Neural mechanisms of stress-based effects on fear circuitry

抽象/项目总结

Abstract/Project Summary The ability to form associations between aversive stimuli and their predictors, and to later recall these associations, are imperative to survival. Conversely, the ability to inhibit fear responses following extinction of a fear memory is necessary for adaptation to changing environments. Maladaptive function of fear circuitry is seen in diseases such as post-traumatic stress disorder, depression, and anxiety; as such, fear conditioning is widely used as a model of clinical anxiety disorders. Chronic stress affects the function of the fear circuit, but these deficits develop in only a subset of individuals. One factor in vulnerability to stress is the adopted coping strategy (Veenema et al., 2003), with passive coping and active coping segregating into vulnerable or resilient traits respectively (Wood & Bhatnagar, 2015; Pearson-Leary et al., 2017). However, the specific brain circuits linking stress vulnerability or resilience to differences in fear learning are unknown. The paraventricular nucleus of the thalamus (PVT) is poised both anatomically and functionally to be a prime candidate for the locus of integration for stress and fear. Orexins, neuropeptides synthesized in the lateral hypothalamus, project throughout the limbic system, modulating many of the areas involved in stress-associated disorders and fear, such as the basolateral amygdala, the prefrontal cortex, and the PVT. Reduced OX expression is associated with resilience to stress following stressful events and protection from impairments in fear learning. Aim 1 of this proposal addresses the where question: Where does the integration of stress and fear take place? Our hypothesis is that the location of this integration is the PVT, therefore designer receptors exclusively activated by designer drugs (DREADDs) will be used to block or enhance OX activity within the PVT and compared between vulnerable and resilient populations. Sex will also be analyzed as there is preliminary data from the Bhatnagar lab suggesting that female rats display elevated orexin expression which delays adaptations to stress. Because there is potential for the PVT to not be the locus of integration, surrounding regions also known to be important in both stress and fear will also be examined. Aim 2 will address the how: How does the concentration of OX, which has clear and measurable effects in response to stress, perpetuate these effects? OX receptors are G-protein-coupled receptors, therefore the interactions and subsequent signaling cascades of these receptors will be closely examined to determine the mechanism through which stress affects fear learning. Aim 3 will address a circuit- level what: What is the effect of stress, and subsequent OX variation, on the local field potential within this network? Characterizing and quantifying the effects of stress on the fear network is crucial for developing future treatments for affective disorders. This proposal has been designed to combine the candidate's expertise in in vivo electrophysiology with training in pharmacology and endocrinology to prepare the candidate for an independent career where she plans to further examine the effects of stress on learning and memory.