# Torpor for cerebroprotection

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $449,749

## Abstract

ABSTRACT
Stroke is the leading cause of long-term disability among adults in the United States, with half of all stroke
survivors experiencing moderate to severe impairment in motor, sensory, or cognitive function that require
specialty care. Despite advances in the acute (< 24 hour) care of stroke, such as thrombolysis and
recanalization, stroke patients still experience progression of brain injury that negatively affects patient
outcomes. Cerebroprotection, the mitigation of damage to the entire neurovascular unit of the brain, is an
extremely high priority in stroke care research. Torpor, a state of hypothermia and hypometabolism, has long
been hypothesized to represent a cerebroprotective state. We have identified a previously under-studied,
conserved population of GABAergic neurons expressing the kappa opioid receptor (KOR) in the medial
preoptic area (POA) termed POAKOR+. In preliminary studies, we found that chemogenetic activation of
POAKOR+ neurons induced a hypothermic and hypometabolic state that we refer to as synthetic torpor.
Preliminary data suggest that induction of synthetic torpor immediately after experimental stroke reduces
infarct size and decreases mortality in mice at 72 hours post-stroke. The data also suggest that induction of
synthetic torpor alters metabolism of nucleotides, lipids, and the citric acid cycle, while altering metabolites
such as ceramides and succinate that are associated with the progression of brain injury after stroke. While
promising, these preliminary data highlight several key knowledge gaps that will be addressed in the proposed
research study. First, we will investigate whether the cerebroprotective effects observed 72 hours after stroke
also improve long-term behavioral outcomes (Aim 1). Second, our preliminary data suggests that the
hypothermic depth and duration of synthetic torpor predicts stroke size, thus, we will investigate whether the
cerebroprotective effects of synthetic torpor following stroke are dependent or independent of hypothermia
(Aim 2). Third, while the metabolic pathways that are altered during synthetic torpor overlap with those altered
by stroke, it is unknown if these metabolic changes occur independently of hypothermia and if the altered
pathways and metabolites are related to cerebroprotection. We will investigate these metabolic changes,
identify the pathways and metabolites that are uniquely altered in response to synthetic torpor, and
characterize the temporal-spatial dynamics of cerebroprotection (Aim 3). Identified metabolites and metabolic
pathways may represent targets for future cerebroprotective interventions. Succesful completion of the
proposed research study will characterize the mechanistic underpinnings underlying synthetic torpor-mediated
cerebroprotection and address the knowledge gap on whether induction of a torpor-like state through
modulation of specific neural circuits represents a novel cerebroprotective strategy for the treatment of
ischemic stroke...

## Key facts

- **NIH application ID:** 10878895
- **Project number:** 5R01NS133365-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Eric C Landsness
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $449,749
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878895

## Citation

> US National Institutes of Health, RePORTER application 10878895, Torpor for cerebroprotection (5R01NS133365-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10878895. Licensed CC0.

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