Dataset Information

Early Life Stress and the Fate of Kynurenine Pathway Metabolites.

ABSTRACT: Early life stress (ELS) precedes alterations to neuro-immune activation, which may mediate an increased risk for stress-related psychiatric disorders, potentially through alterations of central kynurenine pathway (KP) metabolites, the latter being relatively unexplored. We hypothesized that ELS in a non-human primate model would lead to a reduction of neuroprotective and increases of neurotoxic KP metabolites. Twelve adult female bonnet macaques reared under conditions of maternal variable foraging demand (VFD) were compared to 27 age- and weight-matched non-VFD-exposed female controls. Baseline behavioral observations of social affiliation were taken over a 12-week period followed by the first cerebrospinal fluid (CSF) sample. Subjects were then either exposed to a 12-week repeated separation paradigm (RSP) or assigned to a "no-RSP" condition followed by a second CSF. We used high-performance liquid chromatography for kynurenine (KYN), tryptophan, 5-hydroxyindoleacetic acid, kynurenic acid (KYNA), and anthranilic acid (ANTH) as a proxy for quinolinic acid determination. At baseline, social affiliation scores were reduced in VFD-reared versus control subjects. CSF log KYNA and log KYNA/KYN ratio were lower in VFD-reared versus control subjects. CSF log KYNA/KYN was positively correlated with CSF log ANTH in VFD only (r = 0.82). Controlling for log KYNA/KYN, log ANTH was elevated in VFD-reared subjects versus controls. CSF log KYNA/KYN obtained post-RSP was positively correlated with mean social affiliation scores during RSP, specifically in VFD. ELS is associated with a reduced neuroprotective and increased neurotoxic pathway products. That the two contrasting processes are paradoxically correlated following ELS suggests a cross-talk between two opposing KP enzymatic systems.

SUBMITTER: Coplan JD

PROVIDER: S-EPMC8117097 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Reports of neurodegenerative and psychiatric disease in former athletes have increased public concern about the acute and chronic effects of sport-related concussions (SRC). The biological factors underlying individual differences in the psychiatric sequalae of SRC and their role in potential long-term negative outcomes have not been determined. One understudied biological consequence of the known inflammatory response to concussion is the activation of a key immunoregulatory pathway, the kynurenine pathway (KP). Activation of the KP produces several neuroactive metabolites that have been associated with psychiatric and neurodegenerative diseases. We tested the hypothesis that SRC results in an elevation of serum KP metabolites with neurotoxic properties (quinolinic acid [QuinA], 3-hydroxykynurenine [3HK]) together with a reduction in the neuroprotective metabolite kynurenic acid (KynA), and that these metabolites would predict post-concussion psychological symptoms. Additionally, because brain injury is thought to prime the immune system, a secondary goal was to test the hypothesis that athletes with acute SRC and a history of prior SRC would have elevated neurotoxic relative to neuroprotective KP metabolites compared to athletes that were concussed for the first time. High school and collegiate football players (N = 1136) were enrolled at a preseason baseline visit that included clinical testing and blood specimen collection. Athletes that suffered a SRC (N = 59) completed follow-up visits within 6-hours (early-acute), at 24-48 h (late-acute) and at 8, 15, and 45 days post-injury. Uninjured contact sport (CC; N = 54) and non-contact sport athletes completed similar visits and served as controls (NCC; N = 30). SRC athletes had significantly elevated psychological symptoms, assessed using the Brief Symptom Inventory-18 (BSI), acutely following injury relative to both control groups. There was a group-by-visit interaction on the ratio of KynA to 3HK in serum, a neuroprotective index, with elevated KynA/3HK in athletes with SRC at the early-acute visit relative to later visits. Importantly, athletes with greater elevation in this neuroprotective index at the early-acute visit reported fewer depressive symptoms at the late-acute visit. Finally, SRC athletes with prior concussion had significantly lower serum KynA/QuinA at all visits compared to SRC athletes with no prior concussion, an effect driven by elevated QuinA in SRC athletes with prior concussion. These results suggest that early-acute activation of the KynA branch of the KP may protect against the development of depressive symptoms following concussion. Furthermore, they highlight the potential of serum QuinA as a biomarker for repetitive head injury and provide insight into possible mechanisms linking prior concussion with subsequent injury.

Dataset Information

Early Life Stress and the Fate of Kynurenine Pathway Metabolites.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets