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.

摘要声明 侵略是跨脊椎动物的一种先天社会行为。但是，超过 积极进取 - 从学校欺凌到恐怖袭击，给我们带来了毁灭性的风险 社会。患有某些精神疾病的人，例如躁郁症和后 创伤性应激障碍，更有可能采取剧烈行动，危害自己的生活， 在他们周围。虽然经典的侵略性模型长期以来一直不当 积极反应的“自上而下”执行控制的功能障碍的积极结果 电路，几乎没有直接的物理或神经回路证据来支持这一点。在这里，我们会的 采用另一种“自下而上”的方法来研究影响 神经基因座在侵略性中起着明显的作用。我们假设这些抑制控制是 确保在正确的时间和向正确的目标表达侵略性的必要条件。我们 已将腹侧下丘脑（VMHVL）的腹侧部分确定为必不可少的 “反应性”和“主动”侵略性的基因座。而光遗传激活 VMHVL可以促进攻击和寻求积极的行为，VMHVL抑制具有 相反的效果。在这项研究中，我们将解决局部和远程抑制输入 调节VMHVL细胞的反应，从而调节侵略性行为。虽然神经元 在VMHVL中是主要的指数，VMHVL被VMHVL直接抑制 位于VMHVL核心的侧面和腹侧的“壳”神经元。那我们假设 VMHVL外壳在兴奋性VMHVL中塑造了侵略性相关活性。 神经元。在研究的第一部分中，我们将采用体内记录，功能操纵， ChannelRhodopsin辅助电路映射和病毒跟踪以定义 VMHVL的这种抑制性外壳和兴奋的“核心”。在研究的第二部分中，我们将 缩小并检查对VMHVL的远程抑制输入的功能。具体来说，我们 将检验以下假设：培养基前区域的抑制作用，下丘脑 繁殖和父母护理至关重要的区域对于抑制VMHVL反应至关重要 面临不当的积极目标并防止误导攻击。总之，这项研究 将提供一个急需的框架，以了解抑制机制如何控制 侵略性行为，为新型电路级疗法铺平道路 控制。