# Kynurenic Acid and Sleep: Focus on Maternal and Offspring Health

> **NIH NIH R01** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2024 · $660,540

## Abstract

Tryptophan metabolism via the kynurenine pathway (KP) and kynurenic acid (KYNA)
accumulation occurs with prenatal insults, including maternal immune activation or excessive
stress. Our goal is to investigate mechanistically how specifically elevating KYNA during
pregnancy influences maternal sleep and the prenatal environment to produce negative outcomes
in the offspring. KYNA is of particular interest because it is an endogenous antagonist of α7nACh
and NMDA receptors. Increased KYNA levels reduce neurotransmission, disrupt sleep
architecture, and impair cognition. Increased brain KYNA levels (post-mortem or cerebrospinal
fluid analysis) are found also in individuals with neurodevelopmental dysfunction. We will explore
the novel hypothesis that accumulated KYNA and elevated KP metabolism, a common
denominator driving homeostatic disruption, exacerbates sleep problems during pregnancy and
contributes to disrupted neurochemical stability, sleep, and cognitive function in young adult
offspring. We predict that reducing KYNA by (i) targeting its primary synthesizing enzyme
kynurenine aminotransferase II (KAT II) or (ii) mechanistically interfering with its sites of action
will lead to improved maternal sleep dynamics and offspring outcomes. KP metabolism and KYNA
levels will be increased by feeding kynurenine-laced chow to pregnant rats (‘EKyn diet’). We will
test the predictions that excessive prenatal KYNA plays a mechanistic role in a) poor sleep during
pregnancy and b) contributes to long-lasting neurochemical and behavioral abnormalities in
offspring. Aim 1: Define sleep problems during pregnancy when KYNA formation is up-regulated.
Hypothesis: Elevated KYNA in dams deteriorates sleep during pregnancy and targeted inhibition
of KAT II can improve sleep quality. Aim 2: Treat neurochemical abnormalities underlying long-
lasting poor outcomes (sleep and cognition) in adult offspring from elevated kynurenine during
prenatal period (EKyn diet). Hypothesis: Elevated brain KYNA in EKyn offspring drives
neurochemical imbalances, deficits in sleep and learning behavior. Aim 3: Prevent adverse
behavioral endophenotypes in offspring via choline-supplementation or dual-orexin receptor
antagonism during prenatal kynurenine treatment (EKyn diet). Adverse consequences of elevated
KYNA during pregnancy can be mitigated by potentiation the 𝛂7nACh-R via choline-
supplementation during neurodevelopment. Dual-orexin receptor antagonism in pregnant rats will
attenuate maternal sleep disruptions. The proposed research will advance our understanding of
common molecular mechanisms between a neurodevelopmental insult, sleep disturbances and
neurocognitive impairments, paving the way for novel therapies to alleviate these outcomes.

## Key facts

- **NIH application ID:** 10940906
- **Project number:** 1R01HL174802-01
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Ana Pocivavsek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $660,540
- **Award type:** 1
- **Project period:** 2024-07-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940906

## Citation

> US National Institutes of Health, RePORTER application 10940906, Kynurenic Acid and Sleep: Focus on Maternal and Offspring Health (1R01HL174802-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10940906. Licensed CC0.

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