Reactivation-dependent amnesia for object recognition memory is contingent on hippocampal theta–gamma coupling during recall

Hippocampal dopamine D1/D5 receptor-dependent destabilization is necessary for object recognition memory (ORM) updating through reconsolidation. Dopamine also regulates hippocampal theta and gamma oscillations, which are involved in novelty and memory processing. We found that, in adult male rats, ORM recall in the presence of a novel object, but not in the presence of a familiar one, triggers hippocampal theta–gamma coupling. Hippocampal theta–gamma coupling (hPAC) does not happen when ORM destabilization is prevented by blocking D1/D5 receptors, but artificial hPAC generation during recall in the presence of a familiar object enables the amnesic effect of reconsolidation inhibitors. Therefore, hPAC controls ORM destabilization, and its modulation could increase reconsolidation-based psychotherapy efficacy.

Complex Interactions Between Sex and Stress on Heroin Seeking

Rationale: Stress plays a dual role in substance use disorders as a precursor to drug intake and a relapse precipitant. With heroin use at epidemic proportions in the United States, understanding interactions between stress disorders and opioid use disorder is vital and will aid in treatment of these frequently comorbid conditions.Objectives: Here, we combine assays of stress and contingent heroin self-administration (SA) to study behavioral adaptations in response to stress and heroin associated cues in male and female rats.Methods: Rats underwent acute restraint stress paired with an odor stimulus and heroin SA for subsequent analysis of stress and heroin cue reactivity. Lofexidine was administered during heroin SA and reinstatement testing to evaluate its therapeutic potential. Rats also underwent tests on the elevated plus maze, locomotor activity in a novel environment, and object recognition memory following stress and/or heroin.Results: A history of stress and heroin resulted in disrupted behavior on multiple levels. Stress rats avoided the stress conditioned stimulus and reinstated heroin seeking in response to it, with males reinstating to a greater extent than females. Lofexidine decreased heroin intake, reinstatement, and motor activity. Previous heroin exposure increased time spent in the closed arms of an elevated plus maze, activity in a round novel field, and resulted in object recognition memory deficits.Discussion: These studies report that a history of stress and heroin results in maladaptive coping strategies and suggests a need for future studies seeking to understand circuits recruited in this pathology and eventually help develop therapeutic approaches.

Domain-selective BET inhibition attenuates transcriptional and behavioral responses to cocaine

Epigenetic pharmacotherapies have emerged as a promising treatment option for substance use disorder (SUD) due to their ability to reverse maladaptive transcriptional and behavioral responses to drugs of abuse. In particular, inhibitors of bromodomain and extra terminal domain (BET) reader proteins have been shown to reduce cocaine- and opioid-seeking behaviors in rodents. However, only pan-BET inhibitors, small molecules that bind to both bromodomains (BD1 and BD2) with all BET proteins, have been investigated in animal models of SUD. Given the potential side effects associated with pan-BET inhibitors, safer and more selective strategies are needed to advance BET therapeutics as a potential treatment for SUD. Here, we show that RVX-208, a clinically tested, BD2-selective BET inhibitor, dose-dependently reduced cocaine conditioned place preference in male mice, similar to the pan-BET inhibitor JQ1. In other behavioral experiments, RVX-208 treatment did not alter distance traveled, anxiety-like behavior, or novel object recognition memory. At the transcriptional level, RVX-208 attenuated the expression of multiple cocaine-induced genes in the nucleus accumbens. RVX-208 produced a distinct transcriptional response in stimulated primary neurons compared to JQ1 but had little effect on gene expression in non-stimulated neurons. Together, these data indicate that targeting domain-specific BET mechanisms may be an effective and safer strategy to reduce cocaine-induced neurobehavioral adaptations.

Bizarreness and Typicality Effects of Color on Object Recognition Memory

The bizarreness effect on object recognition is a strong phenomenon, but its influence has been inconsistent for bizarre object color. In this study, we manipulated three factors in separate experiments to determine whether a color bizarreness effect on object recognition memory would occur and, if not, why. Participants first saw (i.e., learned) object pictures that were either bizarrely or typically colored; they then completed a recognition memory test. In three experiments, we then manipulated (a) degree of color bizarreness (Experiment 1), (b) the orientation task (Experiment 2), and (c) additional demands for object identification (Experiment 3). In Experiment 1, we provided 49 undergraduate participants with object pictures whose colors were typical, moderately atypical, or bizarre and found no color bizarreness effect on recognition memory even for extremely bizarre colors. In Experiment 2, we manipulated the orientation task in that 28 young adult participants expressed their preferences for the pictures on a three-point scale while another 28 participants judged how natural the pictures were. Each orientation task group better recognized typically-colored rather than bizarrely-colored objects (typicality effect). In Experiment 3, we asked 27 young adults to identify the objects during the learning phase to ensure that they paid attention to the objects’ bizarre colors; recognition memory was then unaffected by either color bizarreness or typicality. Thus, despite a general bizarreness effect in recognition memory, bizarre colors are less likely to influence object recognition memory.