Role of preoptic hypothalamus in sleep-dependent cognition after surgery and general anesthesia

PROJECT SUMMARY Perioperative neurocognitive disorder (PND) is a common, debilitating, and distressing complication in surgical patients over the age of 65. Sleep disorders or insufficient sleep are highly prevalent among surgical patients and sleep disturbances are an important factor associated with the development of PND. However, there are scarce mechanistic studies or data on the precise relationship between disrupted sleep and cognitive impairment after surgery and anesthesia. The preoptic region of the hypothalamus is a critical node for the control of sleep onset and sleep homeostasis. Additionally, recent work from our group identified a subset of glutamatergic neurons in the medial and lateral preoptic (MLPO) region that promote wakefulness. Importantly, preliminary data obtained for this application show that chemogenetic activation of neuronal subpopulations in the median preoptic nucleus (MnPO) can improve (GABAergic stimulation) or impair (glutamatergic stimulation) memory performance after anesthesia. Our long-term goal is to understand the mechanisms by which sleep- and wake-related networks influence cognitive function after surgery and anesthesia. The goal of the proposed research is to investigate the role of preoptic neurons in sleep-dependent cognition after surgery. The proposed studies will test the central hypothesis that preoptic neurons in the hypothalamus that regulate sleep-wake states also regulate cognitive disturbances after surgery. Aim 1 will use chemogenetic stimulation and inhibition of GABAergic and glutamatergic neurons in the MnPO and MLPO to investigate the role of these neurons in acute and long-term postoperative cognitive function in a mouse model of surgery. Aim 2 will use calcium imaging technology to assess the activity patterns of GABAergic and glutamatergic neurons in the MnPO and MLPO in relation to sleep-wake states during the postoperative period. Additional experiments will use chemogenetic inhibition to demonstrate a causal role of these neurons in postoperative sleep disturbances and altered cortical dynamics in a mouse model of surgery. Aim 3 will test the effect of caffeine administration on postoperative cognitive function, MnPO and MLPO neuronal activity, sleep-wake architecture, and cortical oscillations and dynamics. In a separate set of experiments, we will test whether chemogenetic modulation of preoptic GABAergic and glutamatergic activity mitigates the effect of caffeine on postoperative cognitive performance. The proposed experiments will significantly advance the field by providing a systems-level mechanistic understanding of the relationship between sleep and cognitive function after surgery and anesthesia. Furthermore, the proposed studies will test a pharmacological approach to improve postoperative cognitive function that can be translated to surgical patients.