Topographic mapping of VMH → arcuate nucleus microcircuits and their reorganization by fasting

In the hypothalamic arcuate nucleus (ARC), pro-opiomelanocortin (POMC) neurons inhibit feeding and neuropeptide-Y (NPY) neurons stimulate feeding. We tested whether neurons in the ventromedial hypothalamic nucleus (VMH), a known satiety center, activate anorexigenic neuronal pathways in the ARC by projecting either excitatory synaptic inputs to POMC neurons and/or inhibitory inputs to NPY neurons. Using laser scanning photostimulation in brain slices from transgenic mice, we found that POMC and NPY neurons, which are interspersed in the ARC, are nevertheless regulated by anatomically distinct synaptic inputs. POMC neurons received strong excitatory input from the medial VMH (mVMH), whereas NPY neurons did not and, instead, received weak inhibitory input only from within the ARC. The strength of the excitatory input from the mVMH to POMC neurons was diminished by fasting. These data identify a new molecularly defined circuit that is dynamically regulated by nutritional state in a manner consistent with the known role of the VMH as a satiety center.

[1]  J. Brobeck,et al.  Hypothalamic Control of Food Intake in Rats and Cats * , 1951, The Yale journal of biology and medicine.

[2]  M. Kreek,et al.  Methadone‐Related Opioid Agonist Pharmacotherapy for Heroin Addiction: History, Recent Molecular and Neurochemical Research and Future in Mainstream Medicine , 2000, Annals of the New York Academy of Sciences.

[3]  Edward M Callaway,et al.  Cell type specificity of local cortical connections , 2002, Journal of neurocytology.

[4]  M. Low,et al.  Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus , 2001, Nature.

[5]  A. Lomniczi,et al.  beta-Endorphin blocks luteinizing hormone-releasing hormone release by inhibiting the nitricoxidergic pathway controlling its release. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[6]  G. Shepherd,et al.  Geometric and functional organization of cortical circuits , 2005, Nature Neuroscience.

[7]  C. Saper,et al.  From Lesions to Leptin Hypothalamic Control of Food Intake and Body Weight , 1999, Neuron.

[8]  S. Bouret,et al.  Trophic Action of Leptin on Hypothalamic Neurons That Regulate Feeding , 2004, Science.

[9]  C. Bielajew,et al.  The effects of chronic ventromedial hypothalamic stimulation on weight gain in rats , 1991, Physiology & Behavior.

[10]  S. W. Ranson,et al.  Hypothalamic lesions and adiposity in the rat , 1940 .

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

[12]  C. Mantzoros,et al.  Role of leptin in the neuroendocrine response to fasting , 1996, Nature.

[13]  J. Friedman,et al.  Virus-Assisted Mapping of Neural Inputs to a Feeding Center in the Hypothalamus , 2001, Science.

[14]  B. Henry.  Hypothalamic Control of Food Intake and Body Weight , 2007 .

[15]  R. Cone,et al.  Targeted Disruption of the Melanocortin-4 Receptor Results in Obesity in Mice , 1997, Cell.

[16]  Gilbert Kennedy.  The hypothalamic control of food intake in rats , 1950, Proceedings of the Royal Society of London. Series B - Biological Sciences.

[17]  E. Callaway,et al.  A Genetic Method for Selective and Quickly Reversible Silencing of Mammalian Neurons , 2002, The Journal of Neuroscience.

[18]  L. Swanson,et al.  Organization of projections from the ventromedial nucleus of the hypothalamus: A Phaseolus vulgaris‐Leucoagglutinin study in the rat , 1994, The Journal of comparative neurology.

[19]  D. Pfaff,et al.  Deficit in the lordosis reflex of female rats caused by lesions in the ventromedial nucleus of the hypothalamus. , 1979, The Journal of physiology.

[20]  T. Ono,et al.  Glucoresponsive neurons in rat ventromedial hypothalamic tissue slices in vitro , 1982, Brain Research.

[21]  David J. Anderson,et al.  Selective Electrical Silencing of Mammalian Neurons In Vitro by the Use of Invertebrate Ligand-Gated Chloride Channels , 2002, The Journal of Neuroscience.

[22]  E. Callaway,et al.  Convergence of magno- and parvocellular pathways in layer 4B of macaque primary visual cortex , 1996, Nature.

[23]  A. N. van den Pol,et al.  The hypothalamic arcuate nucleus of rat—A quantitative golgi analysis , 1982, The Journal of comparative neurology.

[24]  E. Callaway,et al.  Excitatory cortical neurons form fine-scale functional networks , 2005, Nature.

[25]  D. Nance,et al.  Effects of hypothalamic and preoptic lesions on reproductive behavior in male rats , 1977, Brain Research Bulletin.

[26]  C. Saper,et al.  Distributions of leptin receptor mRNA isoforms in the rat brain , 1998, The Journal of comparative neurology.

[27]  E. Callaway,et al.  Laminar sources of synaptic input to cortical inhibitory interneurons and pyramidal neurons , 2000, Nature Neuroscience.

[28]  Charles F Stevens,et al.  Topographic specificity of functional connections from hippocampal CA3 to CA1. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[29]  F. Rohner-Jeanrenaud,et al.  Chronic intracerebroventricular neuropeptide-Y administration to normal rats mimics hormonal and metabolic changes of obesity. , 1993, Endocrinology.

[30]  C. Plata-salamán,et al.  Hyperphagia and obesity in rats with bilateral ibotenic acid-induced lesions of the ventromedial hypothalamic nucleus , 1987, Brain Research.

[31]  J. Besson,et al.  Efferent projections from the external parabrachial area to the forebrain: a Phaseolus Vulgaris leucoagglutinin study in the rat , 1991, Neuroscience Letters.

[32]  D. Poulain,et al.  Activity-dependent neuronal-glial and synaptic plasticity in the adult mammalian hypothalamus , 1993, Neuroscience.

[33]  Karel Svoboda,et al.  Circuit Analysis of Experience-Dependent Plasticity in the Developing Rat Barrel Cortex , 2003, Neuron.

[34]  J. McGarry,et al.  Knockout mice lacking steroidogenic factor 1 are a novel genetic model of hypothalamic obesity. , 2002, Endocrinology.

[35]  Victor J. Hruby,et al.  Role of melanocortinergic neurons in feeding and the agouti obesity syndrome , 1997, Nature.

[36]  E. Callaway,et al.  Photostimulation using caged glutamate reveals functional circuitry in living brain slices. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[37]  P S Kalra,et al.  Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. , 1984, Endocrinology.