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: 8716510
• 负责人: Jessica Jillian Walsh
• 金额: $ 4.99万
• 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/8716510
• 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; base; cell type; effective therapy; hindbrain; hypocretin; improved; nerve supply; neural circuit; novel; optogenetics; paraventricular nucleus; public health relevance; response; stem; stressor; stria terminalis

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）：迫切需要更多的靶向疗法来治疗惊恐障碍（PD），这是一种以反复发作和经常意外的惊恐发作为特征的精神障碍。NIMH估计，目前有600万美国人患有PD，其中约三分之一的患者因症状严重而无法出门。虽然这是一种普遍的精神疾病，但缺乏治疗这种疾病的医学疗法。许多患者被开了抗抑郁药，这些药物并不专门针对PD的症状，具有许多负面副作用，并可能导致某些个体的恐慌发作加剧。另外，苯二氮杂卓类药物，通常作为抗焦虑药物，是非常强大的药物，只能在短时间内使用，并使一个人处于发展依赖的风险。缺乏可用的治疗方法，部分原因是缺乏对焦虑症潜在神经学基础的了解。虽然以前的研究表明，脑干和边缘系统参与PD，很少有人知道负责调解疾病的各个方面的具体电路。最近的研究发现，下丘脑外侧部的下丘脑泌素释放神经元对于PD的发生和维持是必要的。de Lecea博士和他的同事们以前研究过下丘脑泌素在设定唤醒阈值中的作用。这表明下丘脑泌素与焦虑症有关，焦虑症与过度觉醒状态有关。下丘脑泌素还已知参与调节伴随惊恐发作的许多生理改变，包括呼吸和心率增加以及对内感受性刺激的过度反应。这个建议假设，不同亚群的神经元在外侧下丘脑有不同的电生理特性和适应性的焦虑激发刺激。在实验上，我计划通过投射特异性光遗传学激活来研究每个亚群在介导焦虑样行为中可能发挥的作用。此外，初步研究的一组核孤束神经元（A2），接受神经支配的下丘脑外侧的下丘脑泌素细胞，这些细胞的激活灌输焦虑样行为。通过研究这些神经元的投射，该项目旨在识别和表征导致焦虑症的A2神经元的突触靶点。这些拟议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，以开发更有效的焦虑症治疗方法。