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

• 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
• 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

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.

恐惧是人类在感知或认识到危险或威胁时产生的情感。适应不良性恐惧 在焦虑症中很常见恐惧反应是由特定刺激的激活所精心策划的。 在中脑导水管周围灰质（PAG）中会聚的神经回路。靶向5-羟色胺（5-HT）系统的药物 减少焦虑和增加5-HT水平减弱动物的恐惧反应。然而，5-HT如何发挥其 对恐惧行为的影响尚不清楚。为了研究老鼠的恐惧反应，我开发了一种 行为测定，其中捕食者气味存在于一个腔室中，该腔室允许快速开启和关闭 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神经元改善了恐惧样行为。在目标1和目标2中， 确定内源性5-HT信号传导在PAG中对威胁的正常行为反应中的作用。风险 成人焦虑样行为的一个因素是在生命早期5-HT增加，导致5-HT的持久变化 功能然而，具体的电路是如何受到影响的还不清楚。我发现无论是化学遗传学还是药理学 出生后（P）第2至11天期间5-HT信号传导的增加导致成年人恐惧反应加剧。 在该小鼠模型中的功能成像（fMRI）进一步揭示了响应于以下的强烈PAG活动过度： 捕食者的气味这些数据表明，发育过程中升高的5-HT信号产生了持久的变化， 在成人中，5-HT输入dlPAG导致增加的先天恐惧样行为。我将测试这个假设， 目标3.目的1使用基因编码的5-HT和Ca 2+传感器同时监测5-HT输入， 通过纤维光度测定法在行为期间dlPAG中的谷氨酸能或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抑制5-HT输入dlPAG。目标3使用Ca 2+， 5-HT传感器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 在一个实施方案中，使用光遗传学方案来增强dlPAG中的5-HT信号传导，以试图挽救增加的恐惧样反应。 我的目标将揭示5-HT调节PAG的基本原理， 将提供对焦虑症的病理生理学和病因学的深入了解。 在我的整个训练过程中，我将致力于针对发育中断的神经元的转化发现， 这样的电路，适应不良的行为可以逆转，与开发新的治疗的总体目标， 战略布局我的职业发展计划利用了我以前在分子和发展方面的经验， 神经生理学，并增加了电路和行为神经科学的专业知识。我聘请了一位强大的导师 团队来指导我的科学努力和我作为一个独立科学家的成长。我相信K 01的提案 结合了关键的技术，智力和职业发展指导，帮助我解决我的科学目标 并促进我向建立独立研究项目的过渡。