Beta-arrestin signaling dependent modulation of glutamatergic transmission in the extended amygdala mediates stress and anxiety behavior

Project: Research project

Project Details

Description

Anxiety disorders are now the most prevalent psychiatric disease in the US. Several brain regions have been implicated in anxiety behavior in rodents, in particular the bed nucleus of the stria terminalis (BNST) of the extended amygdala has been determined to be a critical region in mediating both stress and anxiety behavior. Stress is a powerful modulator of emotional behavior and is implicated in the etiology of anxiety disorders. Studies have been performed showing that stress can alter neuronal anatomy, physiology and subsequent anxiety behavior in regions such as the BNST, however, the mechanism by how this occurs or critical potential pharmacologic targets for these adaptations have not been identified. G protein coupled receptors (GPCRs) compose the largest family of cell surface receptors and are the signal transducer for many neurotransmitters.
The GPCRs can transduce this signal in many diverse ways. A recently discovered form of GPCR signaling is through the scaffolding proteins beta-arrestin 1 and beta-arrestin 2, which are now known to act as parallel, G Protein independent, transduction systems in addition to their well characterized roles in receptor desensitization and internalization.
There are currently little investigations into the role that beta-arrestin signaling may play in
altering short and long term excitatory signaling in the brain, however, there are recent reports suggesting beta-arrestin signaling is important in neuropsychiatric disease and can be modulated by stress. I have begun to study the role of beta-arrestin signaling in excitatory transmission in the BNST, finding both that acute changes in excitatory transmission are blocked in mice lacking beta-arrestins and that a newly described form of long term depression (LTD) in the BNST is modulated by beta-arrestins. Taken together, given the critical nature of the BNST in mediating stress and anxiety related behavior and these preliminary findings, I hypothesize that beta-arrestin signaling dependent modulation of excitatory glutamatergic transmission in the extended amygdala mediates stress and anxiety behavior. This project will study the effect of beta-arrestin signaling on physiology in the BNST using novel genetic techniques to tie physiologic changes to the behavioral responses to stress. The hope is to identify more selective targets by determining the involvement of beta-arrestins that may be successful treatments for anxiety, stress disorders and other neuropsychiatric disease.
StatusFinished
Effective start/end date7/15/177/31/18

Funding

  • Brain & Behavior Research Foundation (25201)

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