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

项目摘要 早期生活经历可能对健康轨迹产生深远而持久的影响。社会不平等， 如资源不足引起的资源短缺，已被确定为影响发展的重要因素 精神疾病，包括物质使用障碍（SUD）。在这个提议中，一个早期生命的老鼠模型 稀缺性将与药物滥用的行为范式相结合，以更好地了解神经和 分子机制，影响在生命早期经历逆境的个体的奖励处理。 每个大脑区域都包含高度异质的细胞群，其中也包括不同的神经元亚型 作为神经胶质。解释细胞类型的多样性和差异对于提高我们对细胞的理解至关重要。 不平等对大脑和动机行为的影响。在这个提议中，早期生命稀缺的影响 成年奖励处理和动机的特点是在雄性和雌性大鼠使用国家的最先进的 行为方法，其中测试大鼠获得药物（阿片类药物）或自然（社会和 蔗糖）奖励。我们的初步数据表明，性别和生育早期稀缺的具体影响。这项工作 将在这里扩展，在一些实验中，老鼠将在两种可用的替代品中进行选择。给定 SUD的干预措施涉及社会干预者，这些结果可能对社会发展产生深远的影响。 在经历社会经济不平等的人群中预防和治疗SUD。更好地识别 因素，调解影响早期匮乏的动机行为，我们将描绘分子变化， 伏隔核--大脑的中央枢纽，对于积极性和奖励相关行为至关重要-- 并将它们与行为联系起来。为此，我们将进行基因表达的细胞类型特异性测定， 染色质重塑，一种调节基因表达的表观遗传过程。最后，该提案将 研究生命早期稀缺对两种主要神经元亚型的电生理特性的影响， 神经核，描绘细胞类型特异性生理变化引起的改变早期 环境总的来说，这项提案利用了尖端的行为，分子和生理学 方法，以提供更好地了解神经化学和细胞内途径受早期 生命的稀缺性会促使动机行为的改变。重要的是，拟议中的实验将确定性别- 和细胞类型的特定机制，通过这些机制，早期生命的稀缺性改变了物质使用的轨迹， 改善SUD治疗和预防的潜在靶点。

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.