Developmental Engagement of Neural Circuitry Underlying Safety Learning

安全学习背后的神经回路的发展参与

基本信息

批准号：
10528557
负责人：
Heidi Catherine Meyer
金额：
$ 24.9万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
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：
2022-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10528557
关键词：
Address Adolescence Adolescent Adolescent Development Adult Affective Anatomy Animals Anxiety Disorders Attenuated Award Basic Science Behavior Behavior Therapy Behavioral Behavioral Model Behavioral inhibition Biological Brain Buffers Clinical Data Development Diagnosis Economics Effectiveness Equilibrium Exposure to Extinction (Psychology)Failure Fiber Foundations Fright Goals Hippocampus (Brain)Human Image Interneurons Intervention Knowledge Learning Link Literature Measures Mediating Mental disorders Mentors Methods Modeling Mus Neurodevelopmental Disorder Neurons Outcome Output Parvalbumins Pharmacology Phase Photometry Population Positioning Attribute Prefrontal Cortex Process Property Protocols documentation Regulation Research Rodent Model Safety Services Severities Signal Transduction Somatostatin Stimulus System Techniques Testing Time Training Viral Vector anxiety-like behavior associated symptom base career cell type cellular targeting conditioned fear excitatory neuron in vivo calcium imaging ineffective therapies insight learned behavior neural circuit neurobiological mechanism novel optogenetics psychologic relating to nervous system research and development success vulnerable adolescent

项目摘要

Project Summary Anxiety disorders are highly prevalent, with diagnoses peaking during adolescence, creating a significant psychological and economic societal burden. Moreover, existing behavioral treatments to attenuate inappropriate fear responding in anxiety disorders have limited or no success for nearly half of the adolescent population. A critical barrier to developing treatments better suited for this group is a lack of knowledge about how key neural circuits related to fear acquisition and inhibition mature. The principal goal of this project is to identify the mechanisms underlying fear inhibition specifically as it manifests during adolescence. This project integrates adolescent behavioral models with cutting edge neural imaging and manipulation techniques to elucidate the yet unstudied mechanisms by which safety signals inhibit fear during adolescence. A ‘conditioned safety’ paradigm adapted for application during mouse adolescence is used to address key basic science questions about safety learning with far-reaching translational and clinical value. Through this paradigm, mice learn to utilize stimuli explicitly predicting the absence of an aversive outcome (i.e., ‘safety signals’) in service of attenuating fear responding. Research during the Mentored (K99) phase focused on the connection between the the ventral hippocampus (VH) and prelimbic cortex (PL), regions involved in the allocation and regulation of affective behaviors, and that undergo robust changes across adolescence. In-vivo calcium imaging (fiber photometry) was used to record and optogenetics to manipulate activity in VH-PL neurons in adolescent mice, elucidating a link between real-time dynamics of safety and fear behavior to fluctuations VH-PL signaling. Drawing from the literature and integrating preliminary data collected during the K99 phase led to the advancement of the central hypothesis that VH projections to PL interneurons promote safety behavior by producing a net inhibition of PL that is sustained throughout presentations of safety, but not fear signals, and that the heightened plasticity observed within VH and PL during adolescence provides a ‘sensitive window’ for enhanced efficacy of the conditioned inhibition of fear by safety signals. The goal of the Independent (R00) phase is to identify the PL interneuron targets of VH neurons and their relative activity during conditioned safety. Aim 1 will use a spectrally resolved fiber photometry system to record simultaneously from VH projections and select populations of PL interneurons. Aim 2 will use a Fos-activated (TRAP) viral-vector strategy to manipulate functional ensembles of PL interneurons to establish their contributions to the inhibition of fear. A foundation for accomplishing this research has been set through intensive training and discussion with an advisory panel of mentors, consultants, and collaborators with renowned expertise in adolescent development, fear learning, and circuit and cell-type specific neuronal modulation techniques. The candidate is well-positioned for an independent research career investigating behavioral regulation in developmental rodent models relevant to psychiatric illness and identifying circuit-level targets for intervention and treatment.

项目摘要焦虑症是高度高的，创造了和经济的痛苦，而行为特征是减轻焦虑症的恐惧反应的有限或没有成功的人群。关于与恐惧的关键回路有关的知识和成熟。信号通过这种范式来抑制有关安全学习的基本科学问题，这是通过这种范式进行的。。在K99阶段期间从文献中绘制的青少年小鼠的VH-PL神经元中的活性。并且在VH和青春期内观察到的高度可塑性是通过安全信号增强恐惧的效力的“敏感窗口”。 AIM 1将使用Spectraly解决的光纤光学系统来记录VH投影并选择速率。指导者以及在青少年发展，恐惧学习，电路和细胞类型的特定神经元调制技术方面拥有著名的合作者。