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

描述(申请人提供)：5-羟色胺在情绪和焦虑症的病理生理学和药物治疗中起着重要作用。因此，迫切需要了解大脑中控制5-羟色胺能功能的机制。这项任务的一个重要方面是了解控制5-羟色胺分泌神经元活动的因素。以往的研究发现，5-HT1A亚型的5-羟色胺受体是5-羟色胺能神经元活性的重要调节因子。具体地说，这些所谓的“5-羟色胺自身受体”被假设为介导5-羟色胺能核的自我抑制，它们的下调被假设为介导了慢性抗抑郁药物治疗对5-羟色胺能功能的一些影响。然而，令人惊讶的是，尽管做出了相当大的努力，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这一过程如何参与5-羟色胺能细胞活动的调节知之甚少。我们理解中的这一重要差距反映了我们选择性控制5-羟色胺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。在目前的应用中，我们建议使用最新的技术发展，包括在转基因模型小鼠中的光遗传学来解决这个问题。在初步结果中，我们表明，这种方法允许明确地记录中缝背核(支配前脑的主要5-羟色胺能细胞群)中5-HT1a受体介导的自抑制电流。我们建议从三个方面扩展这些发现，1)在突触组织水平上阐明5-羟色胺能神经元如何通过5-HT1A自体受体控制自身活动，2)确定5-HT1A自体受体介导的自抑制发挥作用的条件，3)研究慢性抗抑郁药如何改变5-HT1A受体介导的自抑和其他细胞过程来调节5-HT1A能神经元的活动。通过解决这些问题，我们希望有助于更好地了解5-HT1A自身受体在大脑中的功能和调节，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。

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.