Towards the identification of a mesoscale neural systems logic underlying innate behaviors

识别先天行为背后的中尺度神经系统逻辑

• 批准号: 10734660
• 负责人: Stefanos Stagkourakis
• 金额: $ 12.21万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734660
• 关键词: Address; Affect; Aggressive behavior; Amygdaloid structure; Anatomy; Animals; Anterior; Area; Award; Behavior; Behavior Control; Behavioral; Behavioral Paradigm; Brain; Brain imaging; Brain region; Cell Nucleus; Chronic; Cognition; Communication; Complement; Computer software; Custom; Data; Development; Discipline; Electrophysiology (science); Emotional; Exhibits; FOS gene; Female; Financial Hardship; Fluoxetine; Fright; Goals; Grain; Human; Hypothalamic structure; Image; Instinct; Investigation; Laboratory mice; Learning; Logic; Maps; Measurement; Medical; Mental disorders; Mentors; Methodology; Methods; Molecular; Monitor; Mus; Neurons; Neurosciences; Partner in relationship; Pattern; Phase; Physiological; Population; Prefrontal Cortex; Prevalence; Reagent; Research; Resolution; Risperidone; Role; Sex Offenses; Shapes; Silicon; Social isolation; Societies; Spatial Distribution; System; Technology; Testing; Therapeutic; Training; Vision; Work; activity marker; analysis pipeline; behavior influence; behavior prediction; behavioral plasticity; cell type; cognitive process; conditioned fear; design; experience; experimental study; extracellular; family burden; frontier; generalized anxiety; in vivo; insight; interest; machine learning method; male; neural; new technology; novel; novel therapeutics; pharmacologic; predictive modeling; programs; response; segregation; skills; social; theories; therapeutically effective; tool

Project Summary/Abstract Innate behaviors, also known as instincts, are essential for the survival of all species in the animal kingdom, including humans. Of great interest is understanding how the experience-induced behavioral plasticity observed in innate behaviors can lead to maladaptive behavioral expressions, including uncontrolled aggression, sex offenses, and generalized anxiety. Such mental disorders carry a substantial emotional and financial burden to families and society, rendering the development of effective therapeutic approaches of high significance. The neural substrates of innate behaviors are distributed across numerous brain regions. An essential step towards understanding how the brain orchestrates behavior is to identify how inter-region interactions of neural activity influence behavior in freely moving animals. However, methodological limitations have largely restricted such investigations to single nuclei, while the deep brain remains to date inaccessible to in vivo mesoscale neural recordings in freely moving animals. The research proposed here uses custom-designed technology to break this methodological barrier, making possible recordings with single-unit resolution across twenty subregions of the deep brain (hypothalamus) in freely moving, innate behavior-expressing mice. In Aim 1, using this technology, I will investigate the presence of behavior-specific mesoscale hypothalamic neural features in the innate and learned expressions of social and fear-related behaviors. I will test whether the activity of specific brain regions can predict specific behaviors, and I will identify the spatial distribution of hypothalamic clusters exhibiting behavior-tuning or mixed selectivity. In Aim 2, I will dissect how aggression- or fear-conditioning alters mesoscale neural activity dynamics and test the effect of chronic administration of pharmacological reagents known to reduce the expression of maladaptive social and fear behaviors. Lastly, in Aim 3 – the independent phase of the award, I will expand the use of these tools to investigate mesoscale neural activity dynamics across diverse areas of the corticolimbic system, seeking to identify local and global principles that guide the expression of the physiological and maladaptive forms of innate behaviors. Collectively, the above approaches target the development of an experimental and analytical platform to address fundamental questions of systems neuroscience on the mesoscale mechanisms that govern the expression of innate behaviors. Following these initial steps, this work will be complemented by experimentation aiming to test whether the identified neural features in the behaviors of interest have a causal role. Through the mentored phase of this award, my vision is to build a highly complementary skillset to the one I acquired during my graduate training, and create a unique, state-of-the-art independent research program. By pursuing work spanning diverse disciplines, including molecular, cellular, systems neuroscience, behavioral and computational approaches, I am committed to developing a mechanistic understanding of the neural basis of innate behaviors, with the potential to lead to advanced therapeutic solutions.

项目总结/摘要 天生的行为，也被称为本能，是动物王国中所有物种生存所必需的， 包括人类最有趣的是了解经验诱导的行为可塑性是如何观察到的， 在先天行为中，可能导致适应不良的行为表现，包括不受控制的攻击，性行为， 犯罪和广泛性焦虑这种精神障碍给患者带来了巨大的情感和经济负担， 家庭和社会，使开发有效的治疗方法具有重要意义。 先天行为的神经基质分布在许多大脑区域。一个重要步骤 了解大脑如何协调行为的关键是识别神经元的区域间相互作用， 活动影响自由活动的动物的行为。然而，方法上的局限性在很大程度上限制了 这样的调查单核，而深部脑仍然无法在体内中尺度神经元 自由移动的动物的记录。这里提出的研究使用定制设计的技术来打破 这一方法上的障碍，使得在20个次区域的单一单位分辨率的记录成为可能， 自由活动的先天行为表达小鼠的深层大脑（下丘脑）。 在目标1中，使用这种技术，我将研究行为特异性中尺度下丘脑的存在， 社会和恐惧相关行为的先天和后天表达的神经特征。我将测试 特定大脑区域的活动可以预测特定的行为，我将确定空间分布， 下丘脑簇表现出行为调谐或混合选择性。在目标2中，我将剖析侵略性--或 恐惧调节改变了中尺度神经活动动力学，并测试了长期给予 已知减少适应不良的社交和恐惧行为的表达的药理学试剂。最后，在 目标3 -独立阶段的奖励，我将扩大使用这些工具来调查中尺度神经 皮质边缘系统不同区域的活动动力学，寻求确定局部和全局原则 引导先天行为的生理和不适应形式的表达。 总的来说，上述方法旨在开发一个实验和分析平台， 解决系统神经科学的基本问题的中尺度机制，支配 先天行为的表现。在这些初步步骤之后，将通过实验来补充这项工作 旨在测试感兴趣的行为中的所识别的神经特征是否具有因果作用。 通过这个奖项的指导阶段，我的愿景是建立一个高度互补的技能，我 在我的研究生培训期间获得，并创建一个独特的，最先进的独立研究计划。通过 追求跨越不同学科的工作，包括分子，细胞，系统神经科学，行为和 计算方法，我致力于发展的神经基础的机械理解， 天生的行为，有可能导致先进的治疗方案。