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: 10531250
• 负责人: Patrick Alexander Forcelli
• 金额: $ 61.76万
• 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/10531250
• 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; Magnetic Resonance Imaging; Mediating; Microinjections; Midbrain structure; Modeling; Motor; Muscimol; National Institute of Mental Health; Pathology; Pathway interactions; Patients; Pattern; 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 tracer; antagonist; anxiety treatment; behavioral phenotyping; behavioral response; defense response; designer receptors exclusively activated by designer drugs; disabling symptom; effective therapy; emotion dysregulation; emotional reaction; experimental study; hindbrain; interest; midbrain central gray substance; neural; neural circuit; neuroimaging; nonhuman primate; novel; pharmacologic; response; side effect; social; social contact; 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.

情绪反应过度，社会功能受损，防御行为异常调节，以及 自主神经失调是一系列出现在一系列焦虑中的衰弱症状。 精神错乱。焦虑症作为一个群体，影响着大约20%的美国人口和焦虑的治疗 疾病只有部分有效，而且往往与副作用有关。虽然大多数人的注意力都集中在 在额叶-边缘环路上，知识的当前缺口是后脑环路的贡献。第二个大调 差距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 在啮齿动物模型中发生了这种情况，这导致了知识的第三个主要缺口： 非人灵长类动物的这些回路。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，灵长类动物 大脑的组织方式经常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的组织是必不可少的 大脑。我们先前已经发现，急性去抑制上丘深层(DLSC)，a 通过局部注射GABAA拮抗剂荷包牡丹碱，中脑结构加速了一种夸张的状态。 防御和情绪反应(DER)。基底外侧杏仁核(BLA)的同时抑制作用减弱 部分但不是全部的防御反应，表明在单个组件下面的差异电路 防御性反应。在此应用中，我们建议确定后脑所使用的电路架构 (DLSC，PAG)和前脑(BLA，杏仁中央核，枕)区域相互作用，产生 防御性情绪反应，无条件的恐惧，社会行为的失调，以及自主的唤醒。在……里面 这两个提出的具体目标，我们将检验假设，诱导抑制边缘成分将 减弱从中脑结构诱发的DER，以及引起中脑结构抑制的DER将 减弱从前脑诱发的DER。使用核磁共振引导的脑内微量输液，我们将 瞬间激活和停用该网络的组件，并确定由此产生的对焦虑的影响- 相关的行为反应。在这些实验之后，我们将使用解剖示踪技术来 描述感兴趣的投影路径。我们还将使用Designer进行验证实验 受体仅由设计药物(DREADD)激活，这种药物已在啮齿动物身上使用，但 仍然很少在灵长类动物中使用，以帮助推动这项翻译技术向前发展。我们预计我们的数据将 对理解焦虑症的病理有一定的意义。