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

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $510,882

## Abstract

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.

## Key facts

- **NIH application ID:** 10845662
- **Project number:** 5R01AG078134-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** George Alexander Mashour
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $510,882
- **Award type:** 5
- **Project period:** 2022-08-20 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10845662

## Citation

> US National Institutes of Health, RePORTER application 10845662, Role of preoptic hypothalamus in sleep-dependent cognition after surgery and general anesthesia (5R01AG078134-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10845662. Licensed CC0.

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