Systems level investigation of di-synaptic circuit involved in panic disorder

惊恐障碍双突触回路的系统水平研究

• 批准号: 8889531
• 负责人: Jessica Jillian Walsh
• 金额: $ 5.24万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8889531
• 关键词: Adverse effects; American; Anxiety; Anxiety Disorders; Area; Arousal; Beds; Behavior; Behavioral; Blood Pressure; Body Temperature; Brain Stem; Brain region; Breathing; Carbon Dioxide; Cell Nucleus; Cells; Dependence; Development; Disease; Drug Targeting; Etiology; Exposure to; Frequencies; Fright; Functional disorder; Goals; Heart Rate; Hypothalamic structure; Individual; Innovative Therapy; Investigation; Knowledge; Lateral; Lead; Left; Limbic System; Maintenance; Mediating; Mediator of activation protein; Medical; Mental disorders; Molecular; National Institute of Mental Health; Nature; Neural Pathways; Neuraxis; Neurologic; Neurons; Neurotransmitters; Nucleus solitarius; Panic Attack; Panic Disorder; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Physiological; Pituitary Gland; Play; Population; Property; Research; Risk; Rodent; Role; Severities; Site; Stimulus; Stress; Symptoms; Synapses; System; Techniques; Testing; Time; Viral; Work; anxiety-like behavior; anxiety-related behavior; base; cell type; effective therapy; hindbrain; hypocretin; improved; nerve supply; neural circuit; novel; optogenetics; paraventricular nucleus; public health relevance; response; stem; stressor; stria terminalis; targeted treatment; treatment of anxiety disorders

DESCRIPTION (provided by applicant): There is an urgent need for more targeted therapies to treat Panic Disorder (PD), a mental disorder which is characterized by recurring and often unexpected panic attacks. The NIMH estimates that 6 million Americans currently suffer from PD, with about one-third of patients becoming housebound due to the severity of their symptoms. Although it is a widespread mental illness, there is a dearth of medical therapies to treat the disorder. Many patients are prescribed anti-depressants, which do not specifically target the symptoms of PD, have numerous negative side effects, and can lead to the exacerbation of panic attacks in some individuals. Alternatively, benzodiazapenes, often prescribed as anti-anxiety medication, are extremely powerful drugs that can only be used for short periods of time and put one at risk for developing dependence. The lack of available therapies stems, in part, from the paucity of knowledge of the underlying neurological basis of anxiety disorders. Although previous research has shown that the brain stem and the limbic system are involved in PD, very little is known about the specific circuits responsible for mediating the various aspects of the disorder. Recent studies have found hypocretin-releasing neurons in the lateral hypothalamus to be necessary for the onset and maintenance of PD. Dr. de Lecea and his colleagues have previously studied the role hypocretin plays in setting an arousal threshold. This suggests hypocretin is involved in anxiety disorders, which are associated with a state of hyper-arousal. Hypocretin is also known to be involved in regulating many of the physiological alterations which accompany panic attacks, including increased breathing and heart rate and exaggerated responses to interoceptive stimuli. This proposal hypothesizes that different subpopulations of neurons in the lateral hypothalamus have distinct electrophysiological properties and adaptations in response to anxiety-provoking stimuli. Experimentally I plan to investigate, through projection-specific optogenetic activation, the role each subpopulation may play in mediating anxiety-like behaviors. Furthermore, preliminary studies on a group of nucleus solitarious tract neurons (A2), which receive innervation from hypocretin cells in the lateral hypothalamus, have revealed that activation of these cells instigat anxiety-like behaviors. By studying the projections of these neurons, this project seeks to identify and characterize the synaptic targets of A2 neurons which contribute to anxiety disorders. These proposed molecular and cellular studies will provide very useful and highly novel information, both for improving our knowledge of the circuitry of PD and for identifying new drug targets to develop more effective treatments for anxiety disorders.

描述（由申请人提供）：迫切需要更有针对性的治疗方法来治疗恐慌症（PD），这是一种精神障碍，其特征是反复出现且经常出乎意料的恐慌发作。NIMH估计，目前有600万美国人患有PD，其中约三分之一的患者由于症状严重而无法出门。虽然这是一种普遍存在的精神疾病，但治疗这种疾病的医学疗法却很缺乏。许多患者服用抗抑郁药，这些药并不是专门针对PD的症状，有许多负面的副作用，并且可能导致一些人的恐慌发作加剧。另外，苯二氮杂苯类，通常作为抗焦虑药物，是一种非常强效的药物，只能在短时间内使用，并使人有产生依赖的风险。缺乏可用的治疗方法，部分原因是缺乏对焦虑症的潜在神经学基础的了解。尽管先前的研究表明，脑干和边缘系统与PD有关，但对负责调节该疾病各个方面的特定回路知之甚少。最近的研究发现，下丘脑外侧的下丘脑释放下丘脑分泌素的神经元对PD的发病和维持是必要的。de Lecea博士和他的同事们之前研究过下丘脑分泌素在设定唤醒阈值方面的作用。这表明下丘脑泌素与焦虑障碍有关，而焦虑障碍与高度觉醒状态有关。下丘脑泌素还参与调节许多伴随惊恐发作的生理变化，包括呼吸和心率增加以及对内感受性刺激的夸张反应。该研究假设，下丘脑外侧不同亚群的神经元在对焦虑刺激的反应中具有不同的电生理特性和适应性。实验上，我计划通过投射特异性光遗传激活来研究每个亚群在介导类焦虑行为中可能发挥的作用。此外，对一组接受下丘脑外侧下丘脑下丘脑分泌素细胞神经支配的孤立核束神经元（A2）的初步研究表明，这些细胞的激活会引发类似焦虑的行为。通过研究这些神经元的投射，本项目旨在识别和表征A2神经元的突触靶点，这些靶点有助于焦虑障碍。这些提出的分子和细胞研究将提供非常有用和高度新颖的信息，既可以提高我们对PD电路的认识，也可以确定新的药物靶点，以开发更有效的治疗焦虑症的方法。