Assessing the role of Parvalbumin Interneurons in Adolescent Stress Induced Resilience

评估小白蛋白中间神经元在青少年压力诱导的弹性中的作用

• 批准号: 10405014
• 负责人: Nawshaba Nawreen
• 金额: $ 1.74万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405014
• 关键词: Adolescence; Adolescent; Adult; Affect; Amygdaloid structure; Animals; Area; Behavior; Behavioral; Brain; Chronic; Chronic stress; Complex; Data; Development; Disease; Electrophysiology (science); Equilibrium; Etiology; Exhibits; Extinction (Psychology); FOS Protein; Fright; Future; Generations; Human; Hyperactivity; Impairment; Individual; Interneuron function; Interneurons; Knowledge; Life; Link; Medial; Mediating; Mental Depression; Modeling; Modification; Neurons; Outcome; Output; Parvalbumins; Pathology; Phenotype; Play; Post-Traumatic Stress Disorders; Prefrontal Cortex; Pyramidal Cells; Rattus; Research; Rodent; Role; Signal Transduction; Stress; Symptoms; Synaptic plasticity; Testing; Time; Whole Organism; base; conditioned fear; critical period; designer receptors exclusively activated by designer drugs; early life adversity; early life stress; experience; experimental study; fear memory; hippocampal pyramidal neuron; in vitro testing; in vivo evaluation; innovation; insight; novel; optogenetics; patch clamp; prevent; protective effect; protein expression; resilience; response; stress resilience; stressor; synaptic inhibition; transmission process; traumatic stress

Project Summary Adolescence is a critical period of brain development in humans as well as in other mammalian species. The match-mismatch hypothesis of brain development postulates that early life adversity can promote an adaptive phenotype later in life, allowing individuals to cope with certain adverse situations in adulthood. Preliminary results from our lab show that chronic stress during adolescence makes animals resilient to the deleterious impact of traumatic stress (single prolonged stress) (SPS) in adulthood. SPS is a stress paradigm used to model post-traumatic stress disorder (PTSD) symptoms in rodents, as it impairs extinction of conditioned fear. In humans, PTSD is linked to reduced activation of area 25, homologous to the infralimbic (IL) prefrontal cortex in the rodent (PFC). Rodent studies indicate that extinction of fear memory requires plasticity in the IL and its downstream connections to the basolateral amygdala (BLA). It has been shown that parvalbumin interneurons (PV INs) in the IL play a role in mediating fear responses. Activation of PV INs in the IL mPFC inhibits pyramidal cell output in the IL-BLA circuit, enhancing fear reinstatement. PV INs undergo remarkable maturation during adolescence and are affected by stress during this time period, making them potential targets for modulating IL-BLA circuit function following adolescent stress. The objective of this proposal is to test the hypothesis that adolescent stress promotes stress resilience by modifying PV IN activity in the IL-BLA circuit. Specific Aim 1 which will use an optogenetic and electrophysiological approach to elucidate the effects of adolescent stress on synaptic inhibition within the IL-PFC. Specific Aim 2 which will use a chemogenetic approach to identify the IL-PFC interneurons that promote stress resilience following adolescent stress. We expect that adolescent stress will block the SPS-induced enhancement of PV IN mediated GABAergic signaling in the IL-BLA circuit, and demonstrate that PV INs are necessary and sufficient for promoting stress resilience. Overall, the findings of these studies will contribute to the understanding of the mechanisms through which stress during development can control reactivity to stressors in adulthood, and are anticipated to define a central role for IL PV INs in stress resilience.

项目摘要 青春期是人类和其他哺乳动物大脑发育的关键时期。的 大脑发育的匹配-不匹配假说假定，早期生活的逆境可以促进适应性的发展， 表型在以后的生活中，允许个人科普成年后的某些不利情况。初步 我们实验室的结果表明，青春期的慢性压力使动物对有害的环境有弹性， 创伤性压力（单一长期压力）（SPS）在成年期的影响。SPS是一种压力范例， 创伤后应激障碍（PTSD）症状的啮齿动物模型，因为它损害了条件性恐惧的消退。 在人类中，创伤后应激障碍与25区的激活减少有关，该区域与边缘下（IL）前额皮质同源 在啮齿动物（PFC）。啮齿类动物的研究表明，恐惧记忆的消失需要IL及其 与基底外侧杏仁核（BLA）的下游连接。研究表明，小白蛋白中间神经元 (PV IL中的INs在介导恐惧反应中起作用。IL mPFC中PV IN的激活抑制了 IL-BLA回路中的锥体细胞输出，增强恐惧的恢复。PV IN发生显著变化 在青春期成熟，并在这段时间内受到压力的影响，使他们成为潜在的 调节青少年压力后IL-BLA回路功能的目标。这项建议的目的是 检验青少年压力通过改变IL-BLA中的PV IN活性来促进压力恢复力的假设 电路.具体目标1将使用光遗传学和电生理学方法来阐明 具体目标2将使用化学发生剂， 方法来确定IL-PFC中间神经元，促进压力恢复青春期压力。我们 预期青少年压力将阻断SPS诱导的PV IN介导的GABA能增强 IL-BLA回路中的信号传导，并证明PVIN对于促进应激是必要且充分的 resilience.总的来说，这些研究的结果将有助于通过以下方式了解这些机制： 在发育过程中的压力可以控制成年期对压力源的反应，并预计将定义 IL PV IN在压力恢复中发挥着核心作用。