BIO SCI N156 Lecture 17: Memory Modulation & Memory Reconsolidation

Memory modulation

Post-place learning injection into amygdala

NE: enhanced rat's retention of platform location

Propranolol: impaired retention

Post-inhibitory avoidance training [with strong foot shock] injection into amygdala

Propranolol: impaired retention

NE: enhanced rat's retention of the foot shock

Memory consolidation processes

Stimulation of the BLA

Inject amphetamine into amygdala following training on place-learning lesion of Morris water maze

Enhanced retention performance

Inject amphetamine into amygdala
following training on visible platform task

Improved retention performance

Caudate: critical for visible platform task

Hippocampus: critical for place learning

This coupling of experiments is a double dissociation

Conclusion: BLA is a "promiscuous" modulator

Can modulate memories requiring different brain systems

BLA modulates memory consolidation

Infusions of amphetamine into BLA enhance memory consolidation processes outside of the BLA

Activating BLA after training enhances memory consolidation

Inactivating BLA prior to testing does not affect memory retrieval

BLA not needed for memory retrieval

Epinephrine

Does not cross BBB

Model for its effect on brain processes

Released from adrenal medulla

Binds to adrenergic receptors on vagal nerve

Vagal nerve releases glutamate on neurons in solitary tract nucleus (NTS)

NTS neurons release glutamate onto neurons in locus coeruleus

Releases NE into BLA

Disrupting any component of the model will prevent arousal from enhancing memory

Lesions of vagus nerve, NTS, LC, or BLA block memory modulating effects of systemic epinephrine injections

Arc translation experimental design

Procedure:

Implant cannula into the BLA of rats

Train on inhibitory avoidance task

Inject with a beta-adrenergic agonist (clenbuterol) or lidocaine

Either sacrifice rats or test on IA task

Hippocampus brain tissue sampled for Arc

Results:

Lidocaine injection group: lower levels of Arc

Clenbuterol group: higher levels of Arc

Suggests that BLA modulates memory be influencing the level of Arc in the hippocampus

Locus coeruleus

Major source of norepinephrine (NE) to many brain regions

Project widely throughout the brain

When NE from LC is released into hippocampus, PKA is activated and phosphorylates GluA1 AMPA-R subunit

Facilitates trafficking of GluA1s into dendritic spine, increases memory strength

Emotional stress dives phosphorylation of GluA1 receptors via NE in brain

NE regulation of AMPA-R trafficking

NE acts in time-dependent fashion to facilitate LTP

Design:

Timing of NE on LTP identical to timing needed for post-training epinephrine to facilitate mem. consolidation

Time dependence of NE in GluA1 phos. matches LTP of above

Pre-exposure in chamber: no shock

Next day: placed in chamber for <5 sec., foot shocked

Next day: testing for context-fear memory

Results: with weak conditioning, WT mice, but not GR1AA mice (with mutation blocking GluA1 phos.), showed enhancement of memory by epinephrine

Suggests that epinephrine facilitates memory formation via GluA1 phos. during learning

Glucose mobilization/bioenergetics

Glucocorticoid stress hormone release

Bioenergetics: flow of energy in cells

Glucose: primary source of energy

Enters brain via cerebral vasculature

Arousing event activates adrenal medulla to release epinephrine into blood stream, binds to liver cells

Liver secretes glucose into blood, enters brain

Systemic injections of epinephrine or glucose influence memory strength in dose-dependent manner

Stress hormones: epinephrine and glucocorticoids

Made by diff. regions of adrenal gland

Epinephrine activated quickly via neural route

Glucocorticoids activated more slowly, stay elevated for longer

Cortisol

Bind to GR and MR receptors

Affect:

Postsynaptic function: affect signaling for rapid events in postsynaptic cell (e.g., PKA activation); takes longer to manifest, but longer lasting, effects

Presynaptic function: facilitate NT release; rapid effect

Gene transcription: regulation of stress response genes; longer to manifest, but longer lasting, effects

Delayed response (peaks 15-30 min. after stressor)

Chronic stress hormones are bad for brain

Synaptic loss, impairment of neurogenesis, neuronal loss

Impaired memory processes

Mild and temporary increases in stress hormones can enhance memory processes

NE and glucocorticoids work in concert to influence memory

Facilitate rapid early induction

Facilitate the maintenance of the synaptic strength

Model: experience has two independent effects

  1. Initiate the acquisition and storage of the memory trace
  1. Can activate the release of adrenal hormones that can modulate the processes that store the memory

PTSD

Hypothesis: PTSD occurs when memory modulation goes awry

Stress makes stronger memories, which are then re-experienced frequently

Drives stress and makes the memories stronger yet through many iterations: kind of feed-forward loop

Possible treatments

Beta-blockers: administer the drug during the behavioral therapy, block effect of epinephrine and NE

Behavioral treatment: discuss triggering event, use virtual reality to immerse person back in experience

Re-wiring the circuit so that the memory is not coupled with the stress hormone release

Time-dependent stabilization

Disrupt or facilitate specific cellular processes during consolidation period, impair or enhance memory at testing [respectively]

Retrieved memory

Under some conditions, retrieving or reactivating a consolidated memory can return it to an active, labile state