Behavioral disturbance and day-night rhythm disruption of dementia patients are top reasons for institutionalization and cause of caregiver burden. Patients with dementia or Alzheimer's disease often exhibit """"""""sundowning syndrome,"""""""" a constellation of symptoms including late afternoon/evening hyperactivity, restlessness, confusion, and aggression, along with misaligned core body temperature and activity rhythms. These symptoms suggest a dysregulated circadian network, which normally allows anticipation of and preparation for daily recurring environmental events, including time-of-day-specific variability in cognitive function. Identification of the molecular abnormalities underlying circadin dysregulation would allow for the development of targeted strategies for reinstating rhythmicity and associated behaviors. This project will test the hypothesis that glycogen synthase kinase 3 provides a time-of-day-specific gating mechanism for intrinsic excitability, and that disruptions i daily changes in the phosphorylation state balance of this enzyme within specific brain regions contribute to circadian and cognitive abnormalities of neurodegenerative disease. Specifically, this project will determine whether day-night changes in phosphorylation of glycogen synthase kinase 3 regulate oscillations of clock gene expression and physiology and that cognition and circadian behavioral abnormalities in neurodegenerative disease are mediated by loss of daily glycogen synthase kinase 3 phosphorylation cycles and dysregulated neural activity rhythms. Proposed studies will examine this hypothesis in the suprachiasmatic nucleus and hippocampus under normal physiologic conditions (Aim 1) as well as under pathological conditions (Aim 2) utilizing animal models of neurodegenerative disease. Successful completion of these experiments will establish glycogen synthase kinase 3 as a key player in day-night variation of membrane properties and synaptic physiology, which are critical for appropriately timed cognitive function and rest/activity patterns. They will also lay the groundwork for translational studies designed to target this mechanism for proper therapeutic timing in dementia and neurological disease.
Behavioral disturbance and day-night rhythm disruption of dementia patients are top reasons for institutionalization and cause of caregiver burden. The proposed research will investigate whether disruptions in daily changes in the phosphorylation state balance of an enzyme implicated in neurological disease contribute to circadian and cognitive abnormalities. Successful completion of these experiments will lay the groundwork for translational studies designed to target this mechanism for proper therapeutic timing for patients with dementia and/or Alzheimer's disease.
|McMeekin, Laura J; Lucas, Elizabeth K; Meador-Woodruff, James H et al. (2016) Cortical PGC-1Î±-Dependent Transcripts Are Reduced in Postmortem Tissue From Patients With Schizophrenia. Schizophr Bull 42:1009-17|
|Paul, Jodi R; DeWoskin, Daniel; McMeekin, Laura J et al. (2016) Regulation of persistent sodium currents by glycogen synthase kinase 3 encodes daily rhythms of neuronal excitability. Nat Commun 7:13470|
|Peliciari-Garcia, Rodrigo A; Goel, Mehak; Aristorenas, Jonathan A et al. (2016) Altered myocardial metabolic adaptation to increased fatty acid availability in cardiomyocyte-specific CLOCK mutant mice. Biochim Biophys Acta 1860:1579-95|
|Udoh, Uduak S; Swain, Telisha M; Filiano, Ashley N et al. (2015) Chronic ethanol consumption disrupts diurnal rhythms of hepatic glycogen metabolism in mice. Am J Physiol Gastrointest Liver Physiol 308:G964-74|
|Besing, Rachel C; Paul, Jodi R; Hablitz, Lauren M et al. (2015) Circadian rhythmicity of active GSK3 isoforms modulates molecular clock gene rhythms in the suprachiasmatic nucleus. J Biol Rhythms 30:155-60|
|Hablitz, Lauren M; Molzof, Hylton E; Abrahamsson, Kathryn E et al. (2015) GIRK Channels Mediate the Nonphotic Effects of Exogenous Melatonin. J Neurosci 35:14957-65|
|Hablitz, L M; Molzof, H E; Paul, J R et al. (2014) Suprachiasmatic nucleus function and circadian entrainment are modulated by G protein-coupled inwardly rectifying (GIRK) channels. J Physiol 592:5079-92|
|Young, Martin E; Brewer, Rachel A; Peliciari-Garcia, Rodrigo A et al. (2014) Cardiomyocyte-specific BMAL1 plays critical roles in metabolism, signaling, and maintenance of contractile function of the heart. J Biol Rhythms 29:257-76|
|Gamble, Karen L; Berry, Ryan; Frank, Stuart J et al. (2014) Circadian clock control of endocrine factors. Nat Rev Endocrinol 10:466-75|
|Gamble, Karen L; Resuehr, David; Johnson, Carl Hirschie (2013) Shift work and circadian dysregulation of reproduction. Front Endocrinol (Lausanne) 4:92|
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