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.
Highlights
The role of pathogenic neuro-immune activation is increasingly recognized in serious psychiatric disorders such as major depression, bipolar disorder, and schizophrenia (Doorduin et al, 2009; Rao et al, 2010; Frick et al, 2013)
The findings include a reduction of social affiliative behaviors in variable foraging demand (VFD)-reared versus non-VFD control subjects, confirming behavioral alterations in VFD versus non-VFD subjects during baseline home-cage observations (Rosenblum et al, 2001)
Reduced baseline cerebrospinal fluid (CSF) log kynurenic acid (KYNA) and lower CSF log KYNA/KYN ratio in VFD-reared subjects in comparison to non-VFD controls is suggestive that early life adversity associates with a relative reduction of neuroprotection alongside increases in kynurenine pathway (KP) metabolites within the neurotoxic arm
Summary
The role of pathogenic neuro-immune activation is increasingly recognized in serious psychiatric disorders such as major depression, bipolar disorder, and schizophrenia (Doorduin et al, 2009; Rao et al, 2010; Frick et al, 2013). Early-Life Stress and Kynurenine Metabolism (IFN-γ), induce central expression of the enzyme indoleamine 2,3-dioxygenase (IDO). At “the fork in the road,” kynurenine is metabolized either to KYNA by kynurenine aminotransferases (KATs) or to 3-hydroxykynurenine (3-HK) by kynurenine-3-monooxygenase (KMO). The latter metabolic pathway leads to anthranilic acid (ANTH) and to QUIN. Most of kynurenine in the brain is metabolized to KYNA through KATs (Parrott and O’Connor, 2015). Pro-inflammatory cytokines shift kynurenine metabolism through KMO to 3-HK and the neurotoxic pathway (Parrott et al, 2016a). A preferential expression of either KATs or KMO may have major implications for the maintenance of affective state
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