New Approaches to the study of 5-HT1a autoreceptors in the raphe

中缝5-HT1a自身受体研究的新方法

• 批准号: 8712559
• 负责人: RODRIGO ANDRADE
• 金额: $ 22.74万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712559
• 关键词: Address; Antidepressive Agents; Anxiety; Anxiety Disorders; Autoreceptors; Biological Psychiatry; Brain; Bypass; Calculi; Cell Nucleus; Cell physiology; Cells; Chronic; Clinical; Development; Down-Regulation; Feedback; Functional disorder; Glutamates; Homeostasis; Mediating; Molecular; Mood Disorders; Moods; Nature; Neurons; Neurotransmitters; Pathogenesis; Play; Potassium Channel; Process; Prosencephalon; Recruitment Activity; Regulation; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Serotonin Receptor 5-HT1A; Signal Transduction; Sterile coverings; Surface; Synapses; Synaptic Transmission; Testing; Uncertainty; Work; dorsal raphe nucleus; interest; mouse model; nerve supply; novel; novel strategies; optogenetics; pre-clinical; public health relevance; response; serotonergic regulation; serotonin 5 receptor

DESCRIPTION (provided by applicant): Serotonin plays an important role in the pathophysiology and pharmacotherapeutic treatment of mood and anxiety disorders. Consequently there is an urgent need to understand the mechanisms that control serotonergic function in the brain. An important aspect of this task is understanding the factors that control the activity of serotonin secreting neurons. Previous studies have identified serotonin receptors of the 5-HT1A subtype as important regulators of the activity of serotonergic neurons. Specifically, these so called "serotonin autoreceptors" have been hypothesized to mediate autoinhibition in serotonergic nuclei and their downregulation has been hypothesized to mediate some of the effects of chronic antidepressant treatment on serotonergic function. Yet, surprisingly and in spite of considerable effort, we still know very little about the specific mechanisms supporting 5-HT1A autoreceptor mediated autoinhibition and how this process participates in the regulation of serotonergic cell activity. This important gap in our understanding reflects technical limitations in our ability to selectively control the activity of serotonergic neurons that have made it difficult to directly study autoreceptor mechanisms. In the current application we propose to use recent technical developments including optogenetics in genetically modified model mice to approach this problem. In preliminary results we show that this approach allows for the unambiguous recording of 5-HT1A receptor-mediated autoinhibitory currents in the Dorsal Raphe Nucleus, the principal serotonergic cell group innervating the forebrain. We propose to extend these findings in three directions, 1) to elucidate, at the level o their synaptic organization, how serotonergic neurons control their own activity through 5-HT1A autoreceptors, 2) to determine the conditions under which 5-HT1A autoreceptor-mediated autoinhibition becomes functional and 3) to investigate how chronic antidepressants modify 5-HT1A receptor-mediated autoinhibition and other cellular processes to modulate the activity of serotonergic neurons. By addressing these issues we hope to help develop a better understanding of the function and regulation of 5-HT1A autoreceptors in the brain and thus contribute to the development of more effective pharmacotherapeutic approaches for the treatment of mood and anxiety disorders.

描述（由申请人提供）：血清素在情绪和焦虑症的病理生理学和药物治疗中发挥着重要作用。因此，迫切需要了解控制大脑中血清素功能的机制。这项任务的一个重要方面是了解控制血清素分泌神经元活动的因素。先前的研究已确定 5-HT1A 亚型的血清素受体是血清素能神经元活动的重要调节因子。具体来说，这些所谓的“血清素自身受体”被假设介导血清素能核中的自身抑制，并且假设它们的下调能够介导长期抗抑郁药治疗对血清素能功能的一些影响。然而，令人惊讶的是，尽管付出了相当大的努力，我们仍然对支持 5-HT1A 自身受体介导的自身抑制的具体机制以及该过程如何参与血清素能细胞活性的调节知之甚少。我们理解中的这一重要差距反映了我们选择性控制血清素能神经元活动的能力的技术限制，这使得直接研究自身受体机制变得困难。在当前的应用中，我们建议使用最新的技术发展，包括转基因模型小鼠的光遗传学来解决这个问题。在初步结果中，我们表明这种方法可以明确记录中缝背核（支配前脑的主要血清素能细胞群）中 5-HT1A 受体介导的自抑制电流。我们建议将这些发现扩展到三个方向，1）在突触组织水平上阐明血清素能神经元如何通过 5-HT1A 自身受体控制其自身活动，2）确定 5-HT1A 自身受体介导的自身抑制发挥功能的条件，以及 3）研究慢性抗抑郁药如何改变 5-HT1A 受体介导的自身抑制和其他细胞 调节血清素能神经元活动的过程。通过解决这些问题，我们希望帮助更好地了解大脑中 5-HT1A 自身受体的功能和调节，从而有助于开发更有效的药物治疗方法来治疗情绪和焦虑症。