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: 9789935
• 负责人: Travis Todd
• 金额: $ 16.28万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789935
• 关键词: Advisory Committees; Alzheimer' s Disease; Animals; Award; Behavior; Behavioral; Biological Markers; Brain region; Cells; Clinical; Code; Communication; Complex; Cues; Development; Disease; 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或 “安全”刺激，并且很难知道以前具有威胁性的刺激现在是安全的。虽然受损，但 安全学习是创伤后应激障碍的生物标记物，这种损害的确切机制是 不清楚。值得注意的是，人类成像研究显示，前额叶腹内侧皮质活动不足。 创伤后应激障碍患者(VmPFC)和脾后皮质(RSC)(Hayes等人，2012年；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 对创伤后应激障碍患者进行观察。与RSC在安全学习中的角色一致，我们最近的一项研究 实验室发现，RSC的永久性损伤特别损害了安全学习(Todd等人，2016a；另见 Gabriel，Sparenborg，&Stole，1987)。然而，尽管RSC在加工安全方面发挥了推定作用 提示，关于RSC内的细胞群体如何编码安全性，或RSC-vmPFC的性质，人们知之甚少 安全学习过程中的互动。 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， 将结合化学遗传学和基于学习理论的行为分析来研究vmPFC- RSC电路中的安全控制学习和行为。因此，拟议的实验将建立 皮层信号如何编码安全性，并探索vmPFC和RSC在两种形式下的相互作用 安全学习的一部分。因此，拟议的研究具有重要意义，因为它将产生对 安全学习的潜在机制，最终揭示了皮质功能障碍和精神障碍之间的联系 疾病，包括创伤后应激障碍。 除了它的意义之外，目前的项目将为学员提供一个掌握的绝佳机会 自由活动大鼠在体电生理记录与分析。实习生打算使用此功能 技术与神经活动的化学遗传操作相结合，建立了一条独立的 探索学习、记忆和行为背后的神经回路的研究。此外，建议的 该奖项将确保学员获得实现其职业目标所需的专业技能。这次培训 将在达特茅斯学院举行，这是一个非凡的研究和教学直觉，在一个 已建立的导师团队以及由以下领域的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。这项建议是精心设计的，旨在为托德博士提供 继续职业发展是必要的，以确立自己作为独立调查员和 菲尔德。