Neural basis underlying the impact of stress on sleep

PROJECT SUMMARY Stress is associated with insufficient sleep and poor quality sleep. In particular, fragmented non-rapid eye movement sleep (NREMs) due to frequent brief arousals (microarousals, MAs) disrupts sleep continuity, and rapid eye movement sleep (REMs) abnormalities are often observed in patients with insomnia and depression. Insufficient sleep and alterations in sleep microarchitecture caused by stress may in turn worsen the stress symptoms, such as cognitive impairment, and have been shown to increase the risk of developing psychiatric disorders. Nevertheless, the identity of the involved stress- and sleep-regulatory circuits, and the mechanisms by which stress perturbs distinct features of the sleep architecture and negatively impacts cognitive behaviors are still largely unclear. We have recently shown that acute psychosocial stress in mice decreases the amount of sleep and disrupts sleep quality by causing frequent MAs and suppressing REMs. We propose that the stress-induced decrease in the amount of sleep and changes in sleep microarchitecture are mediated by different circuit mechanisms. The preoptic area of the hypothalamus (POA), a crucial center regulating macro- and microarchitecture of sleep and wakefulness, is densely innervated by stress-regulatory noradrenergic neurons in the locus coeruleus (NELC) and corticotropin-releasing hormone neurons in the paraventricular nucleus (CRHPVN). The goal of this proposal is to investigate to what extent the NELC and CRHPVN neurons cause stress-induced sleep disturbances and memory impairment via projections to distinct POA subpopulations. Our central hypothesis is that stress-induced MAs and REMs dysregulation are mediated by inputs from NELC neurons to the POA (NELC→POA), while the overall decrease in sleep is mediated by inputs from CRHPVN neurons (CRHPVN→POA) and that reversing sleep disturbances attenuates stress-induced memory deficits. Aim 1 will determine the role of NELC→POA projections in stress-induced MAs and REMs dysregulation as well as related memory deficits. Aim 2 will determine the role of CRHPVN→POA projections in stress-induced wakefulness and related memory deficits. Accomplishing these aims will provide important insights into the neural basis of stress-induced sleep disturbances and the benefits of good quality and quantity sleep in reversing stress symptoms, with potential relevance to understand and develop novel therapeutic interventions for stress-related sleep disorders.