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（由适用提供）：中脑血清素能系统已在潜水员的大脑功能范围内实施，包括调节感觉处理，运动输出，呼吸和情绪。这种多样性大概是由raphe核中少数神经元到前脑几乎所有区域以及大量细胞信号通路的弥漫性项目。当将血清素的细胞效应与系统级现象联系起来时，感觉系统具有显着优势，因为它们具有限制功能，更好地理解电路以及对其在体内刺激输出特性的更容易控制。在该项目中，我们将进行创新的实验，以了解5-羟色素能系统的选择性和自然激活如何在伦理上相关的意义上调节所鉴定的神经元的功能，该含义是在一般可访问的哺乳动物模型的小鼠中。我们将研究嗅球（OB）中的血清素能调节，因为它具有从Raphe Nucitus的富裕神经支配，并且在那里表达了许多5-羟色胺受体。我们将使用光遗传学和物理方法来检验以下假设：血清素能神经元使用多个神经递质以快速且暂时的方式影响OB中的主要神经元。为了实现我们的目标，我们将使用光遗传激活剂有选择地激活5-羟色胺能神经元并触发神经递质的自然分泌。然后，使用我们组中已经建立的一系列方法（遗传编码的钙指标，多光子显微镜和贴片钳电生理学），我们将在OB中主要主神经元中剖析血清能调节的细胞机制。该项目的实验将以三个目标指导。目的1：确定背部raphe核激活对OB中不同类别鉴定神经元的活性的影响。目标2：确定Raphe神经元选择性光遗传激活对OB的单个输出神经元快速时间尺度活性的影响。 AIM 3：确定血清能神经元激活对OB输出神经元的复杂作用的基础的细胞机制。此处提出的研究将提供机械理解，了解串口能系统的自然激活如何改变感觉电路的功能特性。从这项研究中获得的基因可能有助于纠正涉及血清素能系统功能障碍的策略。