The thalamic paraventricular nucleus mediates the influence of early-life adversity on reward-seeking behaviors

丘脑室旁核介导早年逆境对寻求奖励行为的影响

• 批准号: 10509392
• 负责人: Cassandra Leigh Kooiker
• 金额: $ 4.25万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10509392
• 关键词: Adult; Animals; Anterior; Behavior; Brain; Cells; Child; Cognitive; Data; Decision Making; Development; Emotional; Environment; Future; Genetic; Genetic Recombination; Health; Human; Impairment; Intervention; Knowledge; Label; Life; Link; Location; Long-Term Effects; Mediating; Mental Depression; Mental Health; Modeling; Molecular; Mood Disorders; Mus; Neurons; Neuropeptides; Phenotype; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Poverty; Prevention; Process; Psychopathology; Published Comment; Repression; Research; Rewards; Risk; Role; Stimulus; Structure; Structure of paraventricular nucleus of thalamus; Testing; Transgenic Mice; Trauma; United States; Urine; Wild Type Mouse; addiction; behavior influence; behavioral impairment; cell type; density; early life adversity; emotional experience; experience; experimental study; food consumption; motivated behavior; neurobiological mechanism; pharmacologic; pleasure; receptor; severe mental illness; sex

Project Summary This proposal centers on the role of the paraventricular nucleus of the thalamus (PVT) in mediating the impact of early life adversity (ELA) on reward-seeking behaviors later in life. I will identify and characterize PVT neuronal populations that are engaged by ELA, test the hypothesis that these neurons execute the enduring effects of ELA on reward-seeking behaviors, and investigate a potential mechanism behind this process. Early life adversity (ELA) consisting of factors such as poverty, trauma, or chaotic environment impacts the lives of over 30% of children in the United States. ELA is associated with poor cognitive and emotional health and increased risk for affective disorders, including depression, PTSD, and addiction, which involve aberrant reward- circuit function. Studies in animals have demonstrated causal relations between ELA and impaired reward- seeking behaviors and enable the establishment of underlying neurobiological mechanisms. It is crucial to understand these associations, because ELA and its consequences, unlike genetic contributors to vulnerability to psychopathologies, may be amenable to prevention or mitigation. The paraventricular nucleus of the thalamus (PVT) is an important component of the reward circuit that encodes remote emotionally-salient experiences to influence future reward-related behaviors. However, it remains unknown if the PVT encodes experiences as remote as ELA and whether PVT neurons activated during ELA contribute to deficits in reward-seeking behaviors later in life. Building on my robust preliminary data and a potent validated naturalistic model of ELA in mice, which provokes deficits in reward-seeking behaviors later in life, my central hypothesis states that PVT neuronal populations are activated during ELA and contribute to ELA- provoked deficits in reward-seeking behaviors later in life. To test this hypothesis I will (a) capitalize on a transgenic mouse for activity-dependent genetic labeling [Targeted Recombination in Active Populations (TRAP2) mice] to determine the the location of neuronal populations within the PVT that are activated by ELA and establish their molecular identity; (b) use chemogenetics to probe the role of PVT neurons activated during ELA in governing reward behaviors later in life; (c) establish the differential PVT activation during reward-seeking behaviors in adult ELA and control mice, with a potential role in the observed behavioral impairments. Together, the proposed experiments will provide critical information about the developmental functions of the PVT and its contributions to the impact of ELA on reward-seeking behaviors, significantly advancing our understanding of the neurobiological mechanisms underlying reward-related psychopathologies.

项目摘要 这一建议集中在丘脑室旁核（PVT）介导的作用， 早期生活逆境（ELA）对晚年寻求奖励行为的影响。我将识别和描述PVT ELA参与的神经元群体，测试这些神经元执行持久的 ELA对奖励寻求行为的影响，并探讨这一过程背后的潜在机制。早期 生活逆境（ELA）由贫困、创伤或混乱的环境等因素组成，影响着人们的生活 超过30%的美国儿童。ELA与认知和情绪健康状况差有关， 情感障碍的风险增加，包括抑郁症，创伤后应激障碍和成瘾，这涉及异常奖励- 电路功能动物研究已经证明了ELA和奖励受损之间的因果关系- 寻求行为，并使潜在的神经生物学机制的建立。至关重要 我理解这些关联，因为ELA及其后果，不像遗传因素对脆弱性的贡献， 可能是可以预防或减轻的。 丘脑室旁核（PVT）是奖赏回路的重要组成部分， 编码遥远的情绪突出的经验，以影响未来的奖励相关的行为。但 仍然未知的是，PVT是否编码像ELA一样遥远的经历，以及PVT神经元是否在ELA期间激活。 ELA有助于在以后的生活中寻求奖励行为的缺陷。根据我的初步数据和 一种有效的经验证的小鼠ELA自然模型，它在小鼠中引起了寻求奖励行为的缺陷， 生活，我的中心假设指出，PVT神经元群体在ELA期间被激活，并有助于ELA- 在以后的生活中引发了寻求奖励行为的缺陷。为了验证这个假设，我将（a）利用一个 用于活动依赖性遗传标记的转基因小鼠 （TRAP 2）小鼠]以确定由ELA激活的PVT内的神经元群的位置 （B）使用化学遗传学来探测PVT神经元的作用，所述PVT神经元在细胞周期中被激活。 ELA在以后的生活中控制奖励行为;（c）在奖励寻求过程中建立差异PVT激活 成年ELA和对照小鼠的行为，在观察到的行为障碍中具有潜在作用。在一起， 拟议的实验将提供有关PVT发育功能及其 ELA对奖励寻求行为的影响的贡献，大大提高了我们对 奖励相关精神病理学的神经生物学机制