Rab18負調節產後母鼠腦中多巴胺進而誘導其成年神經元新生與育幼行為

Abstract

成年神經元新生的現象會發生在成年哺乳類動物腦中的兩個區域。在側腦室下區中，神經幹細胞會產生神經母細胞並沿著Rostral migratory stream（RMS）遷移到嗅球並分化成成熟神經元，在嗅球的成年神經元新生功能為辨別氣味和育幼行為。在齒狀迴顆粒細胞下區中，神經幹細胞會產生神經母細胞，它們接著分化成海馬迴齒狀迴中的神經元，齒狀迴的成年神經元新生功能為抗焦慮以及依賴海馬迴的學習和記憶。Rab18是Rab蛋白中的其中一員，屬於Ras相關的小GTP水解酶家族。先前，我們發現Rab18基因剔除母鼠的成年神經元新生有缺陷且其育幼行為是受損的。除此之外，在產後母鼠中，我們還發現Rab18會負調節多巴胺的分泌並且正調節催乳素的濃度。因此，我們假設Rab18透過抑制多巴胺和增加催乳素來調節成年神經元新生和育幼行為。我們給Rab18基因剔除處女鼠注射多巴胺D2受體的拮抗劑haloperidol (HAL)，並透過OB / DG神經元新生去測試我們的假設。在我們初步的結果中，發現當Rab18基因剔除處女鼠注射HAL後，側腦室下區中的增殖細胞和神經母細胞會恢復到與野生型處女鼠一樣的程度。同時，當我們將Rab18基因剔除處女鼠注射HAL之後，齒狀迴顆粒細胞下區中的增殖細胞、神經母細胞及神經元也會恢復到與野生型處女鼠一樣的程度。因此，Rab18會透過抑制多巴胺的釋放，進而調節在側腦室下區中的增殖細胞和神經母細胞以及齒狀迴顆粒細胞下區中的增殖細胞、神經母細胞及齒狀迴中的神經元。此外，我們在Rab18基因剔除懷孕鼠注射HAL後，去測試成年神經元新生、育幼行為、氣味辨識和抗焦慮行為能否回復到與野生型產後鼠一樣的狀態。我們發現在Rab18基因剔除懷孕鼠注射HAL後，側腦室下區中的增殖細胞和神經母細胞會恢復到與野生型產後鼠一樣的程度，並且齒狀迴顆粒細胞下區中的神經幹細胞、增殖細胞及神經元也會恢復到與野生型產後鼠一樣的程度，我們也發現到Rab18基因剔除懷孕鼠注射HAL後，氣味辨識並不會恢復到與野生型產後鼠一樣的程度，而焦慮行為並未在Rab18基因剔除產後鼠及野生型產後鼠中發現有任何差異。所以，Rab18會透過抑制多巴胺的釋放，進而調節在側腦室下區中的增殖細胞和神經母細胞以及齒狀迴顆粒細胞下區中的增殖細胞、神經幹細胞及齒狀迴中的神經元。除此之外，Rab18可能會透過抑制多巴胺的的釋放去調節育幼行為並且Rab18對於氣味辨識是必需的。在未來，我們將繼續研究Rab18如何去調節懷孕鼠中的育幼行為及氣味辨識。

There are two places in the mammalian brain with adult neurogenesis. In the subventricular zone (SVZ) of the lateral ventricles, neural stem cells produce neuroblasts, which migrate along the rostral migratory stream (RMS) to the olfactory bulb (OB) and differentiate into mature neurons. The function of adult OB neurogenesis is odor discrimination and maternal behaviors. Neural stem cells of the subgranular zone (SGZ) in the dentate gyrus (DG) generate progenitor cells, which give rise to neurons in the DG of the hippocampus. The function of adult DG neurogenesis is anti-depression and hippocampal-dependent learning and memory. Rab18 is a member of Rab proteins, which belong to Ras-related superfamily of small GTPase. Previously, we find that Rab18 homozygous mutation mice (Rab18-/-) have defective adult neurogenesis and impaired maternal behaviors. In addition, we also discover that Rab18 negatively regulates dopamine secretion and positively regulates prolactin concentration in postpartum female mice. Therefore, we hypothesize that Rab18 regulates adult neurogenesis and maternal behaviors through inhibiting dopamine and increasing prolactin. To test it, Rab18-/- virgin female mice were treated with dopamine D2 receptor (D2Rs) antagonist haloperidol (HAL) and OB/DG neurogenesis was examined. We found that proliferating cells and neuroblasts in the SVZ were rescued when Rab18-/- virgin female mice were injected with HAL. Furthermore, proliferating cells and neuroblasts in the SGZ and neurogenesis in the DG were rescued in Rab18-/- virgin mice with HAL injection. In conclusion, Rab18 regulates proliferating cells and neuroblasts in the SVZ by inhibition of dopamine in virgin mice. Moreover, Rab18 regulates proliferating cell, neuroblast and neuron numbers in the SGZ/DG by inhibition of dopamine in virgin mice. In postpartum mice, Rab18 was required for neural stem cells in the SVZ and dopamine inhibited adult AOB neurogenesis. Furthermore, Rab18 regulated adult DG neurogenesis, the maintenance of neural stem cells in the SGZ, proliferating cells in the SVZ and SGZ and the production of neuroblasts in the SVZ through inhibition of dopamine in postpartum mice. In addition, we found that Rab18 might regulate maternal behaviors through inhibition of dopamine and it was required for odor discrimination, but not through inhibition of dopamine in postpartum mice. In the future, we will continue to study how Rab18 regulates maternal behaviors and odor discrimination in postpartum mice.