Cholinergic regulation of amygdalar circuits in emotional memory

情绪记忆中杏仁核回路的胆碱能调节

基本信息

批准号：
10737193
负责人：
Aaron M Jasnow
金额：
$ 66.59万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
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：
2023-06-07 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737193
关键词：
Acetylcholine Adult Affect Alzheimer&apos s Disease Amygdaloid structure Anti-Anxiety Agents Anxiety Anxiety Disorders Area Behavior Behavioral Brain Brain region Cholecystokinin Communication Cues Data Development Discrimination Disease Disinhibition Drug Addiction Electroencephalography Electrophysiology (science)Emotional Emotional Disturbance Emotional disorder Emotions Frequencies Fright Goals Human Impairment Interneurons Knowledge Learning Life Mammals Medial Memory Mental disorders Muscarinic Acetylcholine Receptor M3 Neurons Neurotransmitters Patients Periodicity Population Prefrontal Cortex Regulation Resolution Role Safety Schizophrenia Series Signal Transduction Somatostatin Symptoms Synapses Techniques Testing Therapeutic Transgenic Mice Trauma basal forebrain cell type cholinergic combat conditioned fear depressive symptoms emotional behavior emotional stimulus hippocampal pyramidal neuron improved in vivo information processing innovation learning extinction mouse model nerve supply neurobiological mechanism novel novel therapeutics optogenetics therapeutic development transmission process

项目摘要

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.

抽象的焦虑和恐惧相关的疾病包括一些最常见的精神疾病。对于焦虑症仅大约三分之一的美国成年人就会在生命中的某个时刻受到影响。目前可用的治疗方法大约 40% 的患者症状没有得到缓解，这凸显了需要新疗法得到开发。合理开发新疗法的关键是提高对新疗法的认识调节涉及恐惧和焦虑行为的神经元和回路的神经生物学机制。大脑中涉及情绪的区域，例如基底外侧杏仁核 (BLa) 和内侧前额皮质 (mPFC) 依靠 θ 频带 (4-12 Hz) 中的同步神经元振荡来带动局部锥体神经元（PN）并同步大脑区域的活动以进行适当的远程通信，以及信息处理。这些回路中的异常同步会导致情绪缺陷，从而是恐惧症的根源。然而，尽管在 mPFC 和 BLa 期间，theta 振荡的作用已确定恐惧状态，BLa 中产生振荡并与 mPFC 同步的机制人们了解甚少。这些区域的功能至关重要的是神经递质乙酰胆碱 (ACh)，它促进 BLa 和 mPFC 的情绪学习和 theta 振荡。支持 ACh 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行为影响，包括致焦虑或抗焦虑状态、抑郁症状以及恐惧和消退障碍学习。此外，在包括人类在内的所有哺乳动物中，BLa 接收迄今为止最强大的胆碱能胆碱能基底前脑任何目标的神经支配。尽管其胆碱能非常密集令人惊讶的是，人们对神经支配以及情绪记忆中的至关重要的机制知之甚少 ACh 通过它调节 BLa 电路。因此，这些研究的目的是确定细胞和回路水平内源性释放的乙酰胆碱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 中不同的抑制微电路，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 BLa 电路并促进通过差异调节 BLa 中不同类型的抑制性中间神经元，实现与 mPFC 的振荡同步。在这里，我们建议使用电生理学、颅内脑电图记录、细胞类型特异性靶向、光遗传学和行为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）和规范安全线索和威胁线索之间的区分（目标 3）。这些研究将带来新的启示焦虑和恐惧症的机制以及乙酰胆碱在情绪处理中的作用。