Bradford B Lowell

Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Are you Bradford B Lowell?

Claim your profile

Publications (164)2102.59 Total impact

  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Agouti-related-peptide (AgRP) neurons—interoceptive neurons in the arcuate nucleus of the hypothalamus (ARC)—are both necessary and sufficient for driving feeding behavior. To better understand the functional roles of AgRP neurons, we performed optetrode electrophysiological recordings from AgRP neurons in awake, behaving AgRP-IRES-Cre mice. In free-feeding mice, we observed a fivefold increase in AgRP neuron firing with mounting caloric deficit in afternoon vs morning recordings. In food-restricted mice, as food became available, AgRP neuron firing dropped, yet remained elevated as compared to firing in sated mice. The rapid drop in spiking activity of AgRP neurons at meal onset may reflect a termination of the drive to find food, while residual, persistent spiking may reflect a sustained drive to consume food. Moreover, nearby neurons inhibited by AgRP neuron photostimulation, likely including satiety-promoting pro-opiomelanocortin (POMC) neurons, demonstrated opposite changes in spiking. Finally, firing of ARC neurons was also rapidly modulated within seconds of individual licks for liquid food. These findings suggest novel roles for antagonistic AgRP and POMC neurons in the regulation of feeding behaviors across multiple timescales.
    eLife Sciences 07/2015; 4. DOI:10.7554/eLife.07122 · 8.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pro-opiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus (ARC) are oppositely regulated by caloric depletion and coordinately stimulate and inhibit homeostatic satiety, respectively. This bimodality is principally underscored by the antagonistic actions of these ligands at downstream melanocortin-4 receptors (MC4R) in the paraventricular nucleus of the hypothalamus (PVH). Although this population is critical to energy balance, the underlying neural circuitry remains unknown. Using mice expressing Cre recombinase in MC4R neurons, we demonstrate bidirectional control of feeding following real-time activation and inhibition of PVH(MC4R) neurons and further identify these cells as a functional exponent of ARC(AgRP) neuron-driven hunger. Moreover, we reveal this function to be mediated by a PVH(MC4R)→lateral parabrachial nucleus (LPBN) pathway. Activation of this circuit encodes positive valence, but only in calorically depleted mice. Thus, the satiating and appetitive nature of PVH(MC4R)→LPBN neurons supports the principles of drive reduction and highlights this circuit as a promising target for antiobesity drug development.
    Nature Neuroscience 04/2015; 18(6). DOI:10.1038/nn.4011 · 14.98 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Binge alcohol drinking is a tremendous public health problem because it leads to the development of numerous pathologies, including alcohol abuse and anxiety. It is thought to do so by hijacking brain systems that regulate stress and reward, including neuropeptide Y (NPY) and corticotropin-releasing factor (CRF). The central actions of NPY and CRF have opposing functions in the regulation of emotional and reward-seeking behaviors; thus, dysfunctional interactions between these peptidergic systems could be involved in the development of these pathologies. We used converging physiological, pharmacological and chemogenetic approaches to identify a precise neural mechanism in the bed nucleus of the stria terminalis (BNST), a limbic brain region involved in pathological reward and anxiety behaviors, underlying the interactions between NPY and CRF in the regulation of binge alcohol drinking in both mice and monkeys. We found that NPY Y1 receptor (Y1R) activation in the BNST suppressed binge alcohol drinking by enhancing inhibitory synaptic transmission specifically in CRF neurons via a previously unknown Gi-mediated, PKA-dependent postsynaptic mechanism. Furthermore, chronic alcohol drinking led to persistent alterations in Y1R function in the BNST of both mice and monkeys, highlighting the enduring, conserved nature of this effect across mammalian species. Together, these data provide both a cellular locus and signaling framework for the development of new therapeutics for treatment of neuropsychiatric diseases, including alcohol use disorders.
    Nature Neuroscience 03/2015; 18(4). DOI:10.1038/nn.3972 · 14.98 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Leptin acts via its receptor (LepRb) on multiple subpopulations of LepRb neurons in the brain, each of which controls specific aspects of energy balance. Despite the importance of LepRb-containing neurons, the transcriptome and molecular identity of many LepRb subpopulations remain undefined due to the difficulty of studying the small fraction of total cells represented by LepRb neurons in heterogeneous brain regions. Here we sought to examine the transcriptome of LepRb neurons directly and identify markers for functionally relevant LepRb subsets. We isolated mRNA from mouse hypothalamic and brainstem LepRb cells by Translating Ribosome Affinity Purification (TRAP) and analyzed it by RNA-seq (TRAP-seq). TRAP mRNA from LepRb cells was enriched for markers of peptidergic neurons, while TRAP-depleted mRNA from non-LepRb cells was enriched for markers of glial and immune cells. Genes encoding secreted proteins that were enriched in hypothalamic and brainstem TRAP mRNA revealed subpopulations of LepRb neurons that contained neuropeptide-encoding genes (including prodynorphin, Pdyn) not previously used as functional markers for LepRb neurons. Furthermore, Pdyn (cre) -mediated ablation of Lepr (flox) in Pdyn-expressing neurons (LepRb (Pdyn) KO mice) blunted energy expenditure to promote obesity during high-fat feeding. TRAP-seq of CNS LepRb neurons defines the LepRb neuron transcriptome and reveals novel markers for previously unrecognized subpopulations of LepRb neurons.
    02/2015; 395(4). DOI:10.1016/j.molmet.2015.01.012
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hypoglycemia engenders an autonomically mediated counterregulatory (CR)-response that stimulates endogenous glucose production to maintain concentrations within an appropriate physiological range. Although the involvement of the brain in preserving normoglycemia has been established, the neurocircuitry underlying centrally mediated CR-responses remains unclear. Here we demonstrate that lateral parabrachial nucleus cholecystokinin (CCK(LPBN)) neurons are a population of glucose-sensing cells (glucose inhibited) with counterregulatory capacity. Furthermore, we reveal that steroidogenic-factor 1 (SF1)-expressing neurons of the ventromedial nucleus of the hypothalamus (SF1(VMH)) are the specific target of CCK(LPBN) glucoregulatory neurons. This discrete CCK(LPBN)→SF1(VMH) neurocircuit is both necessary and sufficient for the induction of CR-responses. Together, these data identify CCK(LPBN) neurons, and specifically CCK neuropeptide, as glucoregulatory and provide significant insight into the homeostatic mechanisms controlling CR-responses to hypoglycemia. Copyright © 2014 Elsevier Inc. All rights reserved.
    Cell Metabolism 12/2014; 20(6):1030-7. DOI:10.1016/j.cmet.2014.11.006 · 16.75 Impact Factor
  • Clifford B Saper · Bradford B Lowell
    [Show abstract] [Hide abstract]
    ABSTRACT: The hypothalamus is one of the oldest and smallest parts of the brain, constituting just 4 gm of the 1400 gm of adult human brain weight. And yet this tiny area contains highly conserved neural circuitry that controls basic life functions: these include energy metabolism, from feeding through digestion, metabolic control, and energy expenditure; fluid and electrolyte balance, from drinking through fluid absorption and excretion; thermoregulation, from choice of environment through heat production and conservation, and fever responses; wake-sleep cycles and emergency responses to stressors in the environment; and reproduction, from reproductive hormone control through mating, pregnancy, birth, and suckling. In this Primer, we will give an overview of the structure of the hypothalamus, and outline what we know about how that relates to its functional circuitry. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Current Biology 12/2014; 24(23):R1111-6. DOI:10.1016/j.cub.2014.10.023 · 9.92 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Please check your proof carefully and mark all corrections at the appropriate place in the proof. Location in article Query / Remark: Click on the Q link to find the query's location in text Please insert your reply or correction at the corresponding line in the proof Q1 In the sentence, ''In contrast, no allodynia developed upon ablation of ChAT (Figure S6) or Npy (described elsewhere)..'' Do you want to provide a more specific citation? Thank you for your assistance.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Previous studies showed that Src homology-2 tyrosine phosphatase (Shp2) is an important regulator of body weight. In this study, we examined the impact of Shp2 deficiency specifically in proopiomelanocortin (Pomc) neurons on metabolic and cardiovascular function and on the chronic blood pressure (BP) and metabolic responses to leptin. Mice with Shp2 deleted in Pomc neurons (Shp2/Pomc-cre) and control mice (Shp2(flox/flox)) were implanted with telemetry probes and venous catheters for measurement of mean arterial pressure (MAP) and leptin infusion. After at least 5-days of stable control measurements, mice received leptin infusion (2 μg/kg/day, iv) for 7 days. Compared to Shp2(flox/flox) controls, Shp2/Pomc-cre mice at 22 weeks of age were slightly heavier (34±1 vs 31±1 g), but consumed a similar amount of food (3.9±0.3 vs 3.8±0.2 g/day). Leptin infusion reduced food intake in Shp2(flox/flox) mice (2.6±0.5 g) and Shp2/Pomc-cre mice (3.2±0.3 g). Despite decreasing food intake leptin infusion increased MAP in control mice, whereas no significant change in MAP was observed in Shp2/Pomc-cre mice. Leptin infusion also decreased plasma glucose and insulin levels in controls (12±1 to 6±1 μU/ml and 142±12 to 81±8 mg/100 ml) but not in Shp2/Pomc-cre mice. Leptin increased VO2 by 16 ± 2% in controls and 7 ± 1% in Shp2/Pomc-cre mice. These results indicate that Shp2 signaling in Pomc neurons contributes to the long-term BP and antidiabetic actions of leptin and may play a modest role in normal regulation of body weight.
    AJP Regulatory Integrative and Comparative Physiology 10/2014; 307(12):ajpregu.00131.2014. DOI:10.1152/ajpregu.00131.2014 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Activation of melanocortin-4 receptors (MC4Rs) restrains feeding and prevents obesity; however, the identity, location, and axonal projections of the neurons bearing MC4Rs that control feeding remain unknown. Reexpression of MC4Rs on single-minded 1 (SIM1)(+) neurons in mice otherwise lacking MC4Rs is sufficient to abolish hyperphagia. Thus, MC4Rs on SIM1(+) neurons, possibly in the paraventricular hypothalamus (PVH) and/or amygdala, regulate food intake. It is unknown, however, whether they are also necessary, a distinction required for excluding redundant sites of action. Hence, the location and nature of obesity-preventing MC4R-expressing neurons are unknown. Here, by deleting and reexpressing MC4Rs from cre-expressing neurons, establishing both necessity and sufficiency, we demonstrate that the MC4R-expressing neurons regulating feeding are SIM1(+), located in the PVH, glutamatergic and not GABAergic, and do not express oxytocin, corticotropin-releasing hormone, vasopressin, or prodynorphin. Importantly, these excitatory MC4R-expressing PVH neurons are synaptically connected to neurons in the parabrachial nucleus, which relays visceral information to the forebrain. This suggests a basis for the feeding-regulating effects of MC4Rs.
    Proceedings of the National Academy of Sciences 08/2014; 111(36). DOI:10.1073/pnas.1407843111 · 9.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Whether melanocortin 4 receptors (MC4Rs) in extra-hypothalamic neurons, including cholinergic autonomic pre-ganglionic neurons, are required to control energy and glucose homeostasis is unclear. We found that MC4Rs in sympathetic, but not parasympathetic, pre-ganglionic neurons were required to regulate energy expenditure and body weight, including thermogenic responses to diet and cold exposure and 'beiging' of white adipose tissue. Deletion of Mc4r genes in both sympathetic and parasympathetic cholinergic neurons impaired glucose homeostasis.
    Nature Neuroscience 06/2014; 17(7). DOI:10.1038/nn.3737 · 14.98 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The adipocyte-derived hormone leptin plays a critical role in the central transmission of energy balance to modulate reproductive function. However, the neurocircuitry underlying this interaction remains elusive, in part due to incomplete knowledge of first-order leptin-responsive neurons. To address this gap, we explored the contribution of predominantly inhibitory (GABAergic) neurons versus excitatory (glutamatergic) neurons in the female mouse by selective ablation of the leptin receptor in each neuronal population: Vgat-Cre;Lepr(lox/lox) and Vglut2-Cre;Lepr(lox/lox) mice, respectively. Female Vgat-Cre;Lepr(lox/lox) but not Vglut2-Cre;Lepr(lox/lox) mice were obese. Vgat-Cre;Lepr(lox/lox) mice had delayed or absent vaginal opening, persistent diestrus, and atrophic reproductive tracts with absent corpora lutea. In contrast, Vglut2-Cre;Lepr(lox/lox) females exhibited reproductive maturation and function comparable to Lepr(lox/lox) control mice. Intracerebroventricular administration of kisspeptin-10 to Vgat-Cre;Lepr(lox/lox) female mice elicited robust gonadotropin responses, suggesting normal gonadotropin-releasing hormone neuronal and gonadotrope function. However, adult ovariectomized Vgat-Cre;Lepr(lox/lox) mice displayed significantly reduced levels of Kiss1 (but not Tac2) mRNA in the arcuate nucleus, and a reduced compensatory luteinizing hormone increase compared with control animals. Estradiol replacement after ovariectomy inhibited gonadotropin release to a similar extent in both groups. These animals also exhibited a compromised positive feedback response to sex steroids, as shown by significantly lower Kiss1 mRNA levels in the AVPV, compared with Lepr(lox/lox) mice. We conclude that leptin-responsive GABAergic neurons, but not glutamatergic neurons, act as metabolic sensors to regulate fertility, at least in part through modulatory effects on kisspeptin neurons.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2014; 34(17):6047-56. DOI:10.1523/JNEUROSCI.3003-13.2014 · 6.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pain information processing in the spinal cord has been postulated to rely on nociceptive transmission (T) neurons receiving inputs from nociceptors and Aβ mechanoreceptors, with Aβ inputs gated through feed-forward activation of spinal inhibitory neurons (INs). Here, we used intersectional genetic manipulations to identify these critical components of pain transduction. Marking and ablating six populations of spinal excitatory and inhibitory neurons, coupled with behavioral and electrophysiological analysis, showed that excitatory neurons expressing somatostatin (SOM) include T-type cells, whose ablation causes loss of mechanical pain. Inhibitory neurons marked by the expression of dynorphin (Dyn) represent INs, which are necessary to gate Aβ fibers from activating SOM+ neurons to evoke pain. Therefore, peripheral mechanical nociceptors and Aβ mechanoreceptors, together with spinal SOM+ excitatory and Dyn+ inhibitory neurons, form a microcircuit that transmits and gates mechanical pain.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to the control of hunger. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake. Consistent with their obligatory role in regulating appetite, genetic ablation or chemogenetic inhibition of AgRP neurons decreases feeding. Excitatory input to AgRP neurons is important in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric-state-dependent synaptic plasticity. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques in mice, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase-activating polypeptide (PACAP, also known as ADCYAP1). Chemogenetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric-deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated.
    Nature 02/2014; 507(7491). DOI:10.1038/nature12956 · 42.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The melanocortin receptor 4 (MC4R) is a well-established mediator of body weight homeostasis. However, the neurotransmitter(s) that mediate MC4R function remain largely unknown; as a result, little is known about the second-order neurons of the MC4R neural pathway. Single-minded 1 (Sim1)-expressing brain regions, which include the paraventricular nucleus of hypothalamus (PVH), represent key brain sites that mediate melanocortin action. We conditionally restored MC4R expression in Sim1 neurons in the background of Mc4r-null mice. The restoration dramatically reduced obesity in Mc4r-null mice. The anti-obesity effect was completely reversed by selective disruption of glutamate release from those same Sim1 neurons. The reversal was caused by lower energy expenditure and hyperphagia. Corroboratively, selective disruption of glutamate release from adult PVH neurons led to rapid obesity development via reduced energy expenditure and hyperphagia. Thus, this study establishes glutamate as the primary neurotransmitter that mediates MC4Rs on Sim1 neurons in body weight regulation.
    Cell metabolism 12/2013; 18(6):860-70. DOI:10.1016/j.cmet.2013.11.003 · 16.75 Impact Factor
  • Source
    Alastair S Garfield · Bradford B Lowell
    [Show abstract] [Hide abstract]
    ABSTRACT: Aversive visceral stimuli, such as those associated with sickness, suppress appetite. Yet an understanding of the neural mechanisms underlying illness-related anorexia has remained elusive. Carter et al. (2013) now identify a specific hindbrain → amygdala circuit that contributes to illness-induced loss of appetite.
    Cell metabolism 12/2013; 18(6):769-70. DOI:10.1016/j.cmet.2013.11.010 · 16.75 Impact Factor
  • Source
  • Source
  • Source
  • Source
    Michael J Krashes · Bhavik P Shah · Shuichi Koda · Bradford B Lowell
    [Show abstract] [Hide abstract]
    ABSTRACT: Agouti-related peptide (AgRP) neurons of the hypothalamus release a fast transmitter (GABA) in addition to neuropeptides (neuropeptide Y [NPY] and Agouti-related peptide [AgRP]). This raises questions as to their respective functions. The acute activation of AgRP neurons robustly promotes food intake, while central injections of AgRP, NPY, or GABA agonist results in the marked escalation of food consumption with temporal variance. Given the orexigenic capability of all three of these neuroactive substances in conjunction with their coexpression in AgRP neurons, we looked to unravel their relative temporal role in driving food intake. After the acute stimulation of AgRP neurons with DREADD technology, we found that either GABA or NPY is required for the rapid stimulation of feeding, and the neuropeptide AgRP, through action on MC4 receptors, is sufficient to induce feeding over a delayed yet prolonged period. These studies help to elucidate the neurochemical mechanisms of AgRP neurons in controlling temporally distinct phases of eating.
    Cell metabolism 10/2013; 18(4):588-595. DOI:10.1016/j.cmet.2013.09.009 · 16.75 Impact Factor

Publication Stats

27k Citations
2,102.59 Total Impact Points

Institutions

  • 1996–2015
    • Beth Israel Deaconess Medical Center
      • • Department of Medicine
      • • Division of Endocrinology, Diabetes and Metabolism
      Boston, Massachusetts, United States
  • 1996–2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1992–2013
    • Harvard Medical School
      • • Department of Cell Biology
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 2012
    • University of Texas Southwestern Medical Center
      • Division of Hypothalamic Research
      Dallas, Texas, United States
  • 1990–2001
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 1998
    • University of Ottawa
      Ottawa, Ontario, Canada
    • University of Hamburg
      • Department of Internal Medicine II and Clinic (Oncology Center)
      Hamburg, Hamburg, Germany
  • 1997
    • National Institutes of Health
      • Branch of Surgery
      베서스다, Maryland, United States