DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is one of the most common mental disorders in the United States, with a lifetime prevalence of ~17%. Significantly, the risk of MDD is more than doubled in patients with type 2 diabetes mellitus (T2DM), which is also associated with a 10 fold greater risk for suicide. With the incidence of T2DM growing annually, the need for more rapidly effective treatment strategies for MDD is also growing. We hypothesize that metabolic stress-induced dysfunction of cellular energy-sensing homeostatic mechanisms contributes to the etiology of MDD, and drugs targeting neuronal energy sensors may provide novel, rapid-acting treatments for depression. Imaging studies revealed that hyperactive metabolism of the basolateral amygdala (BLA) correlates with MDD symptom severity and normalizes with successful pharmacotherapy. We have strong preliminary data showing that BLA manipulations of the ubiquitous cellular energy sensor, AMP-activated protein kinase (AMPK), can significantly disrupt affective behavior and dramatically alter electrophysiological properties of principal neurons. Thus, we further hypothesize that AMPK signaling plays a major role in regulating homeostatic plasticity in BLA principal neurons, and dysfunction of this signaling cascade could contribute to the etiology of depression in T2DM. In T2DM, insulin-resistance prevents insulin-induced glucose uptake into cells, thereby disturbing cellular energy balance. Metformin, the drug of choice for treating T2DM, works by activating AMPK. Activated AMPK functions to restore cellular energy balance by inhibiting energy utilizing and enhancing energy producing processes, such as increasing cellular glucose uptake. Significantly, the BLA expresses a high density of insulin receptors and insulin-regulated glucose transporters, suggesting that insulin-dependent regulation of glucose uptake is a key modulator of BLA metabolic function. Importantly, insulin-resistance occurs in both CNS and periphery. However, as metformin does not easily cross the blood brain barrier the central effects of metabolic disruption in T2DM largely remain unchecked. Recent metabolomics studies have shown a significant overlap in biomarkers involved in metabolic- and mood disorders. Indeed, diet-induced obesity in rodents results in insulin-resistance, depression-like behavior, enhanced BLA activation to emotional stimuli, and a reduced threshold for LTP induction. Notably, the insulin- resistance and depression-like behavior could be alleviated by administration of a selective AMPK activator, AICAR, suggesting that targeting the AMPK signaling cascade may be a novel avenue of research for treating depression. However, surprisingly little is known about the role of the AMPK signaling cascade in regulating neuronal function in areas outside the hypothalamus, or how it is affected by metabolic stress. This proposal seeks to address this critical knowledge gap.