On circuit mechanisms of reward behaviors after early-life adversity

论早年逆境后奖赏行为的循环机制

• 批准号: 10735759
• 负责人: Tallie Z. Baram
• 金额: $ 61.02万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735759
• 关键词: Adult; Affect; Amygdaloid structure; Anhedonia; Behavior; Brain; Cells; Consumption; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Depressed mood; Drug usage; Emotional; Equipment; Experimental Models; Exposure to; Feeling; Female; Fiber; Food; Genetic; Genetically Engineered Mouse; Health; Home; Human; Individual; Life; Major Depressive Disorder; Mediating; Mental Depression; Mental Health; Mental disorders; Mental health promotion; Methods; Modeling; Molecular; Motivation; Mus; Neurons; Neuropeptides; Nucleus Accumbens; Pathway interactions; Phenotype; Rattus; Receptor Activation; Recording of previous events; Rewards; Rodent; Role; Signal Transduction; Stress; Technology; Testing; Transgenic Mice; Woman; antagonist; biocytin; brain pathway; cell type; early life adversity; experience; gamma-Aminobutyric Acid; human subject; immunocytochemistry; insight; male; men; neurotransmission; novel; open source; operation; optogenetics; pleasure; sex; substance use; temporal measurement

SUMMARY Early-life adversity (ELA) is associated with vulnerability to mental illnesses that involve disruption of the brain’s reward circuits. These vulnerabilities may manifest as anhedonia, a reduction in reward desire or pleasure that is core feature of major depression. However, whether the association of ELA with anhedonia is causal is difficult to establish in humans, and mechanisms underlying this relationship are not understood. Our well-characterized rodent ELA model reliably leads to reward-circuit disruptions in a sex-dependent manner, yet the circuit nodes and pathways that are most affected remain unclear. In searching for ELA-sensitive reward-circuit components, we discovered and are characterizing a novel projection from basolateral amygdala (BLA) to nucleus accumbens (NAc) that expresses the neuropeptide corticotropin releasing hormone (CRH). Neurons expressing CRH are often stress-sensitive, and our preliminary data suggest this is also the case for the novel CRH+BLA-NAc pathway. Building on these robust data, we will determine the functional roles of the projection in mice and test the hypothesis that ELA- induced plasticity in this pathway contributes to sex-dependent effects of ELA on reward pursuit and consumption, significantly advancing our understanding of the origins of mental illness. Aim 1 will test the hypothesis that the novel CRH+BLA-NAc pathway modulates reward pursuit (motivation) and / or consumption in typically reared male and female mice, capitalizing on the temporal resolution of optogenetics and on formal motivation tasks to probe the specific role of the projection in the motivational vs. consummatory aspects of reward. Aim 2 will use the same technologies to determine the role of the CRH+ BLA-NAc projection in aberrant, sex-specific reward behaviors resulting from ELA. Aim 3 will examine the molecular and cellular mechanisms by which aberrant CRH+ BLA-NAc inputs regulate reward behaviors: we will identify the target cells of the projection following ex vivo optogenetic activation of BLA- origin projection fibers in the NAc, and determine the relative roles of GABA neurotransmission vs CRH receptor activation in the effects of projection stimulation on reward behaviors in male and female mice.

总结 早期生活逆境（ELA）与易患精神疾病有关，这些疾病涉及破坏 大脑的奖赏回路这些弱点可能表现为快感缺乏，奖励欲望的减少， 快乐是抑郁症的核心特征然而，ELA与快感缺乏的关联是否 因果关系在人类中很难确定，这种关系的机制也不清楚。我们 良好表征的啮齿动物ELA模型可靠地以性别依赖的方式导致奖赏回路中断， 然而，受影响最大的回路节点和路径仍然不清楚。 在寻找对ELA敏感的奖励电路元件时，我们发现了一种 基底外侧杏仁核（BLA）到丘脑核（NAc）的新投射， 神经肽促肾上腺皮质激素释放激素（CRH）。表达CRH的神经元通常是应激敏感的， 我们的初步数据表明这也是新的CRH+BLA-NAc途径的情况。根据这些 强大的数据，我们将确定在小鼠的投射功能的作用和测试的假设，ELA- 在这一途径中诱导的可塑性有助于ELA对奖赏追求的性别依赖性效应， 消费，大大推进了我们对精神疾病起源的理解。 目的1将检验新的CRH+BLA-NAc通路调节奖赏追求的假设 （动机）和/或消费的典型饲养的雄性和雌性小鼠，利用时间 决议的光遗传学和正式的动机任务，以探讨具体作用的投影在 奖励的动机和完善方面。Aim 2将使用相同的技术来确定角色 CRH+ BLA-NAc投射在ELA导致的异常、性别特异性奖励行为中的作用。目标3将 研究异常CRH+ BLA-NAc输入调节奖赏的分子和细胞机制 行为：我们将鉴定BLA的离体光遗传学激活后投射的靶细胞。 起源投射纤维在NAc，并确定GABA神经传递与CRH的相对作用 受体激活在投射刺激对雄性和雌性小鼠奖赏行为影响中的作用。