Delineating the epigenetic and neural mechanisms by which early life scarcity alters motivated behavior

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PROJECT SUMMARY Early life experiences can have profound and long-lasting consequences on health trajectories. Social inequities, such as those caused by low resources, have been identified as important factors that influence the development of psychiatric illnesses, including substance use disorders (SUD). In this proposal, a rat model of early life scarcity will be combined with behavioral paradigms of substance abuse to better understand the neural and molecular mechanisms that influence reward processing in individuals who experienced adversity early in life. Each brain region contains highly heterogenous cell populations that include different neuronal subtypes as well as glia. Accounting for the diversity and differences in cell types is essential to improving our understanding of the impact of inequities on the brain and on motivated behavior. In this proposal, the influence of early life scarcity on adult reward processing and motivation will be characterized in male and female rats using state-of-the-art behavioral approaches where rats are tested for their motivation to earn drug (opioid) or natural (social and sucrose) rewards. Our preliminary data indicate sex- and reinforcer-specific effects of early scarcity. This work will be expanded here, and in some of the experiments, rats will choose between two available reinforcers. Given that interventions for SUD involve social reinforcers, these results could have profound implications for the prevention and treatment of SUD in populations who experience socioeconomic inequality. To better identify factors that mediate the effects of early scarcity on motivated behavior, we will delineate molecular changes in the nucleus accumbens—a central hub in the brain that is critical for motivated and reward-related behaviors— and causally link them to behavior. To this end, we will perform cell-type specific assays of gene expression and chromatin remodeling, an epigenetic process that regulates the expression of genes. Lastly, the proposal will examine the impact of early life scarcity on the electrophysiological properties of two major neuron subtypes in the nucleus accumbens, delineating cell type-specific physiological changes induced by altering the early environment. Collectively, this proposal leverages cutting-edge behavioral, molecular, and physiological approaches to provide a better understanding of the neurochemical and intracellular pathways affected by early life scarcity that drive changes in motivated behavior. Importantly, the proposed experiments will determine sex- and cell-type specific mechanisms by which early life scarcity alters the substance use trajectory, identifying potential targets for improving therapeutics and prevention of SUDs.