Rab18透過催乳素調控產後母鼠成年神經元新生、育幼以及抗焦慮行為

Abstract

成年哺乳動物腦中持續有成年神經元新生之區域分別為嗅球 (olfactory bulb, OB)及海馬迴之齒狀迴 (dentate gyrus, DG)。而神經幹細胞所在之區域，分別為側腦室旁區(subventricular zone, SVZ)與海馬迴之齒狀迴內側區(subgranular zone, SGZ)。成年神經元新生於嗅球中主要功能為氣味辨識及產生育幼行為，而海馬迴中主要功能為空間之記憶及焦慮之調節。Rab18屬於Ras相關的小GTP酶Rab家族之成員。由於Rab18-/-之母鼠其育幼行為是受損的，此現象與成年神經元新生受損之小鼠類似，因此我們懷疑Rab18與成年神經元新生有關。先前研究顯示於神經內分泌細胞中Rab18會負調控多巴胺之釋放，而多巴胺會抑制成年神經元新生及催乳素之釋放，此外催乳素所誘導嗅球成年神經元新生為產生育幼行為及抗焦慮所必需的。因此我們假設Rab18-/-之母鼠懷孕第1天到第7天注射催乳素可能可以挽救成年神經元新生、育幼行為及焦慮之行為。我們發現，溶劑注射後Rab18-/-產後母鼠OB及DG之成年神經元新生明顯變少， SVZ中增殖細胞、神經母細胞及神經幹細胞數目也均有減少，而SGZ中增殖細胞及神經幹細胞數目也均有減少。另外接受催乳素注射後Rab18-/-產後母鼠SVZ增殖細胞、神經母細胞及主嗅球(main olfactory bulb, MOB)之成年神經元新生皆有增加，而Rab18-/-母鼠產後焦慮也因催乳素注射後有緩解，不過育幼行為及味辨識能力仍然沒有被挽救回來。這些結果顯示Rab18會透過催乳素誘導MOB成年神經元新生，但Rab18不會透過催乳素調節育幼行為。

Mammalian adult neurogenesis persists in the rodent olfactory bulb (OB) and dentate gyrus (DG). These newborn neurons are produced by neural stem cells in the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ), the innermost cell layer of DG in the adult mammal brain, respectively. The functions of adult neurogenesis are odor discrimination and maternal behaviors in the OB and spatial memory and anti-anxiety in the DG. Rab18 is a member of Rab proteins appertaining to Ras-related small GTPase superfamily. Interestingly, Rab18 null mice have impaired maternal behaviors, which are similar to mice whose adult neurogenesis is blocked. Previous studies show that Rab18 negative regulates Ca2+-mediated exocytosis of dopamine in neuroendocrine cell lines and dopamine inhibits adult neurogenesis and prolactin release. Moreover, prolactin-induced adult OB neurogenesis is required for maternal behaviors and anti-anxiety. Therefore we hypothesized that adult neurogenesis, maternal behaviors and anxiety could be rescued in Rab18-/- mice by prolactin treatments from gestation day 1 (GD1) to GD7. We found that after vehicle treatments, there were reductions of adult neurogenesis in the OB and DG in Rab18-/- postpartum mice. In addition, we observed that proliferating cells, neuroblasts and neural stem cells were decreased in the SVZ in Rab18-/- postpartum mice. Proliferating cells and neural stem cells were also decreased in the SGZ in Rab18-/- postpartum mice. Furthermore, adult neurogenesis in the MOB, proliferating cells and neuroblasts in the SVZ were increased in Rab18-/- postpartum mice after prolactin treatments. Anxiety level was reduced in prolactin-treated Rab18-/- postpartum mice. However, maternal behaviors and odor discrimination were still impaired in these mice. These results suggest that Rab18 regulates adult neurogenesis in the OB through increasing prolactin in postpartum mice.