Monday, April 29, 2024
4/29/2024
ABSTRACT Alcohol use disorder (AUD) is a chronic, relapsing brain disorder. It is well established that stress motivates alcohol use and triggers relapse in individuals with AUD; however, the neural mechanisms that underlie this association are not clear. Preclinical studies have shown that chronic alcohol and chronic stress impact the brain’s stress systems in a way that results in deficits in flexible, adaptive stress coping. These deficits can perpetuate a cycle of enduring stress conditions, and ultimately drive progression of AUD. The vast majority of the literature examining chronic stress and its effects on brain function in AUD has yet to be translated from preclinical to human clinical samples. Furthermore, clinical studies examining chronic stress and its association with brain function in AUD are limited by the nature and quality of chronic stress measures, which primarily rely on self-report questionnaires. To advance the translational impact of the science of the stress neurocircuitry in AUD, it is critical that clinical studies implement methods to objectively measure chronic stress. This F32 NRSA will objectively assess chronic stress and examine dynamic functional connectivity within the brain’s stress coping system, using fMRI, in a clinical sample with AUD (n=32) and matched controls (n=32). Additionally, this F32 will foster the applicant’s development as independent clinical and translational neuroscientist with a focus on the intersection of stress and AUD. This application will draw on resources from the Sponsors’ (Drs. Lara Ray and Erica Grodin) R21 study investigating the effect of stress on decision-making in AUD by adding complimentary, non-overlapping scientific aims and outcome measures. The UCLA Life Stress Interview will be used to objectively assess the psychological experience of chronic stress. Resting state fMRI will be used to examine dynamic functional connectivity within the brain’s stress coping network. The ventromedial prefrontal cortex (vmPFC) is recognized as a key locus in a resilient stress coping network, and recent studies have suggested that dynamic changes in vmPFC activation during acute stress signals resilient coping. The applicant will extend this work by measuring dynamic vmPFC functional connectivity to characterize temporal variability within the network. The applicant will integrate these psychological and neural levels of analysis to examine the effects of chronic stress on temporal variability, or flexibility, within the brain’s stress coping system in AUD versus controls. Aim 1 tests the hypothesis that individuals with AUD will exhibit greater chronic stress compared with controls. Aim 2 tests the hypothesis that individuals with AUD will exhibit diminished temporal variability (flexibility) in vmPFC resting state functional connectivity compared with controls. Aim 3 tests the hypothesis that chronic stress will be associated with decreased flexibility in vmPFC resting state functional connectivity, and that AUD will moderate this relationship. The proposed study represents important steps in: 1) translating preclinical science on the stress neurocircuitry in AUD; and 2) the applicant’s scientific development and maturity as an independent clinical alcohol researcher with an interest in the role of stress in AUD.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
