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Malcolm Low received his Ph.D. in Neuroscience from Tufts University in 1987. He earned his B.S. from Rensselaer Polytechnic Institute and his M.D. from Albany Medical College. He did an internship and residency at Michael Reese Hospital in Chicago and then spent three years as a clinical and research fellow in Neuroendocrinology at the New England Medical Center. From 1985 to 1989, Low held concurrent positions on the faculty at Tufts and as a physician at the Medical Center. He came to the Vollum Institute in 1990 and was promoted to scientist in 1994. He holds a joint appointment as professor in the Department of Behavioral Neuroscience in the School of Medicine and is a founding member of the newly created Center for the Study of Weight Regulation and Associated Disorders at OHSU. Research InterestsThe hypothalamus is a compact area in the center of the brain with widespread and reciprocal connections to other brain regions. Hypothalamic nuclei integrate a variety of neural, hormonal, and metabolic signals to regulate pituitary hormone secretion, homeostasis, autonomic function, and behaviors related to the basic drives for food, water, and reproduction. The Low lab focuses on the hypothalamic neurons that regulate the growth of pituitary cells and hormone secretion from the pituitary gland. In addition, they are studying neuropeptide circuits within the brain that coordinate the neuroendocrine functions of the hypothalamus with emotional responses, conditioned learning, locomotor activity, and brainstem reflexes. Some of these circuits, in particular those using dopamine and the endogenous opioid peptides b-endorphin and enkephalin as neurotransmitters, are usurped by drugs of abuse as the neural substrate mediating their rewarding activity. A longstanding project, conducted in collaboration with Marcelo Rubinstein of the University of Buenos Aires, Argentina, is to characterize the molecular mechanism responsible for restricting proopiomelanocortin (POMC) gene expression to a few thousand neurons in the hypothalamus and brainstem. These neurons produce both β-endorphin and melanocortin peptides from POMC and play a critical role in regulating appetite and feeding. Recently, a neural-specific enhancer region of the POMC gene has been identified and used to direct expression of a green fluorescent protein marker to POMC neurons in transgenic mice. The fluorescently-tagged neurons are being used to study electrophysiological and gene expression profiles that are unique to this group of cells. Recent studies have shown for the first time that a subpopulation of POMC neurons projecting to limbic forebrain areas utilize the inhibitory signaling molecule GABA as a co-transmitter. Other experiments are using mutant mice with partial or complete deletions of the POMC gene to further characterize the physiological role of POMC in stress and the regulation of appetitive and consumatory behaviors. Knockout mice deficient in the hypothalamic neuropeptide somatostatin have also been generated. These mice demonstrate the involvement of somatostatin in the sexually dimorphic regulation of pituitary growth hormone and ACTH secretion. Low and his colleagues are also using several strains of dopamine receptor-deficient mice to tease apart the relative function of each receptor subtype in neuroendocrine and limbic functions. For example, the D2 dopamine receptor tonically inhibits pituitary lactotrophs. In the absence of this receptor, female mice uniformly develop massive pituitary tumors composed of hyperplastic, prolactin-secreting cells. Male D2R-deficient mice are dwarfed because of inadequate pituitary growth hormone secretion before puberty. This appears to be due to an action of dopamine within the hypothalamus to regulate the activity of growth hormone releasing hormone neurons. Selected PublicationsHentges, S.A., Nishiyama, M., Overstreet, L.S., Stenzel-Poore, M., Williams, J.T., and Low, M.J. (2004) GABA release from proopiomelanocortin neurons. J. Neurosci. 24:1578-1583. Appleyard, S.M., Hayward, M.D., Young, J.I., Butler, A.A., Cone, R.D., Rubinstein, M., and Low, M.J. (2003) A role for the endogenous opioid β-endorphin in energy homeostasis. Endocrinology 144:1753-1760. Schuff, K.G., Hentges, S.T., Kelly, M.A., Binart, N., Kelly, P.A., Iuvone, P.M., Asa, S.L., and Low, M.J. (2002) Lack of prolactin receptor signaling in mice results in lactotroph proliferation and prolactinomas by dopamine-dependent and independent mechanisms. J. Clin. Invest. 110:973-981. Hayward, M.D., Pintar, J., and Low, M.J. (2002) Selective reward deficit in mice lacking β-endorphin and enkephalin. J. Neurosci. 22:8251-8258. Low, M.J., Otero-Corchon, V., Parlow, A.F., Ramirez, J.L., Kumar, U., Patel, Y.C., and Rubinstein, M. (2001) Somatostatin is required for the masculinization of growth hormone-regulated hepatic gene expression but not of somatic growth. J. Clin. Invest. 107:1571-1580. Cowley, M.A., Smart, J.L., Rubinstein, M., Cerdán, M.G., Diano, S., Horvath, T.L., Cone, R.D., and Low, M.J. (2001) Leptin activates anorexigenic POMC neurons through a neural network in arcuate nucleus. Nature 411:480-484.
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