Prefrontal circuits underlying the maturation of learned avoidance

习得性回避成熟的前额叶回路

• 批准号: 10523023
• 负责人: Laura Anne DeNardo
• 金额: $ 51万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-19 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523023
• 关键词: Acceleration; Adaptive Behaviors; Address; Adolescence; Adolescent; Adult; Age; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Behavior; Behavioral; Behavioral Assay; Caregivers; Chronic; Cognitive; Companions; Complex; Cues; Decision Making; Development; Disease; Emotional; Event; Exposure to; Fiber; Functional disorder; Goals; Image; Individual; Intervention; Knowledge; Lead; Learning; Link; Medial; Mediating; Mental Depression; Mental Health; Mental disorders; Modeling; Monitor; Moods; National Institute of Mental Health; Nucleus Accumbens; Pathway interactions; Pattern; Photometry; Pilot Projects; Prefrontal Cortex; Research; Risk; Risk Factors; Role; Stimulus; Stress; Symptoms; Testing; Time; Viral; avoidance behavior; design; early experience; early life adversity; effective intervention; emotional behavior; improved; in vivo; innovation; insight; optogenetics; personalized approach; premature; prevent; relating to nervous system; response; therapeutic target; tool; virus genetics

PROJECT SUMMARY The medial prefrontal cortex (mPFC) makes essential contributions to learning, mood, and decision making, including evaluating and responding to threats. Compared to other circuits, mPFC circuits undergo prolonged maturation that is likely necessary in order to support complex behaviors. Yet how the development of prefrontal circuits enables the maturation of adaptive behaviors is poorly understood. Moreover, its extended development renders mPFC circuits highly vulnerable to disruption by environmental insults such as early life adversity (ELA). Even after adverse environmental conditions improve, ELA can produce lasting alterations in cognitive and emotional processing that put individuals at risk for many psychiatric disorders including anxiety disorders and depression. Although mPFC circuits are clear therapeutic targets for psychiatric disorders, substantial gaps in our understanding of typical mPFC circuit development and how this maturation enables emergence of complex cognitive and emotional behaviors prevent us from designing effective interventions. Our research will fill this knowledge gap by combining threat avoidance behavioral assays with projection-specific optogenetic manipulations, activity monitoring, and a model of ELA to test the hypothesis that precisely timed maturation of PL-BLA and PL-NAc circuits determines age-specific avoidance behaviors, and by altering the trajectory of circuit development, ELA leads to age-specific alterations in learned avoidance. In Aim 1, we will use optogenetics to test the hypothesis that the behavioral contribtions of specific mPFC circuits change over development. In Aim 2, we will use fiber photometry to expose circuit and region-specific activity patterns during learned avoidance across development. Finally, in Aim 3, we will apply the aforementioned approaches to a model of early life adversity to understand how chronic early stress impacts the trajectory of threat avoidance circuit development. This proposal directly addresses a pressing need to understand the complex relationships between early adversity, mPFC circuit development, and adaptive threat resposnes. Our research can inform individualized mental health treatments that exploit a variety of developmental opportunities, depending on the stage at which symptoms emerge.

内侧前额叶皮质(MPFC)对学习、情绪、 以及决策，包括评估和应对威胁。与其他电路相比，mPFC电路 经历长时间的成熟，这可能是支持复杂行为所必需的。然而，这是如何 前额叶回路的发展使适应行为的成熟还知之甚少。此外， 它的扩展开发使得mPFC电路非常容易受到环境侮辱的破坏，如 被称为早期生活逆境(ELA)。即使在不利的环境条件改善后，ELA也可以产生持久的 认知和情绪处理的改变，使个人面临许多精神障碍的风险 包括焦虑症和抑郁症。尽管mPFC回路是明确的治疗靶点 精神障碍，我们对典型的mPFC电路发展的理解存在很大差距，以及这是如何 成熟使复杂的认知和情感行为的出现阻碍了我们的设计 有效的干预措施。我们的研究将通过结合威胁回避行为分析来填补这一知识空白 通过投射特定的光遗传操作、活动监测和ELA模型来验证这一假设 PL-BLA和PL-NAC回路的精确定时成熟决定了特定年龄的回避行为， 通过改变回路发育的轨迹，ELA导致了习得性回避中特定年龄的变化。 在目标1中，我们将使用光遗传学来检验这一假设，即特定mPFC电路的行为结构 改变而不是发展。在目标2中，我们将使用光纤光度法来揭示特定于电路和区域的活动 在整个发展过程中的习得回避模式。最后，在目标3中，我们将应用前面提到的 建立早期生活逆境模型的方法，以了解慢性早期应激是如何影响 威胁避免电路的开发。这项建议直接解决了理解 早期逆境、mPFC电路发展和适应性威胁应对之间的复杂关系。我们的 研究可以为利用各种发展机会的个性化心理健康治疗提供信息， 这取决于出现症状的阶段。