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 Barrington'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.
GPR39, an orphan G protein-coupled receptor, has been recently identified as the receptor for the bioactive peptide obestatin. Obestatin is secreted from the stomach and acts as an anti-appetite hormone. This activity is induced whether obestatin is administered intraperitoneally or intracerebroventricularly. GPR39 is known to be expressed in the central nervous system but its precise localization is unknown. In view of the growing importance of this system, we decided to study the sites of GPR39 mRNA expression by in-situ hybridization. We find the highest levels of GPR39 mRNA in the amygdala, the hippocampus, and the auditory cortex and low levels in several other brain regions. Surprisingly, we find no expression of GPR39 in the hypothalamus, expected to be the site of the anorexigenic action of obestatin.
Two glycoprotein hormone subunits, (glycoprotein hormone a2-subunit GPA2) and (glycoprotein hormone b5-subunit GPB5) have been recently discovered which, when expressed in vitro, heterodimerize to form a new hormone called thyrostimulin. Thyrostimulin activates the thyroid-stimulating hormone receptor (TSHR) and has thyrotropic activity. Immunological studies have indicated that both subunits co-localize in pituitary cells. To explore the function of thyrostimulin in the rat, we have cloned rat GPA2 and GPB5, reconstituted the heterodimers in vitro, and confirmed that rat thyrostimulin activates TSHR with an affinity similar to that of TSH. In situ hybridization of the pituitary showed that while GPA2 is expressed in the anterior lobe, GPB5 is not detected in any of the lobes. A quantitative analysis showed that the co-localization of GPA2 and GPB5 is restricted in the rat to the eye and the testis. We found that GPB5 can be detected in the pituitary by quantitative-PCR, but at extremely low levels, 2000-fold lower than TSH b-subunit (GPBtsh). Furthermore, the levels of GPB5 remain constant during the estrus cycle, while those of GPA2 vary. Finally, we found that none of the thyrostimulin subunits was induced by TRH in pituitary cell culture. These data point at the thyrostimulin system as being functionally different to the TSH system.
In the rat, the neuropeptide B/neuropeptide W (NPB/NPW) system is composed of two ligands, neuropeptide B (NPB) and neuropeptide W (NPW), and one receptor, GPR7. Although preliminary analyses show roles in feeding, hormone secretion, and analgesia, the lack of a detailed anatomical map impairs our understanding of the NPB/NPW system. We demonstrate in this report the expression patterns of GPR7, NPB, and NPW precursor messenger ribonucleic acid (mRNA) in the rat brain by using in situ hybridization and in situ binding experiments. The amygdala expresses the highest levels of GPR7 mRNA and binding signals. Other nuclei with high levels of expression and binding are the suprachiasmatic and the ventral tuberomamillary nuclei. Moderate levels are seen in the dorsal endopiriform, dorsal tenia tecta, bed nucleus, and the red nucleus. Low levels are in the olfactory bulb, parastrial nucleus, hypothalamus, laterodorsal tegmentum, superior colliculus, locus coeruleus, and the nucleus of the solitary tract. Although the NPB precursor is mostly expressed at low levels in the brain, moderate expression is seen in anterior olfactory nucleus, piriform cortex, median preoptic nucleus, basolateral amygdala, hippocampus, medial tuberal nucleus, substantia nigra, dorsal raphe nucleus, Edinger-Westphal nucleus, and the locus coeruleus. To our surprise, the expression of NPW precursor was not detected. Our study greatly expands the preliminary in situ data previously reported. With this map of the NPB/NPW system in the rat brain, a better understanding of the functional implications of the system in various behavioral paradigms is now possible.
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