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Distribution of Neuropeptide S Receptor Mrna and Neurochemical Characteristics of Neuropeptide S- Expressing Neurons in the Rat Brain

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Distribution of Neuropeptide S Receptor Mrna and Neurochemical Characteristics of Neuropeptide S- Expressing Neurons in the Rat Brain THE JOURNAL OF COMPARATIVE NEUROLOGY 500:84–102 (2007) Distribution of Neuropeptide S Receptor mRNA and Neurochemical Characteristics of Neuropeptide S- Expressing Neurons in the Rat Brain YAN-LING XU,1 CHRISTINE M. GALL,2 VALERIE R. JACKSON,1,3 OLIVIER CIVELLI,1,3 AND RAINER K. REINSCHEID1,4* 1Department of Pharmacology, University of California Irvine, Irvine, California 92697 2Department of Anatomy and Neurobiology, University of California Irvine, Irvine, California 92697 3Department of Developmental and Cell Biology, University of California Irvine, Irvine, California 92697 4Program in Pharmaceutical Sciences, University of California Irvine, Irvine, California 92697 ABSTRACT Neuropeptide S (NPS) and its receptor (NPSR) constitute a novel neuropeptide system that is involved in regulating arousal and anxiety. The NPS precursor mRNA is highly expressed in a previously undescribed group of neurons located between the locus coeruleus (LC) and Bar- rington’s nucleus. We report here that the majority of NPS-expressing neurons in the LC area and the principal sensory trigeminal nucleus are glutamatergic neurons, whereas many NPS- positive neurons in the lateral parabrachial nucleus coexpress corticotropin-releasing factor (CRF). In addition, we describe a comprehensive map of NPSR mRNA expression in the rat brain. High levels of expression are found in areas involved in olfactory processing, including the anterior olfactory nucleus, the endopiriform nucleus, and the piriform cortex. NPSR mRNA is expressed in several regions mediating anxiety responses, including the amygdaloid complex and the paraventricular hypothalamic nucleus. NPSR mRNA is also found in multiple key regions of sleep neurocircuitries, such as the thalamus, the hypothalamus, and the preoptic region. In addition, NPSR mRNA is strongly expressed in major output and input regions of hippocampus, including the parahippocampal regions, the lateral entorhinal cortex, and the retrosplenial agranular cortex. Multiple hypothalamic nuclei, including the dorsomedial and the ventromedial hypothalamic nucleus and the posterior arcuate nucleus, express high levels of NPSR mRNA, indicating that NPS may regulate energy homeostasis. These data suggest that the NPS system may play a key role in modulating a variety of physiological functions, especially arousal, anxiety, learning and memory, and energy balance. J. Comp. Neurol. 500:84–102, 2007. © 2006 Wiley-Liss, Inc. Indexing terms: G protein-coupled receptor; in situ hybridization; expression pattern; locus coeruleus; glutamate; corticotropin-releasing factor; acetylcholine; GABA Neuropeptide S (NPS) and its receptor (NPSR) form a newly discovered neuropeptide system. In the rat, NPS is encoded by a precursor protein of 89 amino acids, contain- ing a typical amino-terminal signal peptide. The imma- Grant sponsor: National Institutes of Health; Grant number: MH-71313 ture NPS peptide sequence is preceded by a pair of basic (to R.K.R.); Grant number: MH-60231 (to O.C.); Grant number: DK-63001 amino acids (Lys-Arg) that are presumably cleaved by (to O.C.); Grant number: DK-70619 (to O.C.); Grant sponsor: National prohormone convertases to release the 20-amino-acid-long Alliance for Research on Schizophrenia and Depression (to R.K.R.). peptide (primary structure of rNPS: SFRNGVGS- *Correspondence to: Rainer K. Reinscheid, Program in Pharmaceutical Sciences, University of California Irvine, 360 Med Surge II, Irvine, CA GVKKTSFRRAKQ). Pharmacologically, NPS activates 92697-4625. E-mail: [email protected] NPSR at low nanomolar concentration, induces mobiliza- Received 7 April 2006; Revised 16 June 2006; Accepted 31 July 2006 2ϩ tion of intracellular Ca , increases intracellular levels of DOI 10.1002/cne.21159 cAMP, and stimulates phosphorylation of mitogen- Published online in Wiley InterScience (www.interscience.wiley.com). © 2006 WILEY-LISS, INC. The Journal of Comparative Neurology. DOI 10.1002/cne ANATOMICAL CHARACTERIZATION OF RAT NPS SYSTEM 85 activated protein kinase (Xu et al., 2004b; Reinscheid et in the pontine brainstem (Xu et al., 2004b). Thus, the al., 2005). Physiologically, central administration of NPS identity of any classical neurotransmitters in this novel in rodents induces hyperlocomotion, increases arousal and group of neurons in the LC area is still unknown. It is well wakefulness, and suppresses all stages of sleep. NPS ad- established that neuropeptides usually do not exist alone ministration also reduces anxiety-like behaviors in a bat- as neurotransmitters but colocalize with classical neuro- tery of four different tests that measure innate fear or transmitters or with other neuropeptides and may play responses to novelty in rodents (Xu et al., 2004b). Anatom- important roles in modulating the activities of these ically, we have shown that NPS precursor mRNA is ex- neurotransmitters/neuromodulators (Hokfelt et al., 2000). pressed only in several discrete regions in the rat brain. It has been reported that ␥-aminobutyric acid (GABA)- The dorsomedial hypothalamus and amygdala contain ergic neurons (Aston-Jones et al., 2004), cholinergic neu- scattered NPS precursor mRNA signals. Strong expres- rons (Sutin and Jacobowitz, 1988; Rizvi et al., 1994), and sion of NPS precursor mRNA was observed in three brain- glutamatergic neurons (Stornetta et al., 2002; Varoqui et stem regions, including the principle sensory trigeminal al., 2002; Moriyama and Yamamoto, 2004) are present in nucleus, lateral parabrachial nucleus, and locus coeruleus LC and the surrounding peri-LC area. In this study, we (LC) area. The NPS-expressing neurons in the LC area are therefore determined the chemical neuroanatomy of NPS- localized ventromedial to the LC and caudolateral to Bar- expressing cells in the rat brainstem, by using glutamate rington’s nucleus, a neighboring nucleus of LC that is acid decarboxylase 67 (GAD67; Lauterborn et al., 1995), often referred to as the pontine micturition center. The choline acetyltransferase (ChAT; Lauterborn et al., 1993), unique anatomical pattern of this group of NPS- and vesicular glutamate transporters (VGLUTs; Smith et expressing neurons reveals a previously unmapped popu- al., 2001; McCullumsmith and Meador-Woodruff, 2003) as lation of cells between Barrington’s nucleus and the LC. In markers for GABAergic, cholinergic, and glutamatergic our previous study, we have demonstrated that neither neurons, respectively. This study will reveal for the first noradrenaline (NA), the major neurotransmitter synthe- time the neurochemical profiles of NPS-producing neu- sized in LC neurons, nor corticotropin-releasing factor rons and the neurotransmitters/neuromodulators that (CRF), the major peptidergic transmitter in Barrington’s may be coreleased with NPS peptide. Identification of nucleus, is expressed in the NPS-synthesizing cell cluster coexisting transmitters in NPS-producing neurons will Abbreviations 3V third ventricle MPT medial pretectal nucleus 4V fourth ventricle OPT olivary pretectal nucleus ac anterior commissure opt optical tract aca anterior commissure, anterior part ox optic chiasm ACo anterior cortical amygdaloid nucleus PAG periaqueductal gray AH anterior hypothalamic area PaMP medial parvicellular paraventricular hypothalamic nu- AMV anteromedial thalamic nucleus, ventral part cleus AON anterior olfactory nucleus PaPo paraventricular hypothalamic nucleus, posterior part Apir amygdalopiriform transition area PaS parasubiculum aq aqueduct PaV paraventricular hypothalamic nucleus, ventral part Arc P arcuate hypothalamic nucleus, posterior part pc posterior commissure CA1 CA1 region of the hippocampus PeF perifornical nucleus Cb cerebellum PH posterior hypothalamic nucleus cc corpus callosum Pir piriform cortex Cg1 cingulate cortex, area 1 PLi posterior limitans thalamic nucleus Cl claustrum PMCo posteromedial cortical amygdala CLi caudal linear nucleus of raphe PMD premammillary nucleus, dorsal part CM central medial thalamic nucleus PMV premammillary nucleus, ventral part cp cerebral peduncle Post postsubiculum DEn dorsal endopiriform nucleus Pr5 principle sensory 5 nucleus DG dentate gyrus PrC precommissural nucleus DMH dorsomedial hypothalamic nucleus PrS presubiculum DpG deep gray layer of superior colliculus PT paratenial thalamic nucleus DR dorsal raphe DTM dorsal tuberomammillary nucleus PtA parietal association cortex En endopiriform nucleus PVP paraventricular thalamic nucleus, posterior f fornix Re reuniens thalamic nucleus HDB nucleus of the horizontal limb of the diagonal band Rh rhomboid thalamic nucleus Hpx hippocampus RSA retrosplenial agranular cortex I intercalated nuclei of amygdala S subiculum IAM interanteromedial thalamic nucleus SCO subcommissural organ IPR interpeduncular nucleus, rostral part scp superior cerebellar peduncle LC locus coeruleus SG suprageniculate thalamic nucleus LENt lateral entorhinal cortex SNCD substantia nigra, compact part, dorsal tier LH lateral hypothalamic area SuG superficial layer of superior colliculus LPB lateral parabrachial nucleus Tg/PnO tegmental area/pontine reticular nucleus, oral part LPO lateral preoptic area VLPO ventrolateral preoptic nucleus LV lateral ventricle VMH ventromedial hypothalamic nucleus M2 motor cortex 2 VMHDM ventromedial hypothalamic nucleus, dorsomedial part MeAD medial amygdala, anterodorsal part VTA ventral tegmental area MePD/V medial amygdala, posterodorsal/ventral VTM ventral tuberomammillary nucleus MnR median raphe nucleus Xi xiphoid thalamic nucleus The Journal of Comparative Neurology. DOI 10.1002/cne
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