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.

项目摘要内侧前额叶皮层（MPFC）为学习，情绪， 和决策，包括评估和应对威胁。与其他电路相比，MPFC电路 为了支持复杂行为，可能需要长时间的成熟。但是如何 前额叶回路的发展使自适应行为的成熟程度鲜为人知。而且， 它的扩展开发使MPFC电路极易受到环境侮辱的破坏 作为早期逆境（ELA）。即使不利的环境条件改善，ELA也会产生持久的 认知和情感处理的改变，使个人有许多精神疾病的风险 包括焦虑症和抑郁症。尽管MPFC电路是明确的治疗目标 精神疾病，我们对典型MPFC电路发展的理解以及如何理解 成熟使复杂的认知和情感行为的出现使我们无法设计 有效的干预措施。我们的研究将通过结合避免威胁的行为分析来填补这一知识差距 通过投影特异性的光遗传操作，活性监测和ELA模型以检验假设 PL-BLA和PL-NAC电路的准时成熟决定了年龄特异性的回避行为， 通过改变电路开发的轨迹，ELA导致了学习回避的特定年龄变化。 在AIM 1中，我们将使用光遗传学来测试特定MPFC电路的行为贡献的假设 改变发展。在AIM 2中，我们将使用纤维光度法暴露电路和特定区域的活性 在整个开发过程中避免的模式。最后，在AIM 3中，我们将应用上述 采用早期生命逆境模型的方法，以了解慢性早期压力如何影响 威胁回避电路的发展。该建议直接解决了理解的紧迫需求 早期逆境，MPFC电路发展和自适应威胁呼应之间的复杂关系。我们的 研究可以告知个性化的心理健康治疗，以利用各种发展机会， 取决于症状出现的阶段。