Date of Award

Spring 2022

Degree Type

Thesis

Department

Pharmacology, Physiology and Neuroscience

Director of Thesis

Ana Pocivavsek

Second Reader

Katherine Rentschler

Abstract

Abnormalities in the kynurenic pathway (KP) of tryptophan catabolism are implicated in various neurocognitive disorders, including schizophrenia, bipolar disorder, and Alzheimer’s disease. Elevated levels of the astrocyte-derived metabolite kynurenic acid (KYNA) are found in the postmortem brain of individuals with these illnesses. KYNA is a neuroactive metabolite and acts as an antagonist at glutamatergic N-methyl-D-aspartate (NMDA) and cholinergic α7 nicotinic acetylcholine (α7nACh) receptors. As glutamatergic and cholinergic transmission are critically involved in sleep-dependent plasticity and cognition, KYNA is hypothesized to play a key role in cognitive and sleep disruptions present in these brain disorders. Sleep and cognitive disturbances are pathophysiologically linked to dysfunction of lateral hypothalamus orexin neurons. As cholinergic neurons are an important source of this regulation, we presently investigated if KYNA plays a mechanistic role in orexin activation. To explore this hypothesis, we challenged adult male Wistar rats with an acute kynurenine injection to stimulate de novo KYNA production in the brain. Animals (n=7 per group) were treated with either vehicle or kynurenine (100 mg/kg; intraperitoneally) during the early part of the light cycle (Zeitgeber time 4-5). Two hours post treatment, when brain KYNA levels have been found to reach their peak, animals were perfused and brains removed. We employed immunohistochemical analysis to evaluate the number of c-Fos, a marker of rapid activation, and orexin co-labeled neurons. Through histological examination and cell counting, we determined that acute kynurenine treatment significantly induced overexpression of c-Fos within orexin neurons in the lateral hypothalamus compared to vehicle treatment (P < 0.001). This upregulation of double-labelled c-Fos/orexin neurons suggests that KYNA may increase activation of the lateral hypothalamus, thereby influencing arousal. As acute kynurenine challenge results in upregulation of other KP metabolites, including 3-hydroxykynurenine and quinolinic acid, a second cohort of animals was included to explore the specific role of KYNA by inhibiting its synthesis with the compound PF-04859989 (30mg/kg; subcutaneously) prior to kynurenine treatment. Pretreatment with PF-04859989 significantly reduced orexin activation levels in kynurenine-treated animals compared to kynurenine alone treated animals (p

First Page

1

Last Page

25

Rights

© 2022, Hayley A. Nicholson

Included in

Neurosciences Commons

Share

COinS