Research Supplement to Promote Diversity in Health-Related Research

促进健康相关研究多样性的研究补充

基本信息

批准号：
9899606
负责人：
Dayu Lin
金额：
$ 3.16万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899606
关键词：
Address Aggressive behavior Area Behavior Bipolar Disorder Brain region Caring Cells Disputes Electrophysiology (science)Ensure Family Female Fiber Functional disorder Funding Generations Glutamates Health Human Hypothalamic structure In Vitro Individual Lateral Maps Medial Mental disorders Modeling Molecular Neurons Pathway interactions Patients Pharmacogenetics Phase Photometry Physiological Play Population Positioning Attribute Post-Traumatic Stress Disorders Preoptic Areas Rabies Reproduction Research Resources Risk Role Schizophrenia Schools Shapes Slice Social Behavior Societies Terrorism Testing Therapeutic Time Violence Viral autism spectrum disorder bullying cell type executive function experimental study high risk in vivo male neural circuit neuromechanism optogenetics prevent relating to nervous system response social stem

项目摘要

SUMMARY STATEMENT Aggression is an innate social behavior across vertebrate species. However, excessive aggression—ranging from school bullying to terrorist attacks—imposes a devastating risk to our society. Individuals with certain psychiatric disorders, such as bipolar disorder and post- traumatic stress disorder, are more likely to act violently, jeopardizing their own lives and those around them. While classic models of aggression have long-suggested that improper aggression results from dysfunction of “top-down” executive control of aggression-relevant circuitry, there is little direct physiological or neural circuit evidence to support this. Here, we will take an alternative “bottom-up” approach to investigate the inhibitory control impinged onto a neural locus with a clear role in aggression. We hypothesize that these inhibitory controls are essential to ensure aggression is expressed at the right time and towards the right target. We have identified the ventrolateral part of the ventromedial hypothalamus (VMHvl) as an essential locus for both “reactive” and “proactive” aggression. Whereas optogenetic activation of the VMHvl can promote both attack and aggression-seeking behavior, VMHvl inhibition has the opposite effect. In this study, we will address how local and long-range inhibitory inputs modulate responses of VMHvl cells, and consequently aggressive behaviors. Although neurons in the VMHvl are primarily excitatory, the VMHvl is directly and strongly inhibited by VMHvl “shell” neurons that are situated lateral and ventral to the VMHvl core. Thus, we hypothesize that the VMHvl shell is well positioned to shape aggression-relevant activity in excitatory VMHvl neurons. In the first part of the study, we will employ in vivo recording, functional manipulation, channelrhodopsin-assisted circuit mapping, and viral tracing to define the relationship between this inhibitory shell and excitatory “core” of the VMHvl. In the second part of the study, we will zoom out and examine the function of long-range inhibitory inputs to the VMHvl. Specifically, we will test the hypothesis that the inhibitory inputs from the medial preoptic area, a hypothalamic region critical for reproduction and parental care, is essential for suppressing VMHvl responses towards improper aggression targets and preventing misdirected attack. In summary, this study will provide a much needed framework to understand how inhibitory mechanisms control aggressive behavior, and pave the way for new types of circuit-level therapeutics for aggression control.

概要声明攻击性是脊椎动物与生俱来的社会行为，但过度攻击是一种行为。侵略——从学校欺凌到恐怖袭击——给我们带来了毁灭性的风险患有某些精神疾病的个体，例如双相情感障碍和后遗症。创伤性应激障碍患者更有可能采取暴力行为，危及自己和他人的生命虽然经典的侵略模型长期以来都表明这种做法是不恰当的。攻击行为是由于“自上而下”的攻击相关执行控制功能失调造成的电路，几乎没有直接的生理或神经电路证据支持这一点。采用另一种“自下而上”的方法来研究抑制控制对我们发现这些抑制性控制在攻击行为中具有明确的作用。对于确保在正确的时间针对正确的目标表达攻击性至关重要。已经确定下丘脑腹内侧部分（VMHvl）是一个重要的 “反应性”和“主动性”攻击的位点，包括光遗传学激活。 VMHvl 可以促进攻击和寻求攻击行为，VMHvl 抑制具有在这项研究中，我们将讨论局部和远程抑制输入如何产生相反的效果。调节 VMHvl 细胞的反应，从而调节神经元的攻击行为。 VMHvl 中主要是兴奋性的，VMHvl 直接且强烈地受到 VMHvl 抑制 “壳”神经元位于 VMHvl 核心的侧面和腹侧。 VMHvl 外壳的位置很好，可以塑造兴奋性 VMHvl 中与攻击相关的活动在研究的第一部分，我们将采用体内记录、功能操作、通道视紫红质辅助电路图谱和病毒追踪来定义之间的关系在研究的第二部分中，我们将讨论 VMHvl 的抑制性外壳和兴奋性“核心”。缩小并检查 VMHvl 的远程抑制输入的功能。将检验以下假设：来自内侧视前区（下丘脑的一个区域）的抑制输入对于生殖和亲代护理至关重要的区域，对于抑制 VMHvl 反应至关重要综上所述，针对本研究。将提供一个急需的框架来理解抑制机制如何控制攻击性行为，并为新型攻击性电路级疗法铺平道路控制。