Lecture 7 - Learning and Memory in Mammals II Flashcards
How is memory stored in the mammalian brain? There’s no ‘memory module’ as in a computer.
- Information is processed in distributed … networks.
- This information is … (e.g. visual, gustatory) and information is … in different brain areas.
- … of synaptic activity in these … networks can keep the information for the …- or long-term.
- Information is processed in distributed neuronal networks.
- This information is specific (e.g. visual, gustatory) and information is processed in different brain areas.
- Modulation of synaptic activity in these neuronal networks can keep the information for the short- or long-term.
Working memory depends on persistent neural activity in the prefrontal cortex - it requires persistent neuron firing: in vivo recording of neuronal activity in the PFC of non-human primates using a visual ‘delayed match-to-sample’ working memory task.
What happens during the task?
What are the results of the task regarding PFC firing?
Delayed match-to-sample task - primates are shown an image ⇒ image is taken away for seconds to minutes ⇒ then a second image is shown ⇒ they need to press the lever if they recognise the image for a reward.
The results shows that the PFC is persistently firing during the delay period.
What 2 mechanisms can underlie persisten firing of PFC neurons?
- Changes in PFC neuronal membrane properties (e.g. Calcium-activated non-selective cation channels insertion into membrane)
- Alterations in communication between local neurons that promote recurrent firing.
Long-term memory formation:
Unlike … Memory, long-term memory does not depend on persistent neuronal firing but involves … changes in the strength of synaptic connections (synaptic …).
The effects are most well characterised in the …, which has a very well-defined neuronal … .
Synaptic plasticity, and its biological basis, in the hippocampus has been defined using a range of techniques including …, drug challenges and genetic … models.
Unlike Working Memory, long-term memory does not depend on persistent neuronal firing but involves long-lasting changes in the strength of synaptic connections (synaptic plasticity).
The effects are most well characterised in the hippocampus, which has a very well-defined neuronal connectivity.
Synaptic plasticity, and its biological basis, in the hippocampus has been defined using a range of techniques including electrophysiology, drug challenges and genetic mouse models.
What underlies the formation of long-term memory?
Long-term changes in synaptic plasticity.
The brain … events as a complex spatio-temporal pattern of activity across … .
This information is stored in these circuits (memories are formed), when the … of communication between specific neurons in these circuits is … .
The … of the synaptic connections between two neurons is increased when the …- and post-synaptic neuron fire in close … (proven by Hebb, 1949): “Neurons that … together, … together”.
These alterations could form the cellular basis of … traces, such as those generated during Pavlovian conditioning.
The brain encodes events as a complex spatio-temporal pattern of activity across neural circuits.
This information is stored in these circuits (memories are formed), when the efficacy of communication between specific neurons in these circuits is altered.
The strength of the synaptic connections between two neurons is increased when the pre- and post-synaptic neuron fire in close succession (proven by Hebb, 1949): “Neurons that fire together, wire together”.
These alterations could form the cellular basis of memory traces, such as those generated during Pavlovian conditioning.
What is long-term potentiation (LTP)?
Name a pathway of the hippocampus where this is well characterized in.
LTP is a mechanism by which long-lasting, activity-dependent changes in synaptic strength are generated by high frequency stimulation (HFS) of the pre-synaptic neuron, that could underlie long-term memory.
The Schaffer collateral - CA1 pathway in the hippocampus.
Hippocampal slice electrophysiology for LTP: Schaffer collateral – CA1 pathway:
What happens at the pre- and post-synaptic cell?
How do you know that the synapses have been potentiated?/How do you know LTP has happened?
- Pre-synaptic cell - stimulate Schaffer collateral neurons with electrical ‘high frequency stimulation’.
- Post-synaptic cell - record what happens to neurons in the CA1 hippocampal subfield.
LTP measured: an increase in post-synaptic response (detected in CA1 field) in response to the same level of stimulation means that the synapses involved have been potentiated.
Inducing LTP at excitatory (glutamergic) synapses:
Many forms of LTP at glutamatergic synapses are dependent on the … receptor and … receptor.
Under basal synaptic conditions NMDA receptors are blocked by … ions (…-dependent block) and do not allow … (Na+, Ca2+) influx into the neuron through this receptor.
… acts on AMPA receptors to depolarise the post-synaptic cell, allowing Na+ and … to enter.
Many forms of LTP at glutamatergic synapses are dependent on the NMDA receptor and AMPA receptor.
Under basal synaptic conditions NMDA receptors are blocked by Mg2+ ions (voltage-dependent block) and do not allow cation (Na+, Ca2+) influx into the neuron through this receptor.
Glutamate acts on AMPA receptors to depolarise the post-synaptic cell, allowing Na+ and K+ to enter.
Triggering NMDA-receptor dependent LTP 1+2:
- High pre-synaptic activity (…) causes a strong … in post-synaptic dendrite.
- The post-synaptic … releases the (…-dependent) Mg2+ block from the NMDA receptor, allowing a large … influx into dendritic spine.
- NMDA receptors are … detectors - they must have … bound & post-synaptic membrane must be depolarised (Mg2+ block …).
- Intracellular Ca2+ stimulates intracellular signalling cascades (activation of protein … and …-signalling).
- CREB-signalling promotes the generation of … signalling molecules that cause synaptic … and … neurotransmitter release.
- CAMKII promotes the integration of additional … receptors into the dendritic membrane.
- LTP is established: the synapse is strengthened as the likelihood and … of presynaptic neurotransmitter release is increased AND there is synaptic … (more AMPA receptors).
- High pre-synaptic activity (HFS) causes a strong depolarisation in post-synaptic dendrite.
- The post-synaptic potential releases the (voltage-dependent) Mg2+ block from the NMDA receptor, allowing a large Ca2+ influx into dendritic spine.
- NMDA receptors are coincidence detectors - they must have glutamate bound & post-synaptic membrane must be depolarised (Mg2+ block removed).
- Intracellular Ca2+ stimulates intracellular signalling cascades (activation of protein kinases and CREB-signalling).
- CREB-signalling promotes the generation of retrograde signalling molecules that cause synaptic growth and enhanced neurotransmitter release.
- CAMKII promotes the integration of additional AMPA receptors into the dendritic membrane.
- LTP is established: the synapse is strengthened as the likelihood and quantitiy of presynaptic neurotransmitter release is increased AND there is synaptic growth (more AMPA receptors).
Briefly describe triggering NMDA-receptor dependent LTP 1+2 in 4 steps:
HFS –> release of Mg2+ block –> Ca2+ influx and stimulation –> CREB-signalling and CAMKII stimulation –> enhanced neurotransmitter release and synaptic growth.
- High pre-synaptic activity (e.g. HFS) causes strong depolarisation in post-synaptic dendrite.
- Post-synaptic potential releases the voltage-dependent Mg2+ block from the NMDA receptor, allowing Ca2+ influx.
- Intracellular Ca2+ stimulates intracellular signalling cascades (activation of protein kinases and CREB)
- CREB induces an enhanced neurotransmitter release and synaptic growth. CAMKIII promotes integration of additional AMPA receptors.
LTP is established.
Morris et. al. study: What are the consequences of blocking LTP with NMDA-R antagonist AP5?
Morris et. al. showed that blocking of LTP in the hippocampus (dentate gyrus) with NMDA-R antagonist AP5, can correlate with learning abilities. It also impair spatial water maze task.
What are caveats of Morris’s study of blockade of LTP?
- Animals were still able to learn the task, but were …
- Not all similar experiments show a … correlation between … and learning and memory
- LTP in other … could be involved
- Other, non-… receptor-dependent forms of LTP may be involved
- LTP is induced … and may not resemble actual synaptic … in the living learning brain
- Animals were still able to learn the task, but were slower
- Not all similar experiments show a clear correlation between LTP and learning and memory
- LTP in other brain areas could be involved
- Other, non-NMDA receptor-dependent forms of LTP may be involved
- LTP is induced artificially and may not resemble actual synaptic potentiation in the living learning brain
What happens when there’s a selective knockout of the NMDA receptor in the CA1 subfield?
Selective knockout of the NMDA receptor in the CA1 subfield impairs memory & LTP. Also, morris water maze performance is impaired during the “probe trial”.
Phases of LTP: induction (via HFS) > expression (early LTP) > stabilisation (late LTP).
Early LTP: … hours. Doesn’t require protein …, … or … activation.
Late LTP: … hours.
- Requires cAMP and … activation.
- Requires change in gene … (CREB pathway)
- Requires protein … (inhibited by …)
- Involves growth of new … between neurons
Early LTP: 1-3 hours. Doesn’t require protein synthesis, cAMP or PKA activation.
Late LTP: 2-24 hours.
- Requires cAMP and PKA activation.
- Requires change in gene transcription (CREB pathway)
- Requires protein synthesis (inhibited by anisomycin)
- Involves growth of new synaptic connections between neurons
The hippocampus guides the reorganisation of the information in the neocortex, so that it becomes permanently stored and separate from the hippocampus (think of HM!).
There are two models of standard systems consolidation. Describe them.
Model A = during learning new information is stored in hippocampus and cortex –> hippocampus guides the binding of cortical modules together during consolidation.
Model B = cortical modules are already connected by prior knowledge (existing schema), hippocampus guides the assimilation of new information into these existing schemas.
