[R01] Histone Acetylation and Synaptic Mechanisms in D1-MSNs Underlying Resilience to Compulsive-like Alcohol Drinking

Ente: National Institute on Alcohol Abuse and Alcoholism

Scadenza: 2030-07-31

Importo max: 3.112.314 EUR

Paese: US

Descrizione

PROJECT SUMMARY While significant progress has been made in characterizing the molecular and neurobiological signatures of Alcohol Use Disorder (AUD), much less is known about the molecular and cellular mechanisms that shape its onset, particularly those conferring vulnerability or resilience. Clarifying these early determinants is essential for designing more effective, targeted interventions. Our long-term goal is to elucidate the molecular and synaptic mechanisms that underlie individual differences in susceptibility to AUD. The overarching objective of this proposal is to identify mechanisms that promote resilience to compulsive alcohol drinking, a clinically relevant phenotype of AUD characterized by continued drinking despite adverse consequences. Specifically, we will investigate the role of Sirt7, a histone deacetylase, in D1-type medium spiny neurons (D1-MSNs) within the dorsomedial striatum (DMS), focusing on how it shapes synaptic plasticity and modulates resilience to compulsive alcohol drinking. Our central hypothesis is that that epigenetic changes in D1-MSNs of the dorsomedial striatum, driven primarily by histone acetylation and modulated by Sirt7, promote transcriptional and synaptic adaptations that jointly confer resilience to compulsive-like drinking. The rationale for this project is grounded in compelling preliminary data suggesting that transcriptional changes in the histone acetylation process, particularly those regulated by Sirt7, are associated with reduced compulsive-like drinking in mice through the transcriptional control of synaptic pathways. We will test this hypothesis by training mice to self- administer alcohol and evaluating their drinking behavior in response to aversive stimuli (e.g., quinine adulteration and foot shock), which serve as well-established operational model of punishment-resistant or compulsive-like alcohol drinking. This will be addressed through two Specific Aims: Aim 1: Determine the contribution of Sirt7 in D1-MSNs to the regulation of histone acetylation and compulsive-like alcohol drinking; Aim 2: Define synaptic and intrinsic adaptations in D1-MSNs associated with resilience to compulsive-like drinking and assess their modulation by Sirt7. The proposed research is innovative in its integration of epigenetic and synaptic mechanisms to uncover how their interaction contributes to resilience to compulsive alcohol drinking. By combining precise molecular and physiological manipulations with unbiased genome-wide profiling, this study will dissect genetically independent contributors to AUD vulnerability. Departing from prevailing paradigms, this cell-type–specific and mechanistically grounded approach provides a powerful framework for novel therapeutic discoveries in alcohol use disorder Istituzione: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI PI: Daniel Almeida da Silva e Silva Progetto: 1R01AA033111-01

Settori: National Institute on Alcohol Abuse and Alcoholism

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