Role of lateral hypothalamus projections in opioid withdrawal-induced sleep deficits

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Project Summary. Prescription opioids such as oxycodone are highly effective analgesics and hence almost ubiquitously prescribed, resulting in high rates of abuse and opioid use disorder (OUD), which has resulted in an estimated 400,000 deaths in the US since 1999. The treatment course of OUD is primarily challenged by the opioid withdrawal syndrome: one of the most ubiquitous opioid withdrawal symptoms in humans is disrupted sleep—primarily a reduction in REM sleep and insomnia. Despite the debilitating effects of insomnia in OUD, there is little known on the impact of opioid withdrawal on sleep dynamics and the relevant role of sleep-related brain circuits. However, promising linkages have been shown between regions related to OUD and known arousal networks involved in sleep. In particular, opioid withdrawal stimulates lateral hypothalamic (LH) release of the neuropeptide orexin (ORX) into the paraventricular nucleus of the thalamus (PVT). Activation of the PVT, in turn, has been shown to promote wakefulness and negative affect, two hallmarks of opioid withdrawal. By probing LH ORX-mediated transmission within the PVT, we can therefore determine if these networks are necessary for the effect of opioid withdrawal on sleep. Additionally, current approaches to sleep electroencephalogram (EEG) analysis greatly limit the degree to which sleep dynamics can be described— discretizing the brain state during sleep by averaging over subjectively-identified sleep stages. By using objective, high-resolution EEG statistical signal processing and modeling approaches, we can better understand the effect of opioid use and withdrawal on neural oscillatory dynamics during sleep. Based on the literature and our own preliminary data showing oxycodone withdrawal-induced activation of the PVT and robust changes in sleep architecture and dynamics, we hypothesize that opioid withdrawal disrupts sleep via changes in the function of LHPVT ORX neurons. Specific Aim 1 will characterize the effect of oxycodone withdrawal on sleep architecture and sleep dynamics in male and female rats. We will characterize the time-varying effects of 10-d of withdrawal from chronic, escalating-dose oxycodone on sleep architecture and oscillatory dynamics using continuous recording of EEG, EMG, and temperature. Specific Aim 2 will determine if ORX LH neurons are necessary for oxycodone withdrawal-induced changes in sleep. We will use an intersectional viral vector approach with DREADDs to selectively activate or inhibit LHPVT neurons, quantifying the effect of on sleep architecture and dynamics. To test for a specific role of ORX, the ORX antagonist suvorexant will be administered with or without DREADD-mediated LHPVT modulation. If activation of LHPVT ORX projections mediates opioid-induced sleep disruptions, then inhibition of these projections will reduce, whereas activation will increase, oxycodone withdrawal-induced sleep deficits. Paired with a knowledge of EEG oscillatory mechanisms, these experiments will provide an enhanced understanding of the role LH and PVT, suggesting more specific mechanistic targets for future interventional studies.