depolarizing stimulus has …
  • Molecular switch which maintains increased … of neuron for minutes to hours
A
  • Ca2+ entry though 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
Q

Presynaptic events in LTP

  • Long term potentiation also involves presynaptic events
  • Postsynaptic neuron can feed back to presynaptic neuron by retrograde NT - … …
  • Ca2+ through the NMDA channel activates … synthase
  • … 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 … release from the synaptic button
A
  • Long term potentiation also involves presynaptic events
  • Postsynaptic neuron can feed back to presynaptic neuron by retrograde NT - Nitric oxide
  • Ca2+ through the NMDA channel activates NO 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
Q

Presynaptic events in LTP

  • Long term potentiation also involves presynaptic events
  • Postsynaptic neuron can feed back to presynaptic neuron by retrograde NT - Nitric oxide
  • Ca2+ through the … channel activates NO synthase
  • NO diffuses from site of production and activates guanylyl cyclase in the presynaptic terminal
  • Guanylyl cyclase produces the … … cGMP
  • Signal transduction cascade leads to … glutamate release from the synaptic button
A
  • Long term potentiation also involves presynaptic events
  • Postsynaptic neuron can feed back to presynaptic neuron by retrograde NT - Nitric oxide
  • Ca2+ through the NMDA channel activates NO 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
21
Q

Late phase LTP

  • Protein … required for long-lasting LTP (Days, months)
  • Protein … inhibitors prevent the … of long term memories and LTP
  • Stages of memory formation
    • Acquisition (training)
    • Consolidation
    • Recall (testing)
  • Protein … inhibitor injected just post-acquisition (training) inhibits recall - necessary for …
A
  • 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
22
Q

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
    • … (training)
    • …
    • … (testing)
  • Protein synthesis inhibitor injected just post-… (training) inhibits … - necessary for …
A
  • 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
23
Q

Early vs Late phase LTP (short vs long term events)

  • Early phase LTP lasts a … to an … and can be explained by the actions of Ca2+ through the … receptor and subsequent enhancement of … receptor efficiency, presynaptic events etc.
  • Late phase LTP lasts hours, days or months - requires new protein … and can involve morphological changes and the establishment of new …
  • 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
A
  • 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 syntheses 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
24
Q

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 …, … or … - requires new protein … and can involve morphological changes and the establishment of new synapses
  • Ca2+ activated signal transduction cascades:
    • Activate new protein … from dendritically localized mRNAs
    • Filter back to the cell body to stimulate new gene transcription (CREB-mediated), protein … and recruitment of new proteins to the synapse
A
  • 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 syntheses 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
25
Q

Always an opposite - Long term depression (LTD)

  • Long term potentiation is created in slice preparations by … frequency stimulation (…: 100x 100Hz)
  • … frequency stimulation (…: 100X 1 Hz) actually causes the opposite and rather than getting an increase in EPSP amplitude on further stimulation you get a decrease
  • Same players involved:
    • … dependent process
    • … receptors are de-phosphorylated and removed from the membrane
  • Prolonged low level rises in Ca2+ activate phosphatases rather than kinases
A
  • Long term potentiation is created in slice preparations by high frequency stimulation (HFS: 100x 100Hz)
  • 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
  • Same players involved:
  • NMDA dependent process
  • AMPA receptors are de-phosphorylated and removed from the membrane
  • Prolonged low level rises in Ca2+ activate phosphatases rather than kinases
26
Q

Always an opposite - Long term depression (LTD)

  • Long term … is created in slice preparations by high frequency stimulation (HFS: 100x 100Hz)
  • 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
  • Same players involved:
    • … dependent process
    • AMPA receptors are de-phosphorylated and removed from the membrane
  • Prolonged … level rises in Ca2+ activate … rather than kinases
A
  • Long term potentiation is created in slice preparations by high frequency stimulation (HFS: 100x 100Hz)
  • 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
  • Same players involved:
  • NMDA dependent process
  • AMPA receptors are de-phosphorylated and removed from the membrane
  • Prolonged low level rises in Ca2+ activate phosphatases rather than kinases
27
Q

LFS - leads to long term …

A

LFS - leads to long term depression

28
Q

LTP and LTD reflect bidirectional regulation of:

  • P…
  • Number of postsynaptic … receptors
A
  • Phosphorylation
  • Number of postsynaptic AMPA receptors
29
Q

Do all these changes in synaptic activity really lead to learning?

  • … receptor activity in the hippocampus essential for both … and spatial learning
    • AP5 - … receptor antagonist
    • Blocks hippocampal …
    • Blocks learning in the Morris Water Maze
A
  • 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
30
Q

Studies on animals - relevance to humans? - learning and memory

  • LTP recorded in human brain? yes or no
A
  • LTP in human brain? yes or no
  • HFS - produced LTP
  • LFS - produced LTD
31
Q

Drug effects on learning and memory - ALCOHOL

  • … receptor antagonist (as well as other sites)
  • Blackouts and … caused by drinking
  • Directly blocking normal … 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)
A
  • 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)
32
Q

Drug effects on learning and memory - ALCOHOL

  • NMDA receptor antagonist (as well as other sites)
  • Blackouts and amnesia caused by drinking
  • Directly blocking normal LTP processes???
  • Alcohol disrupts … theta rhythms and disrupts … term memory
  • Chronic alcoholism and associated nutritional deficiency can result to … syndrome or psychosis: loss of recent memory, and tendency to fabricate accounts of recent events (…)
A
  • 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)
33
Q

Chronic alcoholism and associated nutritional deficiency can result to … syndrome or psychosis: loss of recent memory, and tendency to fabricate accounts of recent events (C…)

A

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)

34
Q

Drug effects on learning and memory - BENZODIAZEPINES

  • … agonist of GABA…. receptors:
    • Binding increases the receptor affinity for GABA
    • … frequency of channel opening
    • Anxiolytic and hypnotic drugs
  • Side effect to anxiolytic and sedative properties - … amnesia
A
  • Indirect agonist of GABAalpha 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
35
Q

Drug effects on learning and memory - BENZODIAZEPINES

  • Indirect … of GABAalpha receptors:
    • Binding … the receptor affinity for GABA
    • Increase frequency of channel …
    • Anxiolytic and hypnotic drugs
  • Side effect to anxiolytic and sedative properties - anterograde …
A
  • Indirect agonist of GABAalpha 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
36
Q

Drug effects on learning and memory - CHOLINERGICS/ANTICHOLINERGICS

  • Acetylcholine …:
  • Basal forebrain bundle: medial septum to hippocampus, basal nucleus to cortex
  • Septum to hippocampus projection regulates … waves
  • Scopolamine (muscarinic receptor …) suppresses theta waves and impairs spatial learning
A
  • Acetylcholine projections:
  • Basal forebrain bundle: medial septum to hippocampus, basal nucleus to cortex
  • Septum to hippocampus projection regulates theta waves
  • Scopolamine (muscarinic receptor antagonist) suppresses theta waves and impairs spatial learning
37
Q

Drug effects on learning and memory - CHOLINERGICS/ANTICHOLINERGICS

  • Acetylcholine projections:
  • Basal forebrain bundle: … septum to hippocampus, basal … to cortex
  • Septum to hippocampus projection regulates theta waves
  • Scopolamine (muscarinic receptor antagonist) … theta waves and … spatial learning
A
  • Acetylcholine projections:
  • Basal forebrain bundle: medial septum to hippocampus, basal nucleus to cortex
  • Septum to hippocampus projection regulates theta waves
  • Scopolamine (muscarinic receptor antagonist) suppresses theta waves and impairs spatial learning
38
Q

Drug effects on learning and memory - Alzheimer’s disease

  • Alzheimer’s disease - … inhibitors (E.g. physostigmine) boost cholinergic function and improve memory …
A
  • Alzheimer’s disease - Acetylcholinesterase inhibitors (E.g. physostigmine) boost cholinergic function and improve memory impairments
39
Q

Drug effects on learning and memory - Healthy brain?

  • In alzheimers - Acetylcholinesterase … (E.g. physostigmine) boost cholinergic function and improve memory impairments
  • In a healthy brain:
    • Controversial as to whether they improve memory, may increase …
    • Most cognitive enhancing effects of both acetylcholinesterase and other cholinergic drugs e.g. nicotine, seen in in impaired subjects, i.e. Alzheimer’s patients, or in restoring performance of animals with lesions.
A
  • In alzheimers - Acetylcholinesterase inhibitors (E.g. physostigmine) boost cholinergic function and improve memory impairments
  • In a healthy brain:
    • Controversial as to whether they improve memory, may increase attention
    • Most cognitive enhancing effects of both acetylcholinesterase and other cholinergic drugs e.g. nicotine, seen in in impaired subjects, i.e. Alzheimer’s patients, or in restoring performance of animals with lesions.
40
Q

Other learning processes which use LTP or similar mechanism:

  • Activity dependent … (Development)
  • … learning - e.g. riding a bike - cerebellar
A
  • Activity dependent synaptogenesis (Development)
  • Motor learning - e.g. riding a bike - cerebellar

Year 2 Medicine (162 decks)

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