Faculty and Staff
|Department:||Pharmacology, Physiology and Neuroscience
School of Medicine
Pocivavsek lab website
B.S. Psychology, Duke University
Ph.D. Neuroscience, Georgetown University
Postdoctoral: Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine
We aim to understand the underlying molecular mechanisms of cognitive dysfunction. Poor sleep quality is associated with impairments in cognitive function. Our research strives to unravel common molecular mechanisms between sleep disturbances and cognitive impairments and introduce new therapeutic approaches to alleviate these outcomes.
Role of kynurenic acid (KYNA) in cognition
Metabolites of the kynurenine pathway of tryptophan degradation, including kynurenic acid (KYNA) and quinolinic acid, are increasingly understood to play major roles in nervous system development, function as neuromodulators in adulthood, and participate causally in pathological states, including severe mental illness. KYNA acts as an endogenous antagonist at N-methyl-d-aspartate (NMDA) and the α7nACh receptors, both richly endowed in the hippocampus and implicated in mediating cognitive function. KYNA has also been extensively implicated in the pathology of psychiatric disorders, including schizophrenia, where studies using cerebrospinal fluid or post-mortem brain tissue of patients with schizophrenia suggest that an excess of KYNA might play a causative role in the disease. This suggested causality is directly supported by our own work, which show cognitive dysfunctions reminiscent of schizophrenia when brain KYNA levels are elevated acutely. Targeted inhibition of KYNA formation is being investigated as a therapeutic approach to overcoming cognitive impairments.
Kynurenic acid (KYNA) as a molecular link between sleep and cognition
Only about 5% of dietary tryptophan, which is elevated in serum and brain after prolonged wakefulness and implicated in modulating sleep, is degraded to serotonin and melatonin. The vast majority of tryptophan is metabolized in the kynurenine pathway, which is also responsible for the neosynthesis of KYNA. However, the direct relationship between sleep and kynurenine pathway metabolism remains elusive. Our work demonstrates that KYNA levels are elevated in the hippocampus after sleep deprivation in rats. Additionally, at concentrations that adversely impact learning and memory, peripheral administration of kynurenine, the direct bioprecursor of KYNA, adversely impacts sleep architecture, determined by data from polysomnographic recordings that combine electroencephalography (EEG) and electromyography (EMG) with implantable telemetry devices. We are investigating whether sleep disruption and resulting elevations in brain KYNA instigate instability in sleep-wake homeostasis and downstream cognitive dysfunction.
- Baratta AM, Viechweg SS, Mong JA, Pocivavsek A. A High-performance Liquid Chromatography Measurement of Kynurenine and Kynurenic Acid: Relating Biochemistry to Cognition and Sleep in Rats. J Vis Exp. 2018 Aug 19;(138). doi: 10.3791/58129.
- Notarangelo FM, Pocivavsek A, Schwarcz R. Exercise Your Kynurenines to Fight Depression. Trends Neurosci. 2018 Aug;41(8):491-493. doi: 10.1016/j.tins.2018.05.010.
- Chiappelli J, Rowland LM, Notarangelo FM, Wijtenburg SA, Thomas MAR, Pocivavsek A, Jones A, Wisner K, Kochunov P, Schwarcz R, Hong LE. Salivary kynurenic acid response to psychological stress: inverse relationship to cortical glutamate in schizophrenia. Neuropsychopharmacology. 2018 Apr 18. doi: 10.1038/s41386-018-0072-2.
- Baratta AM, Buck SA, Buchla AD, Fabian CB, Chen S, Mong JA, Pocivavsek A. Sex Differences in Hippocampal Memory and Kynurenic Acid Formation Following Acute Sleep Deprivation in Rats. Sci Rep. 2018 May 3;8(1):6963. doi: 10.1038/s41598-018-25288-w.
- Chiappelli J, Notarangelo FM, Pocivavsek A, Thomas MAR, Rowland LM, Schwarcz R, Hong LE. Influence of plasma cytokines on kynurenine and kynurenic acid in schizophrenia. Neuropsychopharmacology. 2018 Jul;43(8):1675-1680. doi: 10.1038/s41386-018-0038-4. Epub 2018 Feb 27.
- Pocivavsek A, Rowland LM. Basic Neuroscience Illuminates Causal Relationship Between Sleep and Memory: Translating to Schizophrenia. Schizophr Bull. 2018 Jan 13;44(1):7-14. doi: 10.1093/schbul/sbx151.
- Hahn B, Reneski CH, Pocivavsek A, Schwarcz R. Prenatal kynurenine treatment in rats causes schizophrenia-like broad monitoring deficits in adulthood. Psychopharmacology (Berl). 2018 Mar;235(3):651-661. doi: 10.1007/s00213-017-4780-9. Epub 2017 Nov 11.
- Goeden N, Notarangelo FM, Pocivavsek A, Beggiato S, Bonnin A, Schwarcz R. Prenatal Dynamics of Kynurenine Pathway Metabolism in Mice: Focus on Kynurenic Acid. Dev Neurosci. 2017;39(6):519-528. doi: 10.1159/000481168. Epub 2017 Oct 28.
- Pocivavsek A, Baratta AM, Mong JA, Viechweg SS. Acute Kynurenine Challenge Disrupts Sleep-Wake Architecture and Impairs Contextual Memory in Adult Rats. Sleep. 2017 Nov 1;40(11). doi: 10.1093/sleep/zsx141.
- Erhardt S, Pocivavsek A, Repici M, Liu XC, Imbeault S, Maddison DC, Thomas MAR, Smalley JL, Larsson MK, Muchowski PJ, Giorgini F, Schwarcz R. Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders. Biol Psychiatry. 2017 Nov 15;82(10):756-765. doi: 10.1016/j.biopsych.2016.12.011. Epub 2016 Dec 16.
- Clark SM, Pocivavsek A, Nicholson JD, Notarangelo FM, Langenberg P, McMahon RP, Kleinman JE, Hyde TM, Stiller J, Postolache TT, Schwarcz R, Tonelli LH. Reduced kynurenine pathway metabolism and cytokine expression in the prefrontal cortex of depressed individuals. J Psychiatry Neurosci. 2016 Oct;41(6):386-394.
- Pershing ML, Phenis D, Valentini V, Pocivavsek A, Lindquist DH, Schwarcz R, Bruno JP. Prenatal kynurenine exposure in rats: age-dependent changes in NMDA receptor expression and conditioned fear responding. Psychopharmacology (Berl). 2016 Oct;233(21-22):3725-3735. Epub 2016 Aug 16.
- Notarangelo FM, Pocivavsek A. Elevated kynurenine pathway metabolism during neurodevelopment: Implications for brain and behavior. Neuropharmacology. 2017 Jan;112(Pt B):275-285. doi: 10.1016/j.neuropharm.2016.03.001. Epub 2016 Mar 2. Review.
- Pershing ML, Bortz DM, Pocivavsek A, Fredericks PJ, Jørgensen CV, Vunck SA, Leuner B, Schwarcz R, Bruno JP. Elevated levels of kynurenic acid during gestation produce neurochemical, morphological, and cognitive deficits in adulthood: implications for schizophrenia. Neuropharmacology. 2015 Mar;90:33-41. doi: 10.1016/j.neuropharm.2014.10.017. Epub 2014 Nov 1.
- Chiappelli J, Pocivavsek A, Nugent KL, Notarangelo FM, Kochunov P, Rowland LM, Schwarcz R, Hong LE. Stress-induced increase in kynurenic acid as a potential biomarker for patients with schizophrenia and distress intolerance. JAMA Psychiatry. 2014 Jul 1;71(7):761-8. doi: 10.1001/jamapsychiatry.2014.243.
- Pocivavsek A, Thomas MA, Elmer GI, Bruno JP, Schwarcz R. Continuous kynurenine administration during the prenatal period, but not during adolescence, causes learning and memory deficits in adult rats. Psychopharmacology (Berl). 2014 Jul;231(14):2799-809. doi: 10.1007/s00213-014-3452-2. Epub 2014 Mar 4.
- Wu HQ, Okuyama M, Kajii Y, Pocivavsek A, Bruno JP, Schwarcz R. Targeting kynurenine aminotransferase II in psychiatric diseases: promising effects of an orally active enzyme inhibitor. Schizophr Bull. 2014 Mar;40 Suppl 2:S152-8. doi: 10.1093/schbul/sbt157.
- Pocivavsek A, Wu HQ, Elmer GI, Bruno JP, Schwarcz R. Pre- and postnatal exposure to kynurenine causes cognitive deficits in adulthood. Eur J Neurosci. 2012 May;35(10):1605-12. doi: 10.1111/j.1460-9568.2012.08064.x. Epub 2012 Apr 20.
- Pocivavsek A, Wu HQ, Potter MC, Elmer GI, Pellicciari R, Schwarcz R. Fluctuations in endogenous kynurenic acid control hippocampal glutamate and memory. Neuropsychopharmacology. 2011 Oct;36(11):2357-67. doi: 10.1038/npp.2011.127. Epub 2011 Jul 27.