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The Journal of Neuroscience, February 4, 2009, 29(5):1503-1513; doi:10.1523/JNEUROSCI.5147-08.2009

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Behavioral/Systems/Cognitive
Neuroendocrine Proopiomelanocortin Neurons Are Excited by Hypocretin/Orexin

Claudio Acuna-Goycolea and Anthony N. van den Pol

Department of Neurosurgery, Yale Medical School, New Haven, Connecticut 06520

Correspondence should be addressed to Anthony N. van den Pol, Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520. Email: anthony.vandenpol{at}yale.edu

Hypocretin/orexin, produced by a group of neurons in the lateral hypothalamus/perifornical area, enhances cognitive arousal and also may play a crucial role in modulating the neuroendocrine system. How hypocretin modulates the endocrine system remains an open question. Hypocretin cells innervate the mediobasal hypothalamus where they can potentially influence the activity of specific cell populations within the arcuate nucleus. Here, we examine whether hypocretin modulates the median eminence-projecting proopiomelanocortin (POMC) neurons identified by selective green fluorescent protein expression and antidromic stimulation or retrograde Evans blue dye tracing in transgenic mice. We find that POMC neurons, in general, and, in addition, those that project their axons to the median eminence, were robustly activated by hypocretin in a dose-dependent manner. These excitatory actions included a threefold increase in spike frequency and direct membrane depolarization of up to 22 mV (mean, 17.9 ± 7.2 mV). Direct postsynaptic depolarization was decreased at more positive membrane potentials, inhibited by the sodium–calcium exchanger antagonist KB-R7943, and reduced by lowering the bath temperature, or by buffering the postsynaptic calcium with BAPTA, suggesting that the primary mechanism for hypocretin-mediated excitation is the activation of the sodium–calcium exchanger. Hypocretin also enhanced excitatory inputs to POMC cells via a presynaptic mechanism and indirectly increased the release of GABA onto these cells in a spike-dependent manner. However, these synaptic actions were not necessary to cause postsynaptic membrane depolarization and spiking. Thus, in contrast to previous suggestions that hypocretin inhibited POMC cells, our results demonstrate robust direct excitation of POMC neurons by hypocretin.

Key words: arcuate nucleus; glutamate; postsynaptic; food intake; hypothalamus; peptidergic

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Received Oct. 24, 2008; revised Dec. 10, 2008; accepted Dec. 20, 2008.

Correspondence should be addressed to Anthony N. van den Pol, Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520. Email: anthony.vandenpol{at}yale.edu

This article has been cited by other articles:

				A. N. van den Pol, Y. Yao, L.-Y. Fu, K. Foo, H. Huang, R. Coppari, B. B. Lowell, and C. Broberger Neuromedin B and Gastrin-Releasing Peptide Excite Arcuate Nucleus Neuropeptide Y Neurons in a Novel Transgenic Mouse Expressing Strong Renilla Green Fluorescent Protein in NPY Neurons J. Neurosci., April 8, 2009; 29(14): 4622 - 4639. [Abstract] [Full Text] [PDF]

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