Optogenetic inhibition of the dorsal hippocampus CA3 region during early-stage cocaine-memory reconsolidation disrupts subsequent context-induced cocaine seeking in rats

The dorsal hippocampus (DH) is key to the long-term maintenance of cocaine memories following retrieval-induced memory destabilization; even though, it is not the site of protein synthesis-dependent memory reconsolidation. Here, we took advantage of the temporal and spatial specificity of an optogenetic manipulation to examine the role of the cornu ammonis 3 subregion of the DH (dCA3) in early-stage cocaine-memory reconsolidation. Male Sprague-Dawley rats expressing eNpHR3.0 in the DH were trained to self-administer cocaine in a distinct context and underwent extinction training in a different context. Rats then received a 15-min memory-reactivation session, to destabilize cocaine memories and trigger reconsolidation, or remained in their home cages (no-reactivation controls). Optogenetic inhibition of the dCA3 for 1 h immediately, but not 1 h, after memory reactivation resulted in cocaine-memory impairment as indicated by reduction in drug-seeking behavior selectively in the cocaine-paired context 3 d later, at test, relative to responding in no-inhibition, no-reactivation, and no-eNpHR3.0 controls. Cocaine-memory impairment was associated with reduced c-Fos expression, an index of neuronal activation, in the dCA3 stratum lucidum (SL) and stratum pyramidale (SP) at test. Based on these observations and extant literature, we postulate that recurrent circuits in the SP are activated during early-stage memory reconsolidation to maintain labile cocaine memories prior to protein synthesis-dependent restabilization in another brain region, such as the basolateral amygdala. Furthermore, SL and SP interneurons may enhance memory reconsolidation by limiting synaptic noise in the SP and also contribute to recall as elements of the updated cocaine engram or retrieval links.

Growth Hormone Secretagogue Receptor 1A Antagonist JMV2959 Effectively Prevents Morphine Memory Reconsolidation and Relapse

Relapse to drug seeking after prolonged abstinence is a major problem in the clinical treatment of drug addiction. The use of pharmacological interventions to disrupt established drug reward memories is a promising strategy for the treatment of drug addiction. A growth hormone secretagogue receptor 1 A antagonist, JMV2959, has been shown to reduce morphine-induced conditioned place preference (CPP) in rats within hours of intervention; thus, JMV2959 is a potential candidate for drug addiction treatment. However, the effect of JMV2959 on reconsolidation to disrupt drug seeking remains unknown. In this study, we assessed the effect of JMV2959 on morphine induced memory reconsolidation to inhibit drug seeking after drug withdrawal. Our results showed that the administration of JMV2959 (6 mg/kg) significantly reduced environmental cue induced CPP, which suggested a preventive effect of JMV2959 on morphine induced memory reconsolidation. Additionally, JMV2959 administration significantly altered the locomotor activity and food and water intake but did not significantly alter the natural reward preference. We concluded that JMV2959 may be an effective candidate to treat drug addiction.

Reconsolidation behavioral updating of human emotional memory: A comprehensive review and unified analysis of successes, replication failures, and clinical translation

The annulment of a human emotional memory through reconsolidation behavioral updating has been documented in over twenty laboratory studies since the first such report in 2010. However, fourteen studies have reported non-replication, the cause(s) of which remain unclear. This review examines all successful and unsuccessful studies in detail, in an attempt to identify (a) the specific probable causes of non-replication and (b) how clinical translation might optimally be designed. For analyzing non-replications, a set of criteria is defined for principled identification of specific moments of prediction error (PE) in experimental procedures, including latent cause transitions, based on a preponderance of empirical evidence. A previously overlooked element of experimental procedure is in that way identified as being potentially decisive, and a unified, testable explanation is proposed for behavioral updating successes and failures in terms of the presence or absence of a PE experience. That in turn allows successful studies to be compared for the internal experiences induced in subjects, rather than compared for their external procedures, revealing an invariant set of three experiences shared by all successful updating studies despite their diverse procedures. Clinical translation, defined as replication of those experiences, not any particular procedure, is illustrated by an actual case, one of many published cases that have documented prompt transformational change produced by that specific methodology, suggesting memory reconsolidation as the mechanism of change. Lastly, the core empirical findings of successful reconsolidation updating studies are compared with previously proposed frameworks of memory reconsolidation in psychotherapy, exposing significant departures from scientific fidelity.

Avoidance memory requires CaMKII activity to persist after recall

Avoidance memory is destabilized when recalled concurrently with conflicting information, and must undergo a hippocampus-dependent restabilization process called reconsolidation to persist. CaMKII is a serine/threonine protein kinase essential for memory processing; however, its possible involvement in avoidance memory reconsolidation has not yet been studied. Using pharmacological, electrophysiological and optogenetic tools, we found that in adult male Wistar rats hippocampal CaMKII is necessary to reconsolidate avoidance memory, but not to keep it stored while inactive, and that blocking reconsolidation via CaMKII inhibition erases learned avoidance responses.