Biology subjects

Frizzell, N.

Publications and source records attributed to Frizzell, N..

6 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↗

bioRxiv2024

Parental kynurenine 3-monooxygenase genotype in mice directs sex-specific behavioral outcomes in offspring

BackgroundDisruptions in brain development can impact behavioral traits and increase the risk of neurodevelopmental conditions such as autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder, often in sex-specific ways. Dysregulation of the kynurenine pathway (KP) of tryptophan metabolism has been implicated in cognitive and neurodevelopmental disorders. Increased brain kynurenic acid (KYNA), a neuroactive metabolite implicated in cognition and sleep homeostasis, and variations in the Kmo gene, which encodes kynurenine 3-monooxygenase (KMO), have been identified in these patients. We hypothesize that parental Kmo genetics influence KP biochemistry, sleep behavior and brain energy demands, contributing to impairments in cognition and sleep in offspring through the influence of parental genotype and genetic nurture mechanisms. MethodsA mouse model of partial Kmo deficiency, Kmo heterozygous (HET-Kmo+/-), was used to examine brain KMO activity, KYNA levels, and sleep behavior in HET-Kmo+/- compared to wild-type control (WT-Control) mice. Brain mitochondrial respiration was assessed, and KP metabolites and corticosterone levels were measured in breast milk. Behavioral assessments were conducted on wild-type offspring from two parental groups: i) WT-Control from WT-Control parents, ii) wild-type Kmo (WT-Kmo+/+) from Kmo heterozygous parents (HET-Kmo+/-). All mice were C57Bl/6J background strain. Adult female and male offspring underwent behavioral testing for learning, memory, anxiety-like behavior and sleep-wake patterns. ResultsHET-Kmo+/- mice exhibited reduced brain KMO activity, increased KYNA levels, and disrupted sleep architecture and electroencephalogram (EEG) power spectra. Mitochondrial respiration (Complex I and complex II activity) and electron transport chain protein levels were impaired in the hippocampus of HET-Kmo+/- females. Breast milk from HET-Kmo+/- mothers increased kynurenine exposure during lactation but corticosterone levels were unchanged. Compared to WT-Control offspring, WT-Kmo+/+ females showed impaired spatial learning, heightened anxiety, reduced sleep and abnormal EEG spectral power. WT-Kmo+/+ males had deficits in reversal learning but no sleep disturbances or anxiety-like behaviors. ConclusionsThese findings suggest that Kmo deficiency impacts KP biochemistry, sleep behavior, and brain mitochondrial function. Even though WT-Kmo+/+ inherit identical genetic material as WT-Control, their development might be shaped by the parents physiology, behavior, or metabolic state influenced by their Kmo genotype, leading to phenotypic sex-specific differences in offspring. Plain English summaryInteractions between genetic and environmental factors are carefully regulated during the intricate process of brain development. While genetic information is directly inherited from parents, emerging evidence suggests that parental genetic factors can also shape the environment influencing childrens development in a sex-specific ways. Disruptions in brain development can impact cognitive and behavioral traits and increase the risk of neurodevelopmental conditions such as autism spectrum disorder, attention-deficit/hyperactivity disorder, schizophrenia, and bipolar disorder. This study explored how kynurenine 3-monooxygenase (Kmo) genotype affects female and male mice, focusing on potential sex-specific behavioral changes in offspring born to parents with a genetic disruption in Kmo. We found that female and male mice with partial Kmo deficiency experienced reduced sleep and increased sleep pressure. In female mice, Kmo deficiency impaired mitochondrial energy production in the brain. We also observed alterations in tryptophan metabolism and nutrient composition in the breast milk of Kmo-deficient females. In adult offspring born to Kmo-deficient parents, females exhibited learning difficulties, heightened anxiety-like behaviors, and sleep disturbances. In contrast, male offspring showed mild cognitive impairments but no major sleep issues. These findings highlight that parental Kmo genotype can influence sex differences in cognitive and sleep-related behaviors in offspring. This underscores the importance of considering parental genetic factors when studying neurodevelopmental disorders and associated behavioral outcomes. HighlightsO_LIMice with a partial Kmo deficiency, Kmo heterozygous (HET-Kmo+/-), were used to evaluate the impact of parental Kmo genetics on kynurenine pathway biochemistry, brain mitochondrial function, sleep patterns, and cognitive performance. C_LIO_LIFemale and male HET-Kmo+/- mice exhibited elevated brain KYNA levels and had reduced sleep, prolonged wakefulness, and altered spectra power during sleep. In HET-Kmo+/- females, hippocampal mitochondrial respiration and electron transport chain protein levels were significantly altered. Breast milk from HET-Kmo+/- females increased kynurenine exposure during lactation to offspring, including their wild-type (WT-Kmo+/+) offspring. C_LIO_LISex differences were observed in learning and memory, anxiety-like behavior, and sleep-wake patterns between WT-Control, from wild-type parents, and WT-Kmo+/+ offspring from HET-Kmo+/- parents. Female WT-Kmo+/+ offspring had impaired spatial learning, increased anxiety-like behavior, reduced sleep, but elevated delta power during sleep. Male WT-Kmo+/+ offspring exhibited deficits in reversal learning only and not sleep impairments. C_LI

neuroscience↗

bioRxiv2023

Suppression of HIV and cocaine-induced neurotoxicity and inflammation by cell penetrable itaconate esters

HIV-associated neurological disorder (HAND) is a serious complication of HIV infection, marked by neurotoxicity induced by viral proteins like Tat. Substance abuse exacerbates neurocognitive impairment in people living with HIV. There is an urgent need for effective therapeutic strategies to combat HAND comorbid with Cocaine Use Disorder (CUD). Our analysis of the HIV and cocaine-induced transcriptomes in primary cortical cultures revealed a significant overexpression of the macrophage-specific gene, aconitate decarboxylase 1 (Acod1), caused by the combined insults of HIV and cocaine. ACOD1 protein converts the tricarboxylic acid intermediate cis-aconitate into itaconate during the activation of inflammation. The itaconate produced facilitates cytokine production and subsequently activates anti-inflammatory transcription factors, shielding macrophages from infection-induced cell death. While the role of itaconate in limiting inflammation has been studied in peripheral macrophages, its immunometabolic function remains unexplored in HIV and cocaine-exposed microglia. We assessed in this model system the potential of 4-octyl-itaconate (4OI), a cell-penetrable esterified form of itaconate known for its potent anti-inflammatory properties and potential therapeutic applications. We administered 4OI to primary cortical cultures exposed to Tat and cocaine. 4OI treatment increased the number of microglial cells in both untreated and Tat{+/-}Cocaine-treated cultures and also reversed the morphological altercations induced by Tat and cocaine. In the presence of 4OI, microglial cells also appeared more ramified, resembling the quiescent microglia. Consistent with these results, 4OI treatment inhibited the secretion of the proinflammatory cytokines IL-1, IL-1{beta}, IL-6, and MIP1- induced by Tat and cocaine. Transcriptome profiling further determined that Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (Nqo1), Glutathione S-transferase Pi (Gstp1), and glutamate cysteine ligase catalytic (Gclc), were most significantly activated in Tat-4OI treated cultures, relative to Tat alone. Further, genes associated with cytoskeleton dynamics in inflammatory microglia were downregulated by 4OI treatment. Together, the results strongly suggest 4-octyl-itaconate holds promise as a potential candidate for therapeutic development aimed at addressing HAND coupled with CUD comorbidities. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/559154v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@bfffa8org.highwire.dtl.DTLVardef@129ad8dorg.highwire.dtl.DTLVardef@1412ea2org.highwire.dtl.DTLVardef@5cb968_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Model of 4OI-mediated neuroprotection against Tat-Cocaine toxicity Tat and Tat-Cocaine treatment induce neuronal damage, which is mitigated by 4OI through microglia cells. This cartoon shows the reduction of harmful effects such as proinflammatory cytokine release, upregulation of P2R, PDE, and Acod1 by the presence of 4OI. This ester modified itaconate triggers anti-inflammatory responses and activates antioxidant pathways. C_FIG

neuroscience↗

bioRxiv2020

Succination of Dihydrolipoyllysine Succinyltransferase (DLST) Exacerbates Mitochondrial ATP Deficiency in a Mouse Model of Leigh Syndrome

The NDUFS4 knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. The irreversible succination of protein thiols by fumarate is increased in select regions of the NDUFS4 KO brain affected by neurodegeneration, suggesting a mechanistic role in neurodegenerative decline. We report that dihydrolipoyllysine-residue succinyltransferase (DLST), a component of the -ketoglutarate dehydrogenase complex (KGDHC) of the tricarboxylic acid (TCA) cycle, is succinated in the NDUFS4 KO brain. Succination of DLST reduced KGDHC activity in the brainstem (BS) and olfactory bulb (OB) of KO mice. The defective production of KGDHC derived succinyl-CoA resulted in decreased mitochondrial substrate level phosphorylation (SLP), further aggravating the OXPHOS ATP deficit. Protein succinylation, an acylation modification that requires succinyl-CoA, was reduced in the KO mice. Modeling succination of a cysteine in the spatial vicinity of the DLST active site or introduction of succinomimetic mutations recapitulates these metabolic deficits. Our data demonstrate that the biochemical deficit extends beyond impaired Complex I assembly and OXPHOS deficiency, functionally impairing select components of the TCA cycle to drive metabolic perturbations in affected neurons.

biochemistry↗

bioRxiv2018

A chemoproteomic portrait of the oncometabolite fumarate

Hereditary cancer disorders often provide an important window into novel mechanisms supporting tumor growth and survival. Understanding these mechanisms and developing biomarkers to identify their presence thus represents a vital goal. Towards this goal, here we report a chemoproteomic map of the covalent targets of fumarate, an oncometabolite whose accumulation marks the genetic cancer predisposition syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). First, we validate the ability of known and novel chemoproteomic probes to report on fumarate reactivity in vitro. Next, we apply these probes in concert with LC-MS/MS to identify cysteine residues sensitive to either fumarate treatment or fumarate hydratase (FH) mutation in untransformed and human HLRCC cell models, respectively. Mining this data to understand the structural determinants of fumarate reactivity reveals an unexpected anti-correlation with nucleophilicity, and the discovery of a novel influence of pH on fumarate-cysteine interactions. Finally, we show that many fumarate-sensitive and FH-regulated cysteines are found in functional protein domains, and perform mechanistic studies of a fumarate-sensitive cysteine in SMARCC1 that lies at a key protein-protein interface in the SWI-SNF tumor suppressor complex. Our studies provide a powerful resource for understanding the influence of fumarate on reactive cysteine residues, and lay the foundation for future efforts to exploit this distinct aspect of oncometabolism for cancer diagnosis and therapy.

cancer biology↗