Lecture 7 Flashcards
How is information processed?
Distributed neuronal networks
What does working memory depend on?
Persistent neural activity in the prefrontal cortex
Experiment on how working memory depends on persistent neural activity
non-human primates
Visual delayed match-to-sample (DMTS) working memory task
Shown an image > taken away for seconds to minutes > shown second image > press lever if recognise image for reward
Neurons in the PFC persistently fire during the delay period
2 mechanisms can underlie persistent firing:
- Changes in PFC neuronal membrane properties (e.g. Ca2+-activated non-selective cation (CAN) channels insertion into membrane)
- Alterations in communication between local neurons that promote recurrent firing
Long-term memory formation
- Involves long-lasting changes in the strength of synaptic connections, not on persistent neuronal firing
- Effects well-characterised in the hippocampus - has well defined neuronal connectivity
- Synaptic plasticity defined using electrophysiology, drug challenges, and genetic mouse models
Long term changes in synaptic plasticity underlie long-term memory
- Brain encodes events such as spatio-temporal pattern across connected neurons
- Info stored in these circuits when the efficacy of communication between specific neurons in these circuits is altered
- Strength of synaptic connections between 2 neurons is increased when pre- and post- synaptic neuron fire in close succession
- these alterations could form the cellular basis of memory traces, such as those generated during Pavlovian conditioning
- Long-term potentiation (LTP) is a mechanism by which long-lasting, activity-dependent changes in synaptic strength are generated by high frequency stimulation (HFS) of the presynaptic neuron, that could underlie long term memory
Well characterised in the hippocampus (e.g. Schaffer collateral - CA1 pathway)
Hippocampal Slice Electrophysiology
Presynaptic Cell - Stimulate Schaffer collateral neurons with electrical “High Frequency Tetanic Stimulation (HFS)”
Post-synaptic Cell - Record what happens to neurons in the CA1 hippocampal subfield
Recording synaptic activity and LTP in the hippocampus
Electrical stimulation of projections (Schaffer Collaterals) to CA1 pyramidal neurons will activate these neurons
The response can be measured as “field potentials” (electrical depolarisations) or action potentials (neuronal firing) in the CA1 field
An increase in the post-synaptic response (detected in CA1 field) in response to the same level of stimulation means that the synapses involved have been potentiated
LTP in the Schaffer-CA1 projection
- Negative deflection of the excitatory field response represents depolarisation of post-synaptic neurons
- Response grows after high-frequency stimulation (HFS) if LTP has occurred
Inducing LTP at excitatory (glutamatergic) synapses
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-R dependent LTP I
High presynaptic activity (such as than induced by HFS) causes a strong depolarisation in the post-synaptic dendrite
The post-synaptic potential releases the (voltage-dependent Mg2+) block from the NMDA receptor, allowing a large Ca2+ influx into the dendritic spine
NMDA receptors are coincidence detectors – must have glutamate bound & post-synaptic membrane must be depolarised (Mg2+ block removed)
Intracellular Ca2+ stimulates intracellular signalling cascades (activation of various protein kinases and CREB)
CREB signalling promotes the generation of retrograde signalling molecules that act on the presynaptic bouton to enhance neurotransmitter release
CAMKII promotes the integration of additional AMPA receptors into the dendritic membrane
These pathways are conserved in drosophila, aplasia and mammals
The synapse is strengthened as the likelihood and quantity of presynaptic neurotransmitter release is increased AND there post-synaptic membrane is more responsive (more AMPA receptors)
NMDA-R dependence of LTP
Blocking of LTP in the hippocampus, for example with the NMDA-R antagonist D,L-AP5, can correlate with learning abilities
The first study to show a correlation between LTP inducibility and learning abilities in animals
and showed that blocking LTP in the dentate gyrus using a blocker of NMDA receptors also impaired
learning of a spatial water maze task (Morris et al, 1986)
Caveats with study
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
Selective knockout of NMDA receptor in CA1 subfield impairs memory and LTP
Genetic mouse model with NMDA receptor subunit (Grin1) knockout in CA1
LTP not induced in CA1 by HFS
LTP is induced in the dentate gyrus subfield
Morris water maze performance impaired during the “probe trial”
Early & Late Phase LTP
Phases of LTP: Induction (HFS) > Expression (early LTP) > Stabilisation (late LTP)
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 changes in gene transcription (CREB pathway)
Requires protein synthesis (inhibited by anisomycin)
Involves growth of new synaptic connections between neurons
Long-term memory results in structural alterations in the brain that have similarities to Late LTP
Treatment of animals with protein synthesis blockers (e.g. anisomycin) will prevent long term memory formation
Long-term memory is dependent on gene expression and protein synthesis
Changes in the neuronal anatomy become visible (e.g. increased dendritic connections and synapse size and numbers) with prolonged learning
