Date: July 14, 2024

Topic: Synapses, Circuits and Plasticity

Learning Objectives:

• Explain how alterations in the number of synapses, the probability of releasing neurotransmitter and receptor expression levels impact the size of the synaptic potential.

• Understand that neurons integrate information.

• Explain the role of synaptic strength and neuronal excitability in determining neuronal output.

• Understand how changes in synaptic strength could mediate associative learning.

Recall

Notes

• Memories are coded in the ensemble activity of small groups of neurons that are sparsely distributed throughout the brain

• Different memories are encoded by different neuronal ensembles

• Memory formation involves a rewiring of the brain; making new or stronger connections between some neurons, and breaking or weakening connections between other neurons

• Neurons can integrate information from other neurons + connections can vary between neurons

• Synaptic connections as a physiological substrate for memory

  • Spines comes in different shapes and sizes

    • Large spines heads contain more AMPA receptors → bigger EPSP

    • Spines can be dynamic/plastic (transient), they change over time

    • Many spines can be stable (persistent)

Basic Principles of Synaptic Transmission

• Basic steps of synaptic communication

  1. Stimuli are converted into localised electrical signals (opening of ion channels)

     1. Spreads decrementally to soma and axon

     2. Integrated

  2. AP generated if threshold potential is reached

  3. AP propagation (non-decremetal) along the axon

  4. AP reaches synaptic terminal

     1. Calcium influx

     2. Release of neurotransmitter

  5. Activation of target cell after NT binds to synaptic cleft

• Transmitter release is quantal and stochastic

  • NTs are packaged into vesicles

  • Each vesicle has a similar number of NTs (a quanta)

  • Only a small % of vesicles are docked and ready to be released

    • So you could trigger a different number of vesicles to be released using the same stimulation each time (stochastic)

  • Thus probability of releasing transmitter (Pr) varies between synapses

  • Pr depends on:

    • of docked vesicles

    • [Ca2+] at exocytosis site

• Range of NT molecules

  • Small molecules

    • Acetylcholine

    • Amino acids

      • Glutamate, GABA, glycine

    • Biogenic Amines

      • Noradrenaline, adrenaline, dopamine, serotonin, histamine

    • Purines

      • ATP, GTP, adenosine

  • Neuropeptides (100+) - packaged in dense core vesicles

    • Substance P, Neuropeptide Y, Opioids, Brain-derived neurotrophic factor (BDNF), Galanin

  • Glasses

    • CO and NO

  • Lipids

    • Endocannabinoids

  • Neurons may release 1 or more transmitters (co-transmitters)

• Activation of post-synaptic receptors

  • Two types of post-synaptic receptors:

    • Ionotropic receptors (also ion channels) → ions pass through the receptor, very fast process

    • Metabotropic receptors → transmitter binding triggers an exomatic process. Includes:

      • G-protein coupled receptors

      • Tyrosine kinase receptors

      • guanylyl cyclase receptors

  • Neurons generally express a diverse range of post-synaptic receptors

• Diversity of ionotropic channels

  • Multimeric proteins

    • 4-5 subunits

  • Various subunit combinations

  • Subunit composition can affect kinetics, voltage-dependence, ion-permeability, and pharmacology

• AMPA and NMDA ionotropic glutamate receptors

  • AMPA glutamate receptors

    • Fast kinetics (decays in ms)

    • Not voltage dependent

    • Permeable to Na+ and K+

    • Some subunit combinations are permeable Ca2+

    • of receptor varies, scales with synapse surface area

  • NMDA glutamate receptors

    • Slower kinetics (decays in 10s of ms)

    • Blocked to Mg2+, requires depolarisation

    • Permeable to Na+, K+ and Ca2+

    • NMDA receptor expression is relatively constant

    • At resting membrane potentials NMDA receptors are blocked by magnesium. Thus, under “normal” conditions synaptic transmission is mediated by AMP receptors

• Metabotropic Receptors

  • Such as G-protein coupled receptors activate signal transduction cascades

  • Can also mediates slow synaptic transmission

Synaptic Integration

→ process by which multiple synaptic potentials combine within one post-synaptic neuron

• A typical CNS neuron makes thousands of synaptic connections

• CNS synapse are generally ‘weak’

  • Single vesicle released

  • EPSP of few tenths of a millivolt

• Therefore, many synaptic inputs are needed to depolarise the cell enough to generate an action potential (output)

• Weight (w) = Strength of pathway

  • of functional synapses

  • Transmitter release probability

  • of ionotropic receptors

  • Synapse location

• Activation function

  • Intrinsic excitability

  • Propensity to fire APs to a given stimulus

  • Input (synaptic drive - change in membrane potential (delta Vm) → Output (APs)

• Timing is critical for integration

  • Require temporal overlap of synaptic potential (coincident activation)

• Neurons perform logic operations

  • Consider a case where a neuron will fire if depolarised by 10mV

• Coincident detection, categorisation

Synaptic Plasticity as a Memory Substrate

• Pavlovian Conditioning

  

• Amygdala

  • Collection of subcortical nuclei involved in emotional processing and emotional associative learning (including fear conditioning)

  • Damage is associated with severe emotional deficits

  • Electrical stimulation induces feelings of fear and dread and anxiety

  • Inputs:

    • Unimodal sensory inputs (auditory, visual, somatosensory, gustatory) from cortex and thalamus

    • Also connected to Hippocampus and Prefrontal Cortex

    • Convergence of CS & US

  • Outputs:

    • Hypothalamus and brain stem (control emotional arousal, cardiac, hormonal effects)

    • Hippocampus and prefrontal cortex

• Prior to pairing

  

  

• Evidence for changes in synaptic strength underlying associative learning?

  • Two-photon imaging of dendritic spines in vivo over several weeks have demonstrated:

    • Spines can be dynamic (transient)

    • Spines can be stable (persistent)

  • Spines come in different shapes and sizes

    • Large spines heads contain more AMPA receptors → bigger EPSP

  • Several cognitive disorder are thought to result from abnormalities in dendritic spines

    

  • Trace eyeblink conditioning enhances CA3-CA1 synaptic transmission in rabbit hippocampal slices

  

  • Increase in the post-synaptic density area

  • Increase in number of multi synapse boutons (types of spines)

• Trace eyeblink conditioning increases the observation of dendritic spines in hippocampus of rats

• Auditory fear conditioning enhances the auditory evoked potential in the amygdala

Long-term Potentiation

• How can we enhance synaptic connections?

  • Hebb’s postulate on cell assembly

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

    

  • High frequency stimulation (HFS) produced a long-lasting potentiation of synaptic transmission

    • Every time there was HFS, there was a potentiation

    • Change was long-lasting

• Long-term Potentiation can last over a year in vivoS

• LTP is widespread in CNS

  • Example of LTP in the Basolateral amygdala

  

  • LTP has also been shown to occur in the cortex and cerebellum

• LTP is associative

  • Experiment: Two separate pathways are stimulated

    • S1 - weak input

      • Only activates a few synapses (small EPSP)

    • S2 - strong input

      • Activates many synapses (big EPSP)

    1. HFS of S1 → no LTP in either pathway

    2. HFS of S2 → LTP of S2 only

       1. Input specificity

       2. Cooperativity (many synapses of this pathway are activating together to generate LTP)

    3. HFS of S1 & S2 →

       1. LTP in S1

       2. MORE LTP in S2

       Cooperativity / Associativity

• LTP: A cellular analogue of associative learning?

  • Basic properties

    • Activity-Dependent

    • Rapidly induced

    • Persistent

    • Widespread in CNS

    • Input specific

    • Associative

<aside> 📌 SUMMARY:

</aside>

Date: July 16, 2024

Topic: Cellular Mechanisms of Plasticity

Recall

Notes

• As learned in last lecture → CS and US converge on individual neurons in the amygdala

• Also as learned in last lecture → Cells that fire together wire together

• LTP is associative (S1 and S2) experiment

Cellular Mechanisms of LTP

• Stimulation of NMDA-type Glutamate Receptors →

• Increased Post-Synaptic Ca2+ →

• Activation of CaMKII →

• Gene transcription and protein synthesis →

• Enhanced AMPA-type Glutamate Receptor Function →

Remember: Synapses in Hippocampus and Amygdala contain two-types of ionotropic glutamate receptors (AMPA and NMDA)

1. Stimulation of weak input (few synapses)

   1. AMPA mediated EPSPs

   2. Neuron does not reach threshold (No APs)

   3. Glutamate bound to NMDA receptor, but receptor is blocked by Mg2+

   4. Little Ca2+ influx

   

2. Stimulation of strong input (many synapses)

   1. Inputs (AMPA and EPSPs) summate → Big EPSP - APs

   2. Mg2+ is expelled from the NMDA receptor

   3. Large Ca2+ influx through NMDA receptor

   4. Multiple synapses of strong input act cooperatively to activate NMDA receptors

<aside> 💡 If the input is not stimulated, then no transmitter is released and the NMDA receptors are not activated.

</aside>

• Calcium

  • Ubiquitous second messenger

  • Every cellular process (Neurogenesis → apoptosis) is regulated by calcium

  • Kinase / phosphatase balance

  • Calcium is tightly regulated in cells

    • Free intracellular calcium is maintained at 50-100nM, despite being present at mM concentrations in cerebral spinal fluid (25 000 x higher)

  • NMDARs are calcium permeable

• Synaptic contacts are made on spines

  • Synaptic contacts between excitatory neurons are made on spines

  • Thin neck connecting spine and dendrite acts as diffusional barrier

  • Signalling molecules activated by calcium restricted to activated spine (synapse specificity)

• In LTP introduction, the Requirement for Ca2+ is Brief

  • CA1 neuron is loaded with a photosensitive calcium buffer

  • A flash of UV light increases the affinity of the buffer for calcium

  • Thus, UV flashes causes a rapid reduction of intracellular calcium

• Activation of CaMKII

  • NMDA activation → Increased Ca2+ → Activation of CaMKII → Phosphorylation of AMPA-R

• After phosphorylation of AMPA-R → Signal transduction cascades

  • → Expression of LTP OR → Induction of gene transcription

• Expression of LTP

  • Increased AMPA mediated synaptic transmission

    • Increased transmitter release

      • Release probability

    • Increased # of synapses

    • Increased postsynaptic response

      • Insertion of more AMPA receptors into the post-synaptic density

    • LTP expression varies between synaptic pathways and induction protocols

• Repetitive stimulation of spines with glutamate induces a long-term spine-head enlargement

• There are things that need to be maintained in order to maintained LTP:

  1. Protein synthesis

     1. Blocking protein synthesis → causes LTP to decay and only early phase (initial) LTP lasting only minutes

  2. Gene transcription

     1. Gene transcription is not necessary for the expression of LTP (blocking gene transcription 2h after LTP induction has no effect on synaptic transmission)

     2. Genes encode proteins required to stabilise synaptic connections: including growth factors, cytoskeletal proteins

  3. PKM-$\zeta$ (a type of continuous phosphorylation event)

     1. PKM-zeta is a protein Kinase C isoform that lack a regulatory unit, thus it is continuously active

     2. ZIP silences PKM-zeta, and it’s maintenance of LTP

     3. Thus persistent phosphorylation of receptors / signalling molecules is required to maintain the synapse in a potentiated state

• LTP mechanism summary

  • Two types of glutamate receptors

    • AMPA → normal synaptic transmission

      • Expression of LTP

    • NMDA → induction of LTP

      • Calcium permeable coincident detectors

  • Calcium triggers induction of LTP

    • Spines compartmentalise calcium

      • Input specificity

  • Protein synthesis / gene transcription are required for persistent LTP

  • PKM-zeta maintains synaptic plasticity

  • Many molecules and transmitter systems modulate LTP

• Other signalling molecules implicated in LTP

  • Calcium channels

  • Kinases

  • Transcription factors

  • Growth factors

  • Cell adhesion molecules

  • etc etc etc

LTP and Memory

• Associative learning induces an LTP-like synaptic enhancements

• Pharmacological agents that disrupt LTP generally disrupt associative learning

  • Same critical window and time-course

    • Infusion of the NMDA-R antagonists APV or MK801 block acquisition, but not expression of conditioned responses

    • Inhibiting protein synthesis or gene transcription prior or during conditioning produces amnesia 2-3 hours later

    • Disrupting PKM-zeta erases both recent and remote memories

• Making an artificial memory

  • Potentiating auditory synaptic inputs in the amygdala produces an auditory conditioned fear response

    • So you are able to introduce a memory

Other forms of plasticity

• Long-term depression (LTD) ; Classical LTD Pathway

  1. Low frequency stimulation

  2. NMDA receptor activation

  3. Calcium entry

  4. Activation of phosphatase cascade (dephosphorylation)

  5. decrease in AMPA receptor transmission

• Other neuronal mechanisms

  • Changes in intrinsic neuronal excitability

    • The propensity of a neuron to fire APs is its intrinsic excitability

      • It is governed by the ion channels it expresses

      • E-S potentiation (same Excitatory synaptic conductance → more spikes)

    • Learning is often associated with a persistent decrease in specific K+ channel conductances

      • More APs evoked by same current

      • Unlike LTP, this intrinsic excitability change is NOT input specific

  • Neurogenesis

    • The hippocampus, continuously makes new neurons. Disrupting cell proliferation impairs hippocampal dependent learning

      • New neurons continue to be born in the adult hippocampus

      • Mechanism underlying neurogenesis is really unclear

• What about more complex memories?

  • The processes mediating more complex memories such as those for episodic memories are poorly understood

  • It is thought that the same biological processes that underlie “simple” associative learning tasks also underlie more complex memories

• “Neural network” models of AI process signals by sending them through a network of nodes analogous to neurons.

<aside> 📌 SUMMARY:

</aside>

Date: July 17, 2024

Topic: Learning and Memory Mechanisms

Recall

Notes

• Memory is the means by which we draw on our past experience in order to use this information in the present

• It is also, on a more philosophical level, what gives us our sense of self

Early and Modern Approaches to Study of Memory

• Hermann von Ebbinghaus published in 1885 a series of experiments he conducted on himself to describe the processes of learning and forgetting

  • Forgetting curve is a logarithm

    

Multi-Store model of memory: Stages and Processes

• Atkinson-Shiffrin Memory Model

  • Suggests there are three memory store: The Sensory Register → Short Term Memory → Long Term Memory

  • The multi-store model is an explanation of memory which assumes there are three memory stores, and that information is transferred between these stores in a linear sequence

  • Each of the memory stores differ in the way information is processed, how much information can be stored (capacity) and for how long (duration)

  • Memory consolidation is the process by which a newly acquired memory (labile and susceptible) is transformed into a more stable, long-lasting form

  • Long-term memories require changes in protein synthesis and gene transcription regulation, whereas short-term memories do not

• Sensory register (aka Sensory Memory)

  • Sensory memory is a memory buffer that allows individuals to retain impressions of sensory information for a brief time (ms to s) after the original stimulus has ceased

  • Sensory memory is divided into sensory-specific subsystems: iconic, echoic, haptic, olfactory, gustatory

  • Sensory input to the visual system goes into iconic memory

    • It has a duration of 300-500 ms

  • Auditory sensory memory is known as echoic memory and can last a few seconds (relevant factor in language perception)

  • More is seen that can be remembered (Sperling 1960)

    • When stimuli are shown, only a limited number of items can be correctly reported (span of immediate memory)

    • However, observers commonly assert that they can see more than they can report

  

  • Information available in brief visual presentations

    • The partial report demonstrates that observers have 2-3 times as much information available as they can later report

    • The availability of this information declines rapidly

• Short-term memory

  • STM allows holding a small amount of information in an active, readily available state for a brief period of time (< 1 minute)

  • Maintenance rehearsal is the process of repeating information mentally or aloud with the goal of keeping it in memory

  • STM memory is limited in both the length and the amount of information it can hold. The average digit span of most adults is 7.

  • Chunking is the process of organising information into smaller groups (chunks), thereby increasing the number of items that can be held in STM.

• Long-Term memory

  • LTM allows us to hold information for days, months or even a lifetime, without active thinking

  • Long-term memories are not fixed records of the past. They are not flawless, but fallible and sensitive to changes overtime

  • The capacity of LTM is huge → the main constraint may be conditions for retrieval (info recall)

  • Memory retrieval is facilitated by cues (sounds, smells, context, emotions) present during encoding

Multiple memory systems and their underlying brain regions

• In search of the Engram

  • Karl Lashley studied the effects of cortical lesions on maze-learning performance in rats with the goal of finding a localised memory trace or “engram”

  • He failed to find the locus of memory, but he found:

    1. The more cortex is removed, the more learning defects occur

    2. One part of the cortex can take over the function of another

  • The encoding and retrieval of memories is a highly distributed process in the brain: different sets of brain areas participate in the “storage” and recall of events, facts and skills

• The Anatomy of Memory

  • The first demonstrations that focal brain damage can cause profound lifelong memory impairments involved unfortunate brain injuries due to e.g., stroke, viral infections or trauma

  • Systematic studies of amnesic patients with selective lesions to their brains have yielded important insights into the brain regions involved in specific processes of memory

• HM

  • Knocked down by a bicycle at 7, began to have seizures and had a major seizure after 16

  • At 27, neurosurgeon performed a bilateral medial temporal lobe resection in an attempt to control epileptic seizures

  • The ablation also damaged most of the amygdala, the rostral half of the hippocampal region and surrounding cortex

  • Post-surgery, the seizures stopped, but HM exhibited profound memory impairment in the absence of any general intellectual loss or perceptual disorders

  • The systematic study of this catastrophic outcome has helped to establish some fundamental principles of memory organisation

  • HM could not form new memories for facts and events (anterograde amnesia) and also could not access some memories acquired before his surgery (retrograde amnesia)

  • His capacity to recall remote facts and events preceding his operation was intact

  • These results suggested that the medial temporal lobe cannot be the ultimate storage site for LTM. Permanent memory must be retained elsewhere.

  • HM could retain information for short periods of time, but he failed when the material exceeded his immediate memory capacity

  • HM could retain a three digit number for as long as 15 mins by continuous rehearsal. But as soon as his attention was diverted to a new topic, he was unable to recall the whole event

  • Tells us medial temporal lobe structures are not needed for STM but are necessary to process them into LTM through consolidation

  • These findings supported the MSM of memory proposed by Atkinson and Shiffrin

  • The Mirror Tracing Task

    • HM could learn hand-eye coordination tasks over a period of days, despite having no recollection o f practising the task before

    • Also exhibited priming effects E.g., if he was given the word episode and later asked to name a word beginning with epi, he was more likely to say episode

    • These findings supported the idea of multiple memory systems: different brain regions are responsible for different aspects of memory

• Clive Wearing

  • He contracted herpes → bilateral damage to temporal lobes and portions of frontal lobes (more extensive than HM)

  • After awaking from a 16 day coma, had severe anterograde amnesia (memory span of only a few seconds)

  • Normal IQ, musical skills remained intact although he was not aware that he could play the piano

  • Unlike HM, noted to have some semantic memory impairments (facts)

Multiple Memory Systems

• Seems like hippocampus is necessary for forming declarative memories

• Hippocampus: Episodic Memories + Spatial Navigation

  • Episodic memories refers to specific, contextual details of experienced events that occurred at a particular point in time and at a particular place (autobiographical memory)

  • The network for recalling personal past events includes the hippocampus, together with the Parahippocampal cortex, prefrontal, lateral and parietal cortices

  • This brain network overlaps with that supporting navigation in large-scale space and other cognitive functions like imagination and thinking about the future

  • Place cells are neurons in the hippocampus that fire when an animal visits specific regions of its environment

    • Thought to provide the foundation for an internal representation of space, i.e., a spatial map

    • We can mentally imagine routes we have taken in the past to build cognitive maps that are critical for our ability to navigate efficiently

  • Hippocampus lesions impair navigation that relies on a spatial map (allocentric spatial memories); anterograde and retrograde deficit

  • Posterior hippocampus volume increases in London taxi drivers after training + qualifying to be a taxi driver (relative to before training). Increase not observed in those that failed to qualify and controls.

    • Patients with lesions restricted to the hippocampus show impairments at navigational tasks

  Thus, hippocampus is critical for episodic and spatial memories.

  • Hippocampus as a structure for building all kinds of maps? “Cognitive maps” that store the inter-relationships between place, events, time etc

  • Overarching function of hippocampus = building integrated representations of spatiotemporal contexts?

    • I.e., holistic, interconnected concepts of places + events + time

• Motivated behaviour and adaptive choice

  • Our behaviour changes according to its consequences

    • Instrumental conditioning:

      • Actions → reinforced

      • Actions → punished

    • Without instrumental learning, we lose our ability to make better choices in the future

  • Amygdala is critical for learning to avoid what’s bad for you

    • Basolateral amygdala is necessary for learned fear

    • BLA is also necessary for suppressing actions with detrimental consequences

    • Thus, patients amygdala damage have decision-making deficits

      • Patients with amygdala lesions will persistently select the loss-inducing disadvantageous decks in the Iowa gambling task, whereas healthy controls will learn to avoid disadvantageous decks in favour of advantageous decks

      • BLA inactivations can selectively impair learning and retrieval of punishment avoidance

  

  • Amygdala activity encodes punished actions

    • BLA is activated by punishers. As punished action → punisher association is learned and punished actions alone begin to activate BLA neurons

    • Cellular resolution data: same neurons activated by shock are activated by punished actions. Actions evoke the representation (i.e., memory) of its consequences in BLA

    • Amygdala aversion-coding mediates learned avoidance

      • Punished action activity in BLA tracks level of avoidance, including when under influence of benzodiazepines (anxiolytic drug that increases punished behaviour)

• Motor Skill Learning

  • Motor skill learning refers to neuronal changes that allow an organism to accomplish a motor task better, faster or more accurately than before as a result of practice

  • Efficiency is supported by automatism, where many serial actions are chunked and executed as blocks

  • Cortico-basal ganglia circuits play a critical role in acquiring, refining, and executing action sequences

    • The striatum is very important

  • Acquisition of a Motor Sequence

    • The actions of the rat become much more efficient over time

    

    • Learning triggers transcriptional activation of striatal neurons

      • Learning and refinement of new action sequences is associated with transcriptional activation of striatal spiny projection neurons

      • Acquisition of new action repertoires engages dorsomedial striatum, while automatism of action repertoires engages dorsolateral striatum

      • Natural (e.g., ageing) and experimentally-induced aberrations in striatum recruitment impairs learning and updating of action sequences

  • Motor skill learning and Huntington’s Disease

    • HD is a degenerative brain disease that causes atrophy of the striatum and related corticostriatal networks

    • HD patients have difficulty with cognitive tasks that require planning and sequences of actions

<aside> 📌 **SUMMARY:

• Medial-Temporal Lobe in hippcampus involved in episodic memory

• Learning and associations with a motivational component or danger involved require amygdala

• Procedural learning like learning skills + habits involves striatum

• Atkinson+Shiffrin MSM model: -** Information is conditionally transferred between 3 stores in a linear sequence - Memory stores differ in how much and how long memories are stored there

• Other key ideas: - The site of memory foundation is not necessarily the site of memory storage (anterograde vs retrograde amnesia)

</aside>

Date: July 18, 2024

Topic: Modulation of learning and memory

Recall

Notes

• Recap

  • Long-lasting memories are formed through interaction with the world around us

  • Memory consolidation is the process by which short-term memories are converted into LTM

  • The stabilisation of LTMs involve de novo protein synthesis and gene transcription regulation

Consolidation, Reconsolidation and protein synthesis

• Newly formed memories depend on protein synthesis

  • Consistent finding is that systemic administration of protein synthesis inhibitors (e.g. cycloheximide) does not disrupt learning or short-term retrieval, but does impair long-term retrieval

  • Disrupted retention also observed if protein synthesis inhibitor only given soon after training. Not observed if protein synthesis inhibitor only given hours after training

  • De novo protein synthesis required for consolidating long-term memories, not ST learning and memory.

    • Once consolidated, protein inhibitors do not disrupt memory unless…

• New and reactivated memories are susceptible to disruption

  • Fear conditioned task: cue → shock causes cue-elicited suppression of drinking behaviour (”conditioned suppression”)

    • Electroconvulsive shock (ECS) immediately after learning impairs subsequent recall

    • ECS after memory reactivation (via cue presentation) impairs subsequent recall

    • Disruption not observed if ECS is delivered hours after learning/reactivation (outside the “vulnerability window”)

  • Protein synthesis inhibitors into amygdala after fear memory reactivation also disrupts later recall

    • Not a general effect of protein synthesis inhibitor or retrieval alone: good memory retention in anisomycin and CS alone conditions

    • Disruption depends on anisomycin being administered during “reconsolidation window”

    • Disrupting protein synthesis (or other components of long-term plasticity) following memory retrieval “erases” the original memory

• Remembering contributes to memory modification?

  • Consolidated memories, when reactivated, enter a transient, vulnerable state

  • Memories go back to a stable state by the process of reconsolidation, which requires protein synthesis

  • Memory retrieval is an active process

  • Why? leading theory is that retrieval returns memory to a “labile” (changeable) state so that they can be updated as needed

  • Retrieved memories can be strengthened, inhibited and changed (even distorted)

• Strengthening memories throughout retrieval

  • Reactivation of memories through spaced practice improves memory retention (i.e., attenuates forgetting curve)

  • (Don’t cram - spacing out studying is better for long-term retention)

  

  • Testing effect: being tested on material (no re-exposure to study material, no feedback) improved later recall relative to re-studying material

  • Mere retrieval improves memory → Very robust finding

  • Mechanism? Strengthening stored memory vs strengthening the ability to subsequently retrieve (retrieval-practice)?

Malleability of memory

• Misleading post-event information can distort memory of an original event (the misinformation effect)

• The words “Smashed” vs “Hit”

  • Participants were more likely to report that they had seen broken glass in the “smashed” condition and report a higher speed

• Thus, using strong suggestions, investigators are able to implant false memories into participants

  • Lots of people could remember an event that never actually happened to them

  • Confabulation: unintentional memory error (fabricated, distorted, misinterpreted). Can be provoked or spontaneous → Occurs in various neuropsychiatric conditions

<aside> 💡 Memories are reconstructed, not replayed.

</aside>

• Memory as flexible and dynamic

  • Far from being an exact, fixed record of the past, memory is prone to changes → including errors

  • Lability of memory are linked to adaptive processes, including memory updating, creativity, simulation of future events, semantic and contextual encoding

• Memory updating and extinction learning

  • Memory updating allows new information to be integrated into existing knowledge, which is critical for adapting behaviours

  • Updating occurs when some information is downgraded as outdated or irrelevant, and newer information is promoted as its replacement

  • Extinction → is a fundamental form of associative/behavioural updating. when a cue or action no longer leads to an outcome, our behaviour changes to reflect this

• Extinction of punishment association: return of behaviour

  • LP training:

    • PunLP → reward

    • UnPunLP → reward

  • Pun (punishment training):

    • PunLP → Reward, Shock

    • UnpLP → Reward

  • CT (choice test)

    • PunLP vs UnpLP

  • Ext (punishment extinction):

    • PunLP → reward

    • UnpLP reward

• Is extinction learning erasure?

  • Does the original association get erased? Or

  • Retrieve original CS-US association, update with current information (overwrite), reconsolidate?

  • Probably not erased → extinguished behaviour can return without additional CS-US or action-outcome pairings under various conditions

  • Indicates the original memory seems to survive extinction

  • Recovery after extinction effects

    • Extinguished behaviour can spontaneously reappear overtime (spontaneous recovery)

    • Extinguished behaviour will reappear is animal is placed in non-extinction contexts (renewal), even if it is a completely novel context

    • Extinguished behaviour can return if re-exposed to the US (primed reinstatement)

    • If pairings resume, behaviour returns rapidly (rapid reacquisition)

• Extinction as new inhibitory learning?

  • Recovery effects suggest a better explanation of extinction is that the original CS-US association remains intact

  • Instead, extinction likely involves new inhibitory CS-no US learning that competes with original association to influence behaviour

  • New extinction association is gated by context

• Mechanisms for extinction learning

  • Extinction of Pavlovian and instrumental behaviour indicate similar psychological mechanisms

    • Extinction is subject to relapse (spontaneous recovery, reinstatement, rapid reacquisition)

    • Extinction involves new inhibitory learning that competes with original association, primary in the context in which extinction occurs

  • Distinct, elaborate circuitry governing Pavlovian vs instrumental extinction learning

    • Both involve hippocampus, amygdala, and prefrontal cortical regions (e.g. infralimbic cortex)

• New memories vs updated memories?

  • Gradual extinction instead of immediate (standard) extinction reduces re-emergence of extinguished responses

  • High discrepancy between a retrieved memory and the “update” (high prediction error) may increase the chance that current information is encoded as a new, competing memory (i.e., treated as a new state/context)

  • Gradual extinction (low prediction error) promotes updating of the original memory

• Interlacing overlapping memories for flexible behaviour

  • Interference between memories is a major contribution to forgetting and memory failure

  • Protecting motor memories from interference is critical for motor skill learning

  • Contextual cues play a role in the retrieval process to facilitate the use of the required memory

• The role of acetylcholine in memory interlacing

  • Catastrophic interference (or catastrophic forgetting) refers to the loss of previous learning upon learning of new information

  • Acetylcholine (Ach) allows the interlacing between new and existing memories, to reduce interference between them

  • Cholinergic modulation in the striatum is necessary to regularly transition between new and old tasks

  • In the striatum, cholinergic input is provided by local cholinergic interneurons

• Reversal experiment and the interlacing of acetylcholine

  • Found striatal acetylcholine has important role in memory interlacing

  • Mice showed good discrimination in devaluation test

  • Thus acetylcholine is not important for initial discrimination learning or choice

  • BUT when associations reversed, the animals did not show the appropriate discrimination → suggesting it was harder for them to update those sets of memories

    • Acetylcholine seems to be apart of the mechanisms for updating memories or handling two competing memories

Maladaptive memories and psychiatric dysfunction

• Many psychiatric conditions are characterised by problematic and persistent memories

• Anxiety and mood disorders often involve unpleasant and/or traumatic memories that exert an outsized influenced over an individual’s daily life, impacting their wellbeing and functioning

• Addiction and compulsive disorders as forms of learning (i.e., plasticity) that dominate an individual’s behaviour and outlook, even if those behaviours have become extremely detrimental to the individual

• Key aspects of these disorders (aetiology, maintenance) can be framed as issues of maladaptive learning and memory (e.g., problematic associations that require updating)..Targets for intervention?

• Clinical relevance: CBT

  • Updating memories through cognitive reappraisals and behavioural procedures (e.g., extinction training) forms the cornerstone of the most effective psychotherapies

• Extinction and the “erasure” of unwanted memories

  • Extinction learning forms the basis for many of the most effective and well-studied treatments for various anxiety disorders

  • Various forms of extinction training (exposure therapy, response prevention therapy, etc) are effective for treating phobias, OCD, panic disorder, social anxiety disorder, PTSD, etc

  • Relapse can still occur (recovery-from-extinction effects) → How can we improve treatment long-term outcomes?

• Erasing memories by targeting reconsolidation

  • Can a problematic memory or thought process be “erased” by activating them (as done in exposure-based therapies), and then preventing reconsolidation

  • Electroconvulsive shock (ECS) therapy is a well-established treatment for treatment-resistant depression; not intentionally targeting reconsolidation

  • Oral administration of the Beta-Adrenergic receptor antagonist propranolol before reactivation of a fear memory results in substantial weakening of the fear response

• Promoting memory updating

  • Can new cognitive-behavioural approaches and /or pharmacotherapies enhance memory modification and its generalisability across time and contexts?

  • Theorised mechanism of promising effects of psychedelic-assisted therapy

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