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.

当危险或威胁被感知或认可时，恐​​惧是引起人类的情感。适应不良的恐惧 模式在焦虑症中很常见。恐惧反应是通过特异性刺激的激活来精心策划的 在周围灰色（PAG）中汇聚的神经回路。针对5-羟色胺（5-HT）系统的药物 减少焦虑和增加5-HT水平会减轻动物的恐惧反应。但是，5-HT如何施加 对恐惧行为的影响尚未得到充分理解。为了研究小鼠的恐惧反应，我已经开发了 行为测定，其中在室内呈现捕食气味 刺激。我使用深度学习算法来分析行为。使用投影特异性的光遗传学，我已经 发现投射到PAG上的5-HT神经元可以缓解恐惧样的行为。在AIM 1和AIM 2中，我现在将 确定在正常行为对威胁的行为反应期间，内源性5-HT信号在PAG中的作用。风险 成人焦虑行为的因素在早期生命中增加了5-HT，这会导致5-HT的持久变化 功能。然而，尚不了解特定电路的影响。我发现化学发生或药理 在产后（P）第2至11天期间，5-HT信号的增加导致成年人的恐惧反应加剧。 此小鼠模型中的功能成像（fMRI）此外，还揭示了稳健的PAG多动症 捕食者气味。这些数据表明，发育率升高的5-HT信号传导会产生持久的变化 在成人的5-HT输入中，DLPAG导致先天恐惧样行为增加。我将在 AIM 3。AIM 1使用遗传编码的5-HT和CA2+传感器同时监视5-HT输入和 通过纤维光度法，在行为过程中，DLPAG中的谷氨酸能或GABA能输出。 AIM 2使用Cre- 依赖性抑制性古细胞汀可在光遗传学上抑制5-HT输入DLPAG。 AIM 3使用Ca2+和 5-HT传感器在恐惧行为中监测DLPAG中5-HT输入和神经元输出后发育后 升高的5握活性。最后，AIM 3还使用了我已建立的DR（5-HT）-DLPAG途径 在DLPAG中增强5-HT信号传导的光遗传学方案试图增加类似恐惧的反应。 我的目标共同揭示了控制PAG调制PAG的基本原则，5-HT 将提供对焦虑症病理生理学和病因的见解。 在整个培训中，我将致力于针对发展神经的转化发现 电路可以逆转适应不良行为，其总体目标是开发新的治疗性 策略。我的职业发展计划利用了我先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方面的专业知识。我参与了强大的指导 团队指导我的科学努力和作为独立科学家的成长。我相信这个K01提案 结合关键技术，智力和职业发展指导，以帮助我解决我的科学目标 并促进我向建立独立研究计划的过渡。