Cortical ensemble coding and circuit dynamics of fear suppression

皮层整体编码和恐惧抑制的电路动力学

• 批准号: 10417340
• 负责人: Travis Todd
• 金额: $ 16.28万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417340
• 关键词: Advisory Committees; Alzheimer' s Disease; Animals; Award; Behavior; Behavioral; Biological Markers; Brain region; Cells; Clinical; Code; Communication; Complex; Cues; Development; Disease; Distance Learning; Educational process of instructing; Electrophysiology (science); Emotions; Ensure; Episodic memory; Event; Extinction (Psychology); Fright; Functional disorder; Future; Goals; Impairment; Intuition; Knowledge; Lead; Learning; Lesion; Link; Memory; Mental disorders; Mentors; Mission; Modality; National Institute of Mental Health; Nature; Neurons; Neurosciences; Outcome; Pathologic; Patients; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Prefrontal Cortex; Public Health; Rattus; Research; Research Personnel; Retrieval; Role; Safety; Schizophrenia; Sensory; Stimulus; Symptoms; Techniques; Testing; Training; Work; base; career; career development; cognitive control; college; combat; conditioned fear; design; experience; experimental study; fear memory; human imaging; imaging study; in vivo; learned behavior; learning extinction; nervous system disorder; neural circuit; neurobiological mechanism; neuromechanism; performance tests; physical abuse; relating to nervous system; skills; theories

Project Summary Traumatic experiences, such as combat exposure or sexual/physical abuse can lead to the development of post-traumatic stress disorder (PTSD). Patients with PTSD often show generalized fear to non-dangerous or “safe” stimuli, and have difficulty learning that a previously threatening stimulus is now safe. Although impaired safety learning is a suggested biomarker of PTSD, the precise mechanisms that underlie this impairment are unclear. Notably, human imaging studies have revealed hypoactivity of the ventromedial prefrontal cortex (vmPFC) and retrosplenial cortex (RSC) in patients with PTSD (Hayes et al., 2012; Pissiota et al., 2002) suggesting the possibility that vmPFC – RSC dysfunction might underlie impairments in safety learning observed in patients with PTSD. Consistent with a role for the RSC in safety learning, a recent study from our lab found that permanent damage of the RSC specifically impairs safety learning (Todd et al., 2016a; see also Gabriel, Sparenborg, & Stolar, 1987). Nevertheless, although the RSC has a putative role in processing safety cues, little is known about how cell populations within the RSC encode safety, or the nature of RSC – vmPFC interaction during safety learning. In this project, large-scale single unit ensemble recording and analysis, and local field recordings and analysis, will be combined with chemogentics and learning-theory based behavioral analysis to investigate vmPFC – RSC circuitry in the control of safety learning and behavior. The proposed experiments will therefore establish how cortical ensembles encode safety, and explore interaction between the vmPFC and RSC during two forms of safety learning. Thus, the proposed research is significant in that it will yield a detailed understanding of the mechanisms underlying safety learning, ultimately informing the link between cortical dysfunction and mental illness, including PTSD. In addition to its significance, the current project will provide the trainee with an excellent opportunity to master in vivo electrophysiological recordings and analysis in freely behaving rats. The trainee intends to use this technique, combined with chemogenetic manipulation of neural activity to establish an independent line of research probing the neural circuits underlying learning, memory, and behavior. In addition, the proposed award will ensure the trainee acquires the professional skill necessary to reach his career goals. This training will take place at Dartmouth College, an exceptional research and teaching intuition, under the guidance of an established team of mentors as well as an external advisory committee comprised of luminaries in the fields of behavioral neuroscience and PTSD research. This proposal is well-designed to provide Dr. Todd with the continued career development necessary to establish himself as an independent investigator and leader in the field.

项目摘要 创伤经历，如战斗暴露或性/身体虐待，可能导致 创伤后应激障碍（PTSD）。创伤后应激障碍患者通常表现出对非危险性或 在一些实施例中，受试者接受"安全"刺激，并且难以学习以前威胁性的刺激现在是安全的。虽然受损 安全学习是PTSD的一个生物标志物，这种损伤的确切机制是 不清楚值得注意的是，人类成像研究显示，腹内侧前额叶皮层活动减退， （vmPFC）和压后皮质（RSC）的研究（Hayes et al.，2012; Pissiota等人，（2002年） 提示vmPFC-RSC功能障碍可能是安全学习障碍的基础 在PTSD患者中观察到。与RSC在安全学习中的作用一致，我们最近的一项研究 实验室发现RSC的永久性损伤特别地损害安全学习（托德等人，2016年A;参见 Gabriel、Sparenborg和Stolar，1987年）。然而，尽管RSC在加工安全性方面具有假定的作用， 提示，关于RSC内的细胞群如何编码安全性或RSC-vmPFC的性质知之甚少 安全学习期间的互动。 在这个项目中，大规模的单单元合奏记录和分析，以及当地的现场记录和分析， 将结合化学发生学和基于学习理论的行为分析来研究vmPFC- RSC电路在控制安全学习和行为。因此，拟议的实验将建立 皮质合奏如何编码安全性，并探讨在两种形式的vmPFC和RSC之间的相互作用 安全学习。因此，拟议的研究是有意义的，因为它将产生一个详细的了解， 安全性学习的潜在机制，最终告知皮质功能障碍和心理健康之间的联系。 疾病，包括PTSD。 除了它的意义，目前的项目将提供一个极好的机会，掌握 在自由行为大鼠中的体内电生理记录和分析。学员打算用这个 技术，结合神经活动的化学遗传学操作，建立一个独立的细胞系， 探索学习、记忆和行为背后的神经回路的研究。此外，拟议的 奖励将确保受训者获得实现其职业目标所需的专业技能。本次培训 将发生在达特茅斯学院，一个特殊的研究和教学的直觉，指导下， 建立了导师团队以及由以下领域知名人士组成的外部咨询委员会 行为神经科学和创伤后应激障碍研究。本提案旨在为托德博士提供 继续职业发展，使自己成为独立调查员和 领域