Developmental engagement of neural circuitry underlying safety learning

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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.