Biology subjects

Aronovici, C.

Publications and source records attributed to Aronovici, C..

3 recordsLinked to original sources

bioRxiv2023

Transcriptional analysis of neuronal ensembles of alcohol memories within the nucleus accumbens

Alcohol-associated memories play an important role in relapse in alcohol use disorder. Disrupting these memories, which become labile upon retrieval, through interference with their reconsolidation process, could reduce relapse. Memories are thought to be encoded within specific patterns of sparsely distributed neurons, called neuronal ensembles. Here, we explored the role of neuronal ensembles in alcohol-memory reconsolidation and relapse and characterized their transcriptional signature. Upon retrieving alcohol-related memories, we observed increased neuronal activation in the nucleus accumbens (NAc). We established the causal role of these NAc ensembles in alcohol-memory reconsolidation using the Daun02 method with the Fos-LacZ transgenic rat, which expresses {beta}-galactosidase ({beta}-gal) under the Fos promoter, allowing the selective ablation of activated neurons. Selective inactivation of the active NAc neuronal ensemble produced a long-lasting attenuation of relapse. Through fluorescence-activated cell sorting (FACS) and RNA sequencing, we found a unique transcriptional fingerprint in activated Fos-positive neuronal ensembles in NAc following alcohol memory retrieval (vs. no retrieval controls) that was not present in the Fos-negative neurons. Our findings underscore the critical role of NAc neuronal ensembles in alcohol-associated memory reconsolidation. These neurons have a unique transcriptional profile that can provide novel targets for reducing alcohol relapse.

neuroscience↗

bioRxiv2023

Involvement of FKBP5, but not of stress, in alcohol memory reconsolidation

Relapse is a fundamental challenge in drug addiction, often evoked by exposure to drug-associated cues. Upon retrieval, memories become temporarily labile before re-stabilizing in a process termed reconsolidation. Therefore, targeting the reconsolidation process offers a therapeutic approach for relapse prevention via the disruption of the drug-cue memories. We recently demonstrated that retrieval of contextual alcohol memories increased the expression of the mRNA encoding for FK506 binding protein 51 (FKBP51), a regulator of the hypothalamic-pituitary-adrenal (HPA) axis. Here, we explored the role of the HPA axis, and FKBP5/FKBP51 in particular, in the reconsolidation of alcohol memories. We found that the FKBP51 inhibitor SAFit2 given before alcohol-memory retrieval using contextual cues prevented the extinction of alcohol place preference behavior in female mice, suggesting that this protein may play a role in cognitive flexibility in a sex-dependent manner. Conversely, the retrieval of alcohol memories using an odor-taste cue did not affect Fkbp5 expression in rats with a history of chronic alcohol consumption, suggesting that FKBP5 may play a differential role in different alcohol-associated memories. In addition, we provide evidence for HPA axis activation following alcohol memory retrieval, by showing that exposure to an alcohol-associated context led to elevated corticosterone secretion. However, we found that the reconsolidation process was unaffected by HPA axis-related manipulations, namely stress exposure, and administration of corticosterone or the glucocorticoid receptors inhibitor, mifepristone. Our results suggest that although FKBP5 can affect cognitive flexibility, and thereby impact the reconsolidation of alcohol memories, this effect is not likely mediated by HPA axis-related mechanisms.

neuroscience↗

bioRxiv2023

ERK1/2 inhibition disrupts alcohol memory reconsolidation and prevents relapse

Relapse to alcohol abuse after periods of abstinence, often caused by cue-induced alcohol craving, is a major challenge in the treatment of alcohol addiction. Therefore, disruption of the cue-alcohol associative memories can diminish the risk of relapse. Upon retrieval, memories become temporarily labile before they reconsolidate in a process that requires protein synthesis. Accumulating evidence suggests that the mammalian target of rapamycin complex 1 (mTORC1), which is responsible for the translation of a subset of dendritic proteins, is crucial for memory reconsolidation. Here, we explored the involvement of two regulatory pathways of mTORC1, namely phosphoinositide 3-kinase (PI3K)-AKT and extracellular regulated kinase1/2 (ERK1/2), in the reconsolidation process in a rat model of non-operant alcohol self-administration. We found that retrieval of alcohol memories using an odor-taste cue increased ERK1/2 activation in the amygdala, but did not affect the PI3K-AKT pathway. Importantly, inhibition of ERK1/2 shortly after alcohol memory retrieval impaired reconsolidation and led to long-lasting suppression of relapse to alcohol drinking. Additionally, we show that attenuation of alcohol memories and relapse was also induced by post-retrieval administration of lacosamide, an inhibitor of collapsin response mediator protein-2 (CRMP2) - a translational product of mTORC1 that is functionally regulated by PI3K-AKT signaling. Together, our findings provide evidence for the crucial role of ERK1/2 and CRMP2 in the reconsolidation of alcohol memories, and mark the FDA-approved drug, lacosamide, as a potential treatment for alcohol use disorder.

neuroscience↗