Biology subjects

Cox, J. H.

Publications and source records attributed to Cox, J. H..

3 recordsLinked to original sources

bioRxiv2026

Pregnancy Impacts Maternal Sleep: Focus on Kynurenine Pathway Activation in Female Rats

Study Objectives: Poor maternal sleep is associated with adverse health outcomes for women and their offspring, and perturbations to tryptophan metabolism through the kynurenine pathway (KP) may contribute. Kynurenic acid (KYNA), a neuroactive KP metabolite and endogenous modulator of glutamatergic and cholinergic neurotransmission, is of particular interest because elevated KYNA has been linked to altered sleep-wake behavior and neurodevelopmental outcomes. Because sleep patterns and KP metabolism change during pregnancy, we tested whether pregnancy modifies the effects of kynurenine supplementation on sleep-wake architecture. Methods: To model enhanced KP metabolism, we used the embryonic kynurenine (EKyn) model, in which the maternal diet is supplemented with kynurenine, the initial KP metabolite, during the last week of gestation. Using a within-subject design, we evaluated sleep-wake parameters in pregnant and non-pregnant female rats and assessed KYNA in brain and saliva. Results: Pregnancy increased dark phase NREM and REM sleep in control-fed (ECon) dams, a pattern largely maintained in EKyn dams. However, near parturition, EKyn dams exhibited reduced light phase REM sleep that was not observed in controls. In non-pregnant females, kynurenine supplementation produced a stronger phenotype, consistently reducing light phase REM sleep across treatment days. During pregnancy, kynurenine-associated sleep effects were detectable only when compared to within-subject non-pregnant baseline. Salivary KYNA distinguished kynurenine-fed females from matched controls and correlated with brain KYNA levels. Conclusion: These findings show that pregnancy reshapes sleep-wake architecture and attenuates, but does not eliminate, kynurenine-associated REM sleep disruption, implicating KP metabolism and potentially elevated brain KYNA in maternal sleep regulation.

neuroscience↗

bioRxiv2026

Fragmented sleep during pregnancy induces inflammation and tryptophan-kynurenine pathway metabolism: Importance of elevated fetal brain kynurenic acid

Maternal sleep disturbance is an underrecognized risk factor for adverse offspring outcomes. Prolonged sleep disruption can elicit inflammation, an established risk factor for neuropsychiatric disorders in offspring. Sleep disruptions and inflammation elevate tryptophan degradation via the kynurenine pathway (KP), increasing kynurenic acid (KYNA), a metabolite that inhibits glutamatergic and cholinergic neurotransmission and may thereby affect neurodevelopment. Because KYNA is elevated in the brains of individuals with neurodevelopmental psychotic illnesses, we hypothesize that prenatal KYNA elevation may represent a mechanism link between disturbed maternal sleep, inflammation, and adverse offspring neurodevelopmental health. To test this hypothesis, we employed a novel maternal sleep fragmentation (SleepFrag) paradigm during the final week of gestation. We found that six days of SleepFrag increased maternal plasma inflammatory markers, placental KP metabolism, sex-specific placental inflammation, and fetal brain KP metabolism, including elevated KYNA, without altering KP metabolism in maternal plasma or brain. A parallel embryonic kynurenine (EKyn) model was tested to increase prenatal KP metabolism via a maternal kynurenine-supplemented diet. EKyn increased maternal plasma kynurenine and KYNA, and fetal brain KYNA, with a male-specific increase in fetal brain KYNA-to-kynurenine ratio, despite minimal effects on maternal sleep-wake architecture or inflammation. Together, these findings identify elevated fetal brain KYNA as a convergent outcome through which maternal sleep disruption, inflammation, and KP activation may influence sex-specific neurodevelopment. They further support the EKyn model as a translational tool for isolating consequences of increased prenatal KP metabolism. Protecting maternal sleep and stabilizing fetal brain KYNA levels may promote long-term offspring brain health.

neuroscience↗

bioRxiv2023

Sex divergent behavioral responses in platform-mediated avoidance and glucocorticoid receptor blockade

Women are more likely than men to develop anxiety or stress-related disorders. A core behavioral symptom of all anxiety disorders is avoidance of fear or anxiety eliciting cues. Recent rodent models of avoidance show reliable reproduction of this behavioral phenomenon in response to learned aversive associations. Here, a modified version of platform-mediated avoidance that lacked an appetitive task was utilized to investigate the learning and extinction of avoidance in male and female C57BL6/J mice. Here, we found a robust sex difference in the acquisition and extinction of platform-mediated avoidance. Across three experiments, 63.7% of female mice acquired avoidance according to our criterion, whereas 83.8% of males acquired it successfully. Of those females that acquired avoidance, they displayed persistent avoidance after extinction compared to males. Given their role in regulating stress responses and habitual behaviors, we investigated if glucocorticoid receptors (GR) mediated avoidance learning in males and females. Here we found that a subcutaneous injection (25mg/kg) of the GR antagonist, RU486 (mifepristone), significantly reduced persistent avoidance in females but did not further reduce avoidance in males after extinction. These data suggest that GR activation during avoidance learning may contribute to persistent avoidance in females that is resistant to extinction.

neuroscience↗