Neuromodulation of sensory processing by the serotonin system

 描述（由申请人提供）：中脑多巴胺能系统涉及多种脑功能，包括感觉处理、运动输出、呼吸和情绪的调节。这种多样性可能来自中缝核中少数神经元向前脑几乎所有区域的弥散投射，以及大量的细胞信号通路。感觉系统提供了显着的优势时，联系细胞的5-羟色胺的影响，系统水平的现象，因为他们的局限性功能，更好地理解电路和更容易控制其刺激输出特性在体内。在这个项目中，我们将进行创新的实验，以了解选择性和自然激活的神经元系统如何在行为学相关的意义上调节已识别的神经元的功能，在遗传上可访问的哺乳动物模型，小鼠。我们将研究嗅球（OB）中的5-羟色胺能调制，因为它具有来自中缝核的丰富的神经支配，并且许多5-羟色胺受体在那里表达。我们将使用光遗传学和生理学方法来检验这一假设，即多巴胺能神经元使用多种神经递质以快速和时间多样的方式影响OB中的主要神经元。为了实现我们的目标，我们将使用光遗传学激活剂来选择性地激活多巴胺能神经元并触发神经递质的自然分泌。然后，使用一套方法已经建立在我们的小组（遗传编码的钙指标，多光子显微镜和膜片钳电生理学），我们将剖析的细胞机制，在OB的主要神经元的多巴胺能调制。本项目的实验将遵循三个目标。目的1：研究中缝背核激活对嗅球神经元活动的影响。目标二：确定中缝神经元的选择性光遗传学激活对OB单个输出神经元的快时标活动的影响。目的3：探讨多巴胺能神经元激活对OB输出神经元复杂作用的细胞机制。这里提出的研究将提供一个机械的理解如何自然激活的神经系统改变感觉电路的功能特性。从这项研究中获得的见解可能有助于旨在纠正涉及多巴胺能系统功能障碍的策略。

 DESCRIPTION (provided by applicant): The midbrain serotonergic system has been implicated in a diverse range of brain functions, including modulation of sensory processing, motor output, respiration and mood. This diversity presumably arises from diffuse projections from a small number of neurons in the raphe nucleus to nearly all regions of the forebrain, and the large number of cellular signaling pathways. Sensory systems offer significant advantages when linking cellular effects of serotonin to systems-level phenomena because of their circumscribed function, better understood circuitry and the easier control over their stimulus-output properties in vivo. In this project, we will conduct innovative experiments to understand how the selective and natural activation of the serotonergic system modulates the function of identified neurons in an ethologically relevant sense, in a genetically-accessible mammalian model, the mouse. We will investigate serotonergic modulation in the olfactory bulb (OB), since it has rich innervation from the raphe nucleus and many serotonin receptors are expressed there. We will use optogenetic and physiological methods to test the hypothesis that serotonergic neurons affect principal neurons in the OB in a rapid and temporally diverse manner using multiple neurotransmitters. To achieve our goals, we will use optogenetic activators to selectively activate serotonergic neurons and trigger natural secretion of neurotransmitters. Then using a suite of methods already established in our group (genetically-encoded calcium indicators, multiphoton microscopy and patch-clamp electrophysiology), we will dissect the cellular mechanisms of serotonergic modulation in principal neurons in the OB. Experiments in this project will be guided by three Aims. Aim 1: To determine the effects of dorsal raphe nucleus activation on the activity of different classes of identified neurons in the OB. Aim 2: To determine the effects of selective optogenetic activation of raphe neurons on the fast time-scale activity of individual output neurons of the OB. Aim 3: To determine the cellular mechanisms underlying the complex effects of serotonergic neuron activation on the OB output neurons. The research proposed here will provide a mechanistic understanding of how natural activation of the serotonergic system alters the functional properties of a sensory circuit. Insighs gained from this study will may help in strategies aimed at correcting dysfunctions involving the serotonergic system.