Spatiotemporal distribution of vasoactive intestinal polypeptide receptor 2 in mouse suprachiasmatic nucleus

Vasoactive intestinal polypeptide (VIP) signaling is critical for circadian rhythms. For example, the expression of VIP and its main receptor, VPAC2R, is necessary for maintaining synchronous daily rhythms among neurons in the suprachiasmatic nucleus (SCN), a master circadian pacemaker in animals. Where and when VPAC2R protein is expressed in the SCN and other brain areas has not been examined. Using immunohistochemistry, we characterized a new antibody and found that VPAC2R was highly enriched in the SCN and detectable at low levels in many brain areas. Within the SCN, VPAC2R was circadian, peaking in the subjective morning, and abundantly expressed from the rostral to caudal margins with more in the dorsomedial than ventrolateral area. VPAC2R was found in nearly all SCN cells including neurons expressing either VIP or vasopressin (AVP). SCN neurons mainly expressed VPAC2R in their somata and dendrites, not axons. Finally, constant light increased VIP and AVP expression, but not VPAC2R. We conclude that the circadian clock, not the ambient light level, regulates VPAC2R protein localization. These results are consistent with VPAC2R playing a role in VIP signaling at all times of day, broadly throughout the brain and in all SCN cells. J. Comp. Neurol. 520:2730–2741, 2012. © 2012 Wiley Periodicals, Inc.

[1]  H. Okamura,et al.  Localization of vasoactive intestinal peptide (VIP) messenger RNA (mRNA) in amacrine cells of rat retina. , 1992, Current eye research.

[2]  E. Maywood,et al.  The VPAC2 Receptor Is Essential for Circadian Function in the Mouse Suprachiasmatic Nuclei , 2002, Cell.

[3]  Joseph S. Takahashi,et al.  Temperature as a Universal Resetting Cue for Mammalian Circadian Oscillators , 2010, Science.

[4]  Shin Yamazaki,et al.  Constant light desynchronizes mammalian clock neurons , 2005, Nature Neuroscience.

[5]  P. Wise,et al.  Localization of the VIP2 Receptor Protein on GnRH Neurons in the Female Rat. , 2000, Endocrinology.

[6]  C. Colwell,et al.  Vasoactive Intestinal Peptide Is Critical for Circadian Regulation of Glucocorticoids , 2008, Neuroendocrinology.

[7]  Christine Gall,et al.  Distribution of VIP- and NPY-like immunoreactivities in rat main olfactory bulb , 1986, Brain Research.

[8]  S. Yamaguchi,et al.  Synchronization of Cellular Clocks in the Suprachiasmatic Nucleus , 2003, Science.

[9]  J. Hannibal,et al.  Mice lacking the PACAP type I receptor have impaired photic entrainment and negative masking. , 2008, American journal of physiology. Regulatory, integrative and comparative physiology.

[10]  Sara J. Aton,et al.  Come Together, Right…Now: Synchronization of Rhythms in a Mammalian Circadian Clock , 2005, Neuron.

[11]  K. Shinohara,et al.  Temporal profiles of vasoactive intestinal polypeptide precursor mRNA and its receptor mRNA in the rat suprachiasmatic nucleus. , 1999, Brain research. Molecular brain research.

[12]  R. Moore,et al.  Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections , 2001, Brain Research.

[13]  E. Maywood,et al.  A diversity of paracrine signals sustains molecular circadian cycling in suprachiasmatic nucleus circuits , 2011, Proceedings of the National Academy of Sciences.

[14]  P. Taghert,et al.  Widespread Receptivity to Neuropeptide PDF throughout the Neuronal Circadian Clock Network of Drosophila Revealed by Real-Time Cyclic AMP Imaging , 2008, Neuron.

[15]  Imre Kalló,et al.  Expression of VIP and/or PACAP receptor mRNA in peptide synthesizing cells within the suprachiasmatic nucleus of the rat and in its efferent target sites , 2004, The Journal of comparative neurology.

[16]  Gagandeep Kaur,et al.  Regulation of vasoactive intestinal polypeptide release in the suprachiasmatic nucleus circadian clock , 2010, Neuroreport.

[17]  Anthony J. Harmar,et al.  Synchronization and Maintenance of Timekeeping in Suprachiasmatic Circadian Clock Cells by Neuropeptidergic Signaling , 2006, Current Biology.

[18]  T. Bonner,et al.  Two receptors for vasoactive intestinal polypeptide with similar specificity and complementary distributions. , 1994, Endocrinology.

[19]  K. Shinohara,et al.  Luminance-dependent decrease in vasoactive intestinal polypeptide in the rat suprachiasmatic nucleus , 1998, Neuroscience Letters.

[20]  H. Marston,et al.  Overexpression of the human VPAC2 receptor in the suprachiasmatic nucleus alters the circadian phenotype of mice. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[21]  P. Taghert,et al.  PDF receptor expression reveals direct interactions between circadian oscillators in drosophila , 2010, The Journal of comparative neurology.

[22]  A. Harmar,et al.  Circadian changes in the expression of vasoactive intestinal peptide 2 receptor mRNA in the rat suprachiasmatic nuclei. , 1998, Brain research. Molecular brain research.

[23]  N. Heintz.  Gene Expression Nervous System Atlas (GENSAT) , 2004, Nature Neuroscience.

[24]  J. Macdonald,et al.  Vasoactive intestinal peptide acts via multiple signal pathways to regulate hippocampal NMDA receptors and synaptic transmission , 2009, Hippocampus.

[25]  H. Vaudry,et al.  Distribution and functional characterization of pituitary adenylate cyclase–activating polypeptide receptors in the brain of non-human primates , 2009, Neuroscience.

[26]  C. Colwell,et al.  Disrupted circadian rhythms in VIP- and PHI-deficient mice. , 2003, American journal of physiology. Regulatory, integrative and comparative physiology.

[27]  S. T. Inouye,et al.  Photic regulation of peptides located in the ventrolateral subdivision of the suprachiasmatic nucleus of the rat: daily variations of vasoactive intestinal polypeptide, gastrin-releasing peptide, and neuropeptide Y , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[28]  D. Cutler,et al.  Vasoactive intestinal polypeptide (VIP) phase‐shifts the rat suprachiasmatic nucleus clock in vitro , 2001, The European journal of neuroscience.

[29]  A. Harmar,et al.  Transgenic approach reveals expression of the VPAC2 receptor in phenotypically defined neurons in the mouse suprachiasmatic nucleus and in its efferent target sites , 2004, The European journal of neuroscience.

[30]  Erik D. Herzog,et al.  Neurons and networks in daily rhythms , 2007, Nature Reviews Neuroscience.

[31]  T. Horvath,et al.  Vasoactive intestinal peptide fibers innervate neuroendocrine dopaminergic neurons , 2001, Brain Research.

[32]  T. Brown,et al.  Effects of Vasoactive Intestinal Polypeptide on Neurones of the Rat Suprachiasmatic Nuclei In Vitro , 2002, Journal of neuroendocrinology.

[33]  M. A. Rea.  VIP-stimulated cyclic AMP accumulation in the suprachiasmatic hypothalamus , 1990, Brain Research Bulletin.

[34]  F. Stivala,et al.  Pituitary adenylate cyclase activating polypeptide prevents apoptosis in cultured cerebellar granule neurons. , 1996, Molecular pharmacology.

[35]  K. Joo,et al.  Distribution of vasoactive intestinal peptide and pituitary adenylate cyclase‐activating polypeptide receptors (VPAC1, VPAC2, and PAC1 receptor) in the rat brain , 2004, The Journal of comparative neurology.

[36]  R. Maldonado,et al.  Altered emotional behavior in PACAP-type-I-receptor-deficient mice. , 2001, Brain research. Molecular brain research.

[37]  P. Wise,et al.  In vivo antisense antagonism of vasoactive intestinal peptide in the suprachiasmatic nuclei causes aging-like changes in the estradiol-induced luteinizing hormone and prolactin surges. , 1996, Endocrinology.

[38]  John E. Ottenweller,et al.  Diurnal variations in vasoactive intestinal polypeptide-like immunoreactivity in the suprachiasmatic nucleus of congenitally anophthalmic mice , 1995, Brain Research.

[39]  D. Cutler,et al.  Aberrant Gating of Photic Input to the Suprachiasmatic Circadian Pacemaker of Mice Lacking the VPAC2 Receptor , 2004, Journal of Neuroscience.

[40]  Erik D Herzog,et al.  Vasoactive intestinal polypeptide requires parallel changes in adenylate cyclase and phospholipase C to entrain circadian rhythms to a predictable phase. , 2011, Journal of neurophysiology.

[41]  H. Piggins,et al.  Neuropeptide Signaling Differentially Affects Phase Maintenance and Rhythm Generation in SCN and Extra-SCN Circadian Oscillators , 2011, PloS one.

[42]  David K Welsh,et al.  Suprachiasmatic nucleus: cell autonomy and network properties. , 2010, Annual review of physiology.

[43]  R. Schrier,et al.  Role of glucocorticoid hormones in arginine vasopressin gene regulation. , 2001, Biochemical and biophysical research communications.

[44]  C. Colwell,et al.  Vasoactive intestinal peptide and the mammalian circadian system. , 2007, General and comparative endocrinology.

[45]  J. Francon,et al.  Heterogeneity of microtubule-associated proteins and brain development. , 1982, European journal of biochemistry.

[46]  C. Colwell,et al.  Circadian regulation of cardiovascular function: a role for vasoactive intestinal peptide. , 2011, American journal of physiology. Heart and circulatory physiology.

[47]  H. Kobayashi,et al.  Effects of vasoactive intestinal peptide (VIP) on scopolamine-induced amnesia in the rat , 1994, Neuropeptides.

[48]  C. Colwell,et al.  Disrupted neuronal activity rhythms in the suprachiasmatic nuclei of vasoactive intestinal polypeptide-deficient mice. , 2007, Journal of neurophysiology.

[49]  I. Gozes,et al.  Learning and sexual deficiencies in transgenic mice carrying a chimeric vasoactive intestinal peptide gene , 2007, Journal of Molecular Neuroscience.

[50]  S. Honma,et al.  Two distinct oscillators in the rat suprachiasmatic nucleus in vitro. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[51]  S. Gammeltoft,et al.  The regional distribution of receptors for vasoactive intestinal polypeptide (VIP) in the rat central nervous system , 1985, Brain Research.

[52]  Erik D Herzog,et al.  Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons , 2005, Nature Neuroscience.

[53]  G. Banker,et al.  Activated c-Jun N-Terminal Kinase Is Required for Axon Formation , 2006, The Journal of Neuroscience.

[54]  J. Takahashi,et al.  Targeted Deletion of the Vgf Gene Indicates that the Encoded Secretory Peptide Precursor Plays a Novel Role in the Regulation of Energy Balance , 1999, Neuron.