Neuromodulation of sensory processing by the serotonin system

血清素系统对感觉处理的神经调节

• 批准号: 9015426
• 负责人: VENKATESH N MURTHY
• 金额: $ 35.91万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9015426
• 关键词: Adverse effects; Affect; Aggressive behavior; Amino Acid Neurotransmitters; Animals; Axon; Brain; Brain region; Cell physiology; Cells; Complex; Diffuse; Electrodes; Electrophysiology (science); Fiber; Functional disorder; Gene Targeting; Glutamates; Goals; Health; Image; Impaired cognition; Individual; Investigation; Lead; Learning; Light; Link; M cell; Major Depressive Disorder; Measures; Mental Depression; Mental disorders; Methods; Microscopy; Midbrain structure; Modeling; Monitor; Mood Disorders; Moods; Motor output; Mus; Neurons; Neurosciences; Neurotransmitters; Olfactory Pathways; Output; Pattern; Pharmaceutical Preparations; Pharmacology; Physiologic pulse; Physiological; Physiological Processes; Physiology; Population; Process; Property; Prosencephalon; Psychological reinforcement; Receptor Signaling; Research; Respiration; Rest; Role; Sensory; Sensory Process; Serotonergic System; Serotonin; Shapes; Signal Pathway; Signal Transduction; Slice; Smell Perception; Specificity; Stimulus; Structure; Synapses; System; T-Lymphocyte; Testing; Time; calcium indicator; cellular targeting; dorsal raphe nucleus; extracellular; gamma-Aminobutyric Acid; improved; in vivo; innovation; mouse model; nerve supply; neuroregulation; neurotransmitter release; olfactory bulb; olfactory sensory neurons; optical imaging; optogenetics; patch clamp; raphe nuclei; receptor; research study; sensory input; sensory system; serotonin receptor

 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.

 描述（由申请人提供）：中脑血清素能系统涉及多种大脑功能，包括感觉处理、运动输出、呼吸和情绪的调节。这种多样性可能源于从中缝核中的少量神经元到前脑几乎所有区域的弥漫性投射，以及大量的细胞信号传导通路。当将血清素的细胞效应与系统级现象联系起来时，感觉系统具有显着的优势，因为它们的功能受到限制，电路更易于理解，并且更容易控制其体内刺激输出特性。在这个项目中，我们将进行创新实验，以了解在基因可访问的哺乳动物模型小鼠中，血清素能系统的选择性和自然激活如何在行为学相关意义上调节已识别神经元的功能。我们将研究嗅球 (OB) 中的血清素调节，因为它具有来自中缝核的丰富神经支配，并且许多血清素受体在那里表达。我们将使用光遗传学和生理学方法来检验以下假设：血清素能神经元使用多种神经递质以快速且暂时多样化的方式影响 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激活血清素能神经元并触发神经递质的自然分泌。然后使用我们小组已经建立的一套方法（基因编码的钙指示剂、多光子显微镜和膜片钳电生理学），我们将剖析 OB 中主要神经元的血清素调节的细胞机制。该项目的实验将遵循三个目标。目标 1：确定中缝背核激活对 OB 中不同类别已识别神经元活动的影响。目标 2：确定中缝神经元选择性光遗传学激活对 OB 单个输出神经元快速时间尺度活动的影响。目标 3：确定血清素能神经元激活对 OB 输出神经元产生复杂影响的细胞机制。这里提出的研究将从机制上理解血清素系统的自然激活如何改变感觉回路的功能特性。从这项研究中获得的见解可能有助于制定旨在纠正涉及血清素系统的功能障碍的策略。