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Hypothalamic neurons expressing gonadotropin‐releasing hormone (GnRH), the "master molecule" regulating reproduction and fertility, migrate from their birthplace in the nose to their destination using a system of guidance cues, which include the semaphorins and their receptors, the neuropilins and plexins, among others. Here, we show that selectively deleting neuropilin‐1 in new GnRH neurons enhances their survival and migration, resulting in excess neurons in the hypothalamus and in their unusual accumulation in the accessory olfactory bulb, as well as an acceleration of mature patterns of activity. In female mice, these alterations result in early prepubertal weight gain, premature attraction to male odors, and precocious puberty. Our findings suggest that rather than being influenced by peripheral energy state, GnRH neurons themselves, through neuropilin–semaphorin signaling, might engineer the timing of puberty by regulating peripheral adiposity and behavioral switches, thus acting as a bridge between the reproductive and metabolic axes. Synopsis: By regulating GnRH neuronal survival, migration and activity, the expression of Neuropilin 1 in GnRH neurons regulates sexual attraction, prepubertal weight gain and the timing of puberty. Nrp1 expression in GnRH neurons controls their number and distribution during embryogenesis.The lack of Nrp1 expression in GnRH neurons triggers early sexual behavior.GnRH neurons are directly involved in prepubertal weight gain.Disrupting Nrp1 signaling in GnRH neurons leads to central precocious puberty. [ABSTRACT FROM AUTHOR]

Mitral and tufted cells are the projection neurons of the olfactory bulb ( OB). We previously reported that somata location and innervation patterns were different between early- and late-born mitral cells (Imamura et al., 2011). Here, we introduced a plasmid that drives the expression of a GFP gene into the mouse OB using in utero electroporation, and demonstrated that we can deliver the plasmid vectors into distinct subsets of OB projection neurons by changing the timing of electroporation after fertilisation. The electroporation performed at embryonic day (E)10 preferentially labeled mitral cells in the accessory OB and main OB mitral cells in dorsomedial mitral cell layer ( MCL). In contrast, the E12 electroporation introduced the plasmid vectors preferentially into main OB mitral cells in the ventrolateral MCL and tufted cells. Combining these data with BrdU injections, we confirmed that E10 and E12 electroporation preferentially labeled early- and late-born projection neurons, respectively. This work introduces a novel method for segregated labeling of mouse olfactory bulb projection neurons based on their birthdates. With this technique we found that early- and late-born projection neurons extend their secondary dendrites in the deep and superficial external plexiform layer ( EPL), respectively. Although a similar segregation has been suggested for mitral vs. tufted cell dendrites, we found mitral cells projecting secondary dendrites into the superficial EPL in E12-electroporated main OB. Our observations indicate that timing of neurogenesis regulates not only somata location and innervation patterns but also the laminar organisation of projection neuron dendrites in the EPL. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 2 ( SCA2) is a hereditary neurodegenerative disorder caused by the expansion of the trinucleotide CAG repeats encoding elongated polyglutamine tract in ataxin-2, the SCA2 gene product. Polyglutamine diseases comprise nine genetic entities, including seven different forms of spinocerebellar ataxias, Huntington's disease, and spinal and bulbar muscular atrophy. These are pathologically characterized by neuronal loss and intranuclear aggregates or inclusions of mutant proteins including expanded polyglutamine in selected neuronal groups. Previously, we examined immunolocalization of ubiquitin, expanded polyglutamine (probed by 1 C2 antibody), and ataxin-2 in genetically confirmed SCA2 patients. In the present study, we expanded this approach by distinguishing different patterns of subcellular 1 C2 immunoreactivity ('granular cytoplasmic,' 'cytoplasmic and nuclear' and 'nuclear with inclusions.') and by quantifying their regional frequencies in three autopsied SCA2 brains at different stage of the disease. Comparison with neuronal loss and gliosis revealed that overall 1 C2 immunoreactivity was paralleled with their severity. Furthermore, appearance of granular cytoplasmic pattern corresponded to early stage, cytoplasmic and nuclear pattern to active stage, and nuclear with inclusions pattern to final stage. We conclude that this 1 C2-immunoreactive typing may be useful for evaluating the overall severity and extent of affected regions and estimating the neuropathological stage of SCA2. [ABSTRACT FROM AUTHOR]

Gene transfer has proven to be an effective neurobiological tool in a number of neurodegenerative diseases, but it is not known if it can correct a sleep disorder. Narcolepsy is a neurodegenerative sleep disorder linked to the loss of neurons containing the neuropeptide orexin, also known as hypocretin. Here, a replication-defective herpes simplex virus-1 amplicon-based vector was constructed to transfer the gene for mouse prepro-orexin into mice with a genetic deletion of the orexin gene. After in vitro tests confirmed successful gene transfer into cells, the gene vector was delivered to the lateral hypothalamus of orexin knockout (KO) mice where the orexin peptide was robustly expressed in the somata and processes of numerous neurons, and the peptide product was detected in the cerebrospinal fluid. During the 4-day life-span of the vector the incidence of cataplexy declined by 60%, and the levels of rapid eye movement sleep during the second half of the night were similar to levels in wild-type mice, indicating that narcoleptic sleep–wake behavior in orexin KO mice can be improved by targeted gene transfer. [ABSTRACT FROM AUTHOR]

Down syndrome (DS) patients suffer from mental retardation, but also display enhanced β-APP production and develop cortical amyloid plaques at an early age. As β-APP and Notch are both processed by γ-secretase, we analyzed expression of the Notch signaling pathway in the adult DS brain and in a model system for DS, human trisomy 21 fibroblasts by quantitative PCR. In adult DS cortex we found that Notchl, Dll1 and Hes1 expression is up-regulated. Moreover, DS fibroblasts and Alzheimer disease cortex also show overexpression of Notchl and Dll1, indicating that enhanced β-APP processing found in both DS and AD could be instrumental in these changes. Using pull-down studies we could demonstrate interaction of APP with Notch 1, suggesting that these transmembrane proteins form heterodimers, but independent of γ-secretase. We could demonstrate binding of the intracellular domain of Notch1 to the APP adaptor protein Fe65. Furthermore, activated Notch1 can transactivate an APP target gene, Kail, and vice versa, activated APP can trans-activate the classical Notch target gene Hes1. These data suggest that Notch expression is activated in Down syndrome, possibly through cross-talk with APP signaling. This interaction might affect brain development, since the Notch pathway plays a pivotal role in neuron-glia differentiation. [ABSTRACT FROM AUTHOR]