Abstract
Adult neurogenesis, a process that consists in the generation of new neurons from adult neural stem cells, represents a remarkable illustration of the brain structural plasticity abilities. The hypothalamus, a brain region that plays a key role in the neuroendocrine regulations including reproduction, metabolism or food intake, houses neural stem cells located within a hypothalamic neurogenic niche. In adult sheep, a seasonal mammalian species, previous recent studies have revealed photoperiod-dependent changes in the hypothalamic cell proliferation rate. In addition, doublecortin (DCX), a microtubule-associated protein expressed in immature migrating neurons, is highly present in the vicinity of the hypothalamic neurogenic niche. With the aim to further explore the mechanism underlying adult sheep hypothalamic neurogenesis, we first show that new neuron production is also seasonally regulated since the density of DCX-positive cells changes according to the photoperiodic conditions at various time points of the year. We then demonstrate that cyclin-dependant kinase-5 (Cdk5) and p35, two proteins involved in DCX phosphorylation and known to be critically involved in migration processes, are co-expressed with DCX in young hypothalamic neurons and are capable of in vivo interaction. Finally, to examine the migratory potential of these adult-born neurons, we reveal the rostro-caudal extent of DCX labeling on hypothalamic sagittal planes. DCX-positive cells are found in the most rostral nuclei of the hypothalamus, including the preoptic area many of which co-expressed estrogen receptor-α. Thus, beyond the confirmation of the high level of neuron production during short photoperiod in sheep, our results bring new and compelling elements in support of the existence of a hypothalamic migratory path that is responsive to seasonal stimuli.
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Acknowledgments
The authors wish to thank Dr. Joëlle Dupont for her help with Western blotting experiments and the experimental unit PAO No. 1297 (EU0028; INRA Val de Loire) for animal care. This work was funded by the French National Research Agency (Agence Nationale pour la Recherche: ANR-09-JCJC-0049-01).
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Supplemental Fig. 1: Kinetic of adult neurogenesis in the adult sheep hypothalamus depending on the rostro-caudal levels. Densities of DCX-positive cells at various time points of the year, i.e., in September and January, in May and July, corresponding to short and long photoperiod exposure, respectively. Results are presented as median and interquartile ranges from the more rostral (level 1) to the more caudal level (level 5) of the sections in the AN (A) and the VMH (B). *P < 0.05, **P < 0.01, ***P < 0.001. Supplemental Fig. 2: Seasonal and region-specific quantification of Cdk5-positive cells. Number of Cdk5-positive cells counted in July (yellow bars) and September (blue bars) in the AN (left-side bars) and the VMH (right-side bars). **P < 0.01, ***P < 0.001. Supplemental Fig. 3: Percentages of cells co-expressing DCX and Cdk5 in function of season. Percentage of Cdk5-positive cells also expressing DCX in the AN (A) and the VMH (B), in July (yellow bars) and September (blue bars). Percentage of DCX-positive cells also expressing Cdk5 in the AN (C) and the VMH (D), in July (yellow bars) and September (blue bars). *P < 0.05 (PDF 1130 kb)
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Batailler, M., Derouet, L., Butruille, L. et al. Sensitivity to the photoperiod and potential migratory features of neuroblasts in the adult sheep hypothalamus. Brain Struct Funct 221, 3301–3314 (2016). https://doi.org/10.1007/s00429-015-1101-0
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DOI: https://doi.org/10.1007/s00429-015-1101-0