Role of serotonin brain circuit in the developmental emergence ofinnate fear

血清素脑回路在先天恐惧的发展中的作用

基本信息

批准号：
10664638
负责人：
Giulia Zanni
金额：
$ 18.13万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-13 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10664638
关键词：
Acute Address Adult Affect Air Movements Animals Anti-Anxiety Agents Anxiety Anxiety Disorders Attenuated Behavior Behavioral Behavioral Assay Behavioral Paradigm Biological Assay Brain Coupled Cues Data Development Development Plans Diagnosis Disinhibition Drug Targeting Emotional Emotions Ensure Ethology Etiology Experimental Designs Fiber Fiber Optics Fluoxetine Freezing Fright Functional Imaging Functional disorder Gene Silencing Generalized Anxiety Disorder Genetic Glutamates Goals Growth HTR2A gene Harm Reduction Human Hyperactivity Implant Lead Life Mental disorders Mentors Mentorship Modeling Molecular Monitor Mus Neurons Neurosciences Neurotransmitters Odors Organism Output Panic Disorder Pathway interactions Pattern Phenotype Phobias Photometry Population Pregnancy Prevention strategy Protocols documentation Psychiatry Reaction Recurrence Research Risk Assessment Risk Factors Role Scientist Selective Serotonin Reuptake Inhibitor Serotonin Signal Transduction Stimulus System Techniques Testing Training Work anxiety-like behavior anxiety-related disorders avoidance behavior behavior test behavioral response career development deep learning algorithm design designer receptors exclusively activated by designer drugs early life stress experience gamma-Aminobutyric Acid glutamatergic signaling improved in vivo insight maladaptive behavior midbrain central gray substance mouse model nerve supply neural circuit neurophysiology novel therapeutic intervention optical fiber optogenetics pharmacologic postnatal postsynaptic programs receptor response sensor stem treatment strategy

项目摘要

Fear is the human emotion that is elicited when danger or threat are perceived or recognized. Maladaptive fear patterns are common in anxiety disorders. Fear responses are orchestrated by the activation of stimulus-specific neural circuits that converge in the periaqueductal gray (PAG). Drugs targeting the serotonin (5-HT) system decrease anxiety and increasing 5-HT levels attenuates fear responses in animals. Yet, how 5-HT exerts its effects on fear behavior is not well understood. To study fear-like responses in mice I have developed a behavioral assay, in which a predator odor is presented in a chamber that allows for fast on- and off-set of the stimulus. I use deep learning algorithms to analyze behavior. Using projection-specific optogenetics, I already found that 5-HT neurons projecting to the PAG ameliorate fear-like behavior. In Aim 1 and Aim 2 I will now determine the role of endogenous 5-HT signaling in the PAG during normal behavioral response to threat. A risk factor for adult anxiety-like behavior is increased 5-HT during early life that causes enduring changes in 5-HT function. Yet, how specific circuits are affected is not understood. I found that chemogenetic or pharmacologic increases in 5-HT signaling during postnatal (P) day 2 to 11 lead to exacerbated fear responses in the adult. Functional imaging (fMRI) in this mouse model furthermore revealed robust PAG hyperactivity in response to predator odor. These data suggest that developmentally elevated 5-HT signaling produces long-lasting changes in adult 5-HT input into the dlPAG resulting in increased innate fear-like behaviors. I will test this hypothesis in Aim 3. Aim 1 uses genetically encoded 5-HT and Ca2+ sensors to simultaneously monitor 5-HT input and glutamatergic or GABAergic output in the dlPAG during behavior via fiber photometry. Aim 2 uses Cre- dependent inhibitory Archaerhodopsin to optogenetically inhibit 5-HT input into the dlPAG. Aim 3 uses Ca2+ and 5-HT sensors to monitor 5-HT input and neuronal output in the dlPAG during fear behavior after developmentally elevated 5-HTergic activity. Lastly, Aim 3 also uses my established DR(5-HT)-to-dlPAG pathway specific optogenetic protocol to enhance 5-HT signaling in dlPAG in an attempt to rescue increased fear-like responses. Together my Aims will uncover fundamental principles that govern the modulation of the PAG by 5-HT, which will provide insight into pathophysiology and etiology of anxiety disorders. Throughout my training I will work towards translational discoveries targeting developmentally disrupted neural circuits such that maladaptive behaviors can be reversed, with the overall goal of developing new therapeutic strategies. My career development plan capitalizes on my prior experience in molecular and developmental neurophysiology and adds expertise in circuit and behavioral neuroscience. I have engaged a strong mentoring team to guide my scientific efforts and my growth as an independent scientist. I believe that this K01 proposal combines pivotal technical, intellectual, and career development guidance to help me address my scientific aims and promote my transition towards establishing an independent research program.

恐惧是当感知或认识到危险或威胁时引发的人类情感。适应不良的恐惧模式在焦虑症中很常见。恐惧反应是通过特定刺激的激活来协调的汇聚于导水管周围灰质 (PAG) 的神经回路。针对血清素 (5-HT) 系统的药物减少焦虑，增加 5-HT 水平可以减弱动物的恐惧反应。然而，5-HT如何发挥其作用对恐惧行为的影响尚不清楚。为了研究小鼠的恐惧样反应，我开发了一种行为测定，其中捕食者的气味出现在一个室内，允许快速启动和关闭刺激。我使用深度学习算法来分析行为。使用投影特异性光遗传学，我已经发现投射到 PAG 的 5-HT 神经元可以改善恐惧样行为。在目标 1 和目标 2 中，我现在将确定在对威胁的正常行为反应期间 PAG 中内源 5-HT 信号传导的作用。有风险成人焦虑样行为的因素是生命早期 5-HT 的增加，导致 5-HT 的持久变化功能。然而，具体电路如何受到影响尚不清楚。我发现化学遗传学或药理学出生后 (P) 第 2 至 11 天期间 5-HT 信号传导增加，导致成人恐惧反应加剧。该小鼠模型中的功能成像 (fMRI) 进一步显示，PAG 过度活跃以响应捕食者的气味。这些数据表明，发育过程中升高的 5-HT 信号传导会产生持久的变化成人 5-HT 输入 dlPAG 导致先天恐惧样行为增加。我将在以下时间检验这个假设目标 3。目标 1 使用基因编码的 5-HT 和 Ca2+ 传感器同时监测 5-HT 输入和通过光纤光度测定行为期间 dlPAG 中的谷氨酸或 GABA 能输出。目标 2 使用 Cre- 依赖性抑制性古视紫红质以光遗传学方式抑制 5-HT 输入 dlPAG。目标 3 使用 Ca2+ 和 5-HT 传感器用于监测发育后恐惧行为期间 dlPAG 中的 5-HT 输入和神经元输出 5-HTergic 活性升高。最后，Aim 3 还使用我建立的 DR(5-HT)-to-dlPAG 通路特异性光遗传学协议增强 dlPAG 中的 5-HT 信号传导，试图挽救增加的恐惧样反应。我的目标将共同揭示 5-HT 调节 PAG 的基本原理，将深入了解焦虑症的病理生理学和病因学。在我的整个培训过程中，我将致力于针对发育障碍神经的转化发现可以逆转适应不良行为的回路，总体目标是开发新的治疗方法策略。我的职业发展计划利用了我之前在分子和发育方面的经验神经生理学，并增加了电路和行为神经科学方面的专业知识。我接受了强有力的指导团队指导我的科学努力和我作为一名独立科学家的成长。我相信这个K01提案结合了关键的技术、智力和职业发展指导，帮助我实现我的科学目标并促进我向建立独立研究计划的过渡。