learning and memory

patient EP cause of memory issues

• acute viral infection that destroyed parts of his brain

• destroyed temporal lobes → new items are not recorded but old are intact

patient EP memory issues and role of hippocampus

• can copy complex diagrams, repeated items, repeats stories without realizing

• cannot recall names, words in a few minutes

message

• hippocampus does not store long term memory

  • creates new long-term memories (explicit)

engram

neural representation of memories

cortical lesions

impaired learning

cortical transections

failed to block learning

Lashley findings

• 1st researcher of brain mechanisms of learning/memory

• examined learning in rats following transections and lesions of cortical regions

• size determined impairment

  • larger lesions = bigger impairment

  • location does not matter

Lashley’s conclusions

equipotentiality: all areas of the cortex are equally involved in memory

mass action: ability to form memories depends only on the mass (amount) of brain

patient HM

• epilepsy as a child, center at hippocampus

• doctors removed hippocampus and adjacent structures

• lost the ability to form new episodic memories (anterograde amnesia)

• suffered temporarily from retrograde amnesia

patient HM and learning

could still learn skilled movements (such as tracing outlines of a star)

• evidence of learning

• hippocampus is involved in episodic memories NOT long-term storage site

amnesia types

anterograde: impairs abilities to form new memories

retrograde: impairs ability to recall old memories

clive wearing

• lost memory 20 years ago, can only remember his wife

• 30 second memory (gives the answer, but forgets the question)

• lesions are not limited to just the hippocampus

• mix of retrograde and anterograde amnesia

hippocampus in memory in rodents, Morris Water Maze

Morris Water Maze - Memory test

• hidden platform

• over time, the rat took less time to reach the platform

• lesion of hippocampus showed no change HOWEVER the rat spent more time in the quadrant

• without a hippocampus, the mice could not form memory of the location of the platform

synaptic plasticity hypothesis

experience can leave a memory trace by causing long-lasting changes in synaptic connections

• synapse is not hardwired

• strengthening of the synapse → increase neurotransmitter release

hebbian plasticity/learning

if cell A persistently and repeatedly excites cell B, the efficacy of the synapse between them will increase

• efficacy of the synapse will increase (causing bigger EPSPs)

long-term potentiation (LTP)

potential mechanism for experience-dependent synaptic plasticity

neural circuit in the hippocampus (trisynaptic circuit)

pathway: entorhinal cortex → dentate gyrus → CA3 → CA1 → cortex

experiment

stimulating electrode in dentate gyrus

• before LTP: weak EPSPs (mild depolarization)

• inducing LTP: high-frequency stimulation produces repetitive EPSPs on post-synaptic cell

• after LTP: stronger EPSPs; sensitive post-synaptic neuron

measuring LTPs

stimulating the presynaptic axon causes bigger EPSPs in the postsynaptic cell

NMDA receptor

• opens a calcium channel

• at resting membrane potential, HOWEVER, the NMDA calcium channel is blocked by a magnesium ion

  • when glutamate binds to the NMDA receptor, the channel does not allow calcium to enter

AMPA receptor

• binding of glutamate to an AMPA receptor causes sodium channels to open

• results in depolarization/EPSP

AMPA and NMDA receptors

1. glutamate binding to AMPA causes depolarization

2. strong and persistent depolarization repels the magnesium ion in the NMDA

3. calcium enters the cell

4. calcium activates second messenger cascades (long lasting changes)

calcium → second messenger cascades

1. transport of intracellular AMPA receptors to the membrane

2. changes in gene expression that results in production of more AMPA

how could LTP underline memory in a network of neurons?

example: viewing movies (pattern completion: reinstatement of memory with a partial cue)

• you see a movie; LTP strengthens connections; you see an ad for that movie; reminded of the movie (activation of the same neurons)

• activation over and over → increases LTP strength

pattern completion

reinstatement of memory with a partial cue

• during experience, activity patterns strengthen specific connections in local circuit

• activation of the subset of original representation results in reinstatement of original experience

hippocampus and time-limited role in memory in rodents

experiment

• mice trained to locate position of baited arm

• either day 1 or 30 days, the hippocampus was inactivated and mice tested for memory activation

• inactivation of memory

  • disrupted recent but not remote memory retrieval

  • after 30 days, memory depended on other brain areas

findings

• hippocampus is biredirectionally connected to the cortex

systems-level memory formation (memory encoding and consolidation)

1. during experience (online): info is temporarily stored in the hippocampus via LTP or similar (memory encoding)

2. after experience (offline): info is gradually transferred from the hippocampus to the cortex (memory consolidation)

when memory consolidation occurs

1. at times with no new experiences

2. sleep/rest

3. sleep

   1. beneficial for memory formation

   2. lack of sleep slows memory consolidation

2-stage model for memory formation in the hippocampal cortical circuit

• information to cortex after experience to the hippocampus

• representations in the hippocampus, not in the cortex

• hippocampus → cortex repeatedly (1000 times)

• remains in cortex after memory consolidation

electrophysiological recordings

experiment

• rodents traversing (experience)

• place cells (firing at specific places in the hippocampus)

• trajectory (codes for location and path; left to right)

  • trajectories in space are encoded by sequences of hippocampal place cell spiking

DURING experiment: place and trajectories in space

hippocampus during sleep

• hippocampal replay: time-compressed re-occurrence of same sequence of place-cell firing as during behavior

reflects recent experience

generated in hippocampus and prominent in sleep

coordinated with cortical regions

supports learning

space vs memory

• hippocampus in rodents most strongly encodes/replays spatial locations

• hippocampus in humans critical for episodic memory

  • episodic memory is a mental travel in time / space referenced to self

  • episodic memory may share evolutionary origin with navigation