Lecture 9: synaptic plasticity and memory

Key attributes in the sea slug, aplysia

• water enters gills → extract O2 → exits siphon

• rhinophores: chemical sensors

Aplysia gill withdrawal reflex circuitry (only touched on siphon skin)

• a stimulus to the siphon causes the animal to withdraw its gill

  • gill is used for oxygen, hence needs to protect it

Circuitry:

• siphon skin is touched

• sensory neurons activated

  • carries signal from the siphon to the CNS

• sensory neuron forms a synapse with a motor neuron

  • monosynaptic excitatory connection

• when activated, the motor neuron sends an AP to the gill muscle

• activation of the motor neuron causes the gill to contract and withdraw

habituation

a progressive decrease in response to a repeated stimulus

→ adaptation is CONSTANT stimulus

sensitization

a heightened response to an innocuous (harmless) stimulus, caused by a previous noxious (harmful) stimulus

→ in case of aplysia, it is to the tail

• it is not reversing habituation, but new method

Aplysia gill withdrawal reflex circuitry

tail → sensory neuron →modulatory (faciliatory) interneuron (IN) → motor neuron (axo-axonic synapse) → gill

• modulatory interneuron releases serotonin (serotonergic)

  • acts on the sensory neuron presynaptic terminal

  • increases ca2+ influx and neurotransmitter release from the sensory neuron

    • excites motor neuron more strongly

• result:

  • the same siphon touch produces a larger gill withdrawal

  • modulatory interneuron: changes how strong the connection is (plasticity)

sensitization of the aplysia gill withdrawal reflex

• tail shock causes a broadening of the AP in the siphon sensory neuron’s axon terminal

• this causes more Ca2+ entry in the siphon sensory neuron’s axon terminal and consequently more glutamate release and a greater motor neuron EPSP

• basically, widens the AP length → axon stays depolarized for longer

sensitization of the aplysia gill withdrawal reflex

Explain how an LTP is created in rat hippocampus

• high freq stimulation (tetanus) of axon 1 is created

  • causes an increase in the EPSP amplitude evoked by a subsequent single stimulus on axon 1

  • no change to EPSP evoked by axon 2

• note: axon 2 was NOT given tetanus but just was recorded how it was affected after it was given to axon 1

• the effect: long-term potentiation (LTP)

  • type of specificity

• since only one axons epsps went up, while one did not change much from baseline → example of specificity

Properties of LTPs: compare specificity, associativity, and cooperativity

Property	Definition	What is Required	Classic Example	Why It Matters for Learning

Specificity

Only the active synapses are strengthened during LTP

Activity at a particular synapse; glutamate release + postsynaptic depolarization

One stimulated synaptic pathway is potentiated, while a nearby inactive pathway is unchanged

Ensures memories are precise, not global or diffuse

Associativity

A weak stimulus can undergo LTP when paired with a strong stimulus at the same time

Coincident activation of weak and strong inputs; NMDA receptor activation

Weak pathway gains LTP when paired with a strong pathway

Explains associative learning (linking events together)

Cooperativity

Multiple weak inputs together can induce LTP

Simultaneous activation of many weak synapses to depolarize the postsynaptic neuron

Several weak synapses fire together to trigger LTP

Allows neurons to act as coincidence detectors

what is a LTP

Long-term potentiation

• long-lasting increase in synaptic strength between two neurons that occurs after repeated or strong stimulation

  • neurons that fire together, wire together

• it is a cellular mechanism for learning and memory

  • shows how experiences can produce lasting changes in the brain

• one of the many different types of plasticity at cellular level

What is the NMDA receptor channel?

• channel that is permeable to Na+, K+, and Ca2+

• ligand-gated: opens when glutamate binds

• voltage-gated: also requires postsynaptic depolarization

When can the NMDA channel open/how does it open?

• At resting potential, the NMDA channel is blocked by Mg²⁺.

• Presynaptic neuron releases glutamate, which binds NMDA receptors.

• If the postsynaptic neuron is strongly depolarized (often via AMPA receptors), the Mg²⁺ block is removed.

  • the positive force inside the cell repels the positive Mg

• The NMDA channel opens, allowing Ca²⁺ influx.

• Ca²⁺ triggers intracellular signaling that strengthens the synapse (e.g., AMPA receptor insertion).

  • LTP is initiated

Conditions necessary for LTP induction

ca2+ entry initiates LTP at the synapse:

• when Ca2+ enters the postsynaptic dendrite, LTP occurs at that location

• for ca2+ to enter the dendrite, two conditions must be met:

1. the postsynaptic cell must be depolarized

2. glutamate must be present

→ conditions ensure that Mg2+ will pop out of the NMDA receptor channel and thus ca2+ will be able to enter

Why does LTP specificity occur

ca2+ enters the dendrite at synapse 1 only because:

• the post synaptic cell is depolarized (everywhere) but

• glutamate is present only at synapse 1

why does associativity LTP occur?

Ca2+ enters the dendrite at both synapses because:

• the postsynaptic cell is depolarized (everywhere) and

• glutamate is present at both synapses

why does cooperativity LTP occur?

Ca2+ enters the dendrite at both synapses because:

• the postsynaptic cell is eventually depolarized (by the joint action of both synapses) and

• glutamate is present at both synapses

Possible mechanisms responsible for LTP expression

• enhancement of existing AMPA receptor conductance

• insertion of new AMPA receptors

Enhancement of existing AMPA receptor conductance

• the AMPA receptors already present at the postsynaptic membrane conduct more current in response to glutamate.

• As a result, the same presynaptic input produces a larger EPSP.

How it happens (mechanism):

1. Strong synaptic activity activates NMDA receptors.

2. Ca²⁺ enters the postsynaptic neuron.

3. Ca²⁺ activates protein kinases (e.g., CaMKII, PKC).

4. These kinases phosphorylate AMPA receptors.

5. Phosphorylation increases AMPA channel open probability or conductance.

Importance:

• it is fast

insertion of new AMPA receptors

• Additional AMPA receptors are added to the postsynaptic membrane at an active synapse.

• This increases the neuron’s response to the same amount of glutamate.

How it happens (mechanism):

1. Strong or repeated stimulation activates NMDA receptors.

2. Ca²⁺ enters the postsynaptic neuron.

3. Ca²⁺ activates signaling pathways (especially CaMKII).

4. AMPA receptors stored in intracellular vesicles are trafficked to the synapse.

5. These receptors are inserted into the postsynaptic density.

Importance:

• produces larger and more stable EPSPs

• longer lasting, but slower

Memory can be divided into two:

• declarative → available to consciousness

  • daily episodes

  • words and their meanings

  • history

EXPLICIT

• nondeclarative → generally not available to consciousness

  • motor skills

  • associations

  • priming cues

  • puzzle solving skills

IMPLICIT

Retrograde amnesia

loss of previously stored memory

anterograde amnesia

inability to form new memories

• cannot remember what happened to them after the brain damage but can remember before

the involvement of hippocampus in memory

• involved in:

  • consolidation of new explicit, long-term memory

    • making these new memories BUT NOT STORING them

• NOT involved in:

  • long-term storage of explicit memories

  • consolidation or storage of implicit memories

Henry Molaison (H.M)

• suffered from intractable epilepsy

• had a bilateral hippocampectomy

  • resulted in anterograde amnesia

• also experienced temporally graded retrograde amnesia

• could acquire new implicit memories and had normal WM

  • could learn new sport or skill but would not remember he learned them but could perform it (implicit memory)

temporally graded retrograde amnesia

lost memory of some events in the decade preceding surgery

older memories from earlier life were intact

Connection between hippocampus and possible declarative memory storage sites

wide spread projections from association neocortex converge on the hippocampal region (areas that deal with declarative memory storage)

the output of the hippocampus is ultimately directed back to these same neocortical areas

explain how the memory consolidation and storage model works

→ explicit memory formation, consolidation, and long term storage

two parts involved:

• hippocampus = temporary index/bridge that links different sensory features of a memory

• cortex = long term storage site

• memory formation uses cooperativity and associativity LTPs

simultaneous sigh and smell of a rose → coverage on hippocampal neuron →if only one sense is present, it allows for a weak cortical input with strong hippocampal signal → memory replay over time strengthens in the cortex-cortex connections → cortex gradually learns association on own without stimuli → long term memory consolidation in cortex, not hippocampus

TOW: Multi electrode extracellular recording

• electrodes are outside the cells (not penetrating the membrane)

  • array of electrodes

• they detect voltage changes in the extracellular space

  • measures activity, not stimulating it

    • aps, LFPs

• signals come from ionic currents flowing during neuronal firing

• what is being recorded:

  • when neuron fires, a⁺ influx and K⁺ efflux create small voltage changes outside the cell

  • Each electrode picks up:

    • Spikes from nearby neurons

    • Smaller contributions from more distant neurons

  • Signal size depends on:

    • Distance to neuron

    • Neuron size

    • Electrode impedance

Technique	Location	Records	# neurons
Patch clamp	Inside cell	Vm, currents	1
Single extracellular	Outside cell	Spikes	Few
Multielectrode extracellular	Outside cells	Spikes + LFPs	Many

TOW: hand population vector and dr. andrew schwartz

• population vector is a way to decode intended hand movement direction by combining the activity of many motor cortex neurons

• the neuron fires most when movement is in the direction of the motor cortex neurons preferred direction for hand movement

TOW: how does multi-electode extracellular recording and population vectors connect

Motor cortex neurons (M1)
⬇ (multielectrode extracellular recording)
Spike trains from many neurons
⬇ (population vector decoding)
Estimated hand movement direction
⬇
Cursor / robotic arm / prosthetic hand

🔥 Critical result from Schwartz’s lab:

• The hand does not need to move

• Intention alone is enough to generate population vectors