The Ables Lab of Metabolic Psychiatry

Animal models of diabetes indicate that cholinergic neurons are particularly vulnerable to persistent hyperglycemia and resulting oxidative and nitrosative stress, and we hypothesize that this vulnerability may contribute to the neurocognitive and affective impairments observed in diabetic patients. The medial habenula (MHb) is a highly conserved cholinergic nucleus in the epithalamus that projects to the IPN to regulate levels of serotonin, dopamine and epinephrine and, as a result, mood. The MHb is susceptible to degeneration after repeated administration of drugs of abuse, however, to date no one has examined the effect of persistent hyperglycemia on the functional or structural plasticity of the MHb. Our goal is to understand the molecular, cellular and functional consequences of persistent hyperglycemia on cholinergic neurons in the reward circuitry using cell-type specific epigenomic and transcriptional profiling in combination with viral-mediated gene transfer.

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 during fear learning. Our goal is to determine how translation is locally regulated in response to various stimuli, including stress and metabolic derangements.