# Cellular mechanisms for age-related cognitive dysfunction and its pharmacological reversal: a strategy towards prevention and treatment of postoperative cognitive deficits in elderly patients

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2020 · $33,200

## Abstract

PROJECT SUMMARY
In the parent grant, we proposed to study a cellular mechanism underlying age-related cognitive dysfunction, a
likely risk factor of postoperative cognitive dysfunction (POCD) and to develop pharmacological interventions to
prevent or to reverse POCD. The molecular and cellular mechanisms underlying POCD are unknown, as is the
reason why POCD occurs more frequently in elderly patients than in younger patients. As POCD increases with
age, age-related cognitive dysfunction likely represents a risk factor. It has been shown in rodents that loss of
somatostatin-positive interneurons in the dentate gyrus (DG) hilus results in hyperexcitability of DG and CA3 and
is associated with age-related cognitive dysfunction. However, a cause-effect relationship between loss of
somatostatin-positive interneurons in the DG hilus and cognitive dysfunction has not been demonstrated so far.
We therefore want to chemogenetically inhibit and genetically ablate these neurons to demonstrate that these
changes are sufficient to elicit cognitive dysfunction. Moreover, we want to pharmacologically reverse these
deficits and identify the molecular and cellular basis for this reversal. It has been reported that in aged rats but
not in young rats a GABAA receptor α5-positive allosteric modulator (α5-PAM) improves cognitive function, which
is in line with an α5-PAM reducing the hyperexcitability of DG and CA3 of the hippocampus in aged rats. It has
also been reported that chronic intermittent propofol improves age-related cognitive dysfunction, but the
molecular and cellular substrates of this action have not been identified. We want to test the hypothesis that this
action of propofol is mediated by a sustained increase in expression of α5-containing GABAA receptors on the
cell surface. We also want to identify the neuronal cell population expressing the α5-containing GABAA receptors
that mediate this improvement of cognition. Furthermore, we want to test whether chemogenetic inhibition of
somatostatin-positive interneurons in the DG hilus of young adult mice is sufficient to elicit the cognitive-
enhancing effect of chronic intermittent propofol. Finally, we will study whether postoperative (i.e., post
laparotomy) impairment of cognitive function can be prevented or reduced by chronic intermittent propofol or a
GABAA receptor α5-PAM. The work described in the parent grant requires preparation of mouse brain sections,
e.g., for c-fos staining and immunohistochemistry. The outdated (30 year old) cryostat currently available in the
department makes it difficult to efficiently obtain high-quality slices. Here we request funds for replacing the
existing cryostat with a cryostat from Hacker Instruments/Industries, Inc..

## Key facts

- **NIH application ID:** 10134627
- **Project number:** 3R01GM128183-02S1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Uwe Rudolph
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $33,200
- **Award type:** 3
- **Project period:** 2019-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134627

## Citation

> US National Institutes of Health, RePORTER application 10134627, Cellular mechanisms for age-related cognitive dysfunction and its pharmacological reversal: a strategy towards prevention and treatment of postoperative cognitive deficits in elderly patients (3R01GM128183-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10134627. Licensed CC0.

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