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: 10387895
• 负责人: Cassandra Leigh Kooiker
• 金额: $ 4.09万
• 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/10387895
• 关键词: thalamic; paraventricular; nucleus; mediates; influence

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 这一提议的核心是丘脑室旁核(PVT)在调节 早期生活逆境(ELA)对晚年奖赏行为的影响。我将对PVT进行鉴定和描述 由ELA参与的神经元群体测试了这些神经元执行持久的 ELA对奖赏寻求行为的影响，并探讨这一过程背后的潜在机制。早些时候 生活逆境(ELA)由贫困、创伤或混乱的环境等因素组成，影响着 超过30%的美国儿童。ELA与认知和情绪健康状况不佳有关 增加情感障碍的风险，包括抑郁症、创伤后应激障碍和成瘾，这些涉及异常的奖励- 电路功能。在动物身上的研究表明，ELA和受损的奖赏之间存在因果关系。 寻找行为，并使潜在的神经生物学机制得以建立。这是至关重要的 了解这些关联，因为ELA及其后果不同于导致脆弱性的遗传因素 对精神病来说，可能是可以预防或缓解的。 丘脑室旁核(PVT)是奖赏回路的重要组成部分。 编码远程情绪显著体验，以影响未来与奖励相关的行为。然而，它 PVT是否编码与ELA一样遥远的体验，以及PVT神经元是否在 ELA导致了晚年寻求奖赏行为的缺陷。基于我稳健的初步数据和 在小鼠中有效地验证了ELA的自然主义模型，该模型在以后的奖励寻求行为中引起缺陷 LIFE，我的中心假设是PVT神经元群体在ELA期间被激活，并对ELA- 在以后的生活中引发了寻求奖励行为的缺陷。为了检验这一假设，我将(A)利用一个 用于活性依赖遗传标记的转基因小鼠[在活跃种群中进行靶向重组 (TRAP2)小鼠]以确定ELA激活的PVT内神经元群体的位置 并建立它们的分子特征；(B)使用化学遗传学来探索PVT神经元在 ELA在控制晚年奖赏行为中的作用；(C)在奖赏寻求过程中建立不同的PVT激活 成年ELA和对照小鼠的行为，与观察到的行为损害有潜在的作用。一起， 拟议中的实验将提供关于PVT和其发育功能的关键信息。 ELA对奖赏行为的影响，极大地促进了我们对 奖赏相关精神病态背后的神经生物学机制。