Malcolm J Low

Concordia University–Ann Arbor, Ann Arbor, Michigan, United States

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Publications (189)1296.64 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Peptides derived from the pro-opiomelanocortin (POMC) precursor are critical for normal regulation of many physiological parameters, and POMC deficiency results in severe obesity and metabolic dysfunction. Conversely, augmentation of CNS melanocortin function is a promising therapeutic avenue for obesity and diabetes, but is confounded by detrimental cardiovascular effects including hypertension. Since the hypothalamic population of POMC-expressing neurons is neurochemically and neuroanatomically heterogeneous, there is interest in the possible dissociation of functionally distinct POMC neuron subpopulations. We utilized a Cre recombinase-dependent and hypothalamus-specific reactivatable Pomc(NEO) allele to restrict Pomc expression to hypothalamic neurons expressing leptin receptor (Lepr) in mice. In contrast to mice with total hypothalamic Pomc deficiency, which are severely obese, mice with Lepr-restricted Pomc expression displayed fully normal body weight, food consumption, glucose homeostasis, and locomotor activity. Thus, Lepr(+) Pomc neurons, which constitute approximately two-thirds of the total Pomc neuron population, are sufficient for normal regulation of these parameters. This functional dissociation approach represents a promising avenue for isolating therapeutically relevant Pomc neuron subpopulations.
    Endocrinology 01/2015; · 4.72 Impact Factor
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    ABSTRACT: Distinct male and female patterns of pituitary GH secretion produce sexually differentiated hepatic gene expression profiles, thereby influencing steroid and xenobiotic metabolism. We used a fully automated system to obtain serial nocturnal blood samples every 15 minutes from cannulated wildtype and somatostatin (Sst)-KO mice to determine the role of SST, the principal inhibitor of GH release, in the generation of sexually dimorphic GH pulsatility. Wildtype males had lower mean and median GH values, less random GH secretory bursts and longer trough periods between GH pulses than wildtype females. Each of these parameters was feminized in male Sst-KO mice, whereas female Sst-KO mice had higher GH levels than all other groups but GH pulsatility was unaffected. We next performed hepatic mRNA profiling with high-density microarrays. Male Sst-KO mice exhibited a globally feminized pattern of GH-dependent mRNA levels, but female Sst-KO mice were largely unaffected. Among the differentially expressed female-predominant genes was Serpina6, which encodes corticosteroid-binding globulin (CBG). Increased CBG was associated with elevated diurnal peak plasma corticosterone in unstressed wildtype females and both sexes of Sst-KO mice compared to wildtype males. Sst-KO mice also had exaggerated ACTH and corticosterone responses to acute restraint stress. However, consistent with their lack of phenotypic signs of excess glucocorticoids, cerebrospinal fluid concentrations of free corticosterone in Sst-KO mice were not elevated. In summary, SST is necessary for the prolonged interpulse troughs that define masculinized pituitary GH secretion. SST also contributes to sexual dimorphism of the HPA axis via GH-dependent regulation of hepatic CBG production.
    Endocrinology 12/2014; · 4.72 Impact Factor
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    ABSTRACT: The phenomenon commonly described as "the middle-age spread" is the result of elevated adiposity accumulation throughout adulthood until late middle-age. It is a clinical imperative to gain a greater understanding of the underpinnings of age-dependent obesity and in turn, how these mechanisms may impact the efficacy of obesity treatments. In particular, both obesity and aging are associated with rewiring of a principal brain pathway modulating energy homeostasis, promoting reduced activity of satiety melanocortin pro-opiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus (ARC). Utilizing a selective ARC deficient POMC mouse line, here we report that former obesity medications augmenting endogenous 5-hydroxytryptamine (5-HT) activity d-fenfluramine and sibutramine require ARC POMC neurons to elicit therapeutic appetite suppressive effects. We next investigated whether age-related diminished ARC POMC activity therefore impacts the potency of 5-HT obesity pharmacotherapies, lorcaserin, d-fenfluramine and sibutramine and report that all compounds reduced food intake to a comparable extent in both chow fed young lean (3-5 months old) and middle-aged obese (12-14 months old) male and female mice. We provide a mechanism through which 5-HT anorectic potency is maintained with age, via preserved 5-HT-POMC appetitive anatomical machinery. Specifically, the abundance and signalling of the primary 5-HT receptor influencing appetite via POMC activation, the 5-HT2CR, is not perturbed with age. These data reveal that though 5-HT obesity medications require ARC POMC neurons to achieve appetitive effects, the anorectic efficacy is maintained with aging; findings of clinical significance to the global aging obese population.
    Endocrinology 07/2014; · 4.72 Impact Factor
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    ABSTRACT: Hypothalamic proopiomelanocortin (POMC) neurons constitute a critical anorexigenic node in the CNS for maintaining energy balance. These neurons directly affect energy expenditure and feeding behavior by releasing bioactive neuropeptides, but are also subject to signals directly related to nutritional state such as the adipokine leptin. To further investigate the interaction of diet and leptin on hypothalamic POMC peptide levels, we exposed 8-10 wk old male POMC-DsRed transgenic reporter mice to either 24-48 h (acute) or 2 wk (chronic) food restriction, high-fat diet (HFD) or leptin treatment. Using semiquantitative immunofluorescence and radioimmunoassays, we discovered that acute fasting and chronic food-restriction decreased the levels of ACTH, α-MSH and β-endorphin in the hypothalamus, together with decreased DsRed fluorescence, compared to control ad libitum fed mice. Furthermore, acute but not chronic HFD or leptin administration selectively increased α-MSH levels in POMC fibers and increased DsRed fluorescence in POMC cell bodies. HFD and leptin treatments comparably increased circulating leptin levels at both time points, suggesting that transcription of Pomc and synthesis of POMC peptide products are not modified in direct relation to the concentration of plasma leptin. Our findings indicate that negative energy balance persistently downregulated POMC peptide levels, and this phenomenon may be partially explained by decreased leptin levels, as these changes were blocked in fasted mice treated with leptin. In contrast, sustained elevation of plasma leptin by HFD or hormone supplementation did not significantly alter POMC peptide levels, indicating that enhanced leptin signaling does not chronically increase Pomc transcription and peptide synthesis.
    AJP Endocrinology and Metabolism 02/2014; · 4.51 Impact Factor
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    ABSTRACT: Competition between adult males for limited resources such as food and receptive females is shaped by the male pattern of pituitary growth hormone (GH) secretion that determines body size and the production of urinary pheromones involved in male-to-male aggression. In the brain, dopamine (DA) provides incentive salience to stimuli that predict the availability of food and sexual partners. Although the importance of the GH axis and central DA neurotransmission in social dominance and fitness is clearly appreciated, the two systems have always been studied unconnectedly. Here we conducted a cell-specific genetic dissection study in conditional mutant mice that selectively lack DA D2 receptors (D2R) from pituitary lactotropes (lacDrd2KO) or neurons (neuroDrd2KO). Whereas lacDrd2KO mice developed a normal GH axis, neuroDrd2KO mice displayed fewer somatotropes; reduced hypothalamic Ghrh expression, pituitary GH content, and serum IGF-I levels; and exhibited reduced body size and weight. As a consequence of a GH axis deficit, neuroDrd2KO adult males excreted low levels of major urinary proteins and their urine failed to promote aggression and territorial behavior in control male challengers, in contrast to the urine taken from control adult males. These findings reveal that central D2Rs mediate a neuroendocrine-exocrine cascade that controls the maturation of the GH axis and downstream signals that are critical for fitness, social dominance, and competition between adult males.
    Journal of Neuroscience 03/2013; 33(13):5834-5842. · 6.75 Impact Factor
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    ABSTRACT: Central proopiomelanocortin (POMC) neurons form a potent anorexigenic network, but our understanding of the integration of this hypothalamic circuit throughout the central nervous system (CNS) remains incomplete. POMC neurons extend projections along the rostrocaudal axis of the brain, and can signal with both POMC-derived peptides and fast amino acid neurotransmitters. Although recent experimental advances in circuit-level manipulation have been applied to POMC neurons, many pivotal questions still remain: how and where do POMC neurons integrate metabolic information? Under what conditions do POMC neurons release bioactive molecules throughout the CNS? Are GABA and glutamate or neuropeptides released from POMC neurons more crucial for modulating feeding and metabolism? Resolving the exact stoichiometry of signals evoked from POMC neurons under different metabolic conditions therefore remains an ongoing endeavor. In this review, we analyze the anatomical atlas of this network juxtaposed to the physiological signaling of POMC neurons both in vitro and in vivo. We also consider novel genetic tools to further characterize the function of the POMC circuit in vivo. Our goal is to synthesize a global view of the POMC network, and to highlight gaps that require further research to expand our knowledge on how these neurons modulate energy balance.
    Frontiers in Neuroscience 01/2013; 7:19.
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    ABSTRACT: Mutations in regulatory regions including enhancers are an important source of variation and innovation during evolution. Enhancers can evolve by changes in the sequence, arrangement and repertoire of transcription factor binding sites, but whole enhancers can also be lost or gained in certain lineages in a process of turnover. The proopiomelanocortin gene (Pomc), which encodes a prohormone, is expressed in the pituitary and hypothalamus of all jawed vertebrates. We have previously described that hypothalamic Pomc expression in mammals is controlled by two enhancers-nPE1 and nPE2-that are derived from transposable elements and that presumably replaced the ancestral neuronal Pomc regulatory regions. Here, we show that nPE1 and nPE2, even though they are mammalian novelties with no homologous counterpart in other vertebrates, nevertheless can drive gene expression specifically to POMC neurons in the hypothalamus of larval and adult transgenic zebrafish. This indicates that when neuronal Pomc enhancers originated de novo during early mammalian evolution, the newly created cis- and trans-codes were similar to the ancestral ones. We also identify the neuronal regulatory region of zebrafish pomca and confirm that it is not homologous to the mammalian enhancers. Our work sheds light on the process of gene regulatory evolution by showing how a locus can undergo enhancer turnover and nevertheless maintain the ancestral transcriptional output.
    Philosophical Transactions of The Royal Society B Biological Sciences 01/2013; 368(1632):20130027. · 6.23 Impact Factor
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    ABSTRACT: Obesity is a chronic metabolic disorder affecting half a billion people worldwide. Major difficulties in managing obesity are the cessation of continued weight loss in patients after an initial period of responsiveness and rebound to pretreatment weight. It is conceivable that chronic weight gain unrelated to physiological needs induces an allostatic regulatory state that defends a supranormal adipose mass despite its maladaptive consequences. To challenge this hypothesis, we generated a reversible genetic mouse model of early-onset hyperphagia and severe obesity by selectively blocking the expression of the proopiomelanocortin gene (Pomc) in hypothalamic neurons. Eutopic reactivation of central POMC transmission at different stages of overweight progression normalized or greatly reduced food intake in these obesity-programmed mice. Hypothalamic Pomc rescue also attenuated comorbidities such as hyperglycemia, hyperinsulinemia, and hepatic steatosis and normalized locomotor activity. However, effectiveness of treatment to normalize body weight and adiposity declined progressively as the level of obesity at the time of Pomc induction increased. Thus, our study using a novel reversible monogenic obesity model reveals the critical importance of early intervention for the prevention of subsequent allostatic overload that auto-perpetuates obesity.
    The Journal of clinical investigation 10/2012; · 15.39 Impact Factor
  • Malcolm J Low
    Gastroenterology 10/2012; · 12.82 Impact Factor
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    ABSTRACT: The proopiomelanocortin (Pomc) gene encodes a prepropeptide with essential functions in the response to stress and energy balance, which is expressed in the pituitary and hypothalamus of vertebrate animals. Neuronal expression of Pomc is controlled by two distal enhancers named nPE1 and nPE2. Using transgenic mice, we observed that both enhancers drive identical expression patterns in the mammalian hypothalamus, starting at embryonic day 10.5, when endogenous Pomc expression commences. This overlapping enhancer activity is maintained throughout hypothalamic development and into adulthood. We also found that nPE1 and nPE2 were exapted as neuronal enhancers into the POMC locus after the sequential insertion of two unrelated retroposons. Thus, nPE1 and nPE2 are functional analogs and represent an authentic first example of convergent molecular evolution of cell-specific transcriptional enhancers. In this Commentary we discuss the following questions that remain unanswered: (1) how does transcriptional control of POMC operate in hypothalamic neurons of non-mammalian vertebrates? (2) What evolutionary forces are maintaining two discrete neuronal POMC enhancers under purifying selection for the last ~100 million years in all placental mammals? (3) What is the contribution of MaLRs to genome evolution?
    Mobile genetic elements. 03/2012; 2(2):106-109.
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    ABSTRACT: The proopiomelanocortin gene (POMC) is expressed in a group of neurons present in the arcuate nucleus of the hypothalamus. Neuron-specific POMC expression in mammals is conveyed by two distal enhancers, named nPE1 and nPE2. Previous transgenic mouse studies showed that nPE1 and nPE2 independently drive reporter gene expression to POMC neurons. Here, we investigated the evolutionary mechanisms that shaped not one but two neuron-specific POMC enhancers and tested whether nPE1 and nPE2 drive identical or complementary spatiotemporal expression patterns. Sequence comparison among representative genomes of most vertebrate classes and mammalian orders showed that nPE1 is a placental novelty. Using in silico paleogenomics we found that nPE1 originated from the exaptation of a mammalian-apparent LTR retrotransposon sometime between the metatherian/eutherian split (147 Mya) and the placental mammal radiation (≈ 90 Mya). Thus, the evolutionary origin of nPE1 differs, in kind and time, from that previously demonstrated for nPE2, which was exapted from a CORE-short interspersed nucleotide element (SINE) retroposon before the origin of prototherians, 166 Mya. Transgenic mice expressing the fluorescent markers tomato and EGFP driven by nPE1 or nPE2, respectively, demonstrated coexpression of both reporter genes along the entire arcuate nucleus. The onset of reporter gene expression guided by nPE1 and nPE2 was also identical and coincidental with the onset of Pomc expression in the presumptive mouse diencephalon. Thus, the independent exaptation of two unrelated retroposons into functional analogs regulating neuronal POMC expression constitutes an authentic example of convergent molecular evolution of cell-specific enhancers.
    Proceedings of the National Academy of Sciences 08/2011; 108(37):15270-5. · 9.81 Impact Factor
  • Marcelo Rubinstein, Malcolm J Low
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    ABSTRACT: Hypothalamic pro-opiomelanocortin (POMC) neurons are the major source of anorectic melanocortin peptides in the brain. A recent study (Mineur et al., 2011) demonstrates that nicotine directly stimulates arcuate POMC neurons through nicotinic acetylcholinergic α3β4 receptors, suggesting a new mechanism to understand the inverse relationship between tobacco smoking and body weight.
    Cell metabolism 08/2011; 14(2):145-7. · 17.35 Impact Factor
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    ABSTRACT: Dopamine (DA) D2 receptors expressed in DA neurons (D2 autoreceptors) exert a negative feedback regulation that reduces DA neuron firing, DA synthesis and DA release. As D2 receptors are mostly expressed in postsynaptic neurons, pharmacological and genetic approaches have been unable to definitively address the in vivo contribution of D2 autoreceptors to DA-mediated behaviors. We found that midbrain DA neurons from mice deficient in D2 autoreceptors (Drd2(loxP/loxP); Dat(+/IRES-cre), referred to as autoDrd2KO mice) lacked DA-mediated somatodendritic synaptic responses and inhibition of DA release. AutoDrd2KO mice displayed elevated DA synthesis and release, hyperlocomotion and supersensitivity to the psychomotor effects of cocaine. The mice also exhibited increased place preference for cocaine and enhanced motivation for food reward. Our results highlight the importance of D2 autoreceptors in the regulation of DA neurotransmission and demonstrate that D2 autoreceptors are important for normal motor function, food-seeking behavior, and sensitivity to the locomotor and rewarding properties of cocaine.
    Nature Neuroscience 07/2011; 14(8):1033-8. · 14.98 Impact Factor
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    ABSTRACT: The central melanocortin system, consisting of melanocortin peptides, agouti gene related peptide and their receptors plays a critical role in the homeostatic control of energy balance. Loss of function mutations in the genes encoding proopiomelanocortin or melanocortin MC(4) receptors cause profound obesity and hyperphagia. However, little is known about the functional relationship of melanocortin neurocircuits to the temporal organization of meal-taking behavior. We used an operant paradigm that combined lever pressing for food pellet deliveries with free water intake monitored by lickometers to quantify meal patterns in mutant mice that selectively lack proopiomelanocortin expression in hypothalamic neurons (nPOMCKO). Compared to wildtype siblings, nPOMCKO mice consumed 50% more food and water daily and exhibited a more stereotyped feeding pattern characterized by reduced inter-meal and inter-mouse variations. Average meals were larger in size but shorter in duration, with no change in meal number. Consequently, intermeal intervals were prolonged in nPOMCKO mice. Similar patterns were observed in pre-obese juvenile and frankly obese adult mice suggesting that neither age nor degree of obesity was responsible for the altered phenotypes. Spontaneous locomotion and wheel running were decreased in nPOMCKO mice, but circadian variations in locomotor and feeding activity were conserved. These data show that hyperphagia in male nPOMCKO mice is due to increased meal size but not meal number, and this pattern is established by age of 5weeks. The combination of larger, more rapidly consumed meals and prolonged intermeal intervals suggests that proopiomelanocortin peptides are necessary for normal meal termination, but not the maintenance of satiety.
    European journal of pharmacology 06/2011; 660(1):131-8. · 2.59 Impact Factor
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    ABSTRACT: The gene encoding the prohormone proopiomelanocortin (POMC) is mainly expressed in two regions in vertebrates, namely corticotrophs and melanotrophs in the pituitary and a small population of neurons in the arcuate nucleus of the hypothalamus. In this latter region, POMC-derived peptides participate in the control of energy balance and sensitivity to pain. Neuronal expression of POMC is conferred by two enhancers, nPE1 and nPE2, which are conserved in most mammals, but no transcription factors are yet known to bind to these enhancers. In this work, by means of a one-hybrid screening, we identify that nPE2 possesses an element recognized by transcription factors of the nuclear receptor superfamily. This element, named NRBE, is conserved in all known nPE2 enhancers and is necessary to confer full enhancer strength to nPE2-driven reporter gene expression in transgenic mice assays, indicating that the phylogenetic conservation of the element is indicative of its functional importance. In a search for candidate nuclear receptors that might control POMC we observed that estrogen receptor alpha (ESR1) - a known regulator of energy balance at the hypothalamic level - can bind to the NRBE element in vitro. In addition we observed by immunofluorescence that ESR1 is coexpressed with POMC in around 25-30% of hypothalamic neurons of males and females during late embryonic stages and adulthood. Thus, our results indicate that hypothalamic expression of POMC is controlled by nuclear receptors and establish ESR1 as a candidate regulator of POMC.
    European journal of pharmacology 06/2011; 660(1):181-7. · 2.59 Impact Factor
  • Malcolm J Low
    Endocrinology 05/2011; 152(5):1731-3. · 4.72 Impact Factor
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    ABSTRACT: Arachidonic acid (AA) is generated in the anterior pituitary gland upon stimulation by the ACTH secretagogue, CRH. Using the patch clamp technique, we examined the action of AA on the excitability of single pituitary corticotropes obtained from a transgenic mouse strain that expresses the enhanced green fluorescent protein driven by the proopiomelanocortin promoter. CRH evoked depolarization, but AA caused hyperpolarization. Under voltage clamp condition, AA caused a rapid inhibition of the delayed rectifier K(+) current and then increased a background K(+) current. Inhibition of AA metabolism did not prevent the activation of the K(+) current by AA, suggesting a direct action of AA. The sensitivity of the AA-activated K(+) current to fluoxetine, chlorpromazine, extracellular acidification, diphenylbutylpiperidine antipsychotics, and the membrane permeable cAMP analog [8-(4-chlorophenylthio)-cAMP] suggest that the current is mediated via TWIK-related K(+) channel (TREK)-1 channels. Activation of the CRH receptors that are coupled to the adenylate cyclase pathway suppressed the activation of TREK-1 current by AA and reversed the AA-mediated hyperpolarization. Intracellular acidification (pH 7.0) increased the basal amplitude of TREK-1 current and resulted in hyperpolarizaton. CRH suppressed the basal TREK-1 current in cells with intracellular acidification and caused depolarization. Our finding indicates that TREK-1 channels are important in setting the resting potential in corticotropes. The opposing actions of CRH and AA on the excitability of corticotropes raise the possibility that AA may act as a negative feedback regulator to reduce the stimulatory action of CRH and thus prevent excessive ACTH release during chronic stress.
    Endocrinology 02/2011; 152(5):1901-10. · 4.72 Impact Factor
  • Proceedings of the National Academy of Sciences 01/2011; 108(51). · 9.81 Impact Factor
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    ABSTRACT: Evidence showing expression of endogenous opioids in the mammalian retina is sparse. In the present study we examined a transgenic mouse line expressing an obligate dimerized form of Discosoma red fluorescent protein (DsRed) under the control of the pro-opiomelanocortin promoter and distal upstream regulatory elements to assess whether pro-opiomelanocortin peptide (POMC), and its opioid cleavage product, beta-endorphin, are expressed in the mouse retina. Using double label immunohistochemistry we found that DsRed fluorescence was restricted to a subset of GAD-67-positive cholinergic amacrine cells of both orthotopic and displaced subtypes. About 50% of cholinergic amacrine cells colocalized DsRed and a large fraction of DsRed-expressing amacrine cells was positive for beta-endorphin immunostaining, whereas beta-endorphin-immunoreactive neurons were absent in retinas of POMC null mice. Our findings contribute to a growing body of evidence demonstrating that opioid peptides are an integral component of vertebrate retinas, including those of mammals.
    The Journal of Comparative Neurology 08/2010; 518(15):3130-48. · 3.51 Impact Factor
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    ABSTRACT: The role of dopaminergic receptors in the control of GH release remains controversial. The dopamine receptor 2 (D2R) knockout mouse represents a useful model to study the participation of the D2R on growth and GHRH-GH regulation. These knockout mice have hyperprolactinemia and lactotrope hyperplasia, but unexpectedly, they are also growth retarded. In D2R knockout mice there is a significant decrease in somatotrope population, which is paralleled by decreased GH content and output from pituitary cells. The sensitivity of GHRH-induced GH and cAMP release is similar between genotypes, even though the response amplitude is lower in knockouts. We point to an involvement of D2R signaling at the hypothalamic level as dopamine did not release GH acting at the pituitary level, and both somatostatin and GHRH mRNA expression are altered in knockout mice. The similarity of the pituitary defect in the D2R knockout mouse to that of GHRH deficient models suggests a probable mechanism. Loss of dopamine signaling via hypothalamic D2Rs at a critical age may cause inadequate GHRH secretion subsequently leading to inappropriate somatotrope lineage development. Furthermore, GH pulsatility, which depends on a regulated temporal balance between GHRH and somatostatin output might be compromised in D2R knockout mice, leading to lower IGF-I, and growth retardation.
    Frontiers of hormone research 01/2010; 38:59-69. · 1.24 Impact Factor

Publication Stats

12k Citations
1,296.64 Total Impact Points


  • 2011–2013
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2002–2013
    • National Scientific and Technical Research Council
      • • INGEBI - Instituto de Investigaciones en Ingeniería Genética y Biología Molecular
      • • IBYME - Instituto de Biología y Medicina Experimental
      Buenos Aires, Buenos Aires F.D., Argentina
    • Beth Israel Deaconess Medical Center
      • Division of Endocrinology, Diabetes and Metabolism
      Boston, MA, United States
    • Stanford University
      • Department of Comparative Medicine
      Stanford, CA, United States
  • 2009–2012
    • University of Michigan
      • Department of Molecular and Integrative Physiology
      Ann Arbor, Michigan, United States
    • Colorado State University
      • Department of Biomedical Sciences
      Fort Collins, CO, United States
  • 1992–2009
    • Oregon Health and Science University
      • • Department of Behavioral Neuroscience
      • • Department of Physiology & Pharmacology
      • • Department of Biochemistry & Molecular Biology
      Portland, Oregon, United States
  • 2006–2008
    • University of California, San Diego
      • Department of Psychiatry
      San Diego, CA, United States
    • Instituto de Biología y Medicina Experimental
      Buenos Aires, Buenos Aires F.D., Argentina
  • 2005
    • University of Tennessee
      • The Department of Pathology and Laboratory Medicine
      Knoxville, TN, United States
  • 2003
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 1997–2003
    • University of Buenos Aires
      • • Physiology Section
      • • Biological Sciences Department
      • • Institute of Genetic Engineering and Molecular Biology
      Buenos Aires, Buenos Aires F.D., Argentina
  • 1992–1999
    • University of Toronto
      • Department of Laboratory Medicine and Pathobiology
      Toronto, Ontario, Canada
  • 1990
    • Tufts University
      Georgia, United States
    • University of Massachusetts Medical School
      • Program in Molecular Medicine
      Worcester, MA, United States
    • Beverly Hospital, Boston MA
      Beverly, Massachusetts, United States
  • 1987
    • New England Baptist Hospital
      Boston, Massachusetts, United States