Prefrontal circuits underlying the maturation of learned avoidance

习得性回避成熟的前额叶回路

基本信息

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
项目类别：
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

项目摘要

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投影特定的光遗传学操作、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，通过改变回路发展的轨迹，ELA 会导致习得性回避的年龄特异性改变。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

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Developmentally distinct architectures in top-down circuits.

自上而下电路中发展独特的架构。

DOI：
发表时间：
2023-08-28
期刊：
影响因子：
0
作者：
Klune, Cassandra B;Goodpaster, Caitlin M;Gongwer, Michael W;Gabriel, Christopher J;Chen, Rita;Jones, Nico S;Schwarz, Lindsay A;DeNardo, Laura A
通讯作者：
DeNardo, Laura A

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：
发表时间：
2024-01-07
期刊：
影响因子：
0
作者：
Jin, Benita;Gongwer, Michael W;Ohanian, Lilit;Holden;Le, Bryan;Darmawan, Alfonso;Nakayama, Yuka;Rueda Mora, Sophia A;DeNardo, Laura A
通讯作者：
DeNardo, Laura A