Examining Estrogenic Regulation of Orexin Neurons to Reveal Subpopulations - Title: Examining Estrogenic Regulation of Orexin Neurons to Reveal Subpopulations Project Summary: Orexin (ORX) neurons of the hypothalamus are critical regulators of sleep and arousal, but also important players in energy balance, stress, motivation, and reward. A persistent question has been how can such a small (<5,000 out of 71 million neurons in a mouse) and anatomically restricted population carry out these diverse physiological roles? Scattered reports have identified heterogeneity in ORX neurons that suggests at least two broad groupings with the dorsomedial cells associated with arousal/activity and the lateral cells with food and drug reward. Unfortunately, these putative subpopulations are not strictly segregated, and we lack a reliable means of differentiating or pharmacologically targeting subgroups. This limitation has hampered the elucidation of ORX signaling. ORX neurons are linked to sleep disturbances, eating disorders, and anxiety, which are all disproportionately diagnosed in females following puberty. The ORX peptide (their unique neurotransmitter) levels are higher in both rodent and human females compared to males. Following menopause ORX levels rise and the risk of developing many of these diseases becomes elevated. These observations indicate that transitions in estrogen (E2) levels may contribute to disturbances in the ORX system that in turn disrupt the homeostatic function of ORX-associated behaviors. Yet, despite these sex differences, a striking gap exists in our knowledge as to their physiological underpinnings. However, as the hypothalamus functions as a primary link between the nervous and endocrine systems, the majority of hypothalamic neurons are heavily regulated by E2 in females. Typically, E2 influences hypothalamic circuits to decrease food motivation and anxiety while increasing arousal and activity. ORX neuronal activity is associated with increased food motivation, anxiety, arousal, and activity. Therefore, it seems unlikely that E2 can exert a uniform effect on all ORX neurons. Therefore, we propose E2 will have divergent effects on gene expression, protein translation, electrophysiological properties, and neurotransmission in ORX subpopulations based on their roles in behavior. Specifically, we hypothesize that E2 should enhance the function of the arousal/activity subpopulation while attenuating the signaling of the food reward subpopulation. These findings will elucidate ORX signaling while providing insight into the mechanisms underlying sex differences in disease. A better understanding of the ORX system could help others develop treatments to target issues with arousal and anxiety without negatively affecting food and drug reward, or vice versa.
