Lectures 7-9 Flashcards
What is an engram, plus what are two other names for it?
It’s a neural substrate for learning and memory; it’s the idea that something is engraved on an irritable substance (physical representations neurologically of memory).
AKA Memory trace and cell assembly.
How/where is the engram stored in STM?
Persistent activity in the prefrontal and other cortical areas, sometimes called the “working memory buffer”.
How/where is the engram stored in STM -> LTM transition?
Conversion of persistent activity into a latent memory trace by the hippocampal formation.
How/where is the engram stored in LTM?
Consolidated and redistributed across the neocortex, and so is eventually no longer dependent upon the hippocampus.
What is the neocortex and how does it differ from the cerebral cortex?
The neocortex is a part of the cerebral cortex involved in higher-order functions like sensory perception and cognition.
It includes areas such as the frontal, parietal, temporal, and occipital lobes.
The cerebral cortex also includes the allocortex, which has fewer layers and is involved in functions like olfaction and memory.
Explain the model of ‘reverberatory transient trace’ and how it creates a latent engram.
Learning and memory involves an experience that generates neural activity.
This activity reverberates around the components of the CNS which will eventually modify the specific elements of it.
This results in a latent representation being ‘laid down’ so that activation of one component of it elicits the reexperience of that engram.
What did Hebb propose about how memory and cognitive functions are represented in the brain?
Hebb proposed that memory and cognitive functions are represented by “cell assemblies”, which are networks of neurons in the cortex and diencephalon.
These assemblies act as closed systems, with distant neurons recruited during signal processing to support cognitive functions.
Outline the Hampson et al. (2004) into monkey working memory DMTS task.
METHODS:
- Monkeys were put in front of computer displays and trained on a DMTS task.
- Their objective was to shift their gaze to the sample after a delay.
- Recorded from the CA1 and CA3 regions of the hippocampus during the different phases.
RESULTS:
- Found heightened activity in the delay phase, suggesting that there must be some type of cell assembly maintaining the information about the sample to remember it.
Name 3 areas of the brain outside the hippocampus that have been shown to be associated with working memory in DMTS tasks.
Prefrontal cortex, Motor cortex, Entorhinal cortex.
They have subsets of neurons that fired during the ‘delay phase’ of DMTS, suggesting they ‘store’ information or a representation in that brain area.
How does the prefrontal cortex (PFC) function during working memory tasks?
PFC neurons maintain information about spatial or object cues during delay periods.
This persistent cortical activity is a feature of short-term memory, representing stored information about sensory stimuli, intended actions, or items recalled from long-term memory.
Draw the basal ganglia-thalamocortical loop
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What role do positive feedback loops play in persistent brain activity (WM)? Give an example
Positive feedback loops, such as basal ganglia-thalamocortical loops, help maintain activity by passing cortical output through subcortical loops, which is then fed back out the thalamus via excitatory connections, sustaining network activity.
In working memory, how do local recurrent excitatory cortical networks contribute to persistent activity?
These networks maintain activity through reciprocal loops between cortical areas, allowing for continuous reverberation of signals, which supports sustained neural activity.
How do neurons in the entorhinal cortex (EC) maintain graded stability of membrane potential?
In EC layer V, neurons use a combination of membrane ion channels to modulate sustained firing rates through excitatory or inhibitory inputs.
Small depolarisations activate calcium channels, leading to non-specific cation channel activation and increased Ca²⁺ influx.
This keeps the Ica open, maintaining positive feedback.
Brief hyperpolarisation reduces Ica and Ican contributions.
The properties of neurons, not just circuitry, support sustained activity.
Muscarinic ACh receptors modulate Ican, with ACh release enhancing this mechanism, crucial for memory modulation.
What is the relevance to memory of graded stability of membrane potential in neurons?
Graded stability of membrane potential allows neurons to maintain persistent activity, crucial for functions like working memory.
It enables neurons to respond to varying inputs by stabilising their firing rates, supporting sustained information processing and storage.
What is Ican in the context of neuronal activity?
Ican refers to the calcium-activated non-specific cation current. It plays a role in maintaining sustained neuronal activity by allowing calcium influx, which supports positive feedback loops and stabilises membrane potential, crucial for processes like working memory.
How does neuropharmacology affect persistent cortical activity in delayed reaching tasks?
In delayed reaching tasks, persistent cortical activity is crucial for working memory.
NMDA receptors play a key role; blocking them with an antagonist like APV (now called DAP5) disrupts this activity.
In contrast, blocking AMPA receptors with CNQX has less impact, highlighting the importance of NMDA receptor activation in sustaining persistent activity.
What is APV more commonly called today?
DAP5
What role do NMDA receptors play in persistent cortical activity of working memory?
NMDA receptors have slow kinetics and little desensitisation, allowing stable, long-lasting depolarisation during synaptic activation, crucial for maintaining persistent cortical activity.
How do D1 receptors interact with NMDA receptors to affect cortical activity?
D1 receptor activation upregulates NMDA receptor function and trafficking to PSD, enhancing persistent network activity.
This synergy supports “up states” - periods of persistent neural activity - in cortical pyramidal cells, important for working memory.
What does PSD refer to in the context of NMDA receptor function?
PSD stands for “postsynaptic density,” a protein-dense region at the postsynaptic membrane.
It plays a crucial role in synaptic signalling and receptor trafficking, including NMDA receptors, which are important for synaptic plasticity and memory.
What is the effect of combining NMDA and D1 receptor antagonists on working memory?
Combining NMDA and D1 receptor antagonists, which are ineffective alone, can lead to significant deficits in working memory tasks, indicating their synergistic role in cognitive processes.
What has been shown about the use of NMDA-R antagonists in humans working memory?
They inhibit working memory.
What has been shown about short-term D1 activation in aged primates?
It improves working memory.
Define cell assemblies.
A diffuse structure comprising cells in the cortex and diencephalon (and also in the basal ganglia of the cerebrum), capable of acting briefly as a closed system.
What is a memory represented by?
A subset of pyramidal neurons firing in synchrony.
Define a neural network.
Either a subset of biological cells/neurons in the brain or a mathematical model.
What is Kenneth Harris’ definition of cell assemblies
An anatomically dispersed set of neurons among which excitatory connections have been potentiated.
Describe a ‘cell assembly’ in a neural net.
It’s an array of activation patterns across nodes that store some sort of representation.
What is the binding problem?
How are different small aspects or features linked together or integrated in a larger internal representation or perception in the correct way (memory).
What do EEG waves result from?
They are the result of neural network oscillations - theta and gamma - orchestrating the timing of synchronous neuronal activity across networks.
Outline the Buzsaki & Wang (2012) multi-site rat CA1 recording into the organisation of neuronal firing.
METHODS:
- Used a multi-site recording from rat CA1 in hippocampus.
- Recorded the from the rats during spatial exploration.
- Stacked raster plots of the repeated and synchronous (action potential) firing by cell assembly subpopulations.
RESULTS:
* Pyramidal neurons fire (AP) at the falling phase of the 4–12 Hz theta cycle (the troughs). This phase-locking implies that their activity is closely tied to the rhythm of the hippocampal oscillations.
* Within cell assemblies, spikes appear roughly every 23–25 ms, aligning with midrange gamma frequencies. This suggests that neurons not only synchronise with theta but also organise their firing at a faster timing rate, likely optimising communication.
* Together, these patterns indicate that during spatial exploration, the hippocampus coordinates neuron firing in a highly structured, multi-frequency manner, which may be essential for processing and encoding spatial information.
What are the two types of hippocampal CA1 gamma found in freely moving awake rats?
CA3 Schaffer input -> CA1 slow < 60hz
Entorhinal Cortex perforant pathway Input -> CA1 fast > 60hz
What is EC PP input?
- The entorhinal cortex (EC) is a major cortical region that acts as an interface between the neocortex and the hippocampus.
- The perforant path (PP) is the primary fibre pathway through which the EC sends information into the hippocampus, particularly to regions like CA1.
- This input carries sensory and contextual information from the outside world into the hippocampus, and it’s associated with fast gamma rhythms (>60 Hz).
- In essence, the EC PP input helps the hippocampus integrate external cues and sensory experiences with existing memory networks.
What does the discovery of two types of hippocampal CA1 gamma in freely moving awake rats suggest?
These findings indicate that there are two distinct gamma frequency bands in CA1, each associated with a different source of input:
- Slow gamma (<60 Hz):
This rhythm is driven by inputs from the CA3 region through the Schaffer collaterals. It is thought to support memory retrieval and internal processing by synchronizing activity between CA3 and CA1. - Fast gamma (>60 Hz):
This faster rhythm comes from the entorhinal cortex via the perforant path. It likely plays a role in bringing in current sensory information and linking it with stored memories.
In summary, the dual gamma rhythms suggest that CA1 is simultaneously integrating internal memory signals with external sensory inputs, each at its own frequency range.
How does the timing of gamma cycles within theta phases related to encoding and recall in rodent hippocampus?
During the descending phase of theta, slower gamma rhythms indicate CA3 input to CA1, which is associated with recalling stored information.
At the theta trough, faster gamma reflects entorhinal cortex input and encoding of new information. This rapid switching between encoding and recall (multiplexing) allows the hippocampus to update current experiences while retrieving past memories.
What is multiplexing?
By rapidly switching between slow gamma (associated with the descending phase of theta, where stored information is recalled via CA3) and fast gamma (associated with the trough phase, where new sensory information from the entorhinal cortex is encoded), the hippocampus can effectively manage both updating current information and retrieving past memories simultaneously.
Why are multiplexing and routing important in hippocampal function?
They segregate CA3 and entorhinal cortex inputs by aligning recall (slow gamma during the descending theta phase) with new encoding (fast gamma during the theta trough).
This separation prevents interference between old and new associations, ensuring accurate memory processing and updating.
What does “routing” mean in the context of hippocampal function?
Routing is the selective directing of neural inputs in the hippocampus, separating CA3 (stored memory) and entorhinal cortex (new input) signals, so that each is processed in its appropriate channel.
This segregation prevents interference between recalling old information and encoding new associations, maintaining effective memory processing.
How do gamma oscillations contribute to memory sequencing in the brain?
Gamma cycles (30-80 Hz) represent different features of a memory.
Each cycle encodes a specific aspect, allowing precise timing of pyramidal neuron firing through fast membrane potential depolarisation over 10-30ms time scale, crucial for memory representation.
What role do theta cycles play in organising memories?
Theta cycles (4-10 Hz) act as a carrier wave, organizing information about time or place.
They synchronise activity across the hippocampus and cortex, enabling the ordering of memories.
How do gamma and theta cycles work together in memory encoding?
Gamma cycles encode individual memory features within a theta cycle.
The sequence of gamma cycles across theta cycles represents the spatiotemporal relationship of memory components.
What is the significance of sequencing in cortical activity for memory?
Sequencing allows the brain to encode and understand the order of experiences.
It orchestrates the timing of sequences representing spatiotemporal relationships in episodic/spatial memory.
What are the two key oscillations observed in vivo in rats and their significance?
Gamma Oscillations (40-150 Hz): Found in the dentate gyrus during awake exploration, linked to active information processing.
Sharp Wave Ripples (150-250 Hz): Occur in the CA1 region during slow-wave sleep, associated with memory consolidation.
How are theta, gamma and sharp wave ripples modelled in vitro and why?
Theta Oscillations: Modelled to study their role in organizing neural activity.
Gamma Oscillations: Simulated to explore mechanisms and functions in neural processing.
Sharp Wave Ripples: Modelled to understand their role in memory processes and neural communication.
What is the issue with studying the brain in situ?
It’s not very available to modification.
How can gamma activity be modelled in brain slices?
Gamma activity can be modelled by applying a muscarinic agonist like carbachol, which generates voltage deflections in the gamma range.
This allows for the study of receptor contributions to gamma activity.
What happens when different receptors are blocked in gamma activity studies?
Blocking mGluR and NMDA receptors interferes with gamma cycles.
Blocking AMPA and KA receptors causes gamma waves to disappear.
Using Bicuculline (GABA-A antagonist) also eliminates gamma events.
How do kainic acid and KA receptor antagonists affect gamma oscillations?
Kainic acid can model gamma oscillations, showing similar profiles with no NMDA or mGluR involvement.
Broad KA receptor antagonists block gamma waves, as do GABA-B receptor blockers.
What role do interneurons play in gamma oscillations?
Interneurons, targeting the perisomatic region of pyramidal cells, provide timing for gamma cycles.
They create a 23ms interval (50 Hz) through inhibition, coordinating sparse firing of pyramidal cells.
What does the study of theta oscillations in the intact rat hippocampus reveal about CA1 area interactions?
The study focuses on the CA1 area, highlighting:
- Low-frequency fluctuations in membrane potential.
Interaction between interneurons (INs) and pyramidal (PYR) cells, where timing of firing generates IPSPs in PYR cells. - OLM neurons produce long-duration IPSPs, regulating PYR cell membrane potential over time.
- Self-generated theta oscillations are atropine-resistant and bicuculline-sensitive, indicating specific receptor involvement.
What role do OLM neurons play in regulating pyramidal cell activity?
OLM neurons, located in the aureans and projecting to the lacunosa moleculari, produce long-duration IPSPs, regulating pyramidal cell membrane potential and contributing to cortical network function.
What are OLM neurons, what do they stand for and where are they located?
Oriens-lacunosum moleculare interneurons, are inhibitory interneurons found in the hippocampus.
They are located in the stratum oriens and project to the stratum lacunosum-moleculare.
Summarise the role of gamma oscillations in the hippocampus.
Gamma oscillations in the hippocampus synchronise the precise timing of pyramidal neuron firing, enabling the formation of coherent cell assemblies that represent specific memories.
This synchronisation facilitates the integration of diverse memory features, effectively addressing the ‘binding problem’ and ensuring cohesive memory representation.
Summarise the role of theta oscillations in the hippocampus.
Theta cycles organise the relatedness of multiple memory representations (gamma cycles).
What do both gamma and theta rely on to ensure proper timing within the hippocampus?
They depend on local feedback, GABAergic inhibition and rhythmic IPSP input.
What are some extrinsic drivers of theta rhythm in the hippocampus?
What types of input are they?
Entorhinal Cortex - Glutamatergic input
Medial Septal Nucleus (MSn) and diagonal band of Broca (DBB) - both are a mix of GABAergic and cholinergic.
How did Hebb suggest that changes in cell assemblies occurred/what was required?
When a presynaptic cell is firing and it’s eliciting post synaptic activation of a target neuron, and that neuron is able to fire itself, there is modification of synaptic strength between the two.
What does simultaneous presynaptic input that don’t elicit AP’s illustrate about synaptic activity and Hebbian learning?
Simultaneous inputs generate EPSPs that spatially sum but remain subthreshold, not triggering an action potential.
This highlights initial connectivity efficiency without synaptic change, aligning with Hebbian principles that require sustained, coincident activity for synaptic strengthening.
How does sustained presynaptic activity that elicits AP’s affect synaptic efficiency and Hebbian learning?
Persistent activity in all inputs leads to spatial and temporal summation, causing sustained postsynaptic firing.
This meets Hebb’s criteria for synaptic modification, increasing synaptic efficiency over time through metabolic or biochemical changes.
What happens to synaptic efficiency following sustained activity, and how does it relate to LTP?
Sustained activity increases synaptic efficiency, making EPSPs larger and more likely to reach the firing threshold.
This enhances the likelihood of reactivating the cell assembly, aligning with Hebb’s prediction of long-term potentiation (LTP), which strengthens synaptic connections.
What is Hebb’s rule?
It is inputs that fire together, wire together but it requires both the presynaptic and postsynaptic neurons to be generating action potentials.
Non-active inputs do not undergo this change in efficiency.
What does Hebb’s rule allow for?
Selective association between presynaptic inputs that take part in sustained co-activation of the post-synaptic neuron through a selective increase in their synaptic efficiency.
What are simple neural nets called, what is the simple rule that governs them and what is an example of their use?
Auto-associative Neural Nets.
All of the nodes int the network are weak but when they are coactivated the connections are strengthened in a similar style of LTP.
This forms a engram/representation in that neural network.
Very good for image recognition software.
What is the hippocampus broadly involved in?
The forming of spatial/episodic memory, the association between events and place.
What does surgical lesions/strokes affecting the hippocampus tend to do?
Not to affect remote long-term memories but they DO prevent short-term to long-term memory consolidation of new memories (anterograde amnesia).
What role does the hippocampus play in rats’ spatial memory?
How do lesions impair this?
The hippocampus is crucial for early consolidation of spatial/episodic memories.
Lesions impair learning up to 12 weeks after the task, but memory is likely consolidated in the neocortex afterward
Draw a picture of the trisynaptic circuit in rodent hippocampus.
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What are the three main glutamatergic pathways in the rodent hippocampus? Are they excitatory or inhibitory?
Perforant path fibre:
- perforant fibres -> dentate granule cells
Mossy fibre:
- dentate granule cells -> CA3 pyramidal cells
Schaffer collateral:
- CA3 pyramidal cells -> CA1 pyramidal cells
They are excitatory
Outline a BASELINE experimental design of LTP at CA3->CA1 synapses.
METHODS:
- Extra and or/intracellular recording from CA1 pyramidal neurone.
- CONTROL BASELINE: Record synaptic responses to low frequency Schaffer collateral stimulation (LFS) <0.1Hz
- Stimulate Schaffer collateral pathway at 100hz for 1s - high frequency stimulus (HFS)
- Return to LFS to check post HFS responsiveness.
RESULTS:
- 30 mins post HFS, you see persistent modification due to the HF inducing changes.
- You see an augmentation of the size of the field EPSP, thus showing changes in synaptic weight or strength.
**(You measure the initial rising phase of those events because you get complex behaviour later on, presumably because a number of contributing cells are firing action potentials which distorts the waveforms. Thus safest thing to do is measure that initial rising phase - represents the subthreshold rising phase of the underlying EPSP).
Outline a Frequency TRAIN experimental design of LTP at CA3->CA1 synapses and what it shows about biochemical and structural changes at synapses.
METHODS:
- High-frequency stimulation (HFS) at 100Hz for 1 second.
- Either a single train or four trains repeated every 5 minutes.
RESULTS:
- Initial PTP/STP lasts ~10 minutes.
- Single train: Early LTP lasts ~1 hour, then decays to baseline - likely showing local biochemical modification of synaptic strength.
- Four trains: Early and late LTP can last up to 24 hours - suggests other processes have kicked in to support that level of potentiation.
- Increased repetition enhances enduring changes.
What is Theta Burst Stimulation (TBS) in the context of CA3→CA1 LTP?
METHODS:
- 5-Hz burst frequency
- 10 bursts per train
- 3 trains with 20-second intertrain intervals
RESULTS:
- Fewer stimuli, more physiological compared to 100Hz HFS
- Very effective at inducing LTP
Why is TBS considered more physiologically accurate for inducing LTP?
Mimics theta oscillation patterns
Fewer stimuli with a distinct pattern
More effective at inducing synaptic changes compared to extreme conditions like 100Hz HFS
What are the effects of low-frequency stimulation on synaptic strength in CA3→CA1 LTD?
Causes a reduction in synaptic strength
Almost instantaneous modification
Relatively enduring decrease in strength
Input specific and homosynaptic effects
What is the LFS induction protocol for CA3→CA1 LTD and what are the effects?
METHODS:
- 1Hz stimulation for 15 minutes (900 stimuli)
- Low-frequency stimulation (LFS)
RESULTS:
- Decrease in synaptic strength
- Sustained depression to 70-80% of control level for over 60 minutes
What is induction of CA3→CA1 LTP/LTD dependent on occurring postsynaptically? (3)
What can block each of these?
- NMDA Receptor Activation
- Blocked with APV/AP5 - Postsynaptic Rise in Intracellular Ca2+
- Block with intracellular injection of Ca2+ chelator EFTA. - Postsynaptic Depolarisation
- Blocked by direct injection of negative current to hyperpolarised membrane potential and prevent depolarisation during induction stimulation.
What does Ca2+ chelator EGTA do?
Binds/chelates calcium ions, sequestering them and preventing them from participating in cellular processes.
This stops Ca2+ entering and effecting the postsynaptic neuron (no APs).
What is one of the key features of LTD and LTP at CA3→CA1 synapses?
It’s that they have the same principle induction method.
How does frequency affect CA3→CA1 LTP and LTD induction?
Frequencies >10Hz lead to LTP.
Frequencies <10Hz lead to LTD.
Threshold level of postsynaptic activation is required for LTP; otherwise, LTD occurs.
What role does calcium play in CA3→CA1 LTP and LTD?
Both LTP and LTD are NMDA-dependent and blocked by AP5.
Require depolarization and Ca²⁺ entry.
The size of postsynaptic Ca²⁺ entry, generated by presynaptic activity, may determine plasticity changes.
What is the role of Ser831 phosphorylation in CA3→CA1 LTP?
Phosphorylation of the GluR1 subunit of the AMPA receptor at Ser831.
Increases conductance of AMPA receptor ion channels.
Enhances current flow and EPSC amplitude.
How do protein kinases affect LTP at the GluR1 subunit?
LTP is blocked by protein kinase inhibitors (PKC/CaMKII).
High-frequency stimulation increases intracellular calcium.
Activates kinases that phosphorylate Ser831 on the GluR1 subunit.
Modifies AMPA receptor conductance, generating larger EPSPs.
Draw the three steps of AMPA receptor trafficking - insertion/PSD translocation.
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What role does Ser845 phosphorylation play in AMPA receptor trafficking?
Ser845 phosphorylation is crucial for AMPA receptor insertion into the plasma membrane.
Primes receptors for translocation into the postsynaptic density (PSD).
What is PSD?
Post-Synaptic Density
How does AMPA receptor trafficking affect synaptic strength?
Translocation of AMPA receptors into the PSD increases postsynaptic sensitivity.
Leads to increased macroscopic conductance and larger EPSPs.
Supported by phosphorylation at Ser831 for PSD translocation.
How do PKC and CaMKII influence AMPA receptor trafficking?
PKC and CaMKII phosphorylate GluR1 subunits at Ser831 and Ser845.
Activation occurs through increased intracellular calcium from high-frequency stimulation.
This phosphorylation supports receptor insertion and translocation, enhancing synaptic strength.
What happens approximately 15 minutes after LTP induction regarding AMPA receptors?
AMPA receptors translocate into the PSD from extrasynaptic pools.
This process increases macroscopic conductance and synaptic efficacy.
Dependent on phosphorylation status of GluR1 subunit:
- S845P: Insertion into plasma membrane - primed
- S831P: translocation into PSD - potentiated
How does the phosphorylation status of the GluR1 subunit affect AMPA receptor function?
S845P: Facilitates insertion into the plasma membrane, priming receptors.
S831P: Supports translocation into the PSD, potentiating synaptic response.
How does dephosphorylation of GluR1 subunit of AMPA receptor affect postsynaptic responsiveness?
Dephosphorylation reduces postsynaptic responsiveness.
Can be demonstrated with inhibitors of PP1/PP2A or calcineurin (FK506) which prevent LTD induction.
Associated with removal of phosphate from Ser845.
What is the role of Ser845 dephosphorylation in LTD?
Low-frequency stimulation activates protein phosphatases.
Leads to dephosphorylation of Ser845, supporting LTD.
Triggers endocytosis and removal of AMPA receptors from the membrane.
What are the effects of Ser845 dephosphorylation on AMPA receptors?
Decreases open time probability, keeping channels closed longer.
Initiates retrieval of AMPA receptors via endocytosis.
Reverses priming and insertion of AMPA receptors at synapses.
What is the effect of LFS at CA3->CA1 synapses?
LFS seems to trigger pathways that activate protein phosphatases and result in a loss of phosphate from S845 which seems to support LTD.
Has two effects:
- Decreased open time probability
- Initiates retrieval of AMPAR from synaptic membrane by endocytosis (reverse of priming insertion).
How does low intracellular calcium affect phosphatase activation in synaptic plasticity?
Low Ca²⁺ Levels (<1µM):
- Calcium binds to calmodulin, activating calcineurin (PP2B).
- Calcineurin dephosphorylates Inhibitor 1, releasing PP1.
- Active PP1 leads to dephosphorylation of AMPA receptors, promoting LTD.
- Dephosphorylation of Ser845 on GluR1 subunit reduces AMPA - receptor insertion and open time probability.
What is the effect of high intracellular calcium on kinase activation in synaptic plasticity?
High Ca²⁺ Levels (>5µM):
- Calcium binds to calmodulin, activating adenylate cyclase.
- Adenylate cyclase increases cAMP, activating PKA.
- PKA phosphorylates Inhibitor 1, sequestering PP1 and reducing its activity.
- High Ca²⁺ also activates CaMKII and PKC.
- CaMKII and PKC phosphorylate AMPA receptors, particularly at Ser831, enhancing conductance and promoting LTP.
How does calmodulin mediate differential activation of kinases and phosphatases?
Binds calcium, with affinity varying based on Ca²⁺ concentration.
Low Ca²⁺: Activates calcineurin, leading to phosphatase activity and LTD.
High Ca²⁺: Activates adenylate cyclase, increasing cAMP and activating PKA.
PKA activity leads to phosphorylation of Inhibitor 1, inhibiting PP1 and promoting kinase activity.
High Ca²⁺ also activates CaMKII and PKC, shifting balance towards LTP by phosphorylating AMPA receptors.
What is an EPSC
An EPSC, or excitatory postsynaptic current, is the electrical current that flows into a postsynaptic neuron when it receives an excitatory signal from a presynaptic neuron.
This current is typically generated by the opening of ion channels, such as AMPA or NMDA receptors, in response to neurotransmitter release (like glutamate) from the presynaptic neuron.
EPSCs contribute to the depolarisation of the postsynaptic membrane, potentially leading to an action potential if the depolarisation is sufficient.
According to the bidirectional model of AMPA-R phosphorylation status, what occurs due to low/high Ca2+?
Low [Ca2+] -> Increased dephosphorylation of CaMKII and AMPA receptors.
High [Ca2+] -> Increased phosphorylation of CaMKII and AMPA receptors.
What does [Ca2+] denote?
The concentration of calcium ions in a solution, typically expressed in units like moles per litre.
It indicates how much calcium is present in a given volume.
What are the two phosphorylation sites on the AMPA receptor GluR1 subunit that determine the state of the macroscopic conductance?
Ser831 and Ser845
Draw the Bidirectional Model of AMPA-R phosphorylation status in relation to macroscopic conductance.
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Outline what the Bidirectional Model of AMPA-R phosphorylation status shows us.
High-Frequency Stimulation (HFS):
-Drives equilibrium towards a doubly phosphorylated state of AMPA receptors.
- Results in increased insertion into the plasma membrane at the postsynaptic density.
- Enhances receptor conductance, promoting synaptic strength and LTP.
Low-Frequency Stimulation:
- Shifts equilibrium towards dephosphorylation.
- Leads to retrieval of AMPA receptors from the membrane.
- Reduces receptor function and synaptic strength, supporting LTD.
How is genomic involvement crucial for late-phase LTP?
Late LTP requires new protein synthesis and mRNA expression.
Inhibitors like Anisomycin (translational) and Actinomycin D (transcriptional) block late LTP.
In Aplysia, inhibiting translation or transcription prevents late LTP, showing genome-targeted events are essential.
Involves gene expression and new protein synthesis, similar to sensitisation in Aplysia.
What role does high-frequency stimulation (HFS) trains play in late-phase LTP?
Single or four trains of HFS generate late and longer-lasting LTP.
Four trains lead to sustained late-phase LTP.
Blocking PKA with H89 removes the sustained late phase, indicating the response has gone back to biochemical changes only.
What do blockers of Late stage CA3->CA1 LTP show?
H89, a selective PKA inhibitor:
- PKA is involved via increased cAMP
Anisomycin, a translational inhibitor:
- New proteins are involved
Actinomycin D, a transcriptional inhibitor:
- New mRNA involved
How does cAMP influence synaptic plasticity and gene expression in late stage CA3->CA1 LTP?
cAMP activates protein kinase A (PKA), which phosphorylates the CREB protein.
This leads to the transcription of immediate early genes (IEGs) that regulate late response genes (LRGs), essential for long-term synaptic changes.
What are the key outcomes of CREB activation in CA3->CA1 synaptic plasticity?
CREB activation results in the transcription of genes that encode proteins like ion channels and receptors, supporting synaptogenesis and long-term synaptic changes, crucial for learning and memory.
Describe the process in Late stage CA3->CA1 LTP from CREB to Synaptogenesis.
CREB binding to CBP linked RNA polymerase II - starts transcription.
⬇️
New mRNA of IEGs:
transcription factors - c/EBP
effector proteins - BDNF
⬇️
New mRNA of LRGs (a.k.a. LEGs):
Ion channels, Receptors
Intracellular signalling proteins
Cytoskeletal proteins
Synaptic vesicle proteins
⬇️
New protein synthesis
⬇️
Long-term synaptic changes, Synaptogenesis
GLOSSARY:
CREB - cAMP response element-binding protein
CRE - cAMP response element DNA sequence
CBP - CREB binding protein
IEGs - Immediate early genes
C/EBP - CCAAT enhancer binding protein
LRGs - Late response genes
LEGs - Late effector genes
Draw the process in Late stage CA3->CA1 LTP from CREB to Synaptogenesis.
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What are the three relatively rapid postsynaptic changes that occur during the early phase of LTP/LTD (first two hours) at CA3->CA1 synapses?
What are they followed by?
- Phosphorylation/dephosphorylation of AMPA receptors.
- Insertion/removal of AMPA receptors.
- Increase/(decrease?) in the number of synaptic contacts. (*potentially local cytoskeletal changes driven by the kinases that can start the process of synapse building.)
These are followed by both presynaptic and postsynaptic re-modelling to reinforce these changes and help maintain the late phase of LTP/LTD - synaptogenesis/synaptic pruning.
What are some physiological/pathophysiological roles for LTD? Explain why.
Learning, development, stress-induced impairment of cognitive function.
There are paradigms where you want to reverse learnings to show learning is flexible and that learning doesn’t become too rigid.
LTD appears to play a role in dissociating the previous learnt behaviour.
Important in development in the loss of inappropriate synaptic connections.
*If it’s overrecruited it may modify the system that leads to pathology: Psychiatric disorders (depression and schizophrenia)
What did Richard Morris propose in 1989? Outline them.
He proposed five fundamental properties that an ideal memory mechanism should have.
- Be present in areas vital for memory
- Work quickly to encode memories
- Produce changes that last a long time (LTM)
- Exhibit specificity. Only those synapses that form the memory should be affected.
- Be associative.
How does LTP fit onto Richard Morris’s proposed memory mechanisms?
- Be present in areas vital for memory:
- Yes; seen in the hippocampus, cortex and amygdala etc. - Work quickly to encode memories
- Yes; induction <1 min - Produce changes that last a long time (LTM)
- Yes; can last for week in vivo. - Exhibit specificity. Only those synapses that form the memory should be affected.
- Yes; neighbouring unstimulated synapses are not potentiated - Be associative.
- Yes; occurs when multiple inputs drive postsynaptic activation.
Is LTP memory, support the reasoning for your answer.
NO, it’s NOT memory; LTP is a laboratory phenomenon that requires mass activation of neurons. Such activation is not seen during normal brain function (might be present in pathology).
The best hope is that LTP and memory share a common mechanism.
Give three examples of studies that have looked for links between LTP and memory.
Whether learning produces changes in synaptic efficacy similar to those seen after LTP (“behavioural LTP”)
Whether preventing LTP (e.g., with AP5 assuming it is NMDA-R dependent) prevents learning (which is does).
Whether inducing LTP occludes learning or vice versa.
Outline the Moser et al. (1998) study into EC->DG LTP and Morris water maze learning.
METHODS:
- Stimulated the entire EC input to DG to saturate LTP with HFS.
- Two controls: no stimulation/LFS, neither inducing LTP.
- then test MWM learning of location of hidden platform.
RESULTS:
- High freq stimulation so that there is less than 10% possible after stimulation, they tend to swim around the whole tank.
- Controls didn’t.
- Thus saturating a synapse using LTP, disrupts the ability of the rat to learn.
*Highest inhibition in LTP < 10% left to occur (so much had already happened that there was this limited amount left).
What is inhibitory avoidance (IA) training and give an example of how it works.
IA training is a single-trial learning experience where a subject learns to avoid a place associated with an unpleasant stimulus.
In a novel arena with two chambers, when a rat moves from a lit chamber to a dark one, it receives an electric shock.
After one trial, the rat learns to stay in the light chamber to avoid the shock.
How is synaptic strength in the CA1 region of the hippocampus affected by IA training?
IA training modifies synaptic strength in the CA1 region (GluR1 phosphorylation).
Electrophysiological recordings show that some excitatory postsynaptic potentials (EPSPs) increase, indicating that a plastic process has been initiated.
What does the electrophysiological evidence suggest about learning and LTP in IA training?
After IA training, there is less potential for further LTP when high-frequency stimulation (HFS) is applied.
This suggests that the learning mechanism involved in IA training is related to the induction of LTP, as the synaptic connections have already undergone plastic changes.
What is the relationship between LTP induced by IA training and synaptic potential for further LTP?
There is a negative correlation: the more LTP is induced by IA training, the less potential there is for those synaptic connections to show additional LTP.
This indicates that the initial LTP induction is part of the learning mechanism.
What is the experimental setup for studying inhibitory avoidance (IA) training in rats?
The setup involves a novel arena with two chambers: one illuminated and one dark.
Rats can move freely between them.
When a rat enters the dark chamber, it receives an electric shock through the floor.
This setup is used to study single-trial learning by recording synaptic changes in the dorsal CA1 region of the hippocampus using an electrode array.
What is the purpose of optogenetic stimulation in fear memory recall research?
Optogenetic stimulation is used to activate specific hippocampal engrams associated with fear memory recall by expressing channelrhodopsin in active neurons, allowing researchers to control neuronal activity with light.
How is the genetic construct for channelrhodopsin expression activated in neurons? (Fear recall research)
The construct contains a tetracycline-responsive element (TRE) linked to channelrhodopsin (ChR2). In the presence of doxycycline, the tetracycline transactivator (tTA) is inhibited, preventing ChR2 expression.
When doxycycline is absent, tTA activates the construct, leading to ChR2 expression in neurons that were active during training.
What role does the transcription factor c-fos play in neuronal activity?
c-fos is produced in neurons during high activity (action potentials).
Its expression triggers the activation of the genetic construct, allowing channelrhodopsin to be expressed in neurons that were active at that time.
Describe the experimental paradigm for testing fear memory recall using the genetic construct.
Mice are first exposed to Context A with doxycycline present, which inhibits channelrhodopsin expression.
They are then moved to Context B without doxycycline, allowing channelrhodopsin to be expressed in active neurons.
Finally, they are returned to Context A with doxycycline to assess how light activation can reactivate the labelled neurons.
What is the significance of channelrhodopsin in the context of memory recall?
Channelrhodopsin allows for optogenetic activation of specific neurons by shining light of the appropriate wavelength, enabling the reactivation of memory engrams associated with fear conditioning and facilitating the study of memory mechanisms.
What is the overall aim and findings of the optogenetic stimulation study on fear memory recall?
METHODS:
- Genetic Construct: A doxycycline-sensitive construct with a tetracycline-responsive element (TRE) linked to channelrhodopsin (ChR2) was injected into the dentate gyrus (DG) of c-fos-tTA mice.
- Activation Mechanism: Doxycycline inhibits the tetracycline transactivator (tTA), preventing ChR2 expression. In its absence, tTA activates the construct, leading to ChR2 expression in active neurons.
- Training Paradigm: Mice were first exposed to Context A with doxycycline, then to Context B without it, allowing ChR2 expression. They were later returned to Context A to assess memory recall.
- Optogenetic Activation: A fiber optic light guide delivered light to activate ChR2 in labeled neurons.
RESULTS:
-c-fos Expression: Increased neuronal activity during training elevated c-fos levels, confirming successful labeling of active neurons.
- Memory Recall: Light activation of ChR2-expressing neurons in Context A reactivated fear memories, demonstrating the ability to manipulate specific neuronal populations for memory studies.
The study shows the mechanisms of memory formation and recall, emphasising the role of specific circuits in fear conditioning.
How do rodents demonstrate fear learning and context association in new environments?
Rodents are initially fearful of new environments but can be habituated to them.
In a typical experiment, they are first habituated to a novel environment, then exposed to a noxious stimulus (e.g., an electric shock) to create an association between the environment and the negative experience.
When later presented with the same environment, they exhibit a freeze response, indicating learned fear.
Additionally, if rodents are habituated to one environment and then moved to a different one where they receive the noxious stimulus, they will show fear in the new environment.
However, when returned to the original habituated environment, they display no fear, demonstrating their ability to learn and differentiate between contexts based on previous experiences.
Outline the study on activity-dependent expression of engrams in rodent contextual fear conditioning.
METHODS:
- Habituation Phase: Rodents are placed in Context A with doxycycline present, inhibiting the expression of channelrhodopsin (ChR2-EYFP). This prevents the formation of any neuronal representation or engram in this environment, resulting in no labelling of neurons in the dentate gyrus.
- Exposure to Context B: After habituation, rodents are taken off doxycycline and introduced to a new environment, Context B. They recognise this context as novel and receive a foot shock, a noxious stimulus, to condition them to associate Context B with danger.
- Testing Phase: After fear conditioning in Context B, rodents are returned to Context A with doxycycline present, preventing further expression of channelrhodopsin. Researchers then attempt to reactivate the subset of neurons representing the latent engram formed during exposure to Context B.
RESULTS:
- Neuronal Labelling: After habituation in Context A, there is no labelling of neurons. However, after exposure to Context B, significant labelling of neurons occurs, which can persist for several days, indicating successful engram formation in the dentate gyrus.
- Contextual Influence: The presence of ChR2-EYFP-positive cells suggests that the engram can be formed regardless of whether the rodents received a foot shock. This indicates that the recognition of a new context alone can lead to engram formation, allowing the brain to link this context to specific behaviours, such as fear responses.
- Conclusion: The study demonstrates the mechanisms of contextual memory formation and recall in rodents, emphasizing the roles of novelty and negative experiences in establishing fear-related engrams.
What is the role of doxycycline in the study of engram expression?
Doxycycline inhibits the expression of channelrhodopsin (ChR2-EYFP), preventing the formation of neuronal representations or engrams in the environment during the habituation phase.
Outline the electrophysiology study into Aplysia pre and post conditioning.
METHODS:
- Three groups of animals were trained:
1. Paired (received CS followed by US)
2. Unpaired (received CS and US but with large CS-US interval).
3. US alone (received US only; used as a sensitisation control)
- They received 30 training trials with a 5 min interval and then tested with the CS alone.
RESULTS:
Paired group (CS-US):
- Pre-training: CS elicited small EPSPs with minimal gill withdrawal
- Post-training: Same CS produced significantly larger EPSPs, triggering action potentials in motor neurons
- Enhanced synaptic efficacy correlated with increased gill withdrawal response
Unpaired group (CS-US with large interval):
- No significant change in synaptic strength
- CS continued to elicit only small EPSPs comparable to pre-training levels
US-alone group (sensitization control):
- Tail shock exposure without proper CS pairing insufficient to produce associative enhancement
- Confirmed specificity of temporal CS-US pairing for synaptic plasticity
Conclusion: Effective conditioning requires precise CS-US temporal pairing, inducing synaptic strengthening that enables CS to trigger motor neuron APs
Define Induction
The process or action of bringing about or giving rise to something.
In the context of synaptic plasticity, it is the event or process that initiates the change in synaptic strength.
Define Habituation in Aplysia
The progressive loss of gill reflex responsiveness to repeated weak tactile stimulation - gently touch of the siphon (non-noxious)
What is Sensitisation in Aplysia
Enhancement of gill reflex responsiveness following strong stimulation - electrical shock to the tail (noxious).
What are Habituation and Sensitisation both examples of?
Non-associative learning; they’re simply stimulus-response.
You’re not associating a novel stimulus to an already unconditioned stimulus.
What type of learning does Aplysia show?
It’s more adaptation of reflexes as procedural learning is a higher cognitive function.
These are simple creatures hence not using complex skill learning.
What is the precise biochemical mechanism that explains the temporal requirements for effective classical conditioning in Aplysia? (Forward pairing)
Temporal asymmetry in adenylyl cyclase activation: presynaptic Ca²⁺ influx from the CS (siphon stroke) must precede 5-HT receptor activation from the US (tail shock) to optimally upregulate adenylate cyclase activity.
This sequence produces enhanced neurotransmitter release at sensory-motor neuron synapses beyond what occurs in sensitization alone. (Yovell & Abrams, 1992)
What is the molecular mechanism of forward conditioning in Aplysia, and why is it more effective than backward conditioning?
In forward conditioning (CS→US):
- Siphon stroke (CS) activates Ca²⁺ channels in sensory neuron presynaptic membrane
- Ca²⁺ influx activates calmodulin
- Activated calmodulin “primes” adenylyl cyclase
- When tail shock (US) follows (<0.5s later), 5-HT release activates G-protein (Gs)
- The primed adenylyl cyclase shows enhanced catalytic activity
- More cAMP is produced, activating PKA
- Results in significantly increased neurotransmitter release
In backward conditioning (US→CS):
- cAMP production occurs before Ca²⁺/calmodulin activation, preventing the synergistic enhancement of adenylyl cyclase activity.
- This produces only sensitization-level effects rather than the augmented response seen in forward conditioning.
What is the “presynaptic locus for induction” in Aplysia classical conditioning?
The presynaptic locus for induction refers to the sensory neuron’s presynaptic terminal where the molecular coincidence detection occurs during classical conditioning.
This involves:
- Adenylyl cyclase functioning as a molecular coincidence detector
- Ca²⁺/calmodulin (from CS) and G-protein activation (from US) converging on adenylyl cyclase
- The temporal order of these signals determines conditioning effectiveness
- When properly sequenced (CS→US), this mechanism produces enhanced neurotransmitter release beyond sensitization levels
What is the “binding problem” in cortical activity and how do neural oscillations help solve it?
The binding problem refers to how different small aspects/features are linked together or integrated into a larger internal representation/perception in the correct way.
Neural oscillations solve this through:
- Nested rhythms (gamma inside theta)
Synchronous firing of cell assemblies at specific phases of theta oscillations
- Action potentials clustered on troughs of theta waves
- This temporal organization allows the brain to encode when events occurred and their relationships
- Gamma oscillations (30-80Hz) coordinate local assemblies while theta provides the broader temporal framework
- This hierarchical timing mechanism enables accurate representation/recall of spatial and temporal memory dynamics
How do theta and gamma oscillations organise persistent cortical activity during spatial exploration and working memory tasks?
Cell assemblies fire synchronously at specific phases of theta rhythm (visible in raster plots)
Action potentials cluster on theta troughs (with ~23ms median timing)
Gamma oscillations (30-80Hz) manifest on different phases of theta rhythms
This creates a temporal coding system where:
- Spatial locations are represented by specific neuronal assemblies
- The timing of their activation is organised within theta cycles
- Gamma rhythms coordinate local processing
This organisation allows the brain to:
- Maintain persistent activity during delay phases (working memory)
- Distinguish between competing representations
- Encode/retrieve information in the correct temporal order
- Create coherent spatial-temporal representations during exploration
What is the role of pyramidal cells in generating gamma oscillations and how do they interact with interneurons?
Pyramidal cells fire sparsely as individual elements but collectively activate interneurons
Each interneuron forms contacts with multiple pyramidal neurons
Even sparse/intermittent firing of pyramidal neuron populations is sufficient to drive interneurons
Activated interneurons generate IPSPs that set the timing of gamma cycles
This creates a feedback loop where pyramidal cells initiate the rhythm and interneurons regulate it
Excessive synchronous firing of pyramidal neurons can disrupt this balance and cause pathological conditions
This pyramidal-interneuron circuit architecture enables precise temporal coordination while maintaining sparse coding
How does the CA1 region of the hippocampus generate self-sustained theta oscillations and what is the pharmacological profile of these oscillations?
CA1 explants naturally generate theta-like rhythms in vitro
- Pharmacological profile: atropine resistant, bicuculline sensitive (indicating GABA-A mediated inhibition is essential)
- Generated through interplay between pyramidal cells (P) and interneurons (IN)
Mechanism:
- Sparse firing of pyramidal cells recruits interneurons through convergent connectivity
- Activated interneurons generate rhythmic IPSPs that control membrane potential across all pyramidal cells
- Pyramidal cells and interneurons fire in alternating phases
- This creates a reciprocal feedback loop that sustains the oscillation
- The circuit involves basket cells (BC) and oriens lacunosum-moleculare (OLM) interneurons
What is the phase relationship between pyramidal cells, interneurons and local field potentials during hippocampal theta oscillations?
Pyramidal cells (PYR) show phase-specific firing patterns:
- Fire primarily during specific phases of theta (shown in spike probability histogram)
- Generate EPSPs in interneurons
- Their activity creates a “source” in the LFP at stratum pyramidale
Interneurons (INT) also show phase-locked firing:
- Fire at different phases than pyramidal cells
- Generate IPSPs in pyramidal cells
- Their inhibitory action creates a “sink” in the LFP
This creates a cyclical pattern where:
- Pyramidal cell firing → Interneuron activation → Widespread inhibition of pyramidal cells → Pyramidal cells recover and fire again
- The alternating excitation and inhibition generates the theta rhythm (~5-8 Hz)
- Different cell types are active at specific phases of the theta cycle
*LFP = Local Field Potential
