Cholinergic regulation of amygdalar circuits in emotional memory

摘要 焦虑和恐惧相关的障碍包括一些最常见的精神疾病。对焦虑症 仅在美国，就有大约三分之一的成年人会在一生中的某个时候受到影响。目前可用的治疗 大约40%的患者没有症状解决，这强调了对新疗法的需求， 发展。合理开发新疗法的关键是提高对 神经生物学机制，调节神经元和电路参与恐惧和焦虑行为。 大脑中与情绪有关的区域，如基底外侧杏仁核（BLa）和内侧前额叶皮层 （mPFC）依赖于θ波段（4-12 Hz）的同步神经元振荡， 神经元（PN）和同步活动跨大脑区域进行适当的长距离通信， 信息处理.这些回路的异常同步会导致情感缺陷， 是恐惧症的基础然而，尽管mPFC和BLa中θ振荡的作用已经确立， 恐惧状态，即BLa中产生振荡并与mPFC同步的机制 我们对此知之甚少。对这些区域的功能至关重要的是神经递质乙酰胆碱（ACh）， 这促进了BLa和mPFC的情绪学习和θ振荡。支持ACh在以下方面的重要作用： 情绪回路是发现胆碱能信号的扰动产生了一系列的行为 影响，包括致焦虑或抗焦虑状态、抑郁症状以及恐惧和灭绝中断 学习此外，在包括人类在内的所有哺乳动物中，BLa接收到迄今为止最强大的胆碱能， 胆碱能基底前脑的任何靶点的神经支配。尽管它的胆碱能神经非常密集 神经支配，在情绪记忆中至关重要，令人惊讶的是，对机制知之甚少 ACh通过其调节BLa回路。因此，这些研究的目的是确定 内源性ACh如何调节杏仁核微回路来调节恐惧 行为。我们的中心假设是ACh作用于BLa中不同的抑制性微回路， BLa和mPFC之间的局部振荡和同步，并增强情绪记忆。我们的假设是 基于初步数据显示，基底前脑来源的ACh改变BLa回路， 振荡同步与mPFC的差异调制不同类型的抑制性中间神经元在BLa。 在这里，我们建议使用电生理学，颅内EEG记录，细胞类型特异性靶向， 光遗传学和行为来确定突触乙酰胆碱调节的电路机制 局部BLa振荡（目标1），促进BLa-mPFC振荡同步和门恐惧学习（目标2）， 调节安全和威胁线索之间的区别（目标3）。这些研究将揭示新的光 焦虑和恐惧障碍的潜在机制以及ACh在情绪处理中的作用。

Abstract Anxiety and fear related disorders comprise some of most common mental illnesses. For anxiety disorders alone, approximately 1 in 3 U.S adults will be affected at some point in their life. Currently available treatments leave approximately 40% of patients without symptom resolution underscoring the need for new therapies to be developed. A key to the rational development of new treatments is improved understanding of the neurobiological mechanisms that regulate the neurons and circuits involved in fear and anxiety behaviors. Areas of the brain involved in emotion, such as the basolateral amygdala (BLa) and medial prefrontal cortex (mPFC) rely on synchronized neuronal oscillations in the theta band (4-12 Hz) to entrain local pyramidal neurons (PNs) and synchronize activity across brain regions for proper long-range communication, and information processing. Aberrant synchronization in these circuits contributes to deficits in emotion that underlie fear disorders. However, despite the established role for theta oscillations in mPFC and BLa during fear states, the mechanisms through which oscillations are generated in the BLa and synchronize with mPFC are poorly understood. Critical to the function of these regions is the neurotransmitter acetylcholine (ACh), which promotes emotional learning and theta oscillations in BLa and mPFC. Supporting the vital role of ACh in emotional circuits is the finding that perturbations of cholinergic signaling produce a range of behavioral effects, including anxiogenic, or anxiolytic states, depressive symptoms, and disrupted fear and extinction learning. Moreover, in all mammals, including humans, the BLa receives by far the most robust cholinergic innervation of any target of the cholinergic basal forebrain. Despite its remarkably dense cholinergic innervation, and critical importance in emotional memory, surprisingly little is known about the mechanisms through which ACh modulates BLa circuits. Therefore, the objective of these studies is to determine at a cellular and circuit level how endogenously released ACh modulates amygdalar microcircuits to regulate fear behaviors. Our central hypothesis is that ACh acts on distinct inhibitory microcircuits in the BLa to promote local oscillations and synchrony between BLa and mPFC and enhance emotional memory. Our hypothesis is based on preliminary data showing that basal forebrain-derived ACh alters BLa circuitry and facilitates oscillatory synchrony with mPFC by differentially modulating distinct types of inhibitory interneurons in BLa. Here, we propose to use electrophysiology, intracranial EEG recording, cell type specific targeting, optogenetics, and behavior to determine the circuit mechanism by which synaptic acetylcholine modulates local BLa oscillations (Aim 1), facilitates BLa-mPFC oscillatory synchrony and gates fear learning (Aim 2) and regulates discrimination between safe and threatening cues (Aim 3). These studies will shed new light on mechanisms underlying anxiety and fear disorders and the role of ACh in emotional processing.