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

• 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
• 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

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.

简要说明 攻击性是脊椎动物与生俱来的社会行为。但过度 从校园欺凌到恐怖袭击， 社会患有某些精神疾病的人，如双相情感障碍和产后抑郁症。 创伤应激障碍，更有可能采取暴力行为，危及自己的生命和那些 身边虽然经典的攻击模型长期以来一直表明， 攻击性是由“自上而下”的攻击性相关执行控制功能障碍引起的。 虽然没有直接的生理或神经回路证据来支持这一点。在这里，我们将 采取另一种“自下而上”的方法来研究抑制控制冲击到一个 在攻击性中有明显作用的神经位点我们假设这些抑制性控制是 这对于确保在正确的时间和针对正确的目标表达侵略行为至关重要。我们 已经确定腹内侧下丘脑（VMHvl）的腹外侧部分是一个重要的 “反应性”和“主动性”攻击的场所。而光遗传学激活的 VMHvl可以促进攻击行为和攻击寻求行为，VMHvl抑制具有 相反的效果。在这项研究中，我们将讨论如何本地和远程抑制输入， 调节VMHvl细胞的反应，并因此调节攻击性行为。虽然神经元 VMHvl主要是兴奋性的，VMHvl直接强烈地抑制VMHvl 位于VMHvl核心外侧和腹侧的“壳”神经元。因此，我们假设 VMHvl壳被很好地定位以形成兴奋性VMHvl中的攻击相关活动， 神经元在研究的第一部分，我们将采用体内记录，功能操作， 通道视紫红质辅助电路映射和病毒追踪，以确定 VMHvl的抑制性外壳和兴奋性“核心”。在研究的第二部分，我们将 放大并检查VMHvl的远程抑制输入的功能。我们特别 将测试的假设，抑制输入从内侧视前区，下丘脑 对生殖和父母照顾至关重要的区域，是抑制VMHvl反应所必需的 针对不适当的攻击目标，防止错误的攻击。总之，这项研究 将提供一个非常需要的框架，以了解抑制机制如何控制 攻击性行为，并为新型的攻击性回路水平疗法铺平道路 控制