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

描述(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)，这是一种以反复发作且经常是意外的恐慌症为特征的精神障碍。NIMH估计，目前有600万美国人患有帕金森病，大约三分之一的患者由于症状的严重性而呆在家里。尽管它是一种普遍的精神疾病，但治疗这种疾病的药物很少。许多患者被开了抗抑郁药，这些药物不是专门针对帕金森氏症的症状，有许多负面副作用，并可能导致某些人的恐慌症发作加剧。或者，苯二氮烯，通常作为抗焦虑药物处方，是非常有效的药物，只能短期使用，使一个人处于形成依赖的风险中。缺乏可用的治疗方法，部分原因是对焦虑症的潜在神经学基础缺乏了解。尽管之前的研究表明，脑干和边缘系统参与了帕金森氏症，但对负责调节该疾病各个方面的具体回路知之甚少。最近的研究发现，下丘脑外侧区的下丘脑下部下丘脑下部下丘脑下德莱西亚博士和他的同事们此前曾研究过下丘脑泌素在设定唤醒阈值方面所起的作用。这表明下丘脑泌素与焦虑症有关，焦虑症与高度唤醒状态有关。众所周知，下丘脑泌素还参与调节许多伴随恐慌症发作的生理变化，包括呼吸和心率增加以及对内感刺激的夸大反应。这一建议假设，下丘脑外侧区不同的神经元亚群具有不同的电生理特性，并对焦虑刺激做出反应。在实验上，我计划通过投射特定的光基因激活，研究每个亚群在调节焦虑样行为中可能发挥的作用。此外，对一组孤束核神经元(A2)的初步研究表明，这些细胞的激活引发了焦虑样行为，这些神经元接受下丘脑外侧下丘脑下部下丘脑下丘脑下丘脑下丘脑下丘脑下丘脑下部下丘脑干细胞的神经支配。通过研究这些神经元的投射，本项目试图识别和表征A2神经元的突触靶标，这些突触靶标有助于焦虑症的发生。这些拟议的分子和细胞研究将提供非常有用和非常新颖的信息，既可以提高我们对帕金森病回路的了解，也可以识别新的药物靶点，以开发更有效的焦虑症治疗方法。

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.