Rab18在哺乳時期母鼠的成年神經元新生中所扮演的角色

Abstract

在成年哺乳類大腦中，神經元新生持續發生於嗅球與海馬迴的齒狀迴。嗅球神經元新生的功能在於氣味的辨認與產生育幼行為；而齒狀迴神經元新生的功能則是空間學習以及抗憂鬱。Rab18是Ras相關的小GTP水解酶Rab家族中的一員。有趣的是，Rab18基因剃除母鼠的育幼行為是受損的，而成年神經元新生被阻斷的母鼠也無法執行育幼行為，讓我們懷疑Rab18與成年神經元新生有關。文獻指出在神經內分泌細胞中，Rab18負調節多巴胺的分泌；而多巴胺已知會抑制成年神經元新生及泌乳激素釋放。根據這些發現，我們假設在哺乳時期，Rab18會透過負調節多巴胺的釋放，使泌乳激素上升，進而調節成年神經元新生，使母鼠能夠執行育幼行為。我們發現在哺乳時期的Rab18缺失的母鼠成年神經元新生降低，並且在兩個神經幹細胞存在的微環境，即側腦室下區和齒狀迴顆粒細胞下區中，神經幹細胞及神經母細胞的密度和增生也比野生型母鼠低。此外，我們也發現在產後第一天， Rab18剃除母鼠血清中的泌乳激素濃度較低，而中腦的多巴胺則較高。以上研究顯示在哺乳時期，Rab18可能會透過負調節多巴胺的分泌，使得由泌乳激素居中調節的成年神經元新生上升。然而，當對Rab18剃除母鼠皮下注射泌乳激素後，儘管牠們的成年神經元新生回復到和野生型相當的程度，牠們的育幼行為仍然是失常的，顯示由Rab18在哺乳時期透過泌乳激素所調節的成年神經元新生並非誘發育幼行為的唯一因素。In the adult mammalian brain, neurogenesis continuously occurs in the olfactory bulb (OB) and the dentate gyrus (DG) of the hippocampus. The function of adult neurogenesis in the OB and DG is odor discrimination/maternal behaviors and spatial learning/anti-depression, respectively. Rab18 is a member of Rab proteins belongings to Ras-related small GTPase superfamily. Interestingly, Rab18 null mice have impaired maternal behaviors, which are also observed in female mice when their adult neurogenesis is blocked. A previous study shows that Rab18 negatively regulates dopamine secretion in neuroendocrine cells and dopamine is shown to decrease adult neurogenesis and prolactin. Based on these findings, we hypothesize that Rab18 governs prolactin level during lactation by negatively regulating dopamine secretory pathway, which in turn regulates adult neurogenesis and maternal behaviors. We found that Rab18-/- female mice had impaired adult neurogenesis postpartum. Progenitor cells and proliferating cells in the neural stem cell niches of OB and DG, the subventricular zone (SVZ) and the subgranular zone (SGZ), in Rab18-/- female mice were decreased postpartum. Compared to control female mice, lower serum prolactin level and higher midbrain dopamine level in Rab18-/- female mice on postpartum day 1 (PD1) were also found. Moreover, exogenous prolactin rescued adult neurogenesis, but not maternal behavior defects in postpartum Rab18-/- female mice. Our results suggest that prolactin mediates Rab18-modulated adult neurogenesis, which alone is not sufficient to induce maternal behaviors postpartum.