Determining the unique and dynamic neural constellation belonging to acute and chronic stress states

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Project Summary: The objective of this “Biobehavioral Research Awards for Innovative New Scientists” proposal is to determine the contributions of the CRF (corticotropin releasing factor) system to encoding and responding to salient stimuli in the environment in individuals with different life histories of stressor exposure. CRF is a neuropeptide neuromodulator that is expressed in several brain regions and is released in response to both positive and negative arousing environmental stimuli. It is unclear how CRF as a brain wide neural system differentially responds to stimuli with different valences to motivate appropriate approach or avoidance behaviors. In addition, there is evidence that the CRF system is highly plastic and can undergo allostatic adaptations in response to stressor exposure. Moreover, it is thought that in pathological states of allostatic overload, these adaptations in the CRF system persist in suboptimal ways. Yet, it is unclear how the activity patterns of CRF enriched nuclei across the brain are altered in a stress-induced state of allostatic overload, nor is it understood how changes at different CRF loci combine to promote maladaptive behavioral responses. This proposal seeks to resolve these unanswered questions by testing the hypothesis that positive or negative salient environmental stimuli stimulate the activity of unique ensembles of CRF-containing nuclei to drive the appropriate affective behavioral responses. Furthermore, that chronic stress shifts CRF network responsivity toward greater activation to negative stimuli and depressed activation toward positive stimuli which leads to enhanced avoidance of these salient environment stimuli. To test this hypothesis, I propose two specific aims. Aim 1. Generate a whole brain functional map of activity patterns of CRF-containing neurons in response to acute environmental stimuli in control and chronically stressed male and female mice. This aim uses three-dimensional functional neuroanatomy and in vivo calcium imaging techniques to determine the activity patterns of CRF expressing nuclei in response to salient environmental stimuli that carry different valences. We will assess this in control and chronically stressed male and female mice. Collectively, these experiments will offer a holistic perspective on the response(s) of CRF to salient stimuli by viewing it as a whole-brain neural system rather than focusing on a single region or pathway. Aim 2. Determine the effects of site-specific suppression of CRF-containing neurons or deletion of CRF peptide on behavioral responses to acute salient stimuli presented to control and stress-exposed mice. This aim assesses the relative contributions of CRF localized to different brain nuclei in modulating approach and avoidance behavior by utilizing cutting-edge transgenic and optogenetic techniques. The purpose of the BRAINS program is to nurture innovative new investigators by promoting investigation of ambitious and important questions. This proposal answers that call and is poised to transform the way we think about CRF in the brain.