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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：
10312050
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
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/10312050
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 antagonist 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 social contact 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、防卫行为调节异常等