Jon T. Willie, MD, PhD

Assistant Professor
Departments of Neurological Surgery and Neurology

Phone: Academic: 404-727-2354, Clinical: 404-778-5770

Fax: Academic: 404-712-8576, Clinical: 404-778-3279

Biography

Understanding the mechanisms of arousal is a fundamental problem in neuroscience with high potential to impact numerous neurological diseases. The orexin (also called hypocretin) neuropeptide transmitter system critically orchestrates the activity of multiple brain circuits to produce sustained wake and motivation. Indeed, loss of orexin neurons of the hypothalamus causes the sleep-wake disorder narcolepsy with cataplexy. This disorder is characterized by uncontrollable attacks of sleep and attacks of muscle paralysis triggered by emotion. Loss or dysfunction of the orexin system may also play a role in sleepiness associated with Parkinson disease and traumatic brain injury (TBI). Using animal models, we have demonstrating that replacement of orexin into the brain by direct infusion or gene-bases therapy holds great potential for reversing the sleepiness associated with these disorders. Our research involves translating the use of orexin-based therapies and other neuromodulatory techniques (including deep brain stimulation) into surgical practice for the treatment of sleep attacks associated with narcolepsy or Parkinson disease, cataplexy, and minimally conscious state following TBI.

Education & Training:

  • BA Biochemistry with Honors, The University of Texas at Austin (1996) 
  • MD Clinical Medicine, The University of Texas Southwestern Medical Center at Dallas (2005) 
  • PhD Biomedical Sciences, The University of Texas Southwestern Medical Center at Dallas (2005) 
  • Internship in General Surgery, Washington University School of Medicine in St. Louis (2005-06) 
  • Residency in Neurological Surgery, Washington University School of Medicine in St. Louis (2006-09) 
  • Postdoctoral Research Fellow in Neurology, Washington University School of Medicine in St. Louis (2009) 
  • Registrar in Neurological Surgery, Beaumont Public Hospital, Dublin Ireland (2010) 
  • Chief Residency in Neurological Surgery, Washington University School of Medicine in St. Louis (2010-11) 
  • Clinical Fellow in Stereotactic, Functional, and Epilepsy Surgery, Dept. of Neurosurgery, Emory University School of Medicine in Atlanta (2011-12)

Board Eligible:

  • American Board of Neurological Surgeons

Awards:

  • Visiting Professor, University of Utah School of Medicine, Department of Neurosurgery (2011) 
  • Visiting Professor, Louisiana State University School of Medicine, Department of Neurosurgery (2011) 
  • Visiting Professor, University of Virginia School of Medicine, Department of Neurosurgery (2011) 
  • Visiting Professor, University of Iowa School of Medicine, Department of Neurosurgery (2011) 
  • Best Basic Science Research Presentation, 5th Annual Neurosurgery Research Symposium (2011) 
  • Neurosurgery Research Education Fund (NREF), Research Fellow (2010) 
  • Synthes Resident Craniofacial Award, 2010 AANS Annual Meeting (2010) 
  • Cervical Spine Research Society, Resident Research Award (2009) 
  • Resident Teaching Award, Department of Neurosurgery (2009) 
  • Congress of Neurological Surgeons Top Ten Abstracts: Functional (2009) 
  • Best Basic Science Research Presentation, 3rd Annual Neurosurgery Research Symposium (2009) 
  • Resident Teaching Award, Department of Neurosurgery (2008) 
  • Best Basic Science Research Presentation, 1st Annual Neurosurgery Research Symposium (2007) 
  • Recognition for Resident Teaching, Department of General Surgery (2006) 
  • Student Research Award, Association for Academic Surgery, First Annual Academic Surgical Congress, San Diego California (2006)
  • Outstanding Medical Student in Endocrinology, UT Southwestern (2005) 
  • Outstanding Medical Student in Neurology, UT Southwestern (2005) 
  • Finalist, Donald B. Lindsley Prize in Behavioral Neuroscience, The Grass Foundation and the Society for Neuroscience (2004) 
  • Dean’s Discretionary Award recognizing superior achievement by a graduate student, UT Southwestern (2003) 
  • Awardee, Sigma Xi and Graduate Student Organization Annual Abstract and Poster Competition, UT Southwestern (2002) 
  • Inducted into Sigma Xi Scientific Honor Society, UT Southwestern Chapter (2002) 
  • Finalist, Young Investigator Award, American Academy of Sleep Medicine (2001)

Recent & Noteworthy Publications:

Limbrick, D. D., Jr., Lake, S., Talcott, M., Alexander, B., Wight, S., Willie, J. T., Richard, W. D., Genin, G. M. & Leuthardt, E. C. (2012). The baric probe: a novel long-term implantable intracranial pressure monitor with ultrasound-based interrogation. J Neurosurg Pediatr. PMID: 23020257

Willie, J. T., Lim, M. M., Bennett, R. E., Azarion, A. A., Schwetye, K. E. & Brody, D. L. (2012). Controlled cortical impact traumatic brain injury acutely disrupts wakefulness and extracellular orexin dynamics as determined by intracerebral microdialysis in mice. J Neurotrauma 29, 1908-21. PMID: 22607167

Willie, J. T. & Gross, R. E. (2012). Beyond Therapeutic Nihilism? The Neurosurgical Treatment of Intracerebral Hemorrhage. World Neurosurg. PMID: 22381877

Kumar, A., Keyrouz, S. G., Willie, J. T. & Dhar, R. (2012). Reversible obstructive hydrocephalus from hypertensive encephalopathy. Neurocrit Care 16, 433-9. PMID: 22234407

Kalogiannis, M., Hsu, E., Willie, J. T., Chemelli, R. M., Kisanuki, Y. Y., Yanagisawa, M. & Leonard, C. S. (2011). Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice. PLoS One 6, e18697. PMID: 21533254

Willie, J. T., Takahira, H., Shibahara, M., Hara, J., Nomiyama, M., Yanagisawa, M. & Sakurai, T. (2011). Ectopic overexpression of orexin alters sleep/wakefulness states and muscle tone regulation during REM sleep in mice. J Mol Neurosci 43, 155-61. PMID: 20711757

Reynolds, M. R., Willie, J. T., Zipfel, G. J. & Dacey, R. G. (2011). Sexual intercourse and cerebral aneurysmal rupture: potential mechanisms and precipitants. J Neurosurg 114, 969-77. PMID: 20540599

Hondo, M., Nagai, K., Ohno, K., Kisanuki, Y., Willie, J. T., Watanabe, T., Yanagisawa, M. & Sakurai, T. (2010). Histamine-1 receptor is not required as a downstream effector of orexin-2 receptor in maintenance of basal sleep/wake states. Acta Physiol (Oxf) 198, 287-94. PMID: 19694625

Scammell, T. E., Willie, J. T., Guilleminault, C. & Siegel, J. M. (2009). A consensus definition of cataplexy in mouse models of narcolepsy. Sleep 32, 111-6. PMID: 19189786

Funato, H., Tsai, A. L., Willie, J. T., Kisanuki, Y., Williams, S. C., Sakurai, T. & Yanagisawa, M. (2009). Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity. Cell Metab 9, 64-76. PMID: 19117547

Willie, J. T., Sinton, C. M., Maratos-Flier, E. & Yanagisawa, M. (2008). Abnormal response of melanin-concentrating hormone deficient mice to fasting: hyperactivity and rapid eye movement sleep suppression. Neuroscience 156, 819-29. PMID: 18809470

Willie, J. T., Renthal, W., Chemelli, R. M., Miller, M. S., Scammell, T. E., Yanagisawa, M. & Sinton, C. M. (2005). Modafinil more effectively induces wakefulness in orexin-null mice than in wild-type littermates. Neuroscience 130, 983-95. PMID: 15652995

Mieda, M., Willie, J. T., Hara, J., Sinton, C. M., Sakurai, T. & Yanagisawa, M. (2004). Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc Natl Acad Sci U S A 101, 4649-54. PMID: 15070772

Willie, J. T., Chemelli, R. M., Sinton, C. M., Tokita, S., Williams, S. C., Kisanuki, Y. Y., Marcus, J. N., Lee, C., Elmquist, J. K., Kohlmeier, K. A., Leonard, C. S., Richardson, J. A., Hammer, R. E. & Yanagisawa, M. (2003). Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron 38, 715-30. PMID: 12797957

Yamanaka, A., Beuckmann, C. T., Willie, J. T., Hara, J., Tsujino, N., Mieda, M., Tominaga, M., Yagami, K., Sugiyama, F., Goto, K., Yanagisawa, M. & Sakurai, T. (2003). Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38, 701-13. PMID: 12797956

Georgescu, D., Zachariou, V., Barrot, M., Mieda, M., Willie, J. T., Eisch, A. J., Yanagisawa, M., Nestler, E. J. & DiLeone, R. J. (2003). Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal. J Neurosci 23, 3106-11. PMID: 12716916

Chou, T. C., Lee, C. E., Lu, J., Elmquist, J. K., Hara, J., Willie, J. T., Beuckmann, C. T., Chemelli, R. M., Sakurai, T., Yanagisawa, M., Saper, C. B. & Scammell, T. E. (2001). Orexin (hypocretin) neurons contain dynorphin. J Neurosci 21, RC168. PMID: 11567079

Hara, J., Beuckmann, C. T., Nambu, T., Willie, J. T., Chemelli, R. M., Sinton, C. M., Sugiyama, F., Yagami, K., Goto, K., Yanagisawa, M. & Sakurai, T. (2001). Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30, 345-54. PMID: 11394998

Willie, J. T., Chemelli, R. M., Sinton, C. M. & Yanagisawa, M. (2001). To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci 24, 429-58. PMID: 11283317

Chemelli, R. M., Willie, J. T., Sinton, C. M., Elmquist, J. K., Scammell, T., Lee, C., Richardson, J. A., Williams, S. C., Xiong, Y., Kisanuki, Y., Fitch, T. E., Nakazato, M., Hammer, R. E., Saper, C. B. & Yanagisawa, M. (1999). Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437-51. PMID: 10481909

Vashee, S., Willie, J. T. & Kodadek, T. (1998). Synergistic activation of transcription by physiologically unrelated transcription factors through cooperative DNA-binding. Biochem Biophys Res Commun 247, 530-5. PMID: 9642164