Jyoti Watters, Ph.D

Professor
Comparative Biosciences
2015 Linden Drive, Madison, WI 53706
Rm 3466
Madison, WI 53706
Telephone: 
608.262.1016
Focus Groups: 
Neuroscience/Neuropathology
Signal Transduction
Research Summary: 
• Regulation of microglial gene transcription • Microglial signal transduction mechanisms in paradigms of hypoxia • Epigenetic modulation of microglial phenotypes • Sex differences in microglial responses in chronic neuroinflammatory disease
Research Detail: 

The adult CNS (central nervous system) has the amazing ability to adapt to and compensate for deficits in neurologic function after CNS injury or neurodegenerative disease. Our laboratory is interested in understanding the contributions of the CNS immune system to this adaptation. Microglia, the only resident CNS immune cell, display astounding phenotypic plasticity, enabling them to respond and adapt to all aspects of CNS health and pathology via their production of both inflammatory/neurotoxic and reparative/neurosupportive factors. Little is known about endogenous cellular mechanisms used by microglia to self-regulate their transition to the reparative/neurosupportive phenotype during chronic disease, functions that ultimately limit CNS damage and promote protection.

The overall goal of our research is to investigate the cellular and molecular mechanisms that regulate microglial phenotype and function as they contribute to CNS pathology and recovery in chronic neuroinflammatory disorders. To study microglial plasticity in chronic neuroinflammatory disease, one of our main research models is exposure to repetitive episodes of intermittent hypoxia (IH), a hallmark of sleep disordered breathing (e.g. sleep apnea). We have identified critical transitional periods in the microglial phenotype that occur between inflammatory and reparative/neurotrophic phenotypes over the course of IH exposure. The specific timing of these effects and the elaborate shifts in classes of genes expressed at these times suggest that microglia utilize tightly regulated mechanisms to control their activities during CNS adaptation to chronic injury. Our recent evidence implicates a critical role for epigenetic processes (e.g. histone demethylation and microRNAs) in the mechanisms employed by microglia to initiate transitions between inflammatory and neurotrophic phenotypes. We focus in particular on the signal transduction and gene transcriptional mechanisms used by microglia to enable these shifts in their function.

Selected Publications: 
Huxtable, A.G. Smith, S.M.C., Peterson, T.J., Watters, J.J. and Mitchell, G.S. 2015 Intermittent hypoxia-induced spinal inflammation impairs respiratory motor plasticity by a spinal p38 MAP kinase-dependent mechanism. Journal of Neuroscience, 35(17):6871-6880 (PMCID: PMC4412901). http://www.ncbi.nlm.nih.gov/pubmed/25926462
Nikodemova, M., Kimyon, R.S., De, I., Small, A.L., Collier, L.S. and Watters, J.J. 2015 Microglial numbers attain adult levels after undergoing a rapid decrease in cell number in the third postnatal week. Journal of Neuroimmunology, 278:280-288 (PMCID: PMC4297717). http://www.ncbi.nlm.nih.gov/pubmed/25468773
Smith, S.M.C., Kimyon, R.S. and Watters, J.J. 2014 Cell-Type Specific Expression of Jumonji Histone Demethylases in the Healthy Rat CNS: Detection By A Novel Flow Cytometry Method. ASN Neuro, 6(3) pii: e00146 (PMCID: PMC4034710). http://www.ncbi.nlm.nih.gov/pubmed/24735454
Nikodemova, M., Small, A.L., Smith, S.M., Mitchell, G.S. and Watters. J.J. 2014 Spinal but not cortical microglia acquire an atypical phenotype with high VEGF, galectin-3 and osteopontin, and blunted inflammatory responses in ALS rats. Neurobiology of Disease, 69C:43-53. (PMCID: PMC24269728). http://www.ncbi.nlm.nih.gov/pubmed/24269728
Smith, S.M.C., Mitchell, G.S., Friedle, S.A. and Watters, J.J. 2013 Chronic intermittent hypoxia exerts CNS region-specific effects on rat microglial inflammatory and TLR4 gene expression. PLoS One, 8(12):e81584 (PMCID: PMC3852519). http://www.ncbi.nlm.nih.gov/pubmed/24324707
Smith, S.M.C., Mitchell, G.S., Friedle, S.A., Sibigtroth, C.M., Vinit, S. and Watters, J.J. 2013 Hypoxia attenuates purinergic P2X receptor-induced inflammatory gene expression in brainstem microglia. Hypoxia, 1:1-11. (PMCID: PMC3873144) http://www.ncbi.nlm.nih.gov/pubmed/24377098
Crain, J.M., Nikodemova, M. and Watters, J.J. 2013 Microglia Express Distinct M1 and M2 Phenotypic Markers in the Postnatal and Adult Central Nervous System in Male and Female Mice. Journal of Neuroscience Research, 91(4):1143-1151. (PMCID: PMC3715560) http://www.ncbi.nlm.nih.gov/pubmed/23686747
Nikodemova, M. and Watters, J.J. 2012 Efficient isolation of live microglia with preserved phenotypes from adult mouse brain*. Journal of Neuroinflammation, 9:147. (PMCID: PMC3418565) http://www.ncbi.nlm.nih.gov/pubmed/22742584
Nikodemova, M and Watters, J.J. 2011 Outbred ICR/CD1 mice display more severe neuroinflammation mediated by microglial TLR4/CD14 activation than inbred C57Bl/6 mice. Neuroscience, 190:67-74 (PMCID: PMC3156380) http://www.ncbi.nlm.nih.gov/pubmed/21683771
Friedle, S.A., Nikodemova, M., Wright, M.L. and Watters, J.J. 2011 The P2X7-Egr Pathway Regulates Nucleotide-Dependent Inflammatory Gene Expression in Microglia. Glia, 59(1):1-13. (PMCID: PMC2981661) http://www.ncbi.nlm.nih.gov/pubmed/20878769