Prefrontal circuits underlying the maturation of learned avoidance

习得性回避成熟的前额叶回路

• 批准号: 10667631
• 负责人: Laura Anne DeNardo
• 金额: $ 51.34万
• 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/10667631
• 关键词: Acceleration; Adaptive Behaviors; Address; Adolescence; Adolescent; Adult; Age; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Avoidance Learning; Beds; 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; 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; neural; optogenetics; personalized approach; premature; prevent; 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) 对学习、情绪、 和决策，包括评估和应对威胁。与其他电路相比，mPFC 电路 经历长期的成熟，这可能是支持复杂行为所必需的。然而如何 前额叶回路的发展如何使适应性行为成熟，人们对此知之甚少。而且， 其长期发展使得 mPFC 电路极易受到环境损害的破坏，例如 如早年逆境（ELA）。即使在不利的环境条件改善后，ELA也能产生持久的 认知和情绪处理的改变使个体面临许多精神疾病的风险 包括焦虑症和抑郁症。尽管 mPFC 回路是明确的治疗靶点 精神疾病，我们对典型 mPFC 电路发展及其如何发展的理解存在巨大差距 成熟使得复杂的认知和情感行为的出现阻止我们进行设计 有效的干预措施。我们的研究将通过结合威胁规避行为分析来填补这一知识空白 通过特定于投影的光遗传学操作、活动监测和 ELA 模型来检验假设 PL-BLA 和 PL-NAc 电路的精确定时成熟决定了特定年龄的回避行为， 通过改变回路发展轨迹，ELA 会导致习得性回避的特定年龄变化。 在目标 1 中，我们将使用光遗传学来检验特定 mPFC 电路的行为贡献这一假设 转变胜于发展。在目标 2 中，我们将使用光纤光度测定法来暴露电路和区域特定的活动 整个发展过程中习得性回避的模式。最后，在目标 3 中，我们将应用上述内容 建立早期生活逆境模型的方法，以了解慢性早期压力如何影响人生轨迹 威胁规避电路开发。该提案直接解决了了解这一问题的迫切需要 早期逆境、mPFC 电路发展和适应性威胁响应之间的复杂关系。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， 取决于症状出现的阶段。

项目成果

Developmentally distinct architectures in top-down circuits.

自上而下电路中发展独特的架构。

• DOI: 10.1101/2023.08.27.555010
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Klune,CassandraB;Goodpaster,CaitlinM;Gongwer,MichaelW;Gabriel,ChristopherJ;Chen,Rita;Jones,NicoS;Schwarz,LindsayA;DeNardo,LauraA
• 通讯作者: DeNardo,LauraA

A developmental brain-wide screen identifies retrosplenial cortex as a key player in the emergence of persistent memory.

全脑发育筛选将压后皮层识别为持久记忆出现的关键参与者。

• DOI: 10.1101/2024.01.07.574554
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Jin,Benita;Gongwer,MichaelW;Ohanian,Lilit;Holden-Wingate,Lucinda;Le,Bryan;Darmawan,Alfonso;Nakayama,Yuka;RuedaMora,SophiaA;DeNardo,LauraA
• 通讯作者: DeNardo,LauraA