Cholinergic regulation of amygdalar circuits in emotional memory

摘要 焦虑和恐惧相关的障碍构成了一些最常见的精神疾病。治疗焦虑症 仅此一项，大约三分之一的美国成年人就会在一生中的某个时候受到影响。目前可用的治疗方法 让大约40%的患者症状得不到解决，这突显了新疗法的必要性 被开发出来。合理开发新疗法的一个关键是提高对 调节涉及恐惧和焦虑行为的神经元和电路的神经生物学机制。 大脑中与情绪有关的区域，如杏仁基底外侧核(BLA)和内侧前额叶皮质 (MPFC)依靠theta频段(4-12赫兹)的同步神经元振荡来牵连局部锥体 神经元(PN)和跨大脑区域的同步活动，以进行适当的远程交流，以及 信息处理。这些回路中的异常同步会导致情绪缺陷， 恐惧障碍是其基础。然而，尽管在mPFC和BLA中已经确立了theta振荡的作用 恐惧状态，在BLA中产生振荡并与mPFC同步的机制 人们对此了解甚少。对这些区域的功能至关重要的是神经递质乙酰胆碱(ACh)， 这促进了情绪学习和BLA和mPFC中的theta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会产生一系列的行为 影响，包括引起焦虑，或焦虑缓解状态，抑郁症状，以及扰乱恐惧和消退 学习。此外，在包括人类在内的所有哺乳动物中，BLA接收到的胆碱能最强 胆碱能基底前脑任何靶点的神经支配。尽管它非常稠密的胆碱能 神经支配和情绪记忆的关键作用，令人惊讶的是，人们对其机制知之甚少 ACH通过其调制BLA电路。因此，这些研究的目标是确定 细胞和电路水平内源性释放的ACh如何调节杏仁核微电路来调节恐惧 行为。我们的中心假设是ACh作用于BLA中不同的抑制微回路，以促进 BLA和mPFC之间的局部振荡和同步性，并增强情绪记忆。我们的假设是 基于初步数据显示，基底前脑衍生的ACh改变了BLA回路，并促进了 通过差异调制BLA中不同类型的抑制性中间神经元与mPFC的振荡同步性。 在这里，我们建议使用电生理学，颅内脑电记录，细胞类型特异性靶向， 光遗传学和行为，以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，开启恐惧学习(目标2)和 规定安全提示和威胁提示之间的区别(目标3)。这些研究将为以下问题提供新的线索 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.