On circuit mechanisms of reward behaviors after early-life adversity

摘要 早期生活逆境(ELA)与精神疾病的易感性有关，精神疾病涉及精神障碍 大脑的奖赏回路。这些弱点可能表现为快感缺乏、奖励欲望降低或 快感是严重抑郁症的核心特征。然而，ELA与快感缺失的联系是否 在人类身上很难建立因果关系，这种关系背后的机制也不清楚。我们的 特征明确的啮齿动物ELA模型可靠地以性别依赖的方式导致奖赏回路中断， 然而，受影响最大的电路节点和路径仍不清楚。 在寻找ELA敏感的奖励电路元件的过程中，我们发现并表征了一种 杏仁基底外侧核(BLA)至伏核(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，并且 我们的初步数据表明，CRH+BLA-NAC新途径也是如此。建立在这些基础上 稳健的数据，我们将确定投影在小鼠中的功能作用，并测试ELA- 这一途径的诱导可塑性有助于ELA对奖赏追求和性别的性别依赖效应 消费，极大地促进了我们对精神疾病起源的理解。 目标1将验证CRH+BLA-NAC新通路调节奖赏追逐的假设 (动机)和/或消费通常饲养的雄性和雌性小鼠，利用时间 解决光遗传学和形式动机任务，以探索投射的具体作用 奖励的激励方面与消费方面。Aim 2将使用相同的技术来确定角色 CRH+BLA-NAC在由ELA引起的异常的性别特异性奖励行为中的投射。目标3将 研究CRH+BLA-NAC异常输入调节奖赏的分子和细胞机制 行为：我们将在体外光遗传激活BLA-后确定投射的靶细胞。 NAc内投射纤维的起源，并确定GABA神经传递与CRH的相对作用 投射刺激对雄性和雌性小鼠奖赏行为影响的受体激活。

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.