Abstract
The anorexigenic neuropeptide NEFA/nucleobindin 2 (NUCB2)/nesfatin-1-containing neurons are distributed in the brain regions involved in feeding regulation, including the hypothalamic paraventricular nucleus (PVN). Functionally, NUCB2/nesfatin-1 neurons in the PVN regulate feeding through the hypothalamus and brain stem. However, the neural network of PVN NUCB2/nesfatin-1 neurons has yet to be elucidated. Axon collateral branches allow individual neurons to target multiple neurons. In some cases, each target neuron can be located in different nuclei. Here we show that a single neuron in the PVN projects axonal collaterals to both the dorsal vagal complex (DVC) and the arcuate nucleus (ARC), which are important brain regions for feeding regulation. In this study, after injection of different retrograde tracers into the DVC and ARC, both tracer-labeled neurons were detected in the identical PVN neuron, indicating the axon collateral projections from the single PVN neuron to the DVC and ARC. Furthermore, immunohistochemical analysis revealed that approximately 50 % of the neurons with axon collateral projections from the PVN to the DVC and ARC were found to be NUCB2/nesfatin-1 neurons. Our data suggest that a single NUCB2/nesfatin-1 neuron in the PVN projects to both the ARC and the DVC with axon collateral projection. Although the physiological significance remains to be elucidated, our data offer new perspectives on NUCB2/nesfatin-1 function at the neural network level and food intake regulation.
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References
Browning KN, Travagli RA (2011) Plasticity of vagal brainstem circuits in the control of gastrointestinal function. Auton Neurosci 161:6–13
Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8:571–578
Conrad LC, Pfaff DW (1976) Efferent from medial basal forebrain and hypothalamus in rat. IIAn autoradiographic study of anterior hypothalamus. J Comp Neurol 169:221–261
Conte WL, Kamishina H, Reep RL (2009a) Multiple neuroanatomical tract-tracing using fluorescent Alexa fluor conjugates of cholera toxin subunit B in rats. Nat Protoc 4:1157–1166
Conte WL, Kamishina H, Reep RL (2009b) The efficacy of the fluorescent conjugates of cholera toxin subunit B for multiple retrograde tract tracing in the central nervous system. Brain Struct Funct 219:367–373
Fan W, Ellacott KL, Halatchev IG, Takahashi K, Yu P, Cone RD (2004) Cholecystokinin-mediated suppression of feeding involves the brainstem melanocortin system. Nat Neurosci 7:335–336
Foo KS, Brismar H, Broberger C (2008) Distribution and neuropeptide coexistence of nucleobindin-2 mRNA/nesfatin-like immunoreactivity in the rat CNS. Neuroscience 156:563–579
Gallo G (2011) The cytoskeletal and signaling mechanisms of axon collateral branching. Develop Neurobiol 71:201–220
Gonzalez R, Tiwari A, Unniappan S (2009) Pancreatic beta cells colocalize insulin and pronesfatin immunoreactivity in rodents. Biochem Biophys Res Commun 381:643–648
Knobloch HS, Charlet A, Hoffmann LC, Eliava M, Khrulev S, Cetin AH, Osten P, Schwarz MK, Seeburg PH, Stoop R, Grinevich V (2012) Evoked axonal oxytocin release in the central amygdala attenuates fear response. Neuron 73:553–566
Kohno D, Nakata M, Maejima Y, Shimizu H, Sedbazar U, Yoshida N, Dezaki K, Onaka T, Mori M, Yada T (2008) Nesfatin-1 neurons in paraventricular and supraoptic nuclei of the rat hypothalamus coexpress oxytocin and vasopressin and are activated by refeeding. Endocrinol 149:1295–1301
Krashes MJ, Shah BP, Madara JC, Olson DP, Strochlic DE, Garfield AS, Vong L, Pei H, Watabe-Uchida M, Uchida N, Liberles SD, Lowell BB (2014) An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 507:238–242
Maejima Y, Sedbazar U, Suyama S, Kohno D, Onaka T, Takano E, Yoshida N, Koike M, Uchiyama Y, Fujiwara K, Yashiro T, Horvath TL, Dietrich MO, Tanaka S, Dezaki K, Oh-I S, Hashimoto K, Shimizu H, Nakata M, Mori M, Yada T (2009) Nesfatin-1-regulated oxytocinergic signaling in the paraventricular nucleus causes anorexia through a leptin-independent melanocortin pathway. Cell Metab 10:355–365
Maejima Y, Sakuma S, Santoso P, Gantulga D, Katsurada K, Ueta Y, Hiraoka Y, Nishimori K, Tanaka S, Shimomura S, Yada T (2014) Oxytocinergic circuit from paraventricular and supraoptic nuclei to arcuate POMC neurons in hypothalamus. FEBS Lett 588:4404–4412
Oh SW, Harris JA, Ng L, Winslow B, Cain N, Mihalas S, Wang Q, Lau C, Kuan L, Henry AM, Ouellette B, Nguyen TN, Sorensen SA, Slaughterbeck CR, Wakeman W, Li Y, Feng D, Ho A, Nicholas E, Hirokawa KH, Bohn P, Joines KM, Peng H, Hawrylycz MJ, Phillips HW, Hohman JG, Wohnoutka P, Gerfen CR, Koch C, Bernard A, Dang C, Jones AR, Zeng H (2014) A mesoscale connectome of the mouse brain. Nature 508:207–2017
Oh-I S, Shimizu H, Satoh T, Okada S, Adachi S, Inoue K, Eguchi H, Yamamoto M, Imaki T, Hashimoto K, Tsuchiya T, Monden T, Horiguchi K, Yamada M, Mori M (2006) Identification of nesfatin-1 as a satiety molecule in the hypothalamus. Nature 443:709–712
Oldfield BJ, Allen AM, Davern P, Giles ME, Owens NC (2007) Lateral hypothalamic ‘command neurons’ with axonal projections to regions involved in both feeding and thermogenesis. Euro J Neurosci 25:2404–2412
Ramanjaneya M, Chen J, Brown JE, Tripathi G, Hallschmid M, Patel S, Kern W, Hillhouse EW, Lehnert H, Tan BK, Randeva HS (2010) Identification of nesfatin-1 in human and murine adipose tissue: a novel depot-specific adipokine with increased levels in obesity. Endocrinol 151:3169–3180
Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404:661–671
Sedbazar U, Maejima Y, Nakata M, Mori M, Yada T (2013) Paraventricular NUCB2/nesfatin-1 rises in synchrony with feeding suppression during early light phase in rats. Biochem Biophys Res Commun 434:434–438
Stengel A, Goebel M, Yakubov I, Wang L, Witcher D, Coskun T, Taché Y, Sachs G, Lambrecht NW (2009) Identification and characterization of nesfatin-1 immunoreactivity in endocrine cell types of the rat gastric oxyntic mucosa. Endocrinol 150:232–238
Stengel A, Mori M, Taché Y (2013) The role of nesfatin-1 in the regulation of food intake and body weight: recent developments and future endeavors. Obes Rev 14:859–870
Vas S, Ádori C, Könczöl K, Kátai Z, Pap D, Papp RS, Bagdy G, Palkovits M, Tóth ZE (2013) Nesfatin-1/NUCB2 as a potential new element of sleep regulation in rats. PLoS ONE 8:e59809
Yoshida N, Maejima Y, Sedbazar U, Ando A, Kurita H, Damdindorj B, Takano E, Gantulga D, Iwasaki Y, Kurashina T, Onaka T, Dezaki K, Nakata M, Mori M, Yada T (2010) Stressor-responsive central nesfatin-1 activates corticotropin-releasing hormone, noradrenaline and serotonin neurons and evokes hypothalamic-pituitary-adrenal axis. Aging (Albany NY) 2:775–784
Yosten GL, Samson WK (2009) Nesfatin-1 exerts cardiovascular actions in brain: possible interaction with the central melanocortin system. Am J Physiol Regul Integr Comp Physiol 297:R330–R336
Acknowledgments
The authors would like to thank Prof. Kazuto Kobayashi and Dr. Nozomu Yoshioka (Fukushima Medical University) for their critical comments on this paper. The authors also would like to thank Mr. Yoshimasa Kiyomatsu and Mr. Shunsuke Onodera (Olympus Co.), Mr. Shiro Mizogami (KEYENCE Co.) for their technical support. This work was supported by Grant-in-Aid for Scientific Research (C) (24591341, 15K09395) from the Japan Society for the Promotion of Science (JSPS), Takeda Science Foundation to YM.
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Maejima, Y., Kumamoto, K., Takenoshita, S. et al. Projections from a single NUCB2/nesfatin-1 neuron in the paraventricular nucleus to different brain regions involved in feeding. Brain Struct Funct 221, 4723–4731 (2016). https://doi.org/10.1007/s00429-015-1150-4
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DOI: https://doi.org/10.1007/s00429-015-1150-4