Safety Learning and Plasticity in the Insular Cortex

岛叶皮质的安全学习和可塑性

• 批准号: 8088699
• 负责人: John Paul Christianson
• 金额: $ 9万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-25 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8088699
• 关键词: Action Potentials; Amygdaloid structure; Anxiety; Behavior; Behavior Control; Behavioral Genetics; Behavioral Model; Cells; Characteristics; Colorado; Complex; Conditioned Stimulus; Corpus striatum structure; Cues; Dendrites; Deposition; Detection; Development Plans; Diagnosis; Discrimination; Dorsal; Electrodes; Environment; Equipment; Event; Exposure to; Extinction (Psychology); Extramural Activities; Failure; Fright; Funding; Future; Goals; In Vitro; Institutes; Knowledge; Laboratories; Lateral; Lead; Learning; Lesion; Measures; Medial; Mediating; Membrane Potentials; Memory; Mentors; Methods; Modeling; Neuronal Plasticity; Neurons; Neurosciences; Organism; Pathway interactions; Pilot Projects; Positioning Attribute; Post-Traumatic Stress Disorders; Postdoctoral Fellow; Potassium Channel; Prefrontal Cortex; Procedures; Process; Psychology; Psychopathology; Public Health; Rattus; Records; Research; Research Personnel; Research Project Grants; Resources; Role; Safety; Sensory; Shock; Signal Transduction; Stimulus; Stress; Structure; Symptoms; Synapses; Synaptic plasticity; System; Techniques; Testing; Thalamic structure; Time; Tracer; Training; Training Activity; Universities; Vertebral column; Work; base; career development; conditioned fear; density; graduate student; hippocampal pyramidal neuron; inhibitor/antagonist; learning extinction; meetings; neuromechanism; novel; patch clamp; programs; psychologic; reconstruction; relating to nervous system; resilience; safety study; sensory stimulus; skills; stress resilience; stressor; trend

DESCRIPTION (provided by applicant): Dr. John Christianson is a F32-funded research associate with extensive knowledge the neural mechanisms underlying resilience and vulnerability to anxiety and fear behavior. Past research has identified that psychological variables, including behavioral control over stress and safety signals during stress lead to a resilience from stress-induced anxiety. Furthermore, he has identified causal roles for the medial prefrontal cortex and insular cortex, respectively, in these stress-mitigating effects. His immediate goal is to advance his academic and technical skills in order to enact an independent research program studying the neural basis of safety learning and fear inhibition by safety. The K99/R00 proposal is a key component in this pursuit. Career Development Plan: Dr. Christianson<s proposed training activities consist of: 1) training in electrophysiological techniques for the study of neuroplasticity, 2) attendance and participation at scientific meetings in which the scientific content revolves around learning and memory, 3) mentoring and training of undergraduate and graduate students on independent research projects within the sponsors< laboratories. Environment: The research will be conducted in the University of Colorado<s Psychology & Neuroscience Department and the Institute of Behavioral Genetics. Co-sponsors, Drs Steven Maier and Donald Cooper are established investigators in the fields of stress, learning & memory and neuroplasticity. Both labs have a sufficient extramural funding to support the proposed research and excellent records mentoring postdoctoral fellows. Furthermore, the laboratory space is adequate and equipment state-of-the art. Research: The proposed studies test two complementary hypotheses relating safety learning. Safety learning is a Pavlovian process by which sensory stimuli come to predict the non-occurrence of an aversive event. First: Safety learning occurs in the insular cortex. This will be tested in several ways including i) pharmacological inhibition of insular cortex at the times when a rat is learning or recalling the safety cue, ii.) in vitro whole-cell patch clamp assessment of intrinsic excitability of amygdala-projecting insular cortex neurons and iii.) multiple- electrode assessment of plasticity within insular cortex synapses. Second: Exposure to uncontrollable stress, a laboratory model of posttraumatic stress disorder (PTSD), will interfere with learning and expression of safety signals. This hypothesis will be tested by interpolating uncontrollable stress before or after the safety learning. Together these complementary approaches will lead to a significant advancement in understanding of the neural mechanisms underlying safety and provide a paradigm for studying pathological safety learning as occurs in PTSD. PUBLIC HEALTH RELEVANCE: Learning the difference between danger and safety is critical to survival, yet in some psychiatric conditions this process fails. Without veridical detection of safety, someone may express fear or anxiety even when the environmental cues indicate that danger is unlikely. The proposed work tests the hypothesis that the insular cortex is a critical contributor to safety learning and that neuroplastic changes in the insular cortex underlie the storage and recall of safety memory. This work has important implications for the treatment and diagnosis of posttraumatic stress disorder and other conditions that involve heightened fear and anxiety.

描述(申请人提供)：约翰·克里斯汀森博士是一名F32资助的研究人员，对焦虑和恐惧行为的复原力和脆弱性具有广泛的知识。过去的研究已经证实，心理变量，包括对压力的行为控制和压力期间的安全信号，可以从压力诱导的焦虑中恢复过来。此外，他还确定了内侧前额叶皮质和岛叶皮质分别在这些缓解压力的效果中的因果作用。他的直接目标是提高自己的学术和技术技能，以便制定一项独立的研究计划，研究安全学习的神经基础和安全对恐惧的抑制。K99/R00提案是这一努力的关键组成部分。职业发展规划：S博士建议的培训活动包括：1)神经可塑性研究的电生理技术培训；2)出席和参与科学会议，其中的科学内容围绕学习和记忆；3)指导和培训本科生和研究生在赞助商实验室内的独立研究项目。环境：该研究将在科罗拉多大学S心理与神经科学系和行为遗传学研究所进行。共同发起人史蒂文·迈尔博士和唐纳德·库珀博士是压力、学习和记忆以及神经可塑性领域的资深研究人员。这两个实验室都有足够的外部资金来支持拟议的研究和指导博士后研究员的良好记录。此外，实验室空间充足，设备先进。研究：拟议的研究测试了两个与安全学习相关的互补假设。安全学习是一个巴甫洛夫过程，通过这个过程，感觉刺激可以预测厌恶事件不会发生。首先，安全学习发生在岛叶皮质。这将通过几种方式进行测试，包括：i)当大鼠学习或回忆安全提示时，对岛叶皮质的药物抑制；ii)体外全细胞膜片钳对杏仁核投射的岛叶皮质神经元内在兴奋性的评估。岛叶皮质突触可塑性的多电极评估。第二：暴露在无法控制的压力下，这是创伤后应激障碍(PTSD)的实验室模型，将干扰安全信号的学习和表达。这一假设将通过在安全学习之前或之后插入不可控应力来检验。总之，这些互补的方法将导致对潜在安全的神经机制的理解的重大进步，并为研究病理性安全学习提供一个范例，就像在创伤后应激障碍中发生的那样。 公共卫生相关性：了解危险和安全之间的区别对于生存至关重要，但在某些精神疾病中，这一过程失败了。在没有真正检测到安全的情况下，即使环境提示表明不太可能有危险，一些人也可能表现出恐惧或焦虑。这项拟议的工作测试了一种假设，即岛叶皮质是安全学习的关键贡献者，岛叶皮质中的神经可塑性变化是安全记忆存储和回忆的基础。这项工作对创伤后应激障碍和其他涉及高度恐惧和焦虑的疾病的治疗和诊断具有重要意义。