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

描述早期生命匮乏改变动机行为的表观遗传和神经机制

• 批准号: 10631152
• 负责人: Debra A Bangasser
• 金额: $ 63.91万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631152
• 关键词: Accounting; Adult; Affect; Behavior; Behavioral; Behavioral Paradigm; Brain; Brain region; Cells; Data; Development; Electrophysiology (science); Environment; Epigenetic Process; Female; Gene Expression; Gene Expression Profiling; Health; Individual; Inequity; Intervention; Life; Life Experience; Link; Mediating; Mental disorders; Modeling; Molecular; Motivation; Neuroglia; Neurons; Nucleus Accumbens; Opioid; Pathway interactions; Pharmaceutical Preparations; Physiological; Population; Prevention; Property; Rattus; Resources; Rewards; Substance Use Disorder; Substance abuse problem; Sucrose; Testing; Therapeutic; Work; cell type; chromatin remodeling; early life adversity; experience; experimental study; improved; male; motivated behavior; neural; neurochemistry; neuromechanism; outcome disparities; preclinical study; reinforcer; resilience; reward processing; sex; social; social engagement; socioeconomic disparity; substance use; substance use prevention; substance use treatment

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.

项目总结 早期生活经历可能会对健康轨迹产生深远而持久的影响。社会不平等， 如低资源造成的问题，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)。在这个提案中，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，以更好地理解神经和 影响早年经历逆境的个体奖赏过程的分子机制。 每个大脑区域都包含高度不同的细胞群，这些细胞群还包括不同的神经元亚型 作为神经胶质细胞。考虑到细胞类型的多样性和差异对于提高我们对 不平等对大脑和动机行为的影响。在这项建议中，早年生命匮乏的影响 关于成年大鼠的奖励处理和动机将在雄性和雌性大鼠身上使用最先进的技术来表征 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，早期稀缺性的性别和增强剂的特定影响。这部作品 将在这里扩展，在一些实验中，老鼠将在两种可用的增强剂中进行选择。vt.给出 对SUD的干预涉及社会增强者，这些结果可能会对 在经历社会经济不平等的人群中预防和治疗SUD。为了更好地识别 调节早期稀缺性对动机行为的影响的因素，我们将描绘 伏隔核是大脑中的一个中枢，对动机和奖赏相关行为至关重要。 并将它们与行为因果联系起来。为此，我们将进行针对细胞类型的基因表达和 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 研究早期生命匮乏对脑内两种主要神经元亚型电生理特性的影响 伏隔核，描绘了改变早期细胞类型所引起的特定细胞类型的生理变化 环境。总的来说，这一建议利用了行为、分子和生理方面的尖端技术 提供更好地了解早期影响的神经化学和细胞内通路的方法 生命的匮乏推动了动机行为的改变。重要的是，拟议的实验将决定性别- 以及早期生命稀缺改变物质使用轨迹的细胞类型特定机制，识别 改善肥胖症的治疗和预防的潜在目标。