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Vasoactive Intestinal Polypeptide Mediates Circadian Rhythms in Mammalian Olfactory Bulb and Olfaction

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Vasoactive Intestinal Polypeptide Mediates Circadian Rhythms in Mammalian Olfactory Bulb and Olfaction 6040 • The Journal of Neuroscience, April 23, 2014 • 34(17):6040–6046 Systems/Circuits Vasoactive Intestinal Polypeptide Mediates Circadian Rhythms in Mammalian Olfactory Bulb and Olfaction Jae-eun Kang Miller,1,2* Daniel Granados-Fuentes,1* Thomas Wang,1 Luciano Marpegan,1 Timothy E. Holy,2 and Erik D. Herzog1 Departments of 1Biology and 2Anatomy and Neurobiology, Washington University, St. Louis, Missouri 63130 Accumulating evidence suggests that the olfactory bulbs (OBs) function as an independent circadian system regulating daily rhythms in olfactoryperformance.However,thecellsandsignalsintheolfactorysystemthatgenerateandcoordinatethesecircadianrhythmsareunknown. Using real-time imaging of gene expression, we found that the isolated olfactory epithelium and OB, but not the piriform cortex, express similar, sustained circadian rhythms in PERIOD2 (PER2). In vivo, PER2 expression in the OB of mice is circadian, approximately doubling with a peak around subjective dusk. Furthermore, mice exhibit circadian rhythms in odor detection performance with a peak at approximately subjective dusk. We also found that circadian rhythms in gene expression and odor detection performance require vasoactive intestinal polypeptide (VIP) or its receptor VPAC2R. VIP is expressed, in a circadian manner, in interneurons in the external plexiform and periglomerular layers, whereas VPAC2R is expressed in mitral and external tufted cells in the OB. Together, these results indicate that VIP signaling modulates the output from the OB to maintain circadian rhythms in the mammalian olfactory system. Key words: circadian; clock; olfaction; olfactory discrimination; rhythms; VIP Introduction 2011). Furthermore, daily rhythms in the OB and olfactory dis- Daily rhythms, including the sleep–wake and fasting–feeding cy- crimination persist when circadian rhythms are eliminated in cles, have, over the past 40 years, been attributed to a circadian the SCN (Abraham et al., 2005) or when the SCN are ablated pacemaker in the mammalian suprachiasmatic nucleus (SCN). (Granados-Fuentes et al., 2004a). Thus, a circadian system that Recent discoveries that other cell types also exhibit autonomous parallels the canonical SCN-dependent system appears to regu- circadian changes in gene expression highlighted the possibility late olfaction. However, we do not know how olfactory circuits that many tissues may regulate circadian changes in specific phys- generate and coordinate daily rhythms in olfaction. iological and behavioral processes (Dibner et al., 2010; Welsh et The neuropeptide vasoactive intestinal polypeptide (VIP) is al., 2010). The olfactory bulb (OB), for example, may function as produced by neurons sparsely distributed throughout the retina, an independent circadian system controlling daily changes in neocortex, SCN, and OB (Shinohara et al., 1994, 1995; Crespo et olfaction. OB slices exhibit intrinsic circadian rhythms in firing al., 2002; Gracia-Llanes et al., 2003; Brand et al., 2005; Vosko et rate and PERIOD (PER) gene activity in vitro (Granados-Fuentes al., 2007; Hu et al., 2011; Nakamachi et al., 2012; Zou et al., 2014). et al., 2004b). Mice show circadian rhythms in odor detection Coordinated circadian oscillations in locomotion depend on VIP performance in the absence of time cues from the environment, signaling among SCN cells. Loss of VIP or its cognate receptor and this circadian rhythm in olfactory sensitivity depends on the VPAC2R (encoded by the Vipr2 gene) results in a loss of daily expression of canonical clock genes (Granados-Fuentes et al., rhythms in running-wheel behavior and desynchronized rhythms in spontaneous firing and gene expression among SCN neurons (Har- mar et al., 2002; Colwell et al., 2003; Aton and Herzog, 2005; Brown Received Nov. 6, 2013; revised March 12, 2014; accepted March 24, 2014. et al., 2005; Maywood et al., 2006). Here, we tested the hypothesis Author contributions: J.-e.K.M., D.G.-F., L.M., T.E.H., and E.D.H. designed research; J.-e.K.M., D.G.-F., T.W., and that VIP is required for circadian rhythms in the OB and in L.M.performedresearch;J.-e.K.M.,D.G.-F.,T.W.,L.M.,T.E.H.,andE.D.H.analyzeddata;J.-e.K.M.,D.G.-F.,T.E.H.,and olfaction. E.D.H. wrote the paper. This work was supported by National Institute of Mental Health Grant 63104 (E.D.H.) and National Institutes of Health Director’s Pioneer Award DP1 OD006437 and Grant R01 DC005964 (T.E.H.). We thank the members of the Materials and Methods Holy and Herzog laboratories. Animals and locomotor activity recordings. All procedures were in accor- The authors declare no competing financial interests. dance with the guidelines of the Washington University Institutional *J.-e.K.M. and D.G.-F. contributed equally to this work. Animal Care and Use Committee and National Institutes of Health. Male Correspondence should be addressed to Dr. Erik D. Herzog, Department Biology, Washington University, One mice ranging in age from 8 to 12 weeks were maintained on a C57BL/6 Brookings Drive, Box 1137, St. Louis, MO 63130. E-mail: [email protected]. genetic background and selectively crossed to produce heterozygous or J.-e. K. Miller’s present address: Department of Biological Sciences, Columbia University, 550 West 120 Street, Box 4822, New York, NY 10027. homozygous alleles of the PER2::LUCIFERASE (LUC) knock-in gene L. Marpegan’s present address: Department of Science and Technology, National University of Quilmes, Roque (founders generously provided by Dr. J. Takahasi, University of Texas Sa´enz Pen˜a 352, Bernal, Buenos Aires, Argentina, B1876BXD. Southwestern, Dallas, TX), Vip gene deletion (founders generously pro- DOI:10.1523/JNEUROSCI.4713-13.2014 vided by Drs. C. Colwell and J. Waschek, University of California, Los Copyright © 2014 the authors 0270-6474/14/346040-07$15.00/0 Angeles, Los Angeles, CA), Protocadherin–Cre;Ai38 transgene (RIKEN Miller, Granados-Fuentes et al. • VIP Mediates Circadian Rhythms in Mammalian OB J. Neurosci., April 23, 2014 • 34(17):6040–6046 • 6041 BioResource Center and The Jackson Laboratory), and Gad65–EGFP to olfactory marker protein (OMP; goat, 1:2000; catalog #544-10001; transgene (The Jackson Laboratory). Mice were maintained in a 12 h Wako), VIP (rabbit, 1:2000; Immunostar), GFP (chicken, 1:500; Ab- light/dark (LD) cycle or constant darkness (DD) in the Danforth campus cam), and VPAC2R (rabbit, 1:1000; Abcam) were applied in 3% BSA and or the medical campus animal facility at Washington University. 0.25% Triton X-100 in PBS for overnight at 4°C. Secondary antibodies Locomotor activity and olfactory performance were recorded from (1:200 in 3% BSA and 0.25% Triton X-100 in PBS, donkey antibody to mice housed individually in cages with ad libitum access to food, water, goat IgG conjugated with TRITC, donkey antibody to rabbit IgG conju- and a running wheel. Light level and wheel revolutions in 1 min bins were gated with Cy2, or goat antibody to rabbit IgG conjugated with Cy3; stored on a computer (Clocklab; Actimetrics). Animals were in LD Jackson ImmunoResearch) were applied for 2 h at room temperature. (lights on at 7:00 A.M.) for ϳ3 weeks during the olfactory training ses- Cell nuclei were stained with DAPI. Images were taken with a confocal sions and then tested for olfactory discrimination after2dinDDas microscope (A1 confocal laser microscope system; Nikon Instruments). described previously (Granados-Fuentes et al., 2011). Zeitgeber times DAB immunohistochemistry. Mice were perfused at four CTs (CT 6, 12, (ZT) 0 and 12 refer to light onset and offset in LD, respectively. Circadian 18, and 24; n ϭ 3–4 mice per time point), and the brains were processed time (CT) 12 refers to activity onset in DD when the mice began running for immunolabeling of the OB. Briefly, coronal cryosections (30 ␮m Ͼ15 revolutions per minute for at least 6 h each day (Clocklab). Other thick) of the OB were incubated with a VIP antibody (rabbit anti-VIP, CTs were calculated in circadian hours from CT 12 by dividing the free- 1:2000; Immunostar) and then processed according to the avidin–biotin running period of locomotor activity by 24. method (ABC kit, pk6101; Vector Laboratories). Digitized images (Re- Surgery. To record Per2 gene expression in the OB in vivo, we created a tiga 1350EX; QImaging) using QImaging Software were taken using cranial window over the OB. Mice were anesthetized with isoflurane standardized illumination for all sections. The brightness and contrast of (2.5% for induction and 1% for maintenance), warmed at 37°C on a all images were processed identically with NIH ImageJ (http://rsbweb. heating pad, and treated with an ophthalmic ointment to protect the nih.gov/ij). To quantify the intensity of expression, we averaged the pixel eyes. Sterile surgical procedures were used throughout. For the in vivo intensity of VIP-immunoreactive cell bodies in the external plexiform PER2::LUC imaging experiments, a 2.5-mm-diameter craniotomy was layer (EPL; 10 cell bodies per brain in two sections at a certain CT) of the created over the OB using a dental drill (Abraham et al., 2005) during OB and subtracted the average background intensity in the granule cell subjective night. We fixed a glass coverslip (#1 thickness, 3 ϫ 4 mm) layer (GCL). above the OB with dental acrylic and filled the space between the dura Olfactometry. We measured olfactory thresholds using previously and the coverslip with 2% agarose in artificial CSF (in mM: 126 NaCl, 26 published methods (Granados-Fuentes et al., 2011). Briefly, mice were NaHCO3, 3 KCl, 1 NaH2PO4, 2 MgSo4, 2 CaCl2, and 10 mM glucose). For trained in an olfactometer to sniff in a central nose cone and then poke systemic luciferin delivery, a mini-osmotic pump (model 2001; Alzet, their noses into a left or right nose cone to indicate whether they detected Durect) filled with beetle D-luciferin (30 mg/ml in 0.1 M PBS, pH 7.2; the presence of an odor.
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