The Effects of Early Life Stress on the Kynurenic Pathway Contributing to the Development of Affective Disorders.

Abstract

By the year 2030, major depressive disorder is projected to become the top cause of disease and disability worldwide (Won and Kim 2016). Early life stress (ELS) varies greatly in type and severity but has a significant impact on the brain both structurally and functionally (Carpenter et al. 2003; Nemeroff 2004). ELS and the development of treatment-resistant depression (TRD) have been strongly correlated in the clinical setting (Coplan et al. 2014). While several mechanisms have been proposed to account for the link between inflammation and depression, the kynurenic acid pathway has become prominent due to an abundance of evidence (Dantzer et al 2011). An example of the importance of the kynurenic pathway in the development of MDD is that kynurenine has been found at higher concentrations in CSF suicide attempters than in depressed non-attempters and healthy controls (Sublette et al. 2011). The inflammatory model of depression with its basis in the kynurenic system has yet to be investigated with ELS as a contributing factor even though ELS has been linked to increased inflammation (Simons 2019). By using the variable foraging demand animal model of ELS in macaque monkeys, separation stress, and fluoxetine treatment coupled with LC-MS/MS quantitation of kynurenine pathway the relationship between ELS and the inflammatory model of depression was investigated with a focus on the characteristic of treatment resistance. Kynurenine was unchanged between the VFD and non-VFD groups. VFD animals were shown to be biased away from kynurenic acid metabolism and towards increased anthralinic acid production possibly as a protective mechanism against neurotoxicity. Kynurenic acid, a known neuroprotectant (Won and Kin 2011), was found to be decreased in VFD regardless of separation stress or fluoxetine treatment. This biological “switch” of kynurenic acid is vital in the development of understanding the characteristic of treatment resistance in the clinical setting and its link to ELS.