Limbic-midbrain interactions in defense and emotional arousal

边缘系统-中脑在防御和情绪唤醒中的相互作用

基本信息

批准号：
10094260
负责人：
Patrick Alexander Forcelli
金额：
$ 63.57万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-03 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10094260
关键词：
Acoustics Acute Agonist Amygdaloid structure Anatomy Animal Model Animals Anxiety Anxiety Disorders Architecture Arousal Attention Attenuated Behavior Behavioral Bicuculline Blood Pressure Brain Cell Nucleus Data Deep Brain Stimulation Disease Disinhibition Dissection Dissociation Elements Emotional Fright GABA Antagonists Goals Heart Rate Human Impairment Individual Infusion procedures Knowledge Lead Magnetic Resonance Imaging Mediating Microinjections Midbrain structure Modeling Motor Muscimol National Institute of Mental Health Pathology Pathway interactions Patients Pattern Pharmacology Population Primates Prosencephalon Psychiatry Pulvinar structure Refractory Regulation Research Research Domain Criteria Rodent Rodent Model Role Route Science Series Side Site Snakes Social Behavior Social Functioning Social Interaction Stimulus Structure Substantia nigra structure Symptoms Techniques Technology Testing Therapeutic Intervention Validation Visual Withdrawal anatomical tracing anxiety treatment base behavioral phenotyping behavioral response defense response designer receptors exclusively activated by designer drugs disabling symptom effective therapy emotion dysregulation emotional reaction experimental study frontal lobe hindbrain interest midbrain central gray substance neural circuit neuroimaging nonhuman primate novel relating to nervous system response side effect social superior colliculus Corpora quadrigemina treatment of anxiety disorders vocalization

项目摘要

Exaggerated emotional reactivity, impaired social function, aberrant regulation of defense behaviors, and autonomic dysregulation are a constellation of debilitating symptoms that are present in a range of anxiety disorders. Anxiety disorders, as a group, impact about 20% of the US population and treatments for anxiety disorders are only partially effective and often associated with side effects. While most attention has focused on fronto-limbic circuitry, a current gap in knowledge is the contribution of hindbrain circuits. A second major gap is how hindbrain and forebrain sites interact. Moreover, the vast majority of circuit-level characterization has occurred in rodent models, which leads to the third major gap in knowledge: the functional organization of these circuits in non-human primates. Indeed, as evidenced by findings in our lab and by others, the primate brain is organized in often surprisingly different manners than the rodent brain. Thus, understanding the organization of these circuits in the primate brain is essential to understanding the organization of the human brain. We have previously found that acute disinhibition of the deep layers of the superior colliculus (DLSC), a midbrain structure, by focal infusions of the GABAA antagonist, bicuculline, precipitated a state of exaggerated defensive and emotional reactivity (DER). Concurrent inhibition of the basolateral amygdala (BLA) reduced some but not all of the defense responses, suggesting differential circuitry underlying individual components of the defensive response. In this application, we propose to determine the circuit architecture by which hindbrain (DLSC, PAG) and forebrain (BLA, central nucleus of the amygdala, pulvinar) regions interact to produce defensive emotional reactions, unconditioned fear, dysregulation of social behavior, and autonomic arousal. In the two proposed specific aims, we will test the hypotheses that induced inhibition of the limbic components will attenuate the DER evoked from the midbrain structures and that induced inhibition of midbrain structures will attenuate the DER evoked from the forebrain. Using MRI-guided intracerebral microinfusions, we will transiently activate and inactivate components of this network and determine the resulting impact on anxiety- relevant behavioral responses. Following these experiments, we will employ anatomical tracer techniques to characterize projection pathways of interest. We will also perform validation experiments using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), which have grown in use in rodents, but remain rarely used in primates, to help move this translational technology forward. We expect that our data will have implications for understanding the pathology of anxiety disorders.

情绪反应过度、社会功能受损、防御行为调节异常，以及自主神经失调是一系列令人衰弱的症状，存在于一系列焦虑中失调。作为一个整体，焦虑症影响着约 20% 的美国人口以及焦虑症的治疗方法疾病仅部分有效，并且常常伴有副作用。虽然大多数注意力都集中在在额叶边缘回路方面，当前的知识空白是后脑回路的贡献。第二专业间隙是后脑和前脑部位相互作用的方式。此外，绝大多数电路级表征啮齿动物模型中发生了这种情况，这导致了知识上的第三个主要差距：非人类灵长类动物中的这些电路。事实上，正如我们实验室和其他实验室的研究结果所证明的那样，灵长类动物大脑的组织方式通常与啮齿动物大脑的组织方式惊人地不同。因此，了解灵长类动物大脑中这些回路的组织对于理解人类的组织至关重要脑。我们之前发现上丘深层（DLSC）的急性去抑制是一种通过 GABAA 拮抗剂荷包牡丹碱的局部输注，中脑结构引发了一种夸大的状态防御和情绪反应（DER）。基底外侧杏仁核 (BLA) 的同时抑制减少一些但不是全部的防御反应，表明各个组件背后的差分电路防守反应。在此应用中，我们建议确定后脑的电路架构（DLSC、PAG）和前脑（BLA、杏仁核中央核、枕丘）区域相互作用，产生防御性情绪反应、无条件恐惧、社会行为失调和自主神经唤醒。在为了实现这两个提出的具体目标，我们将测试诱导边缘系统抑制的假设减弱中脑结构引起的 DER，并且对中脑结构的诱导抑制将减弱前脑诱发的 DER。使用 MRI 引导的脑内微输注，我们将暂时激活和失活该网络的组成部分，并确定对焦虑产生的影响- 相关的行为反应。在这些实验之后，我们将采用解剖示踪技术来描述感兴趣的投影路径。我们还将使用 Designer 进行验证实验专门由设计药物激活的受体（DREADD）已在啮齿类动物中广泛使用，但仍然很少在灵长类动物中使用，以帮助推动这种转化技术的发展。我们预计我们的数据将对于理解焦虑症的病理学具有重要意义。