Insulin resistance produces a failure of peripheral tissues (e.g. muscle and liver) and the brain to appropriately utilize glucose and generate ATP. The prevalence of this condition in aging individuals, as well as in several pathologies associated with cognitive decline, represents a major challenge for the health care system. Importantly, the brain requires ~20% of the total energy output of the body but contains only limited energy reserves. As a result, the brain is highly vulnerable to hypoglycemia and hypometabolic states that occur in neurological disorders. However, the role of insulin on the complex regulation of energy metabolism and homeostasis in neurons remains unknown. Patients with prediabetes or T2DM13 exhibit both insulin resistance and cognitive impairment. However, despite several studies suggesting an association between brain insulin resistance and cognitive decline, the role of insulin signaling on brain energy homeostasis and cognitive performance remains an enigma. Mechanistic studies on the neuronal actions of insulin have been limited to cultured cells that ignore the complex interactions between neurons and astrocytes that are critical to energy homeostasis. The premise of this application is based on the fact that an integrated view of insulin action on energy metabolism is not available but is required to understand and develop interventions for the effects of diabetes and multiple other diseases that impact cognitive health. The project proposed here is specially focused on advancing our basic understanding of insulin regulation of neuronal energy metabolism, and its consequences for neuronal excitability, neurotransmission, and behavior. We will detect simultaneous readouts of neuronal excitability and metabolism in brain slices, a model that preserves the complex 3D organization and circuitry of native brain tissue. We hypothesize that glycolysis and oxidative phosphorylation in neurons are directly regulated by insulin signaling, which result in an increase in energy metabolism, calcium clearance, neurotransmission, and synaptic plasticity. The following aims are proposed: Aim 1: Define the mechanisms of insulin signaling on energy metabolism in neurons. Aim 2: Characterize the role of neuronal insulin signaling on cytosolic calcium dynamics and synaptic plasticity in the hippocampus. Aim 3: Investigate the role of neuronal insulin resistance on learning and memory. The proposed studies will form the foundation and preliminary data necessary for an R01 application to NIH focused on insulin effects on neuronal metabolism in health and disease.