Effects of Acute Stress on Discriminative Fear Conditioning: A Key Role of Kynurenic Acid in the Medial Prefrontal Cortex

Abstract

Stressful events can profoundly impact physiology and are implicated in multiple brain disorders. Likewise, the kynurenine pathway (KP) of tryptophan degradation is associated with neurological diseases. Both stress and the KP, in particular the metabolite kynurenic acid (KYNA), can affect behavior, specifically learning and memory. Moreover, stress has been shown to manipulate the KP, but an investigation into the link between stress, KYNA, and cognition has yet to happen. To this end, we utilized three acute stressors (predator odor exposure, restraint, and inescapable shocks) of differing degrees of severity to investigate stress-related effects on KYNA levels in the medial prefrontal cortex (mPFC) and cognitive behavior. We focused on fear discrimination because it requires the mPFC, is easily testable in rodents, and is a hallmark of many stress-related disorders, in particular post-traumatic stress disorder. Furthermore, the adrenal gland, critical for an organism’s stress response, has been shown to have effects on the KP and cognition. Therefore, we also examined how adrenalectomy (ADX) affects a stress-induced change in KYNA and behavior. Inescapable shocks stress (ISS) was the most severe form of stress tested, defined by the highest increase in plasma corticosterone levels in naïve rats. ISS induced a significant, sustained elevation of extracellular KYNA in the mPFC and impairments in fear discrimination. A KYNA synthesis inhibitor administered before the initiation of ISS decreased the stress-induced KYNA increase and normalized the fear discrimination impairments, suggesting a causal linkage. Restraint and predator odor exposure did not affect KYNA levels or fear discrimination. However, in ADX rats, the threshold for the severity of stress required appears to be lower to elicit the effects described above. Restraint stress produced an increase in extracellular KYNA levels in the mPFC of ADX rats as well as impairments in fear discrimination, contrary to rats with intact adrenal glands. Additionally, a KYNA synthesis inhibitor attenuated these biochemical and behavioral effects. Together, these findings suggest a causal relationship between the stress-induced increase in KYNA and cognitive deficits. Therefore, targeting the KP by pharmacological or other means may alleviate some of the detrimental symptoms seen in stress-related psychiatric disorders.