Lecture 7 Flashcards
What does working memory depend on?
Prefrontal cortex neural activity
Visual delayed match-to-sample working memory task
Show image > take away for seconds/minutes > show second image > press lever is recognise image for reward
During delay period, neurons persistently fire due to 2 mechanisms:
- Changes in PFC neuronal membrane properties e.g. CAN channels
- Communication alterations that promote recurrent firing
Long term memory formation involvement and where it is characterised
- Involves synaptic strengthening
- Effects most well characterised in hippocampus (has well defined neuronal connectivity)
- Synaptic plasticity has been defined using electrophysiology, drug challenges and genetic mouse models
Concept of synaptic plasticity
- Long term changes in synaptic plasticity lead to long term memory
- Communication between specific neurons leads to information storage
- Strength of synaptic connections between 2 neurons increases when pre and postsynaptic neuron fire in close proximity
- These alterations for cellular basis of memory, such as those generated using Pavlovian conditioning
- Long term potentiation = long lasting changes in synaptic strength generated by high frequency stimulation of presynaptic neuron.
Recording synaptic activity at hippocampus
Electrical stimulation of Schaffer collaterals activates CA1 pyramidal neurons in the hippocampus.
Synaptic response is measured as field potentials or action potentials in the CA1 region.
A larger postsynaptic response to the same stimulation intensity indicates synaptic potentiation (LTP).
A negative deflection in the field potential reflects depolarization of postsynaptic neurons.
After high-frequency stimulation, the synaptic response increases and remains elevated, confirming LTP induction.
Inducing LTP at excitatory synapses
- LTP depends on NMDA/AMPA receptors
- In basal synaptic conditions, NMDA receptors blocked my magnesium ions -> no cation influx through receptor
- Glutamate acts on AMPA receptors to depolarise post-synaptic cell, allowing sodium/potassium ions to enter
Triggering NMDA-R dependent LTP
Intracellular calcium ions stimulate intracellular signalling cascades
CREB signalling promotes generation of retrograde signalling molecules -> act on presynaptic bouton to release neurotransmitter
CAMKII promotes integration of AMPA receptors into dendritic membrane
Pathways conserved
What occurs when LTP is established
- Synapse strengthened
- Likelihood/quantity of presynaptic neurotransmitter release increased
- Post-synaptic membrane more responsive
D,L-AP5 in morris water maze
Slows acquisition in water maze
Rats take longer to find submerged platform
Due to blocked LTP, leading to blocked spatial memory formation
More LTP blocked in hippocampus in D,L-AP5 rats than L-AP5 and control rats
Caveats with D,L-AP5 study
- Animals learned task, but slowly
- Not all experiments showed correlation between LTP and learning/memory
- LTP in other brain areas could be involved
- non-NMDA receptor-dependent forms of LTP may be involved
- LTP induced artificially
Knockout experiment of NMDA receptor
Grin1 (NMDA receptor gene) knocked out
LTP not induced by CA1 by HFS
LTP induced in dentate gyrus subfield
Morris water maze performance impaired
Early vs late LTP
Early: 1-3 hrs
No protein synthesis or cAMP/PKA activation
Late: 2-24 hrs
- cAMP and PKA activated
- CREB gene transcription
- Protein synthesis
- Growth of new synaptic connections
Is LTP associative?
Yes
neuron has specific threshold for LTP induction
Stimulation of input 1 (C1) did not induce LTP
Lower frequency stimulation of C1 and C2 projections induced LTP
Mechanism of conditioning:
Puff of air to eye (US) -> signal to somatosensory neuron -> Synapse P (strong) -> blink
1000Hz tone -> signal to auditory neuron -> Synapse T (weak) -> blink
Long term depression
No synaptic enhancement -> no further synaptic plasticity/learning
Brain has mechanisms to attenuate synaptic efficacy
Requires MNDA-R activity but mechanism are different
LTD mechanism
- Low frequency stimulation -> post-synaptic depolarisation
- NMDA-R Mg2+ block less effective
- Less Ca2+ enters post synaptic neuron
- CAMKII not activated, Calcineurin activated
- Phosphatases activated + AMPA receptor removed by PKC
- Post synaptic excitatory post-synaptic potential reduced
LTD disassociation
LTD may be involved in behavioural flexibility as transgenic mice with impaired LTD but not LTP fail to learn new locations in Morris water maze
Input from independent sources that arrives at same time activates target neuron and increases synaptic activity
Input that doesn’t arrive at same time leads to LTD
Learning and integration of newly born neurons
- New neurons born in dentate gyrus of hippocampus (1,400 a day)
- Mature and become integrated into networks
- High sensitivity to LTP
- Neurogenesis correlates with L+M
- genetic ablation of neurogenesis impairs morris water maze task
- Deficient neurogenesis implicated in many disorders e.g. schizophrenia
Memory consolidation
- Temporary memory -> long-lasting memory
- New memories stored in hippocampus and neural networks of neocortex
- Hippocampus guides reorganisation of info in neocortex so becomes permanently stored and seperate from hippocampus
- Depends on neural replay during sleep
- Involves integration of new info into cortical networks
Novel object recognition test
Mice prefer to explore novel objects in environment
Novel object exploration indicates learning and memory
More exploration = more memory of familiar object
Cav1.2 hypofunction
Voltage gated Ca2+ channel
Mutations in Cacna1c increase risk of schizophrenia which lead to learning and memory deficits
Mice with Cav1.2 hypofunction have NOR deficit at 24hrs but not after 1hr of acquisition
Mice have acquired memory and retrieve at 1 hour, but by 24hrs it’s gone - deficit in memory consolidation
Cav1.2 Khypo mice have reduced hippocampal activity and lose connectivity to cortical regions
