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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

基本信息

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
项目类别：
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

项目摘要

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.

概括早年逆境（ELA）与易患精神疾病有关，这些疾病涉及精神障碍大脑的奖励回路。这些弱点可能表现为快感缺乏、奖励欲望减少或快乐是重度抑郁症的核心特征。然而，ELA 与快感缺失是否存在关联？在人类中很难确定因果关系，并且这种关系背后的机制尚不清楚。我们的特征明确的啮齿动物 ELA 模型以性别依赖性方式可靠地导致奖赏回路中断，然而受影响最严重的电路节点和通路仍不清楚。在寻找 ELA 敏感奖励电路组件时，我们发现并正在表征从基底外侧杏仁核（BLA）到伏隔核（NAc）的新投射表达了神经肽促肾上腺皮质激素释放激素（CRH）。表达 CRH 的神经元通常对压力敏感，并且我们的初步数据表明，新的 CRH+BLA-NAc 途径也是如此。在此基础上可靠的数据，我们将确定投影在小鼠中的功能作用并测试 ELA-的假设该通路中诱导的可塑性有助于 ELA 对奖励追求和性别依赖性的影响消费，极大地增进了我们对精神疾病起源的理解。目标 1 将检验新的 CRH+BLA-NAc 通路调节奖励追求的假设（动机）和/或典型饲养的雄性和雌性小鼠的消耗，利用时间光遗传学和正式动机任务的解决方案，以探讨投影在奖励的动机与完成性方面。目标 2 将使用相同的技术来确定角色 ELA 导致的异常、性别特异性奖赏行为中 CRH+ BLA-NAc 投射的研究。目标3将检查异常 CRH+ BLA-NAc 输入调节奖赏的分子和细胞机制行为：我们将在离体光遗传学激活 BLA-后识别投射的靶细胞 NAc 中的起源投射纤维，并确定 GABA 神经传递与 CRH 的相对作用受体激活对雄性和雌性小鼠的奖励行为的投射刺激的影响。