Alcohol-specific transcriptional dynamics of memory reconsolidation and relapse

Goltseker, Koral; Garay, Patricia M.; Bonefas, Katherine M.; Iwase, Shigeki; Barak, Segev

doi:10.1038/s41398-023-02352-2

Cited by 5 publications

(33 citation statements)

References 90 publications

(156 reference statements)

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“…Importantly, the increase in ERK1/2 activation was observed in the amygdala, but not in the mPFC and the NAc, which are also known as key regions for drug memory reconsolidation 17,33,44,56,62,[74][75][76] . These results are aligned with the findings of Barak et al that demonstrated increased activation of mTORC1, following retrieval of alcohol memories, using two different retrieval methods 17 .…”

Section: Erk1/2 Is Crucial For Alcohol Memory Reconsolidationmentioning

confidence: 95%

“…Western blot procedure was conducted as previously described 62 . Briefly, immediately after dissection, brain tissues were homogenized in a radioimmunoprecipitation assay (RIPA) buffer containing:150 mM NaCl, 5 mM EDTA, 50 mM Tris HCl, 1% Triton X-100, 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate (SDS) and protease and phosphatase inhibitors.…”

Section: Western Blotmentioning

confidence: 99%

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ERK1/2 inhibition disrupts alcohol memory reconsolidation and prevents relapse

Rahamim,

Liran,

Aronovici

et al. 2023

Preprint

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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.

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Section: Erk1/2 Is Crucial For Alcohol Memory Reconsolidationmentioning

confidence: 95%

Section: Western Blotmentioning

confidence: 99%

ERK1/2 inhibition disrupts alcohol memory reconsolidation and prevents relapse

Rahamim,

Liran,

Aronovici

et al. 2023

Preprint

Self Cite

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show abstract

“…Memory reconsolidation involves complex transcriptional and translational processes crucial for stabilizing memories [63][64][65] . For example, our recent RNA sequencing analysis in mice revealed transcriptional changes in the dorsal hippocampus and mPFC during contextual alcohol memory reconsolidation 15 . However, traditional bulk tissue analyses may be limited due to the small proportion of active neurons post drug-memory retrieval.…”

Section: A Unique Transcriptional Fingerprint Within Alcohol Memory N...mentioning

confidence: 99%

“…The neurobiological mechanisms of alcohol memory reconsolidation have been studied over the past decade. Several mesocorticolimbic regions have been implicated in the reconsolidation of alcohol memories, including the central amygdala (CeA) 3 , basolateral amygdala (BLA) 14 , dorsal hippocampus 15 and mPFC 3,10,15 . Interestingly, although the NAc plays an established role in addiction [16][17][18] , its role in alcohol memory processing and reconsolidation has only scarcely been described 19 .…”

Section: Introductionmentioning

confidence: 99%

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

Aronovici,

Prilutski,

Urshansky

et al. 2023

Preprint

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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 β-galactosidase (β-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.

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“…It is well-established that the process of memory reconsolidation requires de-novo protein synthesis 20,23 , and it has been suggested that gene transcription is also required 24,25 . In line with the latter, using RNA sequencing, we recently characterized increases in the mRNA expression of a set of genes in the hippocampus and medial prefrontal cortex (mPFC) of mice following the retrieval of alcohol memories 25 . One of the genes exhibiting increased expression in the mPFC upon alcohol memory retrieval is Fkbp5 , which encodes for FK506 binding protein 51 (FKBP51), an important regulator of the hypothalamic-pituitary-adrenal (HPA) axis stress response system 26 .…”

Section: Introductionmentioning

confidence: 99%

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

Rahamim,

Aronovici,

Liran

et al. 2023

Preprint

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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 affectFkbp5expression 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.

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Alcohol-specific transcriptional dynamics of memory reconsolidation and relapse

Cited by 5 publications

References 90 publications

ERK1/2 inhibition disrupts alcohol memory reconsolidation and prevents relapse

ERK1/2 inhibition disrupts alcohol memory reconsolidation and prevents relapse

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

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

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