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.

1. Deng, W., J.B. Aimone, and F.H. Gage, New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci, 2010. 11(5): p. 339-50.
2. Ming, G.L. and H. Song, Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron, 2011. 70(4): p. 687-702.
3. Sakamoto, M., et al., Continuous postnatal neurogenesis contributes to formation of the olfactory bulb neural circuits and flexible olfactory associative learning. J Neurosci, 2014. 34(17): p. 5788-99.
4. Feierstein, C.E., Linking adult olfactory neurogenesis to social behavior. Front Neurosci, 2012. 6: p. 173.
5. Larsen, C.M. and D.R. Grattan, Prolactin-induced mitogenesis in the subventricular zone of the maternal brain during early pregnancy is essential for normal postpartum behavioral responses in the mother. Endocrinology, 2010. 151(8): p. 3805-14.
6. Oboti, L., et al., Newborn interneurons in the accessory olfactory bulb promote mate recognition in female mice. Front Neurosci, 2011. 5: p. 113.
7. Ge, S., et al., Synaptic integration and plasticity of new neurons in the adult hippocampus. J Physiol, 2008. 586(16): p. 3759-65.
8. Zhao, C., W. Deng, and F.H. Gage, Mechanisms and functional implications of adult neurogenesis. Cell, 2008. 132(4): p. 645-60.
9. Bannerman, D.M., et al., Hippocampal synaptic plasticity, spatial memory and anxiety. Nat Rev Neurosci, 2014. 15(3): p. 181-92.
10. Li, Y., et al., TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron, 2008. 59(3): p. 399-412.
11. Belnoue, L., et al., Plasticity in the olfactory bulb of the maternal mouse is prevented by gestational stress. Sci Rep, 2016. 6: p. 37615.
12. Shingo, T., et al., Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin. Science, 2003. 299(5603): p. 117-20.
13. Christensen, H.R., et al., Estrogen regulation of the dopamine-activated GIRK channel in pituitary lactotrophs: implications for regulation of prolactin release during the estrous cycle. Am J Physiol Regul Integr Comp Physiol, 2011. 301(3): p. R746-56.
14. Larsen, C.M. and D.R. Grattan, Prolactin, neurogenesis, and maternal behaviors. Brain Behav Immun, 2012. 26(2): p. 201-9.
15. Bridges, R.S. and P.M. Ronsheim, Prolactin (PRL) regulation of maternal behavior in rats: bromocriptine treatment delays and PRL promotes the rapid onset of behavior. Endocrinology, 1990. 126(2): p. 837-48.
16. Seabra, M.C., E.H. Mules, and A.N. Hume, Rab GTPases, intracellular traffic and disease. Trends Mol Med, 2002. 8(1): p. 23-30.
17. Ng, E.L. and B.L. Tang, Rab GTPases and their roles in brain neurons and glia. Brain Res Rev, 2008. 58(1): p. 236-46.
18. Li, G., Rab GTPases, membrane trafficking and diseases. Curr Drug Targets, 2011. 12(8): p. 1188-93.
19. Vazquez-Martinez, R. and M.M. Malagon, Rab proteins and the secretory pathway: the case of rab18 in neuroendocrine cells. Front Endocrinol (Lausanne), 2011. 2: p. 1.
20. Bem, D., et al., Loss-of-function mutations in RAB18 cause Warburg micro syndrome. Am J Hum Genet, 2011. 88(4): p. 499-507.
21. Cheng, C.Y., et al., ENU mutagenesis identifies mice modeling Warburg Micro Syndrome with sensory axon degeneration caused by a deletion in Rab18. Exp Neurol, 2015. 267: p. 143-51.
22. Sakamoto, M., et al., Continuous neurogenesis in the adult forebrain is required for innate olfactory responses. Proc Natl Acad Sci U S A, 2011. 108(20): p. 8479-84.
23. Wang, W., et al., Extracellular signal-regulated kinase 5 (ERK5) mediates prolactin-stimulated adult neurogenesis in the subventricular zone and olfactory bulb. J Biol Chem, 2013. 288(4): p. 2623-31.
24. Mak, G.K., et al., Male pheromone-stimulated neurogenesis in the adult female brain: possible role in mating behavior. Nat Neurosci, 2007. 10(8): p. 1003-11.
25. Wagner, K., et al., Prolactin induces MAPK signaling in neural progenitors without alleviating glucocorticoid-induced inhibition of in vitro neurogenesis. Cell Physiol Biochem, 2009. 24(5-6): p. 397-406.
26. O'Hara, M.W., et al., Prospective study of postpartum blues. Biologic and psychosocial factors. Arch Gen Psychiatry, 1991. 48(9): p. 801-6.
27. Seeman, P. and S. Kapur, Schizophrenia: more dopamine, more D2 receptors. Proc Natl Acad Sci U S A, 2000. 97(14): p. 7673-5.
28. Picazo, O. and A. Fernandez-Guasti, Changes in experimental anxiety during pregnancy and lactation. Physiol Behav, 1993. 54(2): p. 295-9.
29. Toufexis, D.J., et al., Altered pituitary sensitivity to corticotropin-releasing factor and arginine vasopressin participates in the stress hyporesponsiveness of lactation in the rat. J Neuroendocrinol, 1999. 11(10): p. 757-64.
30. Torner, L., et al., Increased hypothalamic expression of prolactin in lactation: involvement in behavioural and neuroendocrine stress responses. Eur J Neurosci, 2002. 15(8): p. 1381-9.