Inhibitory Control of Hypothalamic Circuit for Aggression

下丘脑攻击性回路的抑制控制

• 批准号: 9751967
• 负责人: Annegret Lea Falkner
• 金额: $ 24.75万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751967
• 关键词: Aggressive behavior; Amygdaloid structure; Area; Behavior; Behavioral; Behavioral Paradigm; Bipolar Disorder; Brain; Calcium; Chlorides; Conduct Disorder; Data; Disease; Disinhibition; Exhibits; Fiber; Fluorescence Resonance Energy Transfer; Glutamates; Hypothalamic structure; Image; Individual; Island; Lateral; Lead; Link; Maps; Mental disorders; Mentors; Modeling; Monitor; Motivation; Mus; Nature; Neurons; Neurosciences; Optics; Output; Pathology; Pathway interactions; Phase; Phenotype; Photometry; Physiological; Population; Post-Traumatic Stress Disorders; Process; Prosencephalon; Regulation; Role; Schizophrenia; Sensory; Shapes; Source; Structure; Substance abuse problem; Techniques; Testing; Therapeutic; Time; Trauma; Work; cell type; experimental study; insight; intersectionality; male; neural circuit; novel; optogenetics; relating to nervous system; response; sensor; social deficits; tool

Many diverse neural disorders as well as certain types of cortical trauma can result in increased aggression. These behavioral effects can take the form of increased proactive aggression-seeking behavior, increased reactive aggressive action, or both, suggesting that these behaviors may be independently regulated. While these effects are believed to result from “top-down” disinhibition of aggression-relevant circuits, there is little direct circuit-level or physiological evidence to support this. Our recent work has shown that the ventrolateral hypothalamus, ventrolateral area (VMHvl) controls the expression of both reactive and proactive aggressive behaviors and may represent a common pathway for functional inhibitory control of aggression. During the K99 phase of this proposal, we identified how an undescribed source of local inhibition to the VMHvl selectively gates aggression-seeking behavior. In addition to this local inhibition, the VMHvl receives inhibition from a number of upstream structures in the hypothalamus, amygdala and forebrain. These inputs likely have dissociable roles in the regulation of reactive and proactive aggression and may represent multiple independent pathways to dysregulate the circuit. Newly developed techniques for cell-type specific imaging of deep neural structures now allow interrogation of individual circuit components and can also be used to detect real-time changes in inhibition. This proposal leverages recent advances in cell-type and pathway specific targeting in mice in tandem with new strategies for optical recording, chloride FRET sensing, and functional manipulation to describe brain-wide circuits for inhibitory control of aggression. In this proposal, we aim to 1) Characterize and map the regulatory roles of sources of long-range inhibition onto the VMHvl and model their effects on the output of excitatory aggression-relevant neurons, 2) Using a novel optical chloride sensor, explore whether activation of these upstream inhibitory control inputs results in functional inhibitory drive, and 3) Test whether upstream inputs for inhibitory control selectively target subsets of VMHvl neurons for proactive and reactive aggression. Together, these data will potentially lead to a broad new understanding of how activity within canonical circuits for aggression is shaped and gated by inhibition and how these processes may go awry during social dysfunction.

许多不同的神经疾病以及某些类型的皮质创伤可导致增加的 侵略这些行为效应可以表现为主动寻求攻击行为的增加，反应性攻击行为的增加，或两者兼而有之，这表明这些行为可能是独立调节的。虽然这些影响被认为是由“自上而下”的攻击相关回路的去抑制引起的，但几乎没有直接的回路水平或生理证据支持这一点。我们最近的工作表明，腹外侧下丘脑腹外侧区（VMHvl）控制反应性和主动攻击行为的表达，并可能代表一个共同的通路功能抑制控制的攻击。在该提议的K99阶段，我们确定了对VMHvl的未描述的局部抑制源如何选择性地门控攻击寻求行为。除了这种局部抑制之外，VMHvl还受到来自下丘脑、杏仁核和前脑中的许多上游结构的抑制。这些输入可能在反应性和主动性攻击的调节中具有可分离的作用，并且可能代表了多个独立的失调途径。 电路。新开发的深层神经结构细胞类型特异性成像技术现在允许询问单个电路组件，也可用于检测抑制的实时变化。该提案利用了小鼠细胞类型和途径特异性靶向的最新进展，并结合光学记录、氯离子FRET传感和功能操作的新策略，描述了用于抑制性控制攻击的全脑电路。在这个提议中，我们的目标是1）表征和映射远程抑制源对VMHvl的调节作用，并模拟它们对兴奋性攻击相关神经元的输出的影响，2）使用新型光学氯传感器，探索这些上游抑制控制输入的激活是否导致功能性抑制驱动，以及3）测试用于抑制性控制的上游输入是否选择性地以VMHv1神经元的子集为目标，用于主动和反应性攻击。总之，这些数据将可能导致对攻击性典型回路内的活动如何通过抑制来塑造和门控以及这些过程如何在社会功能障碍期间出错的广泛新理解。