A Role for the Orphan Receptor, GPR37, in Estradiol-induced Changes in Sleep-Wake States

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Project Summary Studies have shown that women report more sleep difficulties and are more likely to be diagnosed with insomnia compared to men. Sleep disturbances are more likely to occur in women during times of hormonal fluctuations, including pregnancy and menopause, thus indicating that sex hormones play a role in the sleep-wake cycle. Understanding more about how sex hormones act to influence sleep can help us develop targeted treatments for women who suffer from sleep disorders. There are 2 major sleep centers in the brain, both located in the hypothalamus – the median preoptic nucleus (MnPO) and the ventrolateral preoptic nucleus (VLPO). There are estrogen receptors located in the MnPO, but not in the VLPO, suggesting that estrogen acts via the MnPO to regulate sleep-wake states. The MnPO is thought to promote sleep by inhibiting wake-promoting neurons in the brain. It has been found that estradiol (E2) infusion into the MnPO increases wake and decreases sleep in ovariectomized female rats, however the mechanism by which sleep is disrupted by E2 is largely unknown. During wakefulness, adenosine accumulates in the brain and increases sleep pressure, causing tiredness. The A1 and A2A receptors (A1R and A2AR) are expressed in the MnPO and play an important role in regulating the effects of adenosine in the brain. Infusion of an A1R agonist into the MnPO has been found to increase wake and decrease sleep in rats, while infusion of an A2AR agonist has been found to increase sleep and decrease wake. E2 has been hypothesized to influence the inhibitory/excitatory adenosinergic balance in the MnPO, as, in the presence of E2, the sleep-promoting effects of an A2AR agonist are blocked. One potential target of E2 is G protein-coupled receptor 37 (GPR37), as it has been shown to inhibit A2AR surface expression and function in the striatum. This project will test the hypothesis that E2 is decreasing NREM sleep and increasing wake by attenuating A2AR signaling through GPR37 modulation. To examine the effects of GPR37 in the MnPO, we are going to (1) Determine if E2 is sufficient for GPR37 upregulation in the MnPO, (2) Determine if A2AR and GPR37 form an interaction in the sleep active cells of the MnPO, and (3) Determine if GPR37 is necessary to cause E2-induced changes in sleep-wake states. Understanding estradiol’s role in the disruption of the sleep- wake cycle will help us gain greater insight into one of the unique mechanisms of insomnia in women and ultimately with how we can better treat insomnia in a substantial portion of the population.