Vulnerability and Resilience In Addiction: Integrating Epigenetics, Synapses, Circuits, and Behavioral Trajectories

Objetivo

Individual vulnerability and resilience to drug addiction, resulting from gene-environment (GxE) interplay, remain poorly understood despite their profound implications for personalized interventions. Even with cocaine, a highly addictive drug, ‘only’ ~20% of human cocaine users will lose control and become addicted, a bimodal distribution also observed in rodents. In isogenic C57Bl/6 mice, it is again ~20% of the individuals that transition to addiction, suggesting a role for neuroepigenetic regulation of vulnerability and resilience. VARIANT will unravel the mechanisms underlying behavioral trajectories in addiction-like behaviors within genetically homogeneous mice, with a focus on neuroepigenetic mechanisms that modulate synaptic plasticity, shaping circuit function. Our preliminary data indicate that hallmark behavioral phenotypes—preference for drug over natural food reward, and measures of motivation and impulsivity—exhibit marked inter-individual variability.
VARIANT’s Aim1 will identify behavioral and epigenetic phenotypes predicting vulnerability and resilience for compulsive cocaine self-administration and in an optogenetic mimicry model of addiction. Aim2 will modulate the transition to compulsion through chronic mild stress exposure, while Aim3 will characterize the effects of stress exposure and environmental enrichment rescue on synaptic transmission in key addiction circuits. Aim4 will use behavioral and molecular interventions to ‘erase’ epigenetic changes and reduce addiction vulnerability, restoring resilience.
VARIANT will parse neuroepigenetic sources of variability, uncovering how life experience shapes the expression of identical genomes to yield divergent addiction trajectories. Our findings will inform personalized patient approaches by revealing behavioral and molecular vulnerability biomarkers, guiding circuit-level interventions to promote resilience. Ultimately, VARIANT will enable precision medicine in the field of addiction.

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