The goal of our research is to better understand the effects of chronic metabolic diseases, such as diabetes, on brain function. Given the high utilization of energy by the brain, we aim to explore the implications of altered metabolism at the behavioral, circuit, cellular and molecular levels. Currently, we use animal models of diabetes to identify the ways in which long-term exposure to hyperglycemia can lead to increased susceptibility to stress and to addiction- or depression- or anxiety-like syndromes. A major focus of our work is on hyperglycemia-induced changes in gene expression and chromatin structure within the brain’s reward and aversion circuitry, and the mechanisms by which those lasting adaptations alter neuronal and circuit function to produce behavioral abnormalities. Our goal is to eventually translate these findings to human patients.

The interpeduncular nucleus (IPN) is a GABAergic nucleus that is characterized by high expression of neuronal nitric oxide synthase (Nos1) as well as striking vascularity. We have recently found that Nos1 is increased in IPN after chronic exposure to nicotine. We hypothesize that this increase in Nos1 mediates the development of tolerance to the aversive effects of nicotine, as we found that eliminating Nos1 in the IPN reduces preference for a rewarding dose of nicotine (Ables et al. PNAS 2017). Our goal is to determine if this increase in Nos1 in the IPN generalizes to other drugs of abuse or to stress and might represent a target for treatment of addiction. Future studies will focus on visualizing nitric oxide release from the IPN and the effects of nitric oxide on the epigenome, transcriptome and function of neurons in the reward circuitry.

Recent research has revealed that neuronal axons have specialized mechanisms to regulate delivery and utilization of mRNAs independently of the neuronal cell body, where the nucleus resides. This is not surprising given that in many cases (e.g. motor neurons in the limbs), the axons are far removed from the cell body and require the ability to respond to stimuli on timescales that would prohibit gene expression from the nucleus and subsequent delivery to the distal axon. Projection neurons in the brain provide a unique opportunity to profile the transcripts that are utilized in discrete compartments of the cell, as the axons are physically separate from the cell body. Our lab is currently profiling axonal transcriptomes in specific cell populations in the normal mouse brain. Our goal is to determine how translation is locally regulated in response to various stimuli, including stress and metabolic derangements.