Acute Kynurenine Challenge Disrupts Sleep-Wake Architecture and Impairs Contextual Memory in Adult Rats
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AbstractStudy Objectives: Tryptophan metabolism via the kynurenine pathway may represent a key molecular link between sleep loss and cognitive dysfunction. Modest increases in the kynurenine pathway metabolite kynurenic acid (KYNA), which acts as an antagonist at N-methyl-d-aspartate and α7 nicotinic acetylcholine receptors in the brain, result in cognitive impairments. As glutamatergic and cholinergic neurotransmissions are critically involved in modulation of sleep, our current experiments tested the hypothesis that elevated KYNA adversely impacts sleep quality. Methods: Adult male Wistar rats were treated with vehicle (saline) and kynurenine (25, 50, 100, and 250 mg/kg), the direct bioprecursor of KYNA, intraperitoneally at zeitgeber time (ZT) 0 to rapidly increase brain KYNA. Levels of KYNA in the brainstem, cortex, and hippocampus were determined at ZT 0, ZT 2, and ZT 4, respectively. Analyses of vigilance state-related parameters categorized as wake, rapid eye movement (REM), and non-REM (NREM) as well as spectra power analysis during NREM and REM were assessed during the light phase. Separate animals were tested in the passive avoidance paradigm, testing contextual memory. Results: When KYNA levels were elevated in the brain, total REM duration was reduced and total wake duration was increased. REM and wake architecture, assessed as number of vigilance state bouts and average duration of each bout, and theta power during REM were significantly impacted. Kynurenine challenge impaired performance in the hippocampal-dependent contextual memory task. Conclusions: Our results introduce kynurenine pathway metabolism and formation of KYNA as a novel molecular target contributing to sleep disruptions and cognitive impairments.
α7 nicotinic acetylcholine receptor
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85040841372&doi=10.1093%2fsleep%2fzsx141&partnerID=40&md5=74308e8d84391e7ebff9bc677a75e358; http://hdl.handle.net/10713/11146
- A High-performance Liquid Chromatography Measurement of Kynurenine and Kynurenic Acid: Relating Biochemistry to Cognition and Sleep in Rats.
- Authors: Baratta AM, Viechweg SS, Mong JA, Pocivavsek A
- Issue date: 2018 Aug 19
- Age dependency of inhibition of alpha7 nicotinic receptors and tonically active N-methyl-D-aspartate receptors by endogenously produced kynurenic acid in the brain.
- Authors: Alkondon M, Pereira EF, Eisenberg HM, Kajii Y, Schwarcz R, Albuquerque EX
- Issue date: 2011 Jun
- Pre- and postnatal exposure to kynurenine causes cognitive deficits in adulthood.
- Authors: Pocivavsek A, Wu HQ, Elmer GI, Bruno JP, Schwarcz R
- Issue date: 2012 May
- Continuous kynurenine administration during the prenatal period, but not during adolescence, causes learning and memory deficits in adult rats.
- Authors: Pocivavsek A, Thomas MA, Elmer GI, Bruno JP, Schwarcz R
- Issue date: 2014 Jul
- Exposure to kynurenic acid during adolescence produces memory deficits in adulthood.
- Authors: Akagbosu CO, Evans GC, Gulick D, Suckow RF, Bucci DJ
- Issue date: 2012 Jun