Considerable evidence suggests that dynorphin and neurokinin B (NKB) neurons in the hypothalamic arcuate nucleus participate in the sex-steroid regulation of reproduction. In the present study, we used dual-label immunofluorescence to explore the distribution of prodynorphin and proNKB immunoreactivity in the rat hypothalamus. Additionally, we investigated whether arcuate prodynorphin-ir (immunoreactive) neurons expressed the neurokinin 3 receptor (NK3R) or nuclear estrogen receptor-alpha (ERalpha). We found that the majority of prodynorphin-ir neurons in the rat arcuate nucleus expressed proNKB, whereas nearly all (99%) of the proNKB neurons were immunoreactive for prodynorphin. The arcuate nucleus was the only site in the hypothalamus where neuronal somata coexpressing prodynorphin and proNKB-immunoreactivity were identified. A dense plexus of double-labeled prodynorphin/proNKB-ir fibers was found within the arcuate nucleus extending to the median eminence and throughout the periventricular zone of the hypothalamus. Prodynorphin/proNKB fibers were also identified in the paraventricular nucleus, anterior hypothalamic area, medial preoptic area, median preoptic nucleus, anteroventral periventricular nucleus, and bed nucleus of the stria terminalis in a distribution consistent with previously described arcuate nucleus projections. Interestingly, the majority of prodynorphin-ir neurons in the arcuate nucleus expressed NK3R, and nearly 100% of the prodynorphin-ir neurons contained nuclear ERalpha. Our results suggest that there is a close functional relationship between dynorphin and NKB peptides within the arcuate nucleus of the rat, which may include an autofeedback loop mediated through NK3R. The diverse hypothalamic projections of fibers expressing both prodynorphin and proNKB provide evidence that these neurons may participate in a variety of homeostatic and neuroendocrine processes.

Neurokinin B (NKB) and kisspeptin receptor signaling are essential components of the reproductive axis. A population of neurons resides within the arcuate nucleus of the rat that expresses NKB, kisspeptin, dynorphin, NK3 receptors and estrogen receptor α. Here we investigate the projections of these neurons using NKB-immunocytochemistry as a marker. First, the loss of NKBimmunoreactive (ir) somata and fibers was characterized after ablation of the arcuate nucleus by neonatal injections of monosodium glutamate. Second, biotinylated dextran amine was injected into the arcuate nucleus and anterogradely labeled NKB-ir fibers were identified using dual-labeled immunofluorescence. Four major projection pathways are described: 1) Local projections within the arcuate nucleus bilaterally, 2) Projections to the median eminence including the lateral palisade zone, 3) Projections to a periventricular pathway extending rostrally to multiple hypothalamic nuclei, the septal region and BNST and dorsally to the dorsomedial nucleus and 4) Projections to a ventral hypothalamic tract to the lateral hypothalamus and medial forebrain bundle. The diverse projections provide evidence that NKB/kisspeptin/dynorphin neurons could integrate the reproductive axis with multiple homeostatic, behavioral and neuroendocrine processes. Interestingly, anterograde tracttracing revealed NKB-ir axons originating from arcuate neurons terminating on other NKB-ir somata within the arcuate nucleus. Combined with previous studies, these experiments reveal a bilateral interconnected network of sex-steroid responsive neurons in the arcuate nucleus of the rat that express NKB, kisspeptin, dynorphin, NK3 receptors and ERα and project to GnRH terminals in the median eminence. This circuitry provides a mechanism for bilateral synchronization of arcuate NKB/ kisspeptin/dynorphin neurons to modulate the pulsatile secretion of GnRH. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 March 17. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptLoss of function mutations in neurokinin B (NKB), the neurokinin 3 (NK3) receptor (the primary NKB receptor) or the kisspeptin receptor (GPR54) result in hypogonadotrophic hypogonadism with absence of pubertal development (Seminara et al., 2003;de Roux et al., 2003;Topaloglu et al., 2009). These studies document an essential role of NKB and kisspeptin receptor signaling in the regulation of the human reproductive axis. A key element of this regulatory circuitry is a gro...

Background: The 24-item Early-Onset Scoliosis Questionnaire (EOSQ-24) and 22-item Scoliosis Research Society (SRS-22) questionnaire measure health-related quality of life in patients with scoliosis. The EOSQ-24 has been recently validated in early-onset scoliosis (EOS), including congenital scoliosis (CS). The SRS-22 has been validated in idiopathic scoliosis. The EOSQ-24 is completed by the caregiver and the SRS-22 is completed by the patient. The primary purpose of this study was to compare the EOSQ-24 and SRS-22 in patients with CS. The secondary purpose was to compare scores by age and also in developmentally delayed patients. We hypothesized that the SRS-22 is appropriate for children with EOS from CS who do not have a diagnosis of developmental delay. Methods: This was a prospective comparative study. A prospective institutional CS database was queried to identify patients who had the EOSQ-24 and SRS-22 completed at the same time point. Children without a diagnosis of developmental delay completed both questionnaires if they understood the questions, regardless of age. Otherwise, the caregiver completed both questionnaires. For the analysis, similar questions were matched so that the EOSQ-24 questions fit into the SRS-22 domains of Function, Pain, Mental Health, and Satisfaction. Pearson correlation coefficients (r) were used to compare domain scores, with r≥0.70 indicating a strong relationship. Results: The final study group included 98 patients. The average age at completion of the questionnaires was 9.5 years. A strong correlation was found for all domains except Satisfaction when the patient or caregiver completed both questionnaires. Subanalysis demonstrated the strongest relationship between domains in the age group 0 to 5 years. In developmentally delayed patients, a weak correlation was noted for all domain scores except Pain, which showed a strong correlation. There was a strong correlation for Pain and a weak correlation for Satisfaction domains across all subgroups. Conclusions: The SRS-22 may be appropriate for children with EOS from CS who do not have a diagnosis of developmental delay. Our findings suggest that the results of previous studies that collected the SRS-22 and future studies that collect the EOSQ-24 can be correlated. It remains unclear which questionnaire is more suitable for developmentally delayed patients. Level of Evidence: Level I—diagnostic.

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