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

• 批准号: 9896581
• 负责人: Patrick Alexander Forcelli
• 金额: $ 70.74万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 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/9896581
• 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

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.

夸大的情绪反应，受损的社会功能，防御行为的异常调节， 自主神经失调是一系列使人衰弱的症状，存在于一系列焦虑症中 紊乱焦虑症，作为一个群体，影响约20%的美国人口和治疗焦虑 这些疾病仅部分有效，并且通常伴随副作用。虽然大多数注意力都集中在 关于额边缘电路，目前的知识差距是后脑电路的贡献。第二主 间隙是后脑和前脑部位如何相互作用的。此外，绝大多数电路级特性 在啮齿动物模型中发生，这导致了知识的第三个主要空白： 在非人类的灵长类动物身上发现了这些回路。事实上，正如我们实验室和其他实验室的发现所证明的那样， 大脑的组织方式往往与啮齿动物的大脑惊人地不同。因此，理解 灵长类动物大脑中这些回路的组织对于理解人类大脑的组织至关重要。 个脑袋我们以前发现，急性去抑制的深层上级丘（DLSC）， 中脑结构，由GABAA拮抗剂，荷包牡丹碱局灶性输注，沉淀的状态夸大 防御和情绪反应（Defense and Emotional Reaction，DER）同时抑制基底外侧杏仁核（BLA）减少 一些但不是所有的防御反应，表明差异电路的个别组成部分， 防御性反应。在本应用中，我们建议确定后脑的电路结构 (DLSC，PAG）和前脑（BLA，杏仁核中央核，枕）区域相互作用以产生 防御性情绪反应、无条件恐惧、社会行为失调和自主觉醒。在 这两个提出的具体目标，我们将测试的假设，诱导抑制的边缘成分将 减弱从中脑结构诱发的DER，并且中脑结构的诱导抑制将 减弱前脑诱发的DER。使用MRI引导的脑内微量输注， 瞬时激活和激活这个网络的组成部分，并确定对焦虑的影响- 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， 表征感兴趣的投射路径。我们还将使用Designer执行验证实验 受体专门由设计药物激活（DREADDs），这已经在啮齿动物中使用，但 仍然很少用于灵长类动物，以帮助推动这种转化技术的发展。我们希望我们的数据 对理解焦虑症的病理学有重要意义。