Malcolm J. Low
Senior Scientist and Associate Director, Center for the Study of Weight Regulation, Oregon Health & Science University
Scientist, Vollum Institute, Oregon Health & Science University
Professor, Behavioral Neuroscience, Oregon Health & Science University
email: low@ohsu.edu
Major Areas
Regulation and function of hypothalamic/pituitary neuropeptides; forebrain circuits regulating stress, motivation, and ingestive behaviors; transgenic/KO mice.
Previous Positions
Intern and Resident, Michael Reese Hospital, Chicago
Clinical and Research fellow in Neuroendocrinology, New England Medical Center, Boston
Assistant Professor of Medicine, New England Medical Center, Boston
Education
B.S. (1979) Rensselaer Polytechnic Institute (combined BS/MD Biomedical Program)
M.D. (1979) Albany Medical College
Ph.D. (1987) Tufts University
Research Interests
Malcolm Low and his associates use a combination of molecular genetic, endocrine, and behavioral approaches to characterize the physiological functions of neuropeptides and G-protein coupled receptors that are highly expressed in the hypothalamus. Proopiomelanocortin (POMC) is expressed in the pituitary in addition to hypothalamus and is enzymatically processed into several peptides involved in the stress response and ingestive behaviors. These hormones include ß-endorphin, one of the brain's intrinsic opiate-like compounds, melanocortins, and ACTH, which stimulates the adrenal glands to secrete cortisol. The central melanocortins mediate feeding and homeostasis. Somatostatin modulates pituitary function and is highly expressed in brain areas that are important for learning and memory. Dopamine and its receptors are involved in locomotor function, motivation, reward-oriented behaviors and modulation of pituitary function.
Many of the studies use strains of mice with induced genetic mutations that were generated in the lab. Transgenic mice are produced by microinjection of cloned genes into fertilized mouse eggs. This approach allows study of the molecular events involved in gene regulation under normal physiological conditions. We have identified specific gene regulatory elements, produced novel pituitary cell lines from pituitary tumors induced in transgenic mice, and studied the physiological function of neuroendocrine cells by a cell ablation technique.
A second type of mutation involves homologous recombination in totipotential mouse embryonic stem cells. This method allows the researchers to delete (knockout), modify, or replace intrinsic genes in mice. For example, mice that lack POMC-derived ß-endorphin have been generated and these mice do not show opiate stress-induced analgesia, confirming a fundamental neurophysiological function for this peptide hormone. Other mice have been produced that are deficient in the D2 and D4 forms of dopamine receptors. These mice exhibit specific alterations in locomotor activity and have a dysregulation in pituitary hormones that are normally inhibited by dopamine. We have found that D2 receptor-deficient mice eventually develop large pituitary tumors that model prolactinomas, the most common spontaneously occurring pituitary adenoma in humans. Other recent studies have demonstrated an essential role for somatostatin in the expression of sexual dimorphism of neuroendocrine secretory rhythms and have implicated ß-endorphin as the endogenous opioid peptide predominantly responsible for the mediation of reward to food reinforcement in operant conditioning paradigms. We are currently working to extend these types of studies to include conditionally targeted gene mutations that will permit both temporal and spatial control over gene expression.
Selected Recent Publications
Smart JL, Tolle V, and Low MJ (in press) Glucocorticoids exacerbate obesity and insulin resistance in neuronal-specific proopiomelanocortin deficient mice. Journal of Clinical Investigation Feb 116(2).
Hentges ST, Low MJ, Williams JT (2005) Differential regulation of synaptic inputs by constitutively released endocannabinoids and exogenous cannibinoids in the hypothalamus. J Neuroscience. 25:9746-9751.
Hayward MD, Low MJ (2005) Naloxone's suppression of spontaneous and food conditioned locomotor activity is diminished in mice lacking either the dopamine D2 receptor or enkephalin. Brain Research Molecular Brain Research. 140:91-98.
Appleyard SM, Bailey TW, Doyle MW, Jin Y-H, Smart JL, Low MJ, Andresen MC (2005) Proopiomelanocortin neurons in nucleus tractus solitarius are activated by visceral afferents and modulated by cholecystokinin and opioids. J Neuroscience. 25:3578-3585.
deSouza FSJ, Santangelo AM, Bumaschny V, Avale ME, Smart JL, Low MJ, Rubenstein M (2005) Identification of neuronal enhancers of the proopiomelanocortin genes by transgenic mouse analysis and phylogenetic footprinting. Molecular and Cellular Biology. 25:3076-3086.
Tolle V, Low MJ (2004) Genes, environment, neuroendocrine circuits, and energy balance. Drug Discovery Today: Disease Models. 1(3):365-372.
Hayward MD, Hansen ST, Pintar JE, Low MJ (2004) Operant self-administration of ethanol in C57BL/6 mice lacking beta-endorphin and enkephalin. Pharmacol Biochem Behav. Sep;79(1):171-81.
Overstreet LS, Hentges ST, Bumaschny VF, de Souza FS, Smart JL, Santangelo AM, Low MJ, Westbrook GL, Rubinstein M (2004) A transgenic marker for newly born granule cells in dentate gyrus. J Neuroscience. Mar 31;24(13):3251-9.
Hentges SA, Nishiyama M, Overstreet LS, Stenzel-Poore M, Williams JT, Low MJ (2004) GABA release from proopiomelanocortin neurons. J Neuroscience. 24:1578-1583.
Appleyard SM, Hayward MD, Young JI, Butler AA, Cone RD, Rubinstein M, Low MJ (2003) A role for the endogenous opioid ß-endorphin in energy homeostasis. Endocrinology. 144:1753-1760.