Jyoti Watters, Ph.D

Comparative Biosciences
2015 Linden Drive, Madison, WI 53706
Rm 3466
Madison, WI 53706
Focus Groups: 
Signal Transduction
Research Summary: 
Regulation of microglial gene transcription and signal transduction mechanisms in paradigms of hypoxia; Epigenetic modulation of microglial phenotypes; Maternal hypoxia-induced reprogramming of fetal offspring microglia and adult behavior; Sex differences in microglial function and gene expression
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 data suggest 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. Our exciting recent observations indicate that exposure of pregnant dams to IH (to mimic sleep apnea during pregnancy), can reprogram fetal microglia such that the adult offspring have both impaired cognitive behaviors (sex-specifically), and sleep apnea themselves, propagating the cycle to their own offspring. Current studies are aimed at investigating the epigenetic mechanisms responsible for fetal microglial reprogramming and the consequences on adult offspring behavior.

Selected Publications: 
Cyclooxygenase enzyme activity does not impair respiratory motor plasticity after onenight of intermittent hypoxia.Huxtable AG, Kopp E, Doughtery BJ, Watters JJ, Mitchell GS.Respir Physiol Neurobiol. 2017 Dec 9. pii: S1569-9048(17)30262-8. doi: 10.1016/j.resp.2017.12.004. [Epub ahead of print]PMID: 29233741
P2Y14 receptor activation decreases interleukin-6 production and glioma GL261 cell proliferation in microglial transwellcultures.Curet MA, Watters JJ.J Neurooncol. 2018 Mar;137(1):23-31. doi: 10.1007/s11060-017-2700-9. Epub 2017 Nov 30.PMID: 29189936
Gestational intermittent hypoxia increases susceptibility to neuroinflammation and alters respiratory motor control in neonatal rats.Johnson SM, Randhawa KS, Epstein JJ, Gustafson E, Hocker AD, Huxtable AG, Baker TL, Watters JJ.Respir Physiol Neurobiol. 2017 Nov 22. pii: S1569-9048(17)30275-6. doi: 10.1016/j.resp.2017.11.007. [Epub ahead of print] Review.PMID: 29174411
Antinociceptive and respiratory effects following application of transdermal fentanyl patches and assessment of brain μ-opioid receptor mRNA expression in ball pythons.Kharbush RJ, Gutwillig A, Hartzler KE, Kimyon RS, Gardner AN, Abbott AD, Cox SK, Watters JJ, Sladky KK, Johnson SM.Am J Vet Res. 2017 Jul;78(7):785-795. doi: 10.2460/ajvr.78.7.785.PMID: 28650234
Nongenomic Actions of 17-β Estradiol Restore Respiratory Neuroplasticity in Young Ovariectomized Female Rats.Dougherty BJ, Kopp ES, Watters JJ.J Neurosci. 2017 Jul 12;37(28):6648-6660. doi: 10.1523/JNEUROSCI.0433-17.2017. Epub 2017 Jun 7.PMID: 28592693
Photoreceptor protection via blockade of BET epigenetic readers in a murine model of inherited retinal degeneration.Zhao L, Li J, Fu Y, Zhang M, Wang B, Ouellette J, Shahi PK, Pattnaik BR, Watters JJ, Wong WT, Guo LW.J Neuroinflammation. 2017 Jan 19;14(1):14. doi: 10.1186/s12974-016-0775-4.PMID: 28103888
Microglial P2 Purinergic Receptor and Immunomodulatory Gene Transcripts Vary By Region, Sex, and Age in the Healthy MouseCNS.Crain JM, Watters JJ.Transcr Open Access. 2015 Dec;3(2). pii: 124. Epub 2015 Dec 28.PMID: 26949719
Mechanisms of microglial activation in models of inflammation and hypoxia: Implications for chronic intermittent hypoxia.Kiernan EA, Smith SM, Mitchell GS, Watters JJ.J Physiol. 2016 Mar 15;594(6):1563-77.doi: 10.1113/JP271502. Review.PMID: 26890698
Age-dependent differences in microglial responses to systemic inflammation are evident as early as middle age.Nikodemova M, Small AL, Kimyon RS, Watters JJ.Physiol Genomics. 2016 May;48(5):336-44. doi: 10.1152/physiolgenomics.00129.2015. Epub 2016 Feb 16.PMID: 26884461
Blue Light Modulates Murine Microglial Gene Expression in the Absence of Optogenetic Protein Expression.Cheng KP, Kiernan EA, Eliceiri KW, Williams JC, Watters JJ.Sci Rep. 2016 Feb 17;6:21172. doi: 10.1038/srep21172.PMID: 26883795