While stress is a major risk factor for mood and anxiety disorders, the neurobiological mechanisms by which stress is translated into psychopathology are poorly understood. Current therapeutics that augment monoaminergic transmission ease symptoms but likely do not correct underlying dysfunction as they exhibit long-term success rates of only 40-60%. Novel therapeutic approaches to reduce pathological effects of stress could have broad clinical applications. Anxiety disorders are associated with amygdala hyperactivity. In rodents, stress increases excitatory drive to the basolateral amygdala (BLA). Interventions which temper excitatory drive to the BLA, a key modulator of fear and anxiety, may reduce stress-induced psychopathology. Cannabinoid receptors (CBR) are expressed on glutamatergic terminals within the BLA and activation of CBRs reduces presynaptic release probability. Thus, the endogenous cannabinoid (eCB) system is perfectly poised to buffer stress-induced excitatory drive to the BLA and thereby reduce stress-induced pathology. Enhanced signaling of the eCB, anandamide (AEA), in the BLA reduces stress-induced anxiety-like behavior. However, the role of 2-arachidonoylglycerol (2-AG), the most abundant eCB in the brain, in regulating stress, anxiety, and mood is poorly understood. The relatively recent development of JZL-184, a specific inhibitor of the primary 2-AG degrading enzyme, monoacylglycerol lipase, has spurred progress on this front, but several critical questions remain unanswered. Can 2-AG signaling buffer stress-induced behavioral dysregulation? Does impaired 2-AG signaling exacerbate stress-induced behavioral dysregulation? By what synaptic mechanisms does 2-AG signaling influence stress responses? We have developed novel tools to address these questions from multiple angles. We have functionally validated a lentiviral vector to overexpress the 2- AG synthetic enzyme diacylglycerol lipase a (DAGLa). We have also generated DAGLa knockout (KO) and DAGLa conditional KO (DAGLaf/f) mice. These novel tools permit us to test, for the first time, a causal relationship between 2-AG signaling and stress-induced anxiety- and depressive-like behaviors. Completion of these studies could validate enhancing 2-AG signaling as a viable therapeutic approach for mood and anxiety disorders. This proposal also constitutes a rigorous technical and professional training plan. I will be trained in stereotaxic surgery, mass spectrometry, whole-cell electrophysiology, and viral vector generation. I will present monthly in lab meetings, biannually in Synaptic Journal Club, and yearly in a departmental seminar and retreat. I will gain writing, presentation, and networking experience by presenting my work at 2 conferences per year. I will prepare at least 1 manuscript per year, edit the work of my colleagues, and practice reviewing manuscripts and grants under the supervision of Dr. Patel. Yearly completion of an individual development plan will facilitate formal discussion of my progress and goals with Drs. Colbran and Patel. This training constitutes a solid foundation from which to pursue postdoctoral opportunities and an independent research career.
Stress is a major risk factor for mood and anxiety disorders including major depression and post-traumatic stress disorder. We hypothesize that increasing the brain's production of a signaling molecule, 2- arachidonoylglycerol, will reduce stress-induced anxiety and depression in rodent models and that this may present a new avenue of treatment for major depression and anxiety disorders. Over the course of these studies, I will receive extensive technological training (whole cell electrophysiology, mass spectrometry, stereotaxic surgery) and develop the requisite skills for a successful career in academic biomedical research.
|Shonesy, Brian C; Parrish, Walker P; Haddad, Hala K et al. (2018) Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior. Biol Psychiatry 84:304-315|
|Bluett, Rebecca J; Báldi, Rita; Haymer, Andre et al. (2017) Endocannabinoid signalling modulates susceptibility to traumatic stress exposure. Nat Commun 8:14782|
|Robinson, Stacey L; Alexander, Nancy J; Bluett, Rebecca J et al. (2016) Acute and chronic ethanol exposure differentially regulate CB1 receptor function at glutamatergic synapses in the rat basolateral amygdala. Neuropharmacology 108:474-84|
|Holleran, Katherine M; Wilson, Hadley H; Fetterly, Tracy L et al. (2016) Ketamine and MAG Lipase Inhibitor-Dependent Reversal of Evolving Depressive-Like Behavior During Forced Abstinence From Alcohol Drinking. Neuropsychopharmacology 41:2062-71|
|Shonesy, Brian C; Bluett, Rebecca J; Ramikie, Teniel S et al. (2014) Genetic disruption of 2-arachidonoylglycerol synthesis reveals a key role for endocannabinoid signaling in anxiety modulation. Cell Rep 9:1644-1653|