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Developmental engagement of neural circuitry underlying safety learning

安全学习背后神经回路的发展参与

基本信息

批准号：
10018112
负责人：
Heidi Catherine Meyer
金额：
$ 8.71万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-13 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10018112
关键词：
Address Adolescence Adolescent Adolescent Development Adult Affective Age Animals Anxiety Disorders Attenuated Basic Science Behavior Behavior Therapy Behavioral Behavioral Assay Behavioral Model Biological Brain Clinical Data Development Diagnosis Economics Effectiveness Ensure Exposure to Extinction (Psychology)Failure Fiber Fright Goals Hippocampus (Brain)Human Image Interneurons Intervention Knowledge Learning Link Measures Mediating Mental disorders Mentors Mus Nature Neurodevelopmental Disorder Neurons Outcome Pharmacology Phase Photometry Population Process Property Protocols documentation Regulation Research Rodent Model Safety Services Severities Signal Transduction Stimulus System Techniques Testing Time Training Viral Vector Work anxiety-like behavior associated symptom calcium indicator career cell type cellular targeting conditioned fear conditioning design experimental study ineffective therapies inhibitor/antagonist insight learned behavior neural circuit neurobiological mechanism novel optogenetics psychologic relating to nervous system research and development success vulnerable adolescent

项目摘要

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. To this end, this project will use a novel ‘conditioned safety’ paradigm appropriate for use in adolescent mice 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. The proposed research focuses on 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. Adolescent behavioral models will be integrated with cutting edge neural imaging and manipulation techniques to elucidate the yet unstudied mechanisms by which safety signals inhibit fear during adolescence. Together, the proposed experiments are designed to test the overarching 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. In the Mentored (K99) phase, fiber photometry will be used in developing mice to link neural activity to real-time dynamics of safety and fear behavior via genetically encoded calcium indicators localized in VH-PL neurons. Further, optogenetic techniques will be used to establish whether activity in VH-PL neurons is necessary and sufficient for fear inhibition. To extend this work, in the Independent (R00) phase the downstream PL interneuron targets of VH neurons and their relative activity during conditioned safety will be identified using a spectrally resolved fiber photometry system to record simultaneously from VH projections and select populations of PL interneurons. Finally, a novel Fos-activated (TRAP) viral-vector strategy will be used to manipulate functional ensembles of PL interneurons to establish their contributions to the inhibition of fear. Intensive training with a mentoring team including collaborators and consultants with renowned expertise in adolescent development, fear learning, and circuit- and cell-type specific neuronal modulation techniques will ensure the candidate’s technical and professional development, situating her 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.

焦虑症非常普遍，在青春期诊断达到高峰，造成了显著的