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 PSD Ubiquitin Proteasome Proteins

Proteasomes Degrade Scaffolding Protein Tagged with Ubiquitin PSD Scaffolding proteins Glutamate Calcium AMPA Ubiquitin Proteasome NMDA 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 PSD Scaffolding proteins Glutamate Calcium AMPA Ubiquitin Proteasome NMDA

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 self- administer a drug and become drug addicted. A conditioned stimulus (CS) is also presented when the drug is delivered. The presentation of the drug- associated CS can produce drug- seeking 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?