R D Palmiter

Howard Hughes Medical Institute, Ashburn, Virginia, United States

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Publications (484)5132.93 Total impact

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    ABSTRACT: Although major depressive disorder (MDD) has low heritability, a genome-wide association study in humans has recently implicated type 3 adenylyl cyclase (AC3, ADCY3) in MDD. Moreover, the expression level of AC3 in blood has been considered as a MDD biomarker in humans, Nevertheless, there is lack of supporting evidence from animal studies.
    No preview · Article · Dec 2015
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    ABSTRACT: Despite the well-established role of serotonin signaling in mood regulation, causal relationships between serotonergic neuronal activity and behavior remain poorly understood. Using a pharmacogenetic approach, we find that selectively increasing serotonergic neuronal activity in wild-type mice is anxiogenic and reduces floating in the forced-swim test, whereas inhibition has no effect on the same measures. In a developmental mouse model of altered emotional behavior, increased anxiety and depression-like behaviors correlate with reduced dorsal raphé and increased median raphé serotonergic activity. These mice display blunted responses to serotonergic stimulation and behavioral rescues through serotonergic inhibition. Furthermore, we identify opposing consequences of dorsal versus median raphé serotonergic neuron inhibition on floating behavior, together suggesting that median raphé hyperactivity increases anxiety, whereas a low dorsal/median raphé serotonergic activity ratio increases depression-like behavior. Thus, we find a critical role of serotonergic neuronal activity in emotional regulation and uncover opposing roles of median and dorsal raphé function.
    Preview · Article · Nov 2015 · Cell Reports
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    ABSTRACT: Elevated fumarate concentrations as a result of Krebs cycle inhibition lead to increases in protein succination, an irreversible post-translational modification that occurs when fumarate reacts with cysteine residues to generate S-(2-succino)cysteine (2SC). Metabolic events that reduce NADH re-oxidation can block Krebs cycle activity; therefore we hypothesized that oxidative phosphorylation deficiencies, such as those observed in some mitochondrial diseases, would also lead to increased protein succination. Using the Ndufs4 knockout (Ndufs4 KO) mouse, a model of Leigh syndrome, we demonstrate for the first time that protein succination is increased in the brainstem (BS), particularly in the vestibular nucleus (VN). Importantly, the brainstem is the most affected region exhibiting neurodegeneration and astrocyte and microglial proliferation, and these mice typically die of respiratory failure attributed to VN pathology. In contrast, no increases in protein succination were observed in the skeletal muscle, corresponding with the lack of muscle pathology observed in this model. 2D SDS-PAGE followed by immunoblotting for succinated proteins and MS/MS analysis of BS proteins allowed us to identify the voltage-dependent anion channels (VDAC) 1 and 2 as specific targets of succination in the Ndufs4 KO. Using targeted mass spectrometry, Cys77 and Cys48 were identified as endogenous sites of succination in VDAC2. Given the important role of VDAC isoforms in the exchange of ADP/ATP between the cytosol and the mitochondria, and the already decreased capacity for ATP synthesis in the Ndufs4 KO mice, we propose that the increased protein succination observed in the BS of these animals would further decrease the already compromised mitochondrial function. These data suggest that fumarate is a novel biochemical link that may contribute to the progression of the neuropathology in this mitochondrial disease model.
    Full-text · Article · Oct 2015 · Molecular & Cellular Proteomics

  • No preview · Article · Oct 2015
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    Full-text · Dataset · Aug 2015
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    ABSTRACT: Feeding behavior is exquisitely regulated by homeostatic and hedonic neural substrates that integrate energy demand as well as the reinforcing and rewarding aspects of food. Understanding the net contribution of homeostatic and reward-driven feeding has become critical because of the ubiquitous source of energy-dense foods and the consequent obesity epidemic. Hypothalamic agouti-related peptide-secreting neurons (AgRP neurons) provide the primary orexigenic drive of homeostatic feeding. Using models of neuronal inhibition or ablation, we demonstrate that the feeding response to a fast ghrelin or serotonin receptor agonist relies on AgRP neurons. However, when palatable food is provided, AgRP neurons are dispensable for an appropriate feeding response. In addition, AgRP-ablated mice present exacerbated stress-induced anorexia and palatable food intake-a hallmark of comfort feeding. These results suggest that, when AgRP neuron activity is impaired, neural circuits sensitive to emotion and stress are engaged and modulated by food palatability and dopamine signaling. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Cell metabolism
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    ABSTRACT: Animals learn to avoid harmful situations by associating a neutral stimulus with a painful one, resulting in a stable threat memory. In mammals, this form of learning requires the amygdala. Although pain is the main driver of aversive learning, the mechanism that transmits pain signals to the amygdala is not well resolved. Here, we show that neurons expressing calcitonin gene-related peptide (CGRP) in the parabrachial nucleus are critical for relaying pain signals to the central nucleus of amygdala and that this pathway may transduce the affective motivational aspects of pain. Genetic silencing of CGRP neurons blocks pain responses and memory formation, whereas their optogenetic stimulation produces defensive responses and a threat memory. The pain-recipient neurons in the central amygdala expressing CGRP receptors are also critical for establishing a threat memory. The identification of the neural circuit conveying affective pain signals may be pertinent for treating pain conditions with psychiatric comorbidities.
    No preview · Article · Jul 2015 · Cell
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    Sung Han · Matthew T Soleiman · Marta E Soden · Larry S Zweifel · Richard D Palmiter
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    ABSTRACT: Animals learn to avoid harmful situations by associating a neutral stimulus with a painful one, resulting in a stable threat memory. In mammals, this form of learning requires the amygdala. Although pain is the main driver of aversive learning, the mechanism that transmits pain signals to the amygdala is not well resolved. Here, we show that neurons expressing calcitonin gene-related peptide (CGRP) in the parabrachial nucleus are critical for relaying pain signals to the central nucleus of amygdala and that this pathway may transduce the affective motivational aspects of pain. Genetic silencing of CGRP neurons blocks pain responses and memory formation, whereas their optogenetic stimulation produces defensive responses and a threat memory. The pain-recipient neurons in the central amygdala expressing CGRP receptors are also critical for establishing a threat memory. The identification of the neural circuit conveying affective pain signals may be pertinent for treating pain conditions with psychiatric comorbidities. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Jul 2015 · Cell
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    ABSTRACT: Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons and produces a movement disorder and cognitive impairment that becomes more extensive with the duration of the disease. To what extent cognitive impairment in advanced PD can be attributed to severe loss of dopamine (DA) signaling is not well understood. Furthermore, it is unclear if the loss of DA neurons contributes to the cognitive impairment caused by the reduction in DA signaling. We generated genetic mouse models with equally severe chronic loss of DA achieved by either extensive ablation of DA neurons or inactivation of DA synthesis from preserved neurons and compared their motor and cognitive performance. Motor behaviors were equally blunted in both models, but we observed that DA neuron ablation caused more severe cognitive deficits than DA depletion. Both models had marked deficits in cue-discrimination learning. Yet, deficits in cue-discrimination learning were more severe in mice with DA neuron ablation and only mice with DA neuron ablation had drastically impaired performance in spatial learning, spatial memory and object memory tests. These results indicate that while a severe reduction in DA signaling results in motor and cognitive impairments, the loss of DA neurons promotes more extensive cognitive deficits and suggest that a loss of additional factors that depend on DA neurons may participate in the progressive cognitive decline found in patients with PD. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jun 2015 · Experimental Neurology
  • Richard Palmiter

    No preview · Article · May 2015 · Nature Neuroscience
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    ABSTRACT: During nervous system development, critical periods are usually defined as early periods during which manipulations dramatically change neuronal structure or function, whereas the same manipulations in mature animals have little or no effect on the same property. Neurons in the ventral cochlear nucleus (CN) are dependent on excitatory afferent input for survival during a critical period of development. Cochlear removal in young mammals and birds results in rapid death of target neurons in the CN. Cochlear removal in older animals results in little or no neuron death. However, the extent to which hair-cell-specific afferent activity prevents neuronal death in the neonatal brain is unknown. We further explore this phenomenon using a new mouse model that allows temporal control of cochlear hair cell deletion. Hair cells express the human diphtheria toxin (DT) receptor behind the Pou4f3 promoter. Injections of DT resulted in nearly complete loss of organ of Corti hair cells within 1 week of injection regardless of the age of injection. Injection of DT did not influence surrounding supporting cells directly in the sensory epithelium or spiral ganglion neurons (SGNs). Loss of hair cells in neonates resulted in rapid and profound neuronal loss in the ventral CN, but not when hair cells were eliminated at a more mature age. In addition, normal survival of SGNs was dependent on hair cell integrity early in development and less so in mature animals. This defines a previously undocumented critical period for SGN survival. Copyright © 2015 the authors 0270-6474/15/357878-14$15.00/0.
    Full-text · Article · May 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: Inhibition of mitochondrial complex I activity is hypothesized to be one of the major mechanisms responsible for dopaminergic neuron death in Parkinson's disease. However, loss of complex I activity by systemic deletion of the Ndufs4 gene, one of the subunits comprising complex I, does not cause dopaminergic neuron death in culture. Here, we generated mice with conditional Ndufs4 knockout in dopaminergic neurons (Ndufs4 conditional knockout mice [cKO]) to examine the effect of complex I inhibition on dopaminergic neuron function and survival during aging and on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in vivo. Ndufs4 cKO mice did not show enhanced dopaminergic neuron loss in the substantia nigra pars compacta or dopamine-dependent motor deficits over the 24-month life span. These mice were just as susceptible to MPTP as control mice. However, compared with control mice, Ndufs4 cKO mice exhibited an age-dependent reduction of dopamine in the striatum and increased α-synuclein phosphorylation in dopaminergic neurons of the substantia nigra pars compacta. We also used an inducible Ndufs4 knockout mouse strain (Ndufs4 inducible knockout) in which Ndufs4 is conditionally deleted in all cells in adult to examine the effect of adult onset, complex I inhibition on MPTP sensitivity of dopaminergic neurons. The Ndufs4 inducible knockout mice exhibited similar sensitivity to MPTP as control littermates. These data suggest that mitochondrial complex I inhibition in dopaminergic neurons does contribute to dopamine loss and the development of α-synuclein pathology. However, it is not sufficient to cause cell-autonomous dopaminergic neuron death during the normal life span of mice. Furthermore, mitochondrial complex I inhibition does not underlie MPTP toxicity in vivo in either cell autonomous or nonautonomous manner. These results provide strong evidence that inhibition of mitochondrial complex I activity is not sufficient to cause dopaminergic neuron death during aging nor does it contribute to dopamine neuron toxicity in the MPTP model of Parkinson's disease. These findings suggest the existence of alternative mechanisms of dopaminergic neuron death independent of mitochondrial complex I inhibition. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · May 2015 · Neurobiology of Aging
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    ABSTRACT: Hypothalamic neuronal populations are central regulators of energy homeostasis and reproductive function. However, the ontogeny of these critical hypothalamic neuronal populations is largely unknown. We developed a novel approach to examine the developmental pathways that link specific subtypes of neurons by combining embryonic and adult ribosome-tagging strategies in mice. This new method shows that Pomc-expressing precursors not only differentiate into discrete neuronal populations that mediate energy balance (POMC and AgRP neurons), but also into neurons critical for puberty onset and the regulation of reproductive function (Kiss1 neurons). These results demonstrate a developmental link between nutrient-sensing and reproductive neuropeptide synthesizing neuronal populations and suggest a potential pathway that could link maternal nutrition to reproductive development in the offspring. Copyright © 2015 the authors 0270-6474/15/355549-08$15.00/0.
    No preview · Article · Apr 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    Matthew E Carter · Sung Han · Richard D Palmiter
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    ABSTRACT: Conditioned taste aversion (CTA) is a phenomenon in which an individual forms an association between a novel tastant and toxin-induced gastrointestinal malaise. Previous studies showed that the parabrachial nucleus (PBN) contains neurons that are necessary for the acquisition of CTA, but the specific neuronal populations involved are unknown. Previously, we identified calcitonin gene-related peptide (CGRP)-expressing neurons in the external lateral subdivision of the PBN (PBel) as being sufficient to suppress appetite and necessary for the anorexigenic effects of appetite-suppressing substances including lithium chloride (LiCl), a compound often used to induce CTA. Here, we test the hypothesis that PBel CGRP neurons are sufficient and necessary for CTA acquisition in mice. We show that optogenetic activation of these neurons is sufficient to induce CTA in the absence of anorexigenic substances, whereas genetically induced silencing of these neurons attenuates acquisition of CTA upon exposure to LiCl. Together, these results demonstrate that PBel CGRP neurons mediate a gastrointestinal distress signal required to establish CTA. Copyright © 2015 the authors 0270-6474/15/354582-05$15.00/0.
    Preview · Article · Mar 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: Appropriate responses to an imminent threat brace us for adversities. The ability to sense and predict threatening or stressful events is essential for such adaptive behaviour. In the mammalian brain, one putative stress sensor is the paraventricular nucleus of the thalamus (PVT), an area that is readily activated by both physical and psychological stressors. However, the role of the PVT in the establishment of adaptive behavioural responses remains unclear. Here we show in mice that the PVT regulates fear processing in the lateral division of the central amygdala (CeL), a structure that orchestrates fear learning and expression. Selective inactivation of CeL-projecting PVT neurons prevented fear conditioning, an effect that can be accounted for by an impairment in fear-conditioning-induced synaptic potentiation onto somatostatin-expressing (SOM+) CeL neurons, which has previously been shown to store fear memory. Consistently, we found that PVT neurons preferentially innervate SOM+ neurons in the CeL, and stimulation of PVT afferents facilitated SOM+ neuron activity and promoted intra-CeL inhibition, two processes that are critical for fear learning and expression. Notably, PVT modulation of SOM+ CeL neurons was mediated by activation of the brain-derived neurotrophic factor (BDNF) receptor tropomysin-related kinase B (TrkB). As a result, selective deletion of either Bdnf in the PVT or Trkb in SOM+ CeL neurons impaired fear conditioning, while infusion of BDNF into the CeL enhanced fear learning and elicited unconditioned fear responses. Our results demonstrate that the PVT-CeL pathway constitutes a novel circuit essential for both the establishment of fear memory and the expression of fear responses, and uncover mechanisms linking stress detection in PVT with the emergence of adaptive behaviour.
    No preview · Article · Jan 2015 · Nature
  • M Darvas · R D Palmiter
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    ABSTRACT: Behavioral flexibility is known to be mediated by corticostriatal systems and to involve several major neurotransmitter signaling pathways. The current study investigated the effects of inactivation of glutamatergic N-methyl-d-aspartate-(NMDA) receptor signaling in the dorsal striatum on behavioral flexibility in mice. NMDA-receptor inactivation was achieved by virus-mediated inactivation of the Grin1 gene, which encodes the essential NR1 subunit of NMDA receptors. To assess behavioral flexibility, we used a water U-maze paradigm in which mice had to shift from an initially acquired rule to a new rule (strategy shifting) or had to reverse an initially learned rule (reversal learning). Inactivation of NMDA-receptors in all neurons of the dorsal striatum did not affect learning of the initial rule or reversal learning, but impaired shifting from one strategy to another. Strategy shifting was also compromised when NMDA-receptors were inactivated only in dynorphin-expressing neurons in the dorsal striatum, which represent the direct pathway. These data suggest that NMDA-receptor-mediated synaptic plasticity in the dorsal striatum contributes to strategy shifting and that striatal projection neurons of the direct pathway are particularly relevant for this process. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.
    No preview · Article · Nov 2014 · Neuroscience
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    ABSTRACT: Daily rhythms of food anticipatory activity (FAA) are regulated independently of the suprachiasmatic nucleus, which mediates entrainment of rhythms to light, but the neural circuits that establish FAA remain elusive. In this study, we show that mice lacking the dopamine D1 receptor (D1R KO mice) manifest greatly reduced FAA, whereas mice lacking the dopamine D2 receptor have normal FAA. To determine where dopamine exerts its effect, we limited expression of dopamine signaling to the dorsal striatum of dopamine-deficient mice; these mice developed FAA. Within the dorsal striatum, the daily rhythm of clock gene period2 expression was markedly suppressed in D1R KO mice. Pharmacological activation of D1R at the same time daily was sufficient to establish anticipatory activity in wild-type mice. These results demonstrate that dopamine signaling to D1R-expressing neurons in the dorsal striatum plays an important role in manifestation of FAA, possibly by synchronizing circadian oscillators that modulate motivational processes and behavioral output. DOI: http://dx.doi.org/10.7554/eLife.03781.001
    Full-text · Article · Sep 2014 · eLife Sciences
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    ABSTRACT: Huntington's disease (HD) is caused by an expanded polyglutamine repeat in huntingtin protein that disrupts synaptic function in specific neuronal populations and results in characteristic motor, cognitive and affective deficits. Histopathological hallmarks observed in both HD patients and genetic mouse models include the reduced expression of synaptic proteins, reduced medium spiny neuron (MSN) dendritic spine density and decreased frequency of spontaneous excitatory post-synaptic currents (sEPSCs). Early down-regulation of cannabinoid CB1 receptor expression on MSN (CB1(MSN)) is thought to participate in HD pathogenesis. Here we present a cell-specific genetic rescue of CB1(MSN) in R6/2 mice and report that treatment prevents the reduction of excitatory synaptic markers in the striatum (synaptophysin, vGLUT1 and vGLUT2), of dendritic spine density on MSNs and of sEPSCs, but does not prevent motor impairment. We conclude that loss of excitatory striatal synapses in HD mice is controlled by CB1(MSN) and can be uncoupled from the motor phenotype.
    Full-text · Article · Aug 2014 · Neurobiology of Disease
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    ABSTRACT: Beige fat, which expresses the thermogenic protein UCP1, provides a defense against cold and obesity. Although a cold environment is the physiologic stimulus for inducing beige fat in mice and humans, the events that lead from the sensing of cold to the development of beige fat remain poorly understood. Here, we identify the efferent beige fat thermogenic circuit, consisting of eosinophils, type 2 cytokines interleukin (IL)-4/13, and alternatively activated macrophages. Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced biogenesis of beige fat. Mechanistically, macrophages recruited to cold-stressed subcutaneous white adipose tissue (scWAT) undergo alternative activation to induce tyrosine hydroxylase expression and catecholamine production, factors required for browning of scWAT. Conversely, administration of IL-4 to thermoneutral mice increases beige fat mass and thermogenic capacity to ameliorate pre-established obesity. Together, our findings have uncovered the efferent circuit controlling biogenesis of beige fat and provide support for its targeting to treat obesity.
    Full-text · Article · Jun 2014 · Cell
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    ABSTRACT: Beige fat, which expresses the thermogenic protein UCP1, provides a defense against cold and obesity. Although a cold environment is the physiologic stimulus for inducing beige fat in mice and humans, the events that lead from the sensing of cold to the development of beige fat remain poorly understood. Here, we identify the efferent beige fat thermogenic circuit, consisting of eosinophils, type 2 cytokines interleukin (IL)-4/13, and alternatively activated macrophages. Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced biogenesis of beige fat. Mechanistically, macrophages recruited to cold-stressed subcutaneous white adipose tissue (scWAT) undergo alternative activation to induce tyrosine hydroxylase expression and catecholamine production, factors required for browning of scWAT. Conversely, administration of IL-4 to thermoneutral mice increases beige fat mass and thermogenic capacity to ameliorate pre-established obesity. Together, our findings have uncovered the efferent circuit controlling biogenesis of beige fat and provide support for its targeting to treat obesity.
    Full-text · Article · Jun 2014 · Cell

Publication Stats

56k Citations
5,132.93 Total Impact Points

Institutions

  • 1979-2015
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • Cornell University
      Итак, New York, United States
  • 1975-2015
    • University of Washington Seattle
      • • Department of Biochemistry
      • • Department of Pathology
      • • Department of Pharmacology
      Seattle, Washington, United States
  • 1987-2007
    • University of California, San Francisco
      • • Department of Biochemistry and Biophysics
      • • Department of Pediatrics
      San Francisco, CA, United States
    • Royal Melbourne Hospital
      Melbourne, Victoria, Australia
    • The Scripps Research Institute
      • Department of Molecular and Experimental Medicine
      لا هویا, California, United States
  • 2000
    • Ulsan University Hospital
      Urusan, Ulsan, South Korea
  • 1999
    • Medical University of South Carolina
      Charleston, South Carolina, United States
  • 1996
    • Kansas City VA Medical Center
      Kansas City, Missouri, United States
  • 1987-1995
    • University of Pennsylvania
      • • Department of Animal Biology
      • • School of Veterinary Medicine
      Philadelphia, PA, United States
  • 1994
    • Seattle Children's Hospital
      • Department of Laboratories
      Seattle, Washington, United States
  • 1993
    • University of North Carolina at Chapel Hill
      • Lineberger Comprehensive Cancer Center
      Chapel Hill, NC, United States
    • Albany Medical College
      Albany, New York, United States
  • 1991
    • National Institute of Environmental Health Sciences
      Durham, North Carolina, United States
    • University of South Florida
      • Department of Chemistry
      Tampa, FL, United States
  • 1990
    • Maryland Department Of Agriculture
      Annapolis, Maryland, United States
  • 1989
    • Massachusetts General Hospital
      • Laboratory of Molecular Endocrinology
      Boston, MA, United States
    • Columbia University
      • Department of Genetics and Development
      New York City, NY, United States
  • 1988
    • University of Wisconsin, Madison
      • Department of Pathobiological Sciences
      Madison, MS, United States
  • 1985-1987
    • University of Alabama at Birmingham
      • Department of Medicine
      Birmingham, AL, United States
  • 1983
    • Fred Hutchinson Cancer Research Center
      Seattle, Washington, United States
  • 1969-1973
    • Stanford University
      • Division of Clinical Pharmacology
      Palo Alto, California, United States