Safety Learning and Plasticity in the Insular Cortex

描述（由申请人提供）：John Christianson博士是F32资助的研究助理，对焦虑和恐惧行为的恢复力和脆弱性的神经机制有广泛的了解。过去的研究已经确定，心理变量，包括对压力的行为控制和压力期间的安全信号，导致从压力引起的焦虑中恢复过来。此外，他还发现了内侧前额叶皮层和岛叶皮层在这些缓解压力的作用中的因果关系。他的近期目标是提高他的学术和技术技能，以便制定一项独立的研究计划，研究安全学习和安全恐惧抑制的神经基础。K99/R 00提案是实现这一目标的关键组成部分。职业发展计划：Christianson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实验室内进行独立研究项目。工作环境：这项研究将在科罗拉多大学的心理学和神经科学系以及行为遗传学研究所进行。共同发起人，史蒂芬迈尔博士和唐纳德库珀是建立在压力，学习和记忆和神经可塑性领域的调查员。两个实验室都有足够的校外资金来支持拟议的研究和优秀的记录指导博士后研究员。此外，实验室的空间是足够的和设备的最先进的。研究：建议的研究测试两个互补的假设有关安全学习。安全学习是一个巴甫洛夫过程，通过这个过程，感官刺激来预测不发生的厌恶事件。第一：安全学习发生在岛叶皮层。这将以几种方式进行测试，包括i）在大鼠学习或回忆安全提示时岛叶皮质的药理学抑制，ii）杏仁核投射岛叶皮质神经元内在兴奋性的体外全细胞膜片钳评估和iii.）岛叶皮质突触内可塑性的多电极评估。第二个：暴露于不可控制的压力，创伤后应激障碍（PTSD）的实验室模型，将干扰学习和表达的安全信号。将通过在安全学习之前或之后插入不可控应力来检验该假设。这些互补的方法将导致一个显着的进步，在理解的神经机制的安全性，并提供了一个范式，研究病理安全学习发生在创伤后应激障碍。 公共卫生相关性：学习危险和安全之间的区别是生存的关键，但在某些精神病条件下，这个过程失败了。如果没有对安全的真实检测，即使环境提示表明危险不太可能发生，某人也可能会表达恐惧或焦虑。拟议的工作测试的假设，岛叶皮层是一个重要的贡献者安全学习和岛叶皮层的神经可塑性变化的基础安全记忆的存储和回忆。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。

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.