SWAGÊÓƵ

Dual Ph.D. Pharmacology & Toxicology / Neuroscience, Michigan State University, East Lansing, MI, 1994

B.S., in Psychobiology, University of California at Los Angeles, Los Angeles, CA, 1986

Orange Coast College, Costa Mesa, CA, 1983

Positions and Employment

1994 – 1998 Oregon Health Sciences University, Postdoctoral Fellow,

1998 – 2001 Oregon Health Sciences University, Research Assistant Professor

2001 – 2005 Western University of Health Sciences, Assistant Professor

2005 – 2014 Western University of Health Sciences, Associate Professor

2014 - present Western University of Health Sciences, Professor

2018 - present Western University of Health Sciences, Director of MSBS Program

Professor, Western University of Health Sciecnces, COMP, Pomona, CA 2014-present

Associate Professor, Western University of Health Sciences, COMP, Pomona, CA, 2005-2014

Assistant Professor, Western University of Health Sciences, COMP, Pomona, CA, 2001-2005

Visiting Professor (Adjunct), Department of Neurobiology, UCLA, Los Angeles, CA, 2001-2010

Research Assistant Professor, Department of Physiology & Pharmacology, Oregon Health Sciences University, Portland, OR, 1998-2001

Gastrointestinal Physiology
Reproductive Physiology
Regulatory Neurobiology – Synaptic Integration in the Hypothalamus: The GnRH Neuronal System
Endocrine Physiology
Molecular and Cellular Basis of Medicine Physiology

My research interests focus on how cannabinoids regulate the hypothalamic feeding circuitry to affect changes in feeding behavior and energy homeostasis in male and female subjects, and how gonadal steroids modulate this interaction. I use state-of-the-art instrumentation to assess cannabinoid-induced changes in daily and hourly food intake, as well as meal size, frequency and duration, core body temperature and weight gain/loss, and how these changes correlate with alterations in neurotransmitter release and cell excitability at anorexigenic proopiomelanocortin (POMC) synapses within the hypothalamic arcuate nucleus. I recently have discovered that males are much more sensitive to the appetite-modulating properties of CB1 receptor agonists and antagonists than females, which correlates with marked sex differences in the pre- and post synaptic actions of cannabinoids at POMC synapses. These findings indicate that gender should be taken into account when considering the use of cannabinoids in the treatment of HIV/AIDS- or cancer-related cachexia, or obesity.

Early publications from my graduate work centered on the glutamatergic and GABAergic regulation of A₁₂ dopamine neurons that tonically inhibit prolactin secretion from the anterior pituitary. The seminal findings from this research were that NMDA receptor-mediated excitation of these neurons was sexually differentiated and negatively modulated by estradiol in females. These studies were among the first to recognize the importance of sex differences in, and the activational effects of steroid hormone gonadal steroid hormones on, the regulation of hypothalamic circuitry involved in the control of homeostasis. I served as first author on all of these publications, and executed the vast majority of the experiments by myself.

a. Wagner, E.J., Moore K.E., Lookingland K.J.: Sexual differences in N-methyl-D-aspartate receptor-mediated regulation of tuberoinfundibular dopaminergic neurons in the rat, Brain Research, 611: 139-146, 1993.

b. Wagner, E.J., Moore, K.E., Lookingland, K.J.: Non-NMDA receptor-mediated regulation of hypothalamic dopaminergic neurons in the rat, European Journal of Pharmacology, 254: 105-112, 1994.

c. Wagner, E.J., Goudreau, J.L., Moore, K.E., Lookingland, K.J.: GABAergic regulation of tuberoinfundibular dopaminergic neurons in the male rat. Brain Research, 659: 194-200, 1994.

2. The next phase of my career utilized a more cellular approach to investigate how estradiol rapidly modulates metabotropic, Gprotein-coupled receptors like the GABA_B, µ-opioid, nociceptin opioid receptor (NOP) and α₁-adrenergic receptors from their effector systems like the G protein-gated, inwardly-rectifying K+ channel and small-conductance, Ca2+-activated K+ channel in hypothalamic GABAergic, A₁₂ dopamine, proopiomelanocortin (POMC) and gonadotropin-releasing hormone neurons in females. I also investigated the mechanisms underlying the development of cellular tolerance in these neurons that occurs in response to chronic morphine exposure. These studies provided critical insight into the non-genomic mechanisms by which estradiol modulates neurotransmitter sensitivity in populations of hypothalamic neurons that are vital to the regulation of reproduction and energy homeostasis. Moreover, they also demonstrate how these neuronal populations become tolerant to µ-opioid agonists in the face of prolonged opiate exposure. As above, I was the first author on all of these publications, and performed the vast majority of the experiments by myself.

a. Wagner, E.J., Rønnekleiv, O.K., Grandy, D.K., Kelly, M.J.: The peptide Orphanin FQ inhibits ß-endorphin neurons and neurosecretory cells in the hypothalamic arcuate nucleus by activating an inwardly-rectifying K+ conductance, Neuroendocrinology, 67: 73-82, 1998.

b. Wagner, E.J., Rønnekleiv, O.K., Kelly, M.J.: Protein kinase A maintains cellular tolerance to mu opioid receptor agonists in hypothalamic neurosecretory cells with chronic morphine treatment: convergence on a common pathway with estrogen in modulating mu opioid receptor/effector coupling, Journal of Pharmacology and Experimental Therapeutics, 285: 1266-1273, 1998.

c. Wagner, E.J., Rønnekleiv, O.K., Bosch, M.A., Kelly, M.J.: Estrogen biphasically modifies hypothalamic GABAergic function concomitantly with negative and positive control of luteinizing hormone release, Journal of Neuroscience, 21: 2085-2093, 2001

d. Wagner, E.J., Rønnekleiv, O.K., Kelly, M.J.: The noradrenergic inhibition of an apamin-sensitive, small-conductance Ca2+-activated K+ channel in hypothalamic γ-aminobutyric acidergic neurons: pharmacology, estrogen sensitivity, and relevance to the control of the reproductive axis, Journal of Pharmacology and Experimental Therapeutics, 299: 21-30, 2001

3. More recently, my lab has also uncovered prominent sex differences in, and gonadal steroid hormonal influences on, the cannabinoid CB1 and NOP receptor-mediated regulation of energy balance and reproductive behavior. Using a combination of behavioral, cellular, molecular, optogenetic and chemogenetic approaches, I have demonstrated that cannabinoid-induced hyperphagia is sexually differentiated, diet-sensitive, and due, at least in part, to sexually disparate actions of cannabinoids at steroidogenic factor (SF)-1/POMC synapses. The sex difference is profoundly influenced by the activational effects of gonadal steroid hormones. Estradiol diminishes the cannabinoid-induced hyperphagia, as well as the inhibitory endocannabinoid-mediated signaling at SF-1/POMC synapses. Testosterone and diet-induced obesity enhance these effects in males. These findings demonstrate the need for developing rational, gender-based therapies for the treatment of HIV/AIDS- and cancer-related cachexia, as well as obesity and reproductive dysfunction. I was the principal investigator in all of these studies.

a. Diaz, S., Farhang, B., Hoien, J., Stahlman, M., Adatia, N., Cox, J.M., Wagner, E.J.: Sex differences in the cannabinoid modulation of appetite, body temperature and neurotransmission at POMC synapses. Neuroendocrinology, 89: 424-440, 2009

b. Farhang, B., Pietruszewski, L., Lutfy, K., Wagner, E.J.: The role of the NOP receptor in regulating food intake, meal pattern, and excitability of proopiomelanocortin neurons. Neuropharmacology, 59: 190-200, 2010

c. Borgquist, A., Meza, C., Wagner, E.J.: The role of neuronal nitric oxide synthase in the estrogenic attenuation of cannabinoid-induced changes in energy homeostasis. The Journal of Neurophysiology, 113: 904-914, 2015.

d. Conde, K., Fabelo, C., Krause, W.C., Propst, R., Goethel, J., Fischer D., Hur, J., Meza, C., Ingraham, H.A., Wagner, E.J.: Testosterone rapidly augments retrograde endocannabinoid signaling in proopiomelanocortin neurons to suppress glutamatergic input from steroidogenic factor 1 neurons via upregulation of diacylglycerol lipase-α. Neuroendocrinology, 105: 341-356, 2017.

e. Fabelo, C., Hernandez, J., Chang, R., Seng, S., Alicea, N., Tian, S., Conde, K., Wagner, E.J.: Endocannabinoid signaling at steroidogenic factor-1/proopiomelanocortin synapses is sex- and diet-specific. Frontiers in Molecular Neuroscience, 11, doi: 10.3389/fnmol.2018.00214, 2018.

D. Additional Information: Research Support and/or Scholastic Performance

CURRENT

1) 2R15 DA024314-03 (Wagner) 4/1/17 – 2/29/20

• Sex Differences in the Cannabinoid Regulation of Energy Homeostasis
• NIDA

The major goals of this project are to continue our work resolving how gonadal steroids and diet shape endocannabinoid tone and retrograde signaling at VMN SF-1/ARC POMC synapses in the regulation of energy homeostasis.

• R15 AREA Grant (R15 DA024314), National Institute on Drug Abuse, 08/08 – 04/2020
• R01 Grant (Co-PI Wagner), National Institute on Child Health and Development, 06/09 – 05/16
• Research Scientist Career Development Award (K01 DA00521), National Institute on Drug Abuse, 09/00 - 08/03

Awards and Other Experience (Past 10 years)

2008 Neuroscience State-of-the-Art Speaker, Western Medical Student Research Forum, Carmel, CA

2008 Invited Seminar Speaker, Cal State Long Beach, Dept. of Biology

2008 Invited Seminar Speaker, Pfizer Corp., Div. of Obesity

2009 Symposium Organizer and Speaker, 5th International Congress on Steroids and the Nervous System, Torino, IT

2009 Invited symposium speaker, Spring Workshop on Steroid Hormones and Brain Function, Breckenridge, CO

2010 Invited seminar speaker: Texas A&M Health Science Center, Dept. of Pharmaceutical Sciences

2010 Invited seminar speaker: Oklahoma State University Health Sciences Center, Dept. of Biomedical Sciences

2010 Meeting organizer and speaker, 54th Annual Research Meeting for the American Osteopathic Association, San Francisco, CA

2011 Symposium Organizer and Speaker, 44th Annual Winter Conference on Brain Research, Keystone, CO

2011 Symposium Organizer and Speaker, 5th Annual Meeting of the Organization for the Study of Sex Differences, Oklahoma City, OK

2012 Symposium Organizer and Speaker, 45th Annual Winter Conference on Brain Research, Snowbird, UT

2013 Invited speaker, 46th Annual Winter Conference on Brain Research, Breckenridge, CO

2014 Invited symposium speaker, 44th Annual Meeting of the International Society of Psychoneuroendocrinology, Montreal, Canada

2014 Meeting organizer and speaker, 58th Annual Research Meeting for the American Osteopathic Association, Seattle, WA

2015 Symposium Organizer and Speaker, 8th International Congress on Steroids and the Nervous System, Torino, IT

2015 Distinguished Faculty Award for Research and Scholarship in the College of Osteopathic Medicine

2016 Invited seminar speaker, University of North Texas Health Science Center, Institute for Cardiovascular and Metabolic Diseases

2017 Invited symposium speaker, 1st Annual International Multidisciplinary Cannabis Research Conference, Pueblo, CO (4/17)

2017 Invited seminar speaker, University of California, Riverside, Neuroscience Program

2018 Provost’s Distinguished Scholar Award for Western University of Health Sciences

Society Memberships

1991 – present Society for Neuroscience

2010 – present Organization for the Study of Sex Differences

Recent Publications:

• Le, N., Hernandez, J., Gastelum, C., Perez, L., Vahrson, I., Sayers, S., Wagner, E.J.: Pituitary Adenylate Cyclase Activating Polypeptide Inhibits A10 Dopamine Neurons and Suppresses the Binge-like Consumption of Palatable Food. Neuroscience, 478: 49-64, 2021.
• Gastelum, C., Perez, L., Hernandez, J., Le, N., Vahrson, I., Sayers, S., Wagner, E.J.: Adaptive Changes in the Central Control of Energy Homeostasis Occur in Response to Variations in Energy Status. International Journal of Molecular Sciences, 22, doi: 10.3390/ijms22052728
• Hernandez, J., Perez, L., Soto, R., Le, N., Gastelum, C., Wagner, E.J.: Nociceptin/orphanin FQ neurons in the Arcuate Nucleus and Ventral Tegmental Area Act via Nociceptin Opioid Peptide Receptor Signaling to Inhibit Proopiomelanocortin and A10 Dopamine Neurons and Thereby Modulate Ingestion of Palatable Food. Physiology and Behavior, 228, doi: 10.1016/j.physbeh.2020.113183, 2021.
• Chang, R., Hernandez, J., Gastelum, C., Guadagno, K., Perez, L., Wagner, E.J.: Pituitary adenylate cyclase activating polypeptide excites proopiomelanocortin neurons: implications for the regulation of energy homeostasis. Neuroendocrinology, 111(1-2): 45-69, doi: 10.1159/000506367, 2021
• Hernandez, J., Fabelo, C., Perez, L., Moore, C., Chang, R., Wagner, E.J.: Nociceptin/orphanin FQ modulates energy homeostasis through inhibition of neurotransmission at VMN SF-1/ARC POMC synapses in a sex- and diet-dependent manner. Biology of Sex Differences, 10: doi.org/10.1186/s13293-019-0220-3
• Fabelo, C., Hernandez, J., Chang, R., Seng, S., Alicea, N., Tian, S., Conde, K., Wagner, E.J.: Endocannabinoid signaling at steroidogenic factor-1/proopiomelanocortin synapses is sex- and diet-specific. Frontiers in Molecular Neuroscience, 11, doi: 10.3389/fnmol.2018.00214

Dr. Wagner received his Bachelor of Science degree in Psychobiology from The University of California, Los Angeles in 1986. He then earned a dual Ph.D. degree in Pharmacology and Neuroscience from Michigan State University in 1994. He did his post-doctoral training with Dr. Martin Kelly in the Department of Physiology and Pharmacology at Oregon Health and Science University, where he also landed his first faculty appointment in 1998. Dr. Wagner joined The College of Osteopathic Medicine of the Pacific at Western University of Health Sciences in 2001, and now holds the rank of Professor. His 32 years of graduate and post-graduate experience provide him with the expertise to strategically incorporate principles of neuroendocrinology, neurophysiology, pharmacology and behavior into his current research interests, which center on the synaptic and hormonal determinants underlying the central control of energy balance. He is currently funded by the National Institutes of Health to specifically study sex differences in, as well as hormonal and dietary influences on, the regulation of appetitive behavior and neurotransmission occurring within the homeostatic and hedonic energy balance circuitries in the brain. He uses state of the art in vivo and in vitro optogenetic and chemogenetic experimental approaches, along with cre-lox and AAV technology, to accomplish his experimental objectives. Dr. Wagner has 57 publications in peer-reviewed journals to his credit, many of which have been cited numerous times in the scientific and biomedical literature. He has also served as a mentor to numerous osteopathic medical student research fellows, undergraduate and graduate students in the Master of Science in Biomedical Sciences Program at Western University. His students have won sub-specialty awards for their presentations at the Western Student Medical Research Forum conducted annually in Carmel, CA. Accordingly, he was issued the Distinguished Faculty Award for Research and Scholarship in the College of Osteopathic Medicine at Western University of Health Sciences in 2015, and the Provost’s Distinguished Scholar Award for Western University in 2018.