Transcript NLM2e Ch14 Lecturex

14
The Fate of Retrieved
Memories
Chapter Goals
Under some conditions, retrieving or reactivating a
consolidated memory can return it to an active, labile
state. The goal of this chapter is to provide an
understanding of the empirical facts and theoretical
concepts that are associated with this observation.
This will be done by discussing:
• Key empirical findings
• Active trace theory
• Reconsolidation theory
• How retrieval returns the trace to an unstable, labile
state
• How the trace is restabilized
• The concept of trace updating
Reactivated Memory Disrupted by ECS
(A) A fear-conditioning experiment was
used to study the vulnerability of a
reactivated memory—a noise CS was
paired with a shock US. In one
condition, 24 hours after fear
conditioning, the CS was presented to
reactivate the fear memory. Some
animals received electroconvulsive
shock (ECS), while others did not. In
the second condition, the fear memory
was not reactivated, but animals
received either ECS or no ECS. All
animals were tested for fear of the CS.
(B) The results of the experiment.
When the memory trace was
reactivated by briefly presenting the
CS, ECS disrupted the memory for the
CS–shock experience. ECS had no
effect when it was presented in the
absence of shock.
Active Trace Theory
This figure illustrates the assumptions of active trace theory. Memories
exist in either a short-term memory (STM) active state or a long-term
memory (LTM) inactive state. (A) Novel experience can create an active
STM trace that will decay into the inactive LTM state. (B) Retrieval cues
can retrieve an inactive LTM trace and place it in the active state that
then will decay into the inactive LTM state. Memories in the active state
are more vulnerable to disruption than memories in the inactive state.
Reconsolidation Theory: Nader’s Finding
(A) The design of Nader et al.’s 2000
experiment. Rats were conditioned to
an auditory-cue–CS paired with a
shock–US. Following the reactivation
of the fear memory, the protein
synthesis inhibitor anisomycin or the
vehicle solution in which the drug was
suspended was injected into the lateral
nucleus of the amygdala. Rats were
then given either a short-term memory
(STM) test or a long-term memory
(LTM) test. (B) Anisomycin disrupted
the long-term retention of the
reactivated fear memory but had no
effect on the short-term retention of the
memory. (After Nader et al., 2000.)
Reconsolidation Theory
(A) A retrieval cue activates a well consolidated but inactive memory
trace from long-term memory. The synaptic connections linking the
neurons involved in the trace become unbound. However, retrieval
also initiates protein synthesis and the memory trace is reconsolidated.
Thus, when it returns to the inactive state it will be stable. (B) If protein
synthesis is prevented, the memory trace will be weakened or lost
when it returns to the inactive state.
Comparison of Active Trace and Reconsolidation Theory
Assessing Reconsolidation Theory: Only the Reactivated Trace
Needs to Be Reconsolidated
Rats acquired two fear memories. However, only the
reactivated memory (CS1) was disrupted by U0126, a
drug that interferes with reconsolidation.
How Does Reactivation Destabilize the Trace? A Role for the UPS
This figure illustrates key events that destabilize the
synaptic basis of a memory trace.
Proteasomes Degrade Proteins Tagged with Ubiquitin
Proteins
PSD
Ubiquitin
Proteasome
Proteasomes Degrade Scaffolding Protein Tagged with Ubiquitin
Glutamate
Calcium
NMDA
AMPA
Scaffolding
proteins
Ubiquitin
PSD
Proteasome
The collapse of the scaffold results in AMPA receptor loss from
the spine.
Inhibiting the Proteasome System Prevents Destruction of the
Scaffolding Proteins Tagged by Ubiquitin
Glutamate
Calcium
NMDA
AMPA
Scaffolding
proteins
Ubiquitin
Proteasome
PSD
Reconsolidation Is Unnecessary If Proteasomes Are Inhibited
Normally anisomycin prevents reconsolidation of a reactivated
memory. However, inhibiting proteasome function with βlac
blocks anisomycin’s effect. Thus, if protein is not degraded
there is no need for new protein.
Trace Restabilization and Trace Updating: A Reactivated Trace
Can Be Strengthened
Injecting the PKA
activator 6-BNZ-cAMP,
compared to injecting the
vehicle alone, into the
basolateral amygdala
following reactivation
trials increased the rat’s
fear response to a CS
paired with shock. (After
Tronson et al., 2006.)
Memory Erasure: A Potential Therapy: Preventing Drug Relapse
This figure illustrates the
drug addiction–relapse
cycle. Encountering cues
associated with drug use
can lead to relapse.
Memory Erasure: A Potential Therapy: Cues Associated with
Drugs Induce a Cocaine High
Cues associated with drug
use induce a conditioned
cocaine high, a craving for
cocaine, and a wish to get
high. The graph shows
changes in the subjective
state of recovering cocaine
addicts after viewing a
video showing simulated
purchase, preparation, and
smoking of crack cocaine.
The subjects were patients
in a treatment center and
had not used cocaine for
about 14 days.
Memory Erasure: A Potential Therapy: Preventing Relapse by
Interfering with Reconsolidation
A) The experimental methodology used
to train a rat to press a lever to selfadminister a drug and become drug
addicted. A conditioned stimulus (CS) is
also presented when the drug is
delivered. The presentation of the drugassociated CS can produce drugseeking behavior (relapse) in rats that
have learned that lever pressing no
longer produces the drug.
(B) The vehicle or an antisense that
blocks the translation of the gene
Zif268 is delivered after repeated CS
presentations.
(C) This graph shows that during the test for relapse the rats treated with
Zif268 antisense made fewer bar presses than rats who received the
vehicle. This result suggests that Zif268 antisense prevented the
reconsolidation of the drug memory associated with the CS.
Stepping Back: Boundary Conditions and Unanswered Questions
• How general is reconsolidation?
• Does every retrieved memory destabilize and have
to restabilize?
• What are the boundary conditions that determine
when reconsolidation occurs?
• Does the type of memory matter? For example,
most experiments use training procedures that are
aversive or highly arousing. Does this matter?
• Does the strength of the memory trace matter?
Stepping Back: Boundary Conditions and Unanswered Questions
• Are weak memories more prone to destabilization
than strong memories?
• Does the age of the memory matter?
• Are more recently established memories more
prone to destabilization than old memories?