Electrical Inhibition of Identified Anorexigenic POMC Neurons by Orexin/Hypocretin

Proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus (ARC) suppress appetite, and lack of POMC-derived peptides or electrical silencing of POMC neurons causes obesity. ARC POMC neurons are surrounded by nerve terminals containing the wakefulness-promoting peptides orexins/hypocretins, but whether orexin affects their electrical activity has not been tested directly. Here we identify living ARC POMC cells in mouse brain slices by targeted expression of green fluorescent protein. Using whole-cell patch-clamp recordings, we show that orexin suppresses the spontaneous action potential firing of these neurons. Orexin-induced inhibition involves membrane hyperpolarization, a decreased excitatory synaptic drive, and an increased frequency of GABAergic inputs. Our results suggest a reduction in the electrical activity of ARC POMC neurons, which is mediated by changes in presynaptic inputs, contributes to the appetite-enhancing action of orexins.

[1]  F. Ashcroft,et al.  Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. , 2006, The Journal of clinical investigation.

[2]  Oleg Gerasimenko,et al.  Tandem-Pore K+ Channels Mediate Inhibition of Orexin Neurons by Glucose , 2006, Neuron.

[3]  H. Fields,et al.  Orexin A in the VTA Is Critical for the Induction of Synaptic Plasticity and Behavioral Sensitization to Cocaine , 2006, Neuron.

[4]  J. Elmquist,et al.  Orexin Neurons and the TASK of Glucosensing , 2006, Neuron.

[5]  Robert D. Nowak,et al.  Learning Minimum Volume Sets , 2005, J. Mach. Learn. Res..

[6]  G. Aston-Jones,et al.  A role for lateral hypothalamic orexin neurons in reward seeking , 2005, Nature.

[7]  Thorsten Buch,et al.  Agouti-related peptide–expressing neurons are mandatory for feeding , 2005, Nature Neuroscience.

[8]  R. Cone,et al.  PYY3-36 inhibits the action potential firing activity of POMC neurons of arcuate nucleus through postsynaptic Y2 receptors. , 2005, Cell metabolism.

[9]  O. Hassani,et al.  Discharge of Identified Orexin/Hypocretin Neurons across the Sleep-Waking Cycle , 2005, The Journal of Neuroscience.

[10]  A. Yamanaka,et al.  Input of Orexin/Hypocretin Neurons Revealed by a Genetically Encoded Tracer in Mice , 2005, Neuron.

[11]  Jerome M. Siegel,et al.  Behavioral Correlates of Activity in Identified Hypocretin/Orexin Neurons , 2005, Neuron.

[12]  R. Cone.  Anatomy and regulation of the central melanocortin system , 2005, Nature Neuroscience.

[13]  T. Sakurai,et al.  Orexin Neurons Function in an Efferent Pathway of a Food-Entrainable Circadian Oscillator in Eliciting Food-Anticipatory Activity and Wakefulness , 2004, The Journal of Neuroscience.

[14]  L. Pénicaud,et al.  A new ATP-sensitive K+ channel-independent mechanism is involved in glucose-excited neurons of mouse arcuate nucleus. , 2004, Diabetes.

[15]  B. Lowell,et al.  Leptin Receptor Signaling in POMC Neurons Is Required for Normal Body Weight Homeostasis , 2004, Neuron.

[16]  A. Blanks,et al.  Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus , 2004, Nature Neuroscience.

[17]  A. G. Roseberry,et al.  Rapid Rewiring of Arcuate Nucleus Feeding Circuits by Leptin , 2004, Science.

[18]  A. Yamanaka,et al.  Orexins (hypocretins) directly interact with neuropeptide Y, POMC and glucose‐responsive neurons to regulate Ca2+ signaling in a reciprocal manner to leptin: orexigenic neuronal pathways in the mediobasal hypothalamus , 2004, The European journal of neuroscience.

[19]  T. Sakurai.  Orexin: a link between energy homeostasis and adaptive behaviour. , 2003, Current opinion in clinical nutrition and metabolic care.

[20]  F. Ashcroft,et al.  Orexin Excites GABAergic Neurons of the Arcuate Nucleus by Activating the Sodium—Calcium Exchanger , 2003, The Journal of Neuroscience.

[21]  Takeshi Sakurai,et al.  Hypothalamic Orexin Neurons Regulate Arousal According to Energy Balance in Mice , 2003, Neuron.

[22]  Jon T. Willie,et al.  Distinct Narcolepsy Syndromes in Orexin Receptor-2 and Orexin Null Mice Molecular Genetic Dissection of Non-REM and REM Sleep Regulatory Processes , 2003, Neuron.

[23]  S. Shioda,et al.  Ultrastructural localization of orexin-1 receptor in pre- and post-synaptic neurons in the rat arcuate nucleus , 2002, Neuroscience Letters.

[24]  F. Ashcroft,et al.  Cholecystokinin Tunes Firing of an Electrically Distinct Subset of Arcuate Nucleus Neurons by Activating A-Type Potassium Channels , 2002, The Journal of Neuroscience.

[25]  Ming-Fung Wu,et al.  Release of Hypocretin (Orexin) during Waking and Sleep States , 2002, The Journal of Neuroscience.

[26]  S. Shioda,et al.  Orexin-1 receptor immunoreactivity in chemically identified target neurons in the rat hypothalamus , 2002, Neuroscience Letters.

[27]  G. Hervieu,et al.  Orexin receptor‐1 (OX‐R1) immunoreactivity in chemically identified neurons of the hypothalamus: focus on orexin targets involved in control of food and water intake , 2002, The European journal of neuroscience.

[28]  Jon T. Willie,et al.  Genetic Ablation of Orexin Neurons in Mice Results in Narcolepsy, Hypophagia, and Obesity , 2001, Neuron.

[29]  S. Shioda,et al.  Orexinergic innervation of POMC-containing neurons in the rat arcuate nucleus , 2001, Neuroreport.

[30]  Jon T. Willie,et al.  To eat or to sleep? Orexin in the regulation of feeding and wakefulness. , 2001, Annual review of neuroscience.

[31]  S. Woods,et al.  Central nervous system control of food intake , 2000, Nature.

[32]  L. Yaswen,et al.  Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin , 1999, Nature Medicine.

[33]  R. Cone,et al.  Integration of NPY, AGRP, and Melanocortin Signals in the Hypothalamic Paraventricular Nucleus Evidence of a Cellular Basis for the Adipostat , 1999, Neuron.

[34]  Emmanuel Mignot,et al.  The Sleep Disorder Canine Narcolepsy Is Caused by a Mutation in the Hypocretin (Orexin) Receptor 2 Gene , 1999, Cell.

[35]  Jon T. Willie,et al.  Narcolepsy in orexin Knockout Mice Molecular Genetics of Sleep Regulation , 1999, Cell.

[36]  C. Saper,et al.  Leptin Activates Hypothalamic CART Neurons Projecting to the Spinal Cord , 1998, Neuron.

[37]  A. N. van den Pol,et al.  Presynaptic and Postsynaptic Actions and Modulation of Neuroendocrine Neurons by a New Hypothalamic Peptide, Hypocretin/Orexin , 1998, The Journal of Neuroscience.

[38]  S. Carr,et al.  Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior , 1998, Cell.

[39]  F E Bloom,et al.  The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[40]  S. Carr,et al.  Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. , 1998, Cell.