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  • Michael Lehman, PhD

    lehman, michael NEW.jpg

    Professor and Chair
    Department of Neurobiology and Anatomical Sciences
    Adjunct Professor, Department of Pharmacology, School of Pharmacology
    Office: N713
    Phone: (601) 984-1607
    Lab: R609-617
    Lab phone: (601) 815-5634
    Fax: (601) 984-1655
    E-mail: mlehman@umc.edu

    Education

    • BA - Wesleyan University, Middletown CT, 1975, cum laude with high honors in Biology-Psychology
    • PhD - University of Michigan, Ann Arbor, MI, 1982, Neuroscience. Dissertation title: "Neural pathways of the vomeronasal and olfactory systems controlling sexual behavior in the male golden hamster." Adviser: Sarah W. Newman, PhD
    • Postdoctoral Scholar - Reproductive Endocrinology Program, University of Michigan, Ann Arbor, MI 1982-83. Mentor: Fred J. Karsch, PhD
    • Postdoctoral Fellow - Department of Anatomy and Cell Biology, Columbia University, College of Physicians and Surgeons, New York, NY 1983-86.  Mentor:  Ann-Judith Silverman, PhD

    Teaching responsibilities

    • Medical Neurobiology (Anat 615)
    • Responsible Conduct of Research (ID 709)

    Research interests

    • Reproductive neuroendocrinology
    • Developmental programming of reproduction
    • Neurobiology of circadian rhythms

    Research program

    A major, long-term interest of our lab is the reproductive neuroendocrine system of the brain  In mammals, reproduction is governed by intricate neural and hormonal communication between the brain, pituitary gland and gonads.

    lehman 12.jpgAt the top of this hierarchy are gonadotropin-releasing hormone (GnRH) neurons that are responsible for the pulsatile secretion of luteinizing hormone (LH) from the anterior pituitary gland (Fig. 1). Changes in the frequency of GnRH and LH pulses have a profound effect on the reproductive system, but identification of the “GnRH pulse generator” in the brain has remained a major unanswered question. Similarly, GnRH neurons are under feedback control of gonadal steroid hormones, such as estradiol (E2) and progesterone (P4) secreted by the ovary (Fig. 1). However, since GnRH cells lack the type of receptors responsible for feedback control (Fig. 2), other neurons that are upstream of GnRH cells must be responsible for this feedback. Thus, a second unanswered question concerns the pathways by which steroid hormones regulate GnRH secretion, and thereby play a critical role in control of puberty, the estrous/menstrual cycle, and other reproductive events.

    lehman 34x.jpgTogether with Drs. Robert Goodman (West Virginia University) and Lique Coolen (University of Mississippi Medical Center), in 2007 we identified a single subset of neurons in the arcuate nucleus of the hypothalamus that co-expresses three neuropeptides, kisspeptin, neurokinin B and dynorphin, which we later termed “KNDy” neurons (Fig. 3).  We were among several groups to propose that KNDy neurons comprise a critical component of the GnRH pulse generator (Fig. 4), and since that time compelling evidence has accumulated supporting the view that KNDy cells serve as a final common pathway for external and internal regulatory signals that control GnRH secretion in a wide range of mammals.  

    More recently, working with our colleague, Dr. Vasantha Padmanabhan (University of Michigan), we have also focused on the potential role of KNDy cells in reproductive disease.  Specifically, we found that the balance of KNDy peptides is altered in an animal model of polycystic ovarian syndrome (PCOS), the most common reproductive disorder among adult women, perhaps leading to the dysfunction of steroid feedback control seen in that disease.

    lehman sheep NEW.jpgThe primary animal model we use for our studies of GnRH and KNDy neurons is the sheep. The sheep has several advantages as an experimental model for neuroendocrine research, most notably the ability to directly measure GnRH from blood collected at the surface of the pituitary gland from unanesthesized animals. This allows us to obtain precise and repeated measurements of GnRH release during pulsatile secretion and other endocrine states. Together with the large size of the sheep brain, this also enables us to perform experiments interrogating structure-function relationships in the brain at a detailed level of analysis. In our work, we employ a wide range of molecular, anatomical, and physiological techniques, including protein and mRNA analyses, confocal immunocytochemistry, electron microscopic immunocytochemistry, in situ hybridization, stereotaxic brain surgery, neuroanatomical tract tracing, intracerebral delivery of pharmacological agents and viral vectors, serial sampling of CSF, portal and peripheral blood, and radioimmunoassay of circulating hormones.

    Current funding

    • NIH R01 HD39916-11
      Interactions of Dynorphin, NKB and Kisspeptin in the Control of GnRH Secretion

      PI:  Michael N. Lehman
      Grant period: 7/15/13-4/30/18
    • NIH P01 HD44232
      Prenatal Programming of Reproductive Health and Disease - Project II

      Project PI:  Michael N. Lehman (P01 PI: Vasantha Padmanabhan)
      Grant period: 12/01/09-1/31/16
    • Australian Research Council Discovery Project DP140102495
      Brain Regulation of Reproduction: Challenging the 'KNDy' Hypothesis

      Partner Investigator: Michael N. Lehman (Chief Investigators: Graeme Martin, Jeremy Smith)
      Grant period: 1/1/2014-12/31/2017
    • NIH R01 HD082135-01
      Role of Neurokinin B in the Control of GnRH secretion
      MPI: Michael N. Lehman, Robert L. Goodman
      Grant period: 12/01/15-11/30/20

    Selected publications

    • Lehman, M.N., Silverman, A.J., Robinson, J.E., and F.J. Karsch. 1986. Immunocytochemical localization of luteinizing hormone-releasing hormone (LHRH) pathways in the sheep brain during anestrus and the mid-luteal phase of the estrous cycle, J. Comp. Neurol., 244: 19-35.
    • Xiong, J.J., Karsch, F.J. and M.N. Lehman. 1997. Evidence for seasonal plasticity in the gonadotropin-releasing hormone (GnRH) system of the ewe: changes in the density of synaptic inputs onto GnRH neurons, Endocrinology, 138: 1240-1250.
    • Goodman, R.L., Coolen, L.M., Anderson, G.M., Hardy, S.L., Valent, M., Connors, J., Fitzgerald, M.E., and M.N. Lehman.  2004.  Evidence that dynorphin plays a major role in mediating progesterone negative feedback on gonadotropin-releasing hormone neurons in sheep.  Endocrinology, 145(6): 2959-2967. PMID: 14988383
    • Goodman, R.L., Lehman, M.N., Smith, J.T., Coolen, L.M., de Oliviera, C.V.R., Jafarzadehshirazzi, M.R., Periera, A., Iqbal, J., Caraty, A., Ciofi, P. and I.J. Clarke.  2007.  Kisspeptin cells in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B. Endocrinology, 148(12): 5752-60. PMID: 17823266
    • Smith J.T., Coolen L.M., Kriegsfeld L.J., Sari I.P., Jaafarzadehshirazi M.R., Maltby M., Bateman K., Goodman R.L., Tilbrook A.J., Ubuka T., Bentley G.E., Clarke I.J., and M.N. Lehman.  2008. Variation in kisspeptin and gonadotropin-inhibitory hormone expression and terminal connections to GnRH neurons in the brain: a novel medium for seasonal breeding in the sheep. Endocrinology. 149(11): 5770-82. PMCID: PMC2584593
    • Cheng, G., Coolen, L.M., Padmanabhan, V., Goodman, R.L. and M.N. Lehman. 2010. The kisspeptin/neurokinin B/dynorphin (KNDY) cell population of the arcuate nucleus: sex differences and effects of prenatal testosterone in the sheep.  Endocrinology, 151(1): 301-311. PMCID: PMC2803147
    • Lehman, M.N., Coolen, L.M. and R.L. Goodman.  2010.  KNDy (kisspeptin/neurokinin B/dynorphin) cells of the arcuate nucleus: a central node in the control of GnRH secretion.  Endocrinology, 151(1): 301-11. PMCID: PMC2940527
    • Lehman, M.N., Merkley, C.M., Coolen, L.M. and R.L. Goodman.  2010.  Anatomy of the kisspeptin neuronal network.  Brain Research, Special Issue on “New Insights into the Neurobiology of Reproduction and Puberty”, 1364:90-102. PMCID: PMC2992597
    • Sheppard, K.M., Padmanabhan, V., Coolen, L.M., and M.N. Lehman.  2011.  Prenatal Programming by Testosterone of Metabolic Control Neurons in the Ewe Hypothalamus.  J. Neuroendocrinology, 23(5): 401-11. PMID: 21418339
    • Merkley, C.M., Porter, K.L., Coolen, L.M., Hileman, S.M., Drews, S., Goodman, R.L., Lehman, M.N.  2012.  KNDy (Kisspeptin/Neurokinin B/Dynorphin) neurons are activated during both pulsatile and surge secretion of LH in the ewe. Endocrinology, 153(11): 5406-14 PMID: 22989631.
    • Goodman, R.L., Maltby, M.J., Millar, R.P., Hileman, S.M., Nestor, C.C, Whited, B., Tseng, A.S., Coolen, L.M. and M.N. Lehman.  2012.  Evidence that dopamine acts via kisspeptin to hold GnRH pulse frequency in check in anestrous ewes.  Endocrinology, 153(12): 5918-27. PMID: 23038740.
    • Goodman, R.L. and M.N. Lehman. 2012.  Kisspeptin neurons from mice to men: similarities and differences. Endocrinology, 153(11): 5105-18. PMID: 22989628.
    • Lehman, M.N., Hileman, S.M., and R.L. Goodman.  2013.  Neuroanatomy of the Kisspeptin Signaling System in Mammals: Comparative and Developmental Aspects.  Chapter 3 in Kisspeptin Signaling in Reproductive Biology, A. Kauffman and J. Smith, eds., Advances in Experimental Medicine and Biology Volume 784, 2013, pp 27-62, Springer. PMID: 23550001
    • Goodman, R.L., Hileman, S.M., Nestor, C.C., Porter, K.L., Connors, J.M., Hardy, S.L., Millar, R.P., Cernea, M., Coolen, L.M., and M.N. Lehman.  2013.  Kisspeptin, neurokinin B, and dynorphin act in the arcuate nucleus to control activity of the GnRH pulse generator in ewes, Endocrinology, 154(11): 4259-69. PMID: 23959940.
    • Goodman, R.L., Coolen, L.M., and M.N. Lehman.  2014.  Unraveling the mechanism of action of the GnRH pulse generator: a possible role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons.  Invited review for Cellular Endocrinology in Health and Disease, Eds, Ulloa-Aguirre and Conn, Elsevier.
    • Weems, P.W., Goodman, R.L., and M.N. Lehman.  2015.  Neural mechanisms controlling seasonal reproduction: principles derived from the sheep model and its comparison with hamsters.  Front. Neuroendocrinology, S0091-3022 (14)00110-1. PMID: 25582913
    • Merkley, C.M., Coolen, L.M., Goodman, R.L., and M.N. Lehman.  2015.  Evidence for changes in numbers of synaptic inputs onto KNDy and GnRH neurones during the preovulatory LH surge in the ewe.  J. Neuroendocrinol., May 13. doi: 10.1111/jne.12293. [Epub ahead of print]. PMID: 25976424
    • Cernea, M, Padmanabhan, V, Goodman, R.L., Coolen, L.M., and Lehman, MN.  2015. Prenatal testosterone treatment leads to changes in the morphology of KNDy neurons, their inputs, and projections to GnRH cells in female sheep. Endocrinology. 2015 Jun 10:en20141609. [Epub ahead of print]. PMID: 26061725

    Previous academic appointments

    • 1986-89 - Assistant Professor, Dept. of Anatomy and Cell Biology, Univ. of Cincinnati College of Medicine
    • 1989-94 - Associate Professor, Dept. of Anatomy and Cell Biology, Univ. of Cincinnati College of Medicine
    • 1994-2005 - Professor, Dept. of Cell Biology, Neurobiology and Anatomy, Univ. of Cincinnati
    • 1994-2005 - Director, Neuroscience Graduate Program, University of Cincinnati
    • 2000-05 - Vice Chair for Research, Dept. of Cell Biology, Neurobiology and Anatomy, Univ. of Cincinnati
    • 2005-10 - Professor and Chair, Dept. Anatomy & Cell Biology, University of Western Ontario
    • 2006-10 - Co-Director, Neuroscience Interdisciplinary Development Initiative, Univ. Western Ontario
    • 2009-10 - Associate Scientist, Child Health Research Institute, London, Ontario
    • 2010-12 - Professor, Dept. Molecular & Integrative Physiology, University of Michigan
    • 2010-12 - Co-Director, Reproductive Sciences Program, University of Michigan

    Other experiences and professional roles

    • Ad hoc member, Bio-Psychology Study Section, NIH, 10/88
    • Ad hoc member, Biochemical Endocrinology Study Section, NIH, 2/90
    • Special reviewer, Neurology A Study Section, NIH, 1/95, 2/97, 6/97, 10/97, 3/98
    • Ad hoc member, Neurology B2 Study Section, NIH, June 1996
    • Program Project Grant site visit, National Cancer Institute, 3/95, 10/96, 5/97
    • Special reviewer, IFCN-2 Study Section, NIH, 2/99
    • Site visit, NSF Center for Science and Technology, 5/99
    • Temporary member, IFCN-3 Study Section, NIH, 7/99, 11/99
    • Member, NSF Advisory Panel For Neuroscience, 1997-2000
    • Member, Brain Disorders and Clinical Neuroscience 1 (BDCN-1) Study Section, NIH, 1998-1999
    • Member, Brain Disorders and Clinical Neuroscience 2 (BDCN-2) Study Section, NIH, 1999-2001
    • Regular member, NINDS, NST (Training Grant and Career Development) Review Committee, 2001-2006
    • Chair (2003, 2004), Member (2005, 2007, 2009), T-32 Trans/NIH Neuroscience Study Section (Jointly Sponsored Predoctoral Training Program)
    • Reviewer, Silvio Conte Centers for Collaborative Neuroscience Research, NIMH, March 2007.
    • Reviewer, Cooperative Reproductive Science Research Centers at Minority Institutions, NICHD, April 2007.
    • Reviewer, Specialized Centers Program in Reprod. and Infertility Research (U54), NICHD, November 2008, November 2010, November 2011, November 2013.
    • Reviewer, R25 Research Education Programs in Neurology & Neurosurgery, NINDS, 2008, 2009.
    • Ad hoc member, Integrative and Clinical Endocrinology and Reproduction (ICER) Study Section, 2012-2014
    • President, Association of Neuroscience Departments and Programs (ANDP), 2007-2008.
    • Co-Chair, Professional Development Committee, Society for Neuroscience, 2011-2014
    • Chair, On-line Programming Steering Committee, Society for Neuroscience, 2014-present.
    • Senior Editor, Journal of Neuroendocrinology, 2014-present.