Cholinergic Contribution to Circuits Underlying Depression

摘要 在过去的几十年里，抑郁症的主要药物治疗一直是抑制 单胺类神经递质的突触再摄取。尽管单胺类神经传递的重要性 在抗抑郁剂的疗效不能打折扣，其他神经递质系统已知有助于 抗抑郁药的作用机制。此外，存在一大群没有反应的人 患者需要开发新的化合物来治疗抑郁症。越来越多的数据表明 胆碱能系统可能是开发新型抗抑郁化合物的潜在靶点，以及 过度的胆碱能信号可能参与了抑郁症的病理生理过程。抑郁症可能是 被概念化为一种适应不良的反应，在这种反应中，与压力相关的行为集合不会发生变化 回到允许探索环境和追求自然回报的行为集合。 神经调节剂处于很好的位置，可以协调这些行为集合，并调节开关 在协调的行为状态之间。ACH通过以下途径促进与压力相关的学习和高度警惕 杏仁核中的活动，并通过海马体促进与应激相关的回避。这个 这些大脑区域的影响是不同的，并通过不同的受体亚型来调节，我们 提出这些可以通过释放ACh结合成一系列与应激有关的行为。我们 因此，假设杏仁核和海马区ACh信号的增加促进了向 这种应激相关的行为集合，从而阻断了不同种类的胆碱能受体 促进一种适应性、抗抑郁的反应。在这些研究中，我们将确定神经机制在 杏仁核潜在的应激相关行为的胆碱能调节，检验了相变假说 在应激反应中，海马区ACh信号的增加导致与以下行为相关的行为 抑郁，并确定不同的ACh神经元群体是否投射到杏仁核和 海马区负责胆碱能信号对应激诱导行为的影响。

Abstract The primary pharmacologic treatment for depression over the past several decades has been drugs that inhibit synaptic reuptake of monoamine neurotransmitters. Although the importance of monoamine neurotransmission in antidepressant efficacy cannot be discounted, other neurotransmitter systems are known to contribute to the mechanism of action of antidepressants. Furthermore, the existence of a large group of non-responding patients necessitates development of novel compounds to treat depression. A growing body of data suggests that cholinergic systems may be potential targets for development of novel antidepressant compounds, and that excessive cholinergic signaling may contribute to the pathophysiology of depression. Depression can be conceptualized as a maladaptive response in which the ensemble of stress-related behaviors does not switch back to the collection of behaviors that allow exploration of the environment and pursuit of natural rewards. Neuromodulators are well placed to coordinate these ensembles of behavior and to mediate the switch between coordinated behavioral states. ACh facilitates stress-related learning and hypervigilance through actions in the amygdala and promotes stress-related avoidance mediated through the hippocampus. The effects in each of these brain areas are distinct and mediated through different receptor subtypes, and we propose that these can be bound into an ensemble of stress-related behaviors by release of ACh. We therefore hypothesize that increasing ACh signaling in amygdala and hippocampus facilitates the transition to this stress-related behavioral ensemble and consequently, blocking cholinergic receptors of different kinds promotes an adaptive, antidepressant response. In these studies we will identify neuronal mechanisms in amygdala underlying cholinergic regulation of stress-related behaviors, test the hypothesis that phasic increases in ACh signaling in hippocampus, as occurs in response to stress, induces behaviors related to depression, and determine whether distinct populations of ACh neurons projecting to amygdala and hippocampus are responsible for the effects of cholinergic signaling on stress-induced behaviors.