Hippocampal memory + LTP

Why look for plasticity in the hippocampus? (hint: HM)

Lesions in Henry Molaison’s brain

è Epilepsy lesions tend to be in medial temporal lobe, causing amnesia

Medial temporal lobe structures (5)

-       Hippocampus

-       Entorhinal cortex

-       Rhinal sulcus

-       Perirhinal cortex

-       Parahippocampal cortex

Retrograde amnesia

Retrograde amnesia – loss of info prior to brain injury in slope decreasing

Anterograde amnesia

Anterograde  amnesia – unable to form any memory from injury onwards, immediately

Hippocampal lesions impair memory in rodents

If one rodent eats bad food, will socially transmit to others if a food is good or bad (olfactory cues) so next rodent will not eat bad food

With HPC lesions, % of freezing is lower, forget about preference sooner

Hippocampal circuitry

Hippocampus: Modulatory input -> associational/commissural fibers -> mossy fibers (dentate gyrus) + schaffer collaterals ->

Entorhinal cortex: -> here (very regimented distribution of neurons in single layer) -> perforant path to dentate gyrus ->

Hippocampus: -> here -> perforant path to CA1

-       Simple lamination allows differentiation of synaptic potentials + APs in the hippocampus

What is Hebbian synaptic plasticity?

Hebbian synapses (Donald Hebb)

-       Synaptic plasticity allows changes in post synaptic without pre synaptic

-       Synapse can serve as storage unit to increase storage capacity

-       ‘when an axon of cell A is near enough to excite a cell B + repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that the efficiency of A, as one of the cells firing B, is increased’

Criteria for a physiological implementation of Hebbian plasticity: 5 names only

1. activity-dependence

2. inout specificity

3. cooperativity

4. associativity

5. longevity

Criteria for a physiological implementation of Hebbian plasticity: Activity-dependence

1.    Activity-dependence: modification of synapses requires co-activity between pre + post synaptic neurons (synapse strengthened only when pre-activity contribute to post, need a strong enough pre-activation needs to cause post)

Criteria for a physiological implementation of Hebbian plasticity: Input specificity

2.    Input specificity: only inputs co-active with the post-synaptic cell will undergo modification (change in synaptic strength)

Criteria for a physiological implementation of Hebbian plasticity: Cooperativity

3.    Cooperativity: multiple inputs are required to drive plasticity inducing post-synaptic depolarization

è Most chemical synapses are weak + unlikely to causse effect in post synaptic

è Need lots of inputs active together to cross threshold

Criteria for a physiological implementation of Hebbian plasticity: Associativity

4.    Associativity: weak inputs that are unable to depolarize the post-synaptic neuron sufficient to induce change will nonetheless undergo change (like classical conditioning) if paired with strong depolarizing inputs

Criteria for a physiological implementation of Hebbian plasticity: Longevity

5.    Longevity: the mechanism of change should last for a sufficient period to underlie memory, which can last a lifetime

Intraceullar recording (definition, + precision, method, information obtained, pros + cons)

1.    Intracellular: measures electrical activity from inside a single neuron, providing detailed data on membrane potentials and subthreshold events.

a.    Precise but difficult

b.   Method: microelectrode pierces the cell membrane to measure the potential difference between the inside and a reference electrode outside

c.    Information Obtained: Captures precise action potentials, subthreshold graded potentials, and synaptic potentials

d.   Pros: High precision; enables studying ion channels and synaptic activity, and morphological identification of the cell

e.    Cons: Technically challenging, typically low throughput (single cell), usually limited to slices or anesthetized animals, and can damage the cell.

Extraceullar recording (definition, + precision, method, information obtained, pros + cons)

2.    Extracellular: measures signals from outside cells, allowing for higher throughput and monitoring multiple neurons (spikes/units) in living, moving subjects.

a.    Robust but less precise

b.   Method: A metal or glass electrode is placed near a neuron to detect electrical field changes (action potentials) in the surrounding fluid.

c.    Information Obtained: Primarily detects fast action potentials ("spikes") from nearby cells.

d.   Pros: High throughput (multiple neurons), robust, suitable for chronic, long-term studies in freely moving animals (e.g., EEG or electrocorticogram).

e.    Cons: Misses subthreshold events (graded potentials) and is generally less detailed about the internal state of a single cell.

f.     Synapses are coordinated together, recording field pattern, can interpret signal + find out where in body is creating

Field EPSP recording of LTP

Field recording: stimulus artifact, electrical pulse delivered = peal

Slope downhill: steeper slope = stronger, more synapses, some steepness = stable baseline

High frequency electrical stimulation: high frequency pulses -> fast barrage of activity -> guarantees lots of synapse activity in post (jump in synaptic strength = LTP)

Activity-dependence (LTP in the anaesthetized rabbit) Bliss and Lømo (1973) (summary)

-       synaptic strength increases as a direct result of specific, high-frequency, or repetitive activity patterns (tetanic stimulation)

-       originally demonstrated in the hippocampus of anaesthetized rabbits

-       Rabbits anaesthetized with urethane and chloralose

-       Target pathway: the perforant path, which connects the entorhinal cortex to the granule cells of the dentate gyrus in the hippocampus

Extracellular recording of population EPSPs (excitatory postsynaptic potentials) and population spikes (representing the firing of dentate granule cells)

è Synaptic response (fEPSP) strength dependent on the frequency and intensity of the stimulating train

Spike timing dependent plasticity (STDP) (definiton + how studied)

= biological process where the precise millisecond-level timing between pre- and postsynaptic spikes determines the strengthening (LTP) or weakening (LTD) of synaptic connections

o   looking down microscope for intracellular recording + stimulation

o   artificially depolarize to mimic input to post synaptic

o   acasual: do not need high freq stimulation to meet Hebbian criteria

Spike timing dependent plasticity (STDP) (mechanism + significance)

o   Mechanism: STDP acts as a Hebbian learning rule, refining neural circuits based on causal timing. It typically involves the activation of NMDA-type glutamate receptors

o   Significance: STDP is crucial for memory formation, sensory perception, and cognitive behaviors.

Spike timing dependent plasticity (STDP) (LTP + LTD)

o   LTP (Potentiation): Occurs when the presynaptic neuron fires before the postsynaptic neuron (\(<0-20\text{ms}\)), strengthening the connection

o   LTD (Depression): Occurs when the presynaptic neuron fires after the postsynaptic neuron, weakening the connection

Input specificity definition + what it enables

= the biological mechanism where active synapses are strengthened (LTP) without affecting inactive neighboring synapses, ensuring precise neural connectivity

• -       enables neurons to refine communication, allowing LTP at specific dendritic sites

Input specificity: neural plasticity

Neural Plasticity (LTP): A fundamental property of LTP at synapses, such as hippocampal CA3-CA1 synapses, meaning only stimulated synapses are strengthened, not adjacent inactive ones

Input specificity: neural development

Neural Development: Input specificity of LTP emerges with development, correlating with increased dendritic complexity, though some forms are present early, such as 1 Hz spike-driven plasticity

Input specificity: mechanism (+ method)

-       Mechanism: Mediated by cell adhesion systems, neuroligins, and fibroblast growth factors (FGFs), allowing neurons to selectively fine-tune communication

è stimulate pre-synaptic + evaluate on post

è take hippocampus out of brain + keep alive under microscope

è 2 different stimulating electrodes-> stimulate different areas -> electron pathway experiment, stronger electrical stimulation pathway recruits more inputs

è Tetanic stimulation = effects only on that pathway, no effect on control pathway

è Show synapses sustained baseline when kept alive

Cooperativity definition (+ acts s a threshold mechanism)

= the property where a threshold number of afferent axons must be stimulated simultaneously to induce synaptic strengthening, ensuring that weak, isolated inputs do not trigger plastic changes

• -        acts as a threshold mechanism, ensuring only significant activity causes memory-related, long-lasting LTP

Cooperativity: NMDA Receptor Dependence

-       NMDA Receptor Dependence: In [hippocampal CA3-CA1 synapses], cooperativity allows enough Glutamate to bind, ensuring enough postsynaptic depolarization to remove the Mg2+ block from NMDA receptors.

Cooperativity: Interaction with Other Properties

-       Interaction with Other Properties: Cooperativity is often distinguished from input specificity (only active synapses are strengthened) and associativity (a weak pathway can be strengthened if stimulated concurrently with a strong one).

Associativity definition

= the property where a weak, subthreshold synapse is strengthened (potentiated) when it is activated simultaneously with a separate, strong synapse on the same neuron

-       this mechanism, often linked to classical conditioning, allows neurons to link related inputs, strengthening weak signals when they co-occur with significant ones.

Associativity mechanism

-       Mechanism: It typically depends on NMDA receptors. Strong stimulation (input A) causes sufficient postsynaptic depolarization to remove the Mg2+block from NMDA receptors, allowing calcium influx

-       If a weak pathway (input B) is active simultaneously, the depolarization from input A allows input B to also trigger LTP

Associativity location

-       Location: Widely observed at CA3-CA1 synapses in the hippocampus and the piriform cortex

Associativity temporal requirement

-       Temporal Requirement: For effective associativity, the weak pathway usually must be stimulated within a narrow temporal window—typically within 3-10 ms of the strong pathway

Associativity relation to other properties

-       Relation to other properties: While input specificity limits LTP to active synapses, associativity allows for the pairing of weak, normally non-potentiating inputs with strong ones, and co-operativity allows multiple weak inputs to work together

Longevity defintion

= the persistence of strengthened synaptic connections, ranging from several hours to weeks, months, or potentially the lifetime of an animal

-       While early-phase LTP lasts 1-3 hours, late-phase LTP (L-LTP) requires protein synthesis and structural changes for long-term stability

Longevity duration

-       Duration: While often studied over hours, LTP in the dentate gyrus can persist for weeks to months

Longevity Repetitive Induction

-       Repetitive Induction: Repeated stimulation can produce "repetitive LTP-induced synaptic enhancement" (RISE), a form of plasticity that can last for over 3 weeks and includes new synapse formation

Longevity Behavioral Context

-       Behavioral Context: Inducing LTP during exploration of a novel environment can double its duration, for example, lasting up to 2 weeks

Longevity Aging Impact

-       Aging Impact: Aged brains show reduced LTP maintenance, often lasting only 3 days compared to 7 days in younger subjects, likely due to weakened protein synthesis and altered gene networks

Longevity Stabilization

-       Stabilization: Stable, long-lasting LTP is not instantly locked in; it is initially sensitive to reversal by new behavioral experiences, but it eventually consolidates into a very long-lasting form

è Long-lasting LTP requires protein synthesis

è New proteins synthesized + incorporated to make LTP change robust

LTP induction, expression + maintenance

1.    Induction – ‘learning’ equivalent, post tectonic potentiation

2.    Expression- mechanisms detect Hebbian criteria met -> makes changes, recognition + induction

3.    Maintenance - persistent, late-phase strengthening of synaptic connections (L-LTP) that underlies memory storage, lasting for hours, days or even months

LTP induction: what mechanism detects the special conditions under which Hebbian plasticity occurs?

The NMDA R is necessary for the induction of LTP in CA1 + the dentate gyrus

-       AMPA = main ionotropic R for fast transmission

-       NDMA – fast transmission mediated by ionotropic Rs (Ca here for positive ions)

o   Only opens if post-synaptic is depolarized

o   Ligand-dependent + V=dependent

o   Only if glutamate released + strong depolarization

What is NMDAR

=acts as a coincidence detector that requires both glutamate binding and postsynaptic depolarization to remove the Mg2+ block, allowing calcium influx, which triggers the signaling cascades necessary for synaptic strengthening

NMDAR CA1 region

-       CA1 Region: Genetic deletion of the NMDAR1 subunit specifically in CA1 pyramidal neurons completely abolishes NMDAR-mediated postsynaptic currents and LTP, leading to impaired spatial memory

NMDAR dentate gyrus

-       Dentate Gyrus: LTP induction at the medial perforant path (MPP) to DG synapses is dependent on NMDAR activation

NMDAR mechanisms

-       Mechanisms: In both areas, NMDAR activation increases calcium concentration in the dendritic spine, activating CaMKII

NMDAR co-agonist requirement

-       Co-agonist Requirement: NMDAR activation requires co-agonists (glycine or D-serine). Astrocytes are a source of these, with D-serine being significant in CA1 and glycine playing a key role in the DG

NMDAR as a coincidence detector

-       NMDAR channel is blocked by Mg2+ at resting membrane potentials

-       only opens when glutamate binds (signal from the presynaptic neuron) AND the postsynaptic neuron is depolarized enough to expel Mg2+ ion

-       Mg2+ sits in channel + pushed out when depolarized

-       Mg+ attracted into channel by negative potential across membrane

NMDAR as a coincidence detector: weakly + strongly active synapses

Weakly active synapse: L-glutamate binds extracellular + Na+ -> intracellular

Strongly active synapse: Mg2+ + L-G binds extracellular + Na+/Ca2+ -> intracellular

NMDAR antagonists prevent the R from conducting Ca in response to glutamate

è inhibit the receptor from conducting Ca2+ in response to glutamate by blocking the ion channel pore, preventing the activation of the receptor, or binding to allosteric sites

è this mechanism is crucial for stopping excessive Ca2+ influx that causes excitotoxicity

è e.g. APV (AP5) competes with glutamate

è e.g. PCP/angel dust also + ketamine!

The effects of the NMDAR antagonist AP5 (APV) on LTP induction (3)

è using APV blocks LTP

è eventually, APV wasted away

è therefore can induce LTP again

The NMDAR antagonist AP5 blocks spatial learning in the Morris water maze (intro)

è by inhibiting hippocampal LTP, which is essential for encoding new spatial memories

è Chronic infusion of AP5 into the hippocampus results in a dose-dependent impairment of navigation to a hidden platform, confirming that NMDAR-dependent synaptic plasticity is crucial for learning this task

The NMDAR antagonist AP5 blocks spatial learning in the Morris water maze: impairment mechanism

è Impairment Mechanism: AP5 blocks the induction of hippocampal LTP in vivo at concentrations that impair spatial learning, suggesting a direct link between the two processes

The NMDAR antagonist AP5 blocks spatial learning in the Morris water maze: learning deficits

è Learning Deficits: Rats treated with AP5 fail to learn the location of the hidden platform in the water maze

The NMDAR antagonist AP5 blocks spatial learning in the Morris water maze: context dependency

è Context Dependency: Pretraining in a different water maze can alleviate the learning deficit, suggesting AP5 hinders encoding new spatial information rather than using existing spatial strategies

The NMDAR antagonist AP5 blocks spatial learning in the Morris water maze: spatial specificity

è Spatial Specificity: The impairment is specific to hippocampal-dependent spatial learning, as NMDA receptors might not be required for all types of learning

LTP expression: what happens to change synaptic strength?: AMPAR insertion (Postsynaptic Strengthening):

è The primary mechanism involves recruiting more AMPA receptors and inserting them into the postsynaptic membrane at the synapse, increasing the postsynaptic cell's sensitivity to glutamate

LTP expression: what happens to change synaptic strength?: Increased sensitivity to glutamate

-       Increased Sensitivity to Glutamate: The postsynaptic membrane becomes more responsive to the same amount of neurotransmitter released, resulting in a larger electrical response

LTP expression: what happens to change synaptic strength?: Structural changes (structural LTP)

-       Structural Changes (Structural LTP): Dendritic spines can enlarge or change shape to accommodate more receptors, and new dendritic spines can form, strengthening the connection

LTP expression: what happens to change synaptic strength?: Increased NT release (presynaptic)

-       Increased NT Release (Presynaptic): At some synapses, LTP can also be expressed through an increase in the probability of neurotransmitter release from the presynaptic neuron

LTP expression: what happens to change synaptic strength?: NDMAR activation

-       NMDAR Activation: Crucial for induction, the influx of calcium through NMDA receptors activates signaling pathways that lead to the insertion of new AMPA receptors

Dominant negative system to block AMPAR insertion (process + how it works)

è GluR1 insertion from intracellular to membrane

è GFP dominant negative GluR1-CT tail

è Become binding partners necessary for insertion

è Mimic things that block activation of AMDAR insertion

è Binds to GluR1 on membrane

-       focus on disrupting the trafficking, exocytosis, or synaptic stabilization of GluA-containing subunits

-       these systems often work by competing with endogenous proteins for docking sites or by preventing trafficking vesicle fusion

LTP is prevented by blocking AMPAR insertion (intro, what it does)

è  prevents the expression of LTP)

è  confirms that the synaptic delivery of these specific receptors is a critical, necessary mechanism for enhancing synaptic strength during plasticity

LTP is prevented by blocking AMPAR insertion: preventing insertion blocks LTP

-       Preventing Insertion Blocks LTP: Studies using mutant GluR1 constructs (e.g. inhibiting PDZ-ligand interactions or using phosphorylation-deficient mutants) show that when these mutated receptors cannot enter the synapse -> LTP is blocked

LTP is prevented by blocking AMPAR insertion: mechanism of action

-       Mechanism of Action: During LTP, GluR1-containing AMPARs move from extrasynaptic to synaptic sites, a process mediated by PKC phosphorylation. The cytoplasmic tail of GluR1 is essential for this trafficking, and expressing a disconnected tail (GFP-GluR1-ct) acts as a dominant-negative, disrupting endogenous receptor trafficking and preventing LTP

LTP is prevented by blocking AMPAR insertion: structural plasticity

-       Structural Plasticity: The synaptic insertion of GluR1 is necessary and sufficient to facilitate a stable increase in spine size (structural LTP).

LTP is prevented by blocking AMPAR insertion: imaging insertion

-       Imaging Insertion: By attaching GFP or Super Ecliptic Phluorin (SEP) to the extracellular N-terminus of GluR1, researchers can directly visualize the movement of these receptors into the synapse during LTP.

LTP is prevented by blocking AMPAR insertion: activity-dependent requirement

-       Activity-Dependent Requirement: While constitutive (basal) trafficking might occur, the activity-dependent insertion mediated by the GluR1 subunit is essential for the rapid enhancement in AMPA-current seen in LTP

What is inhibitory avoidance?

= a one-trial learning task used to study fear-motivated memory, where mice learn to avoid a dark compartment associated with a previous foot shock

What does inhibitory avoidance measure?

è  measures memory consolidation, typically requiring the amygdala, hippocampus, and prefrontal cortex, with memory strength dependent on the intensity of the aversive stimulus

Inhibitory avoidance procedure

-       Procedure: Mice are placed in a lighted compartment and, upon entering a dark chamber, receive a mild foot shock. Retention is tested hours later by measuring the latency to enter the dark chamber, with longer times indicating better memory

Brain regions involved in inhibitory avoidance

-       Brain Regions Involved: Consolidation of this memory requires protein synthesis in key limbic structures, including the amygdala (AMG), dorsal hippocampus (DH), and medial prefrontal cortex (mPFC)

Inhibitory avoidance task variations

-       Task Variations:

• 
  

• Step-through avoidance: Mouse moves from a lit to a dark compartment.

• Step-down avoidance: Mouse sits on a platform and receives a shock upon stepping onto a grid

Factors affecting results of inhibitory avoidance

-       Factors Affecting Results: Studies show that results can be influenced by the supplier of the mice and the sex of the animal, highlighting the need for careful study design

Inhibitory avoidance applications

-       Applications: The test is often used to assess cognitive enhancement, impairments, or anxiety-related behaviors in transgenic or drug-treated mice

How is learning blocked by insertion of modified dominant negative AMPAR C-tail?

è Acts as a precise tool to block synaptic plasticity—specifically, the activity-dependent trafficking of receptors—which subsequently impairs learning and memory

è by mimicking the C-terminus of subunits like GluA1 or GluA2, these constructs act as "slot" proteins, interfering with the recruitment or removal of endogenous AMPARs at the postsynaptic density

This approach demonstrates that the dynamic movement of AMPARs into and out of the synapse is a critical, causative step in synaptic changes that underpin cognitive learning

Learning is blocked by insertion of modified dominant negative AMPAR C-tail: Mechanism of Action (Dominant Negative Effect)

-       Mechanism of Action (Dominant Negative Effect): Expression of the isolated GluR1 (GluA1) C-tail inhibits LTP by competing with endogenous AMPARs for synaptic delivery slots during learning-related plasticity

Learning is blocked by insertion of modified dominant negative AMPAR C-tail: Mechanism of Action (Targeted Plasticity Blockade)

-       Targeted Plasticity Blockade: These constructs allow researchers to selectively prevent specific, activity-dependent AMPAR trafficking (either insertion or endocytosis) without disrupting basal synaptic transmission.

Learning is blocked by insertion of modified dominant negative AMPAR C-tail: Mechanism of Action (Impact on Learning)

-       Impact on Learning: Experiments using these constructs have shown that blocking AMPAR trafficking in specific brain regions (such as the hippocampus or barrel cortex) prevents the formation of new memories

Learning is blocked by insertion of modified dominant negative AMPAR C-tail: Mechanism of Action (Specific Subunit Involvement)

-       Specific Subunit Involvement: While GluA1 C-tail constructs often interfere with LTP, specific modified constructs (like the GluR2-3Y peptide) can specifically abolish NMDAR-dependent endocytosis of synaptic AMPARs, blocking LTD

What is PKMZeta?

PKMzeta is a kinase that may serve as a memorase

How is PKMZeta a persistent enzyme? (in context of LTP)

Persistent Enzyme: Unlike most enzymes that act and are then degraded, PKMzeta is an autonomously active isoform of PKC

è It is continuously produced and maintains LTP (when synaptic connections between neurons strengthen)

How PKMzeta maintain memory?

Memory Maintenance: Studies indicate that PKMzeta serves as the "engine" for long-term memory maintenance by strengthening the synapses involved in forming a specific memory, allowing them to remain stable for months or years

How does PKMzeta function as a memorase?

The "Memorase" Function: Its role as a "memorase" is evident through inhibiting its activity:

è When zeta-inhibitory peptide (ZIP) is introduced, it inhibits PKMzeta, which can reverse established long-term memories in animal models (e.g., in the hippocampus) without erasing the brain's capacity for new learnin

PKMzeta key mechanisms (2) + how they work

-       Synaptic Strengthening: PKMzeta increases the number of [GluR2-containing AMPA receptors] at the synapse, which strengthens communication between neurons.

-       KIBRA Interaction: A 2024 study highlights that the protein KIBRA acts as a "synaptic tag" that binds to PKMzeta, allowing it to stick to specific synapses and maintain memory, with the breakage of this bond resulting in memory erasure.

PKMzeta + ZIP - actiotn of ZIP + memory impact

Action of ZIP: ZIP works by acting as a pseudosubstrate inhibitor, targeting PKMζ

Memory Impact: Injected ZIP has been reported to erase or disrupt long-term memories in rodents

How is PKMz required for LTP maintenance in the hippocampus?

è by strengthening synaptic transmission through increased AMPAR insertion

è acts by facilitating the persistent trafficking of GluR2-containing AMPA receptors to the postsynaptic membrane

How is PKMz is required for hippocampus-dependent memory?

• PKMz inhibitors (e.g. ZIP), have been shown to erase established, long-term, hippocampus-dependent memories (e.g., spatial memory, fear conditioning) in rats and mice

• In trained animals, PKMz levels remain elevated in the hippocampus for up to one month, mirroring the duration of long-term memory

• Saline-injected rat experiment

o   One region in circle where shocks are given, mouse actively avoids this area, even when shocks not being delivered, well learned memory

o   ZIP delivered:

o   Rat moves about freely with shock off, forgotten where the shocks are + their significance

Does hippocampal LTP support learning + memory? (Recording hippocampal synaptic potentials during inhibitory avoidance)

-       Implanted electrodes in CA1 of dorsal hippocampus of rats to record fEPSPs before inhibitory avoidance training

-       LTP: inhibitory avoidance training caused a significant, stable increase (potentiation) in the slope of the fEPSPs

-       So learning creates the same synaptic modifications as LTP

How does inhibitory avoidance induce synaptic potentiation?

-       Inhibitory avoidance learning induces LTP in the hippocampal CA1 area

-       strengthening synaptic connections as a direct result of aversive, one-trial training

-       This learning-induced synaptic potentiation increases NMDA and AMPAR-dependent glutamate transmission, effectively mimicking electrically induced LTP

Learning-induced synaptic potentiation occludes LTP - what does this mean + how?

è indicating that learning uses the same molecular mechanisms as electrically induced LTP to strengthen synapses

è because learning brings synapses to a maximum capacity, subsequent artificial, high-frequency stimulation (LTP) yields smaller responses in trained animals

Learning-induced synaptic potentiation occludes LTP - Mechanism of Occlusion

Mechanism of Occlusion: Learning-induced changes at synapses (e.g., insertion of AMPA receptors) bring them near a "ceiling" or maximum modification range. Thus, artificial stimulation cannot strengthen them further

Learning-induced synaptic potentiation occludes LTP - Occlusion Studies

Occlusion Studies: Experiments show that trained behaviours, such as motor skill learning, directly reduce the amount of additional LTP that can be induced in the relevant cortex (e.g., motor cortex or hippocampus)

Learning-induced synaptic potentiation occludes LTP - Fear Conditioning Examples

Fear Conditioning Examples: In the amygdala, fear-conditioned learning creates synaptic changes that "occlude" or prevent further LTP

Learning-induced synaptic potentiation occludes LTP - Bidirectional Nature

Bidirectional Nature: While learning often acts like a "saturating" LTP effect, studies also indicate that it can influence the threshold for further plasticity, where initial learning can make it easier for LTD to occur

IA + relation to learning-induced synaptic potentiation (4)

-       IA occurs and synaptic response increases in those with enhanced output (synapses underwent change when animal learned), those without enhanced output did not change

-       High frequency stimulation (TET) increases those without enhanced output but those with do not change

-       Shared mechanism between learned change + LFP change in synapses

-       So more capacity for LTP if they hadn’t changed as a result of learning

What does saturating LTP do to learning + memory?

= saturating LTP impairs new learning + memory by maxing out synaptic strength, leaving no room for further strengthening required to encode new information

this saturation, often achieved via intense artificial stimulation, mimics "overwriting" or filling memory capacity, leading to deficits in spatial learning tasks

Effects of saturating LTP on learning + memory: impaired new learning

-       Impaired New Learning: When synapses are already fully potentiated, they cannot increase in strength, blocking the formation of new hippocampal-dependent spatial memories

Effects of saturating LTP on learning + memory: occlusion of further LTP

-       Occlusion of Further LTP: Saturated synapses exhibit "occlusion," meaning they fail to show additional LTP in response to new input

Effects of saturating LTP on learning + memory: memory deficits

-       Memory Deficits: Studies show that when hippocampal LTP is saturated, animals display significant spatial learning deficits in tasks such as the Morris water maze

Effects of saturating LTP on learning + memory: evidence of information capacity limits

-       Evidence of Information Capacity Limits: This suggests that neural networks have a finite capacity for storing information via synaptic strengthening

Effects of saturating LTP on learning + memory: distinction from natural learning

-       Distinction from Natural Learning: While intense stimulation (electrical shocks) causes severe saturation, natural learning processes usually do not fully saturate the synapse, leaving capacity for future encoding