Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

时间：2015-05-18

地点：综合楼14楼会议室

主讲人：叶娟

内容简介：

      越来越多的证据表明肠道微生物、肠道以及中枢神经系统有着密切的关系，功能性肠病如肠易激综合征被认为是微生物-肠-脑轴异常调节引起的。已有研究显示益生菌能够调节肠易激综合征病人的应激状态并改善其情绪和焦虑状况，但是乳酸菌如鼠李糖乳杆菌对健康动物中枢神经系统的研究并不多，其对神经系统的调节机制也还不清楚。Bravo et al.主要针对鼠李糖乳杆菌对鼠的神经系统的影响展开研究。
      在焦虑、抑郁相关行为的实验中，与摄入不添加益生菌的同样膳食的小鼠相比，经过鼠李糖乳杆菌喂养的小鼠较少表现出情绪压力和焦虑，压力刺激下皮质酮的水平较低（Fig 1）。
      GABA作为脑内抑制性神经递质，在调节心理和生理功能方面起极大作用。GABA的功能受GABA受体调节，其受体表达量的变化，影响焦虑或紧张状态。经鼠李糖乳杆菌喂养后，小鼠GABAB1b mRNA在皮质区表达增加，但是在海马、杏仁核、蓝斑等部位表达减少（Fig 2）。GABAAα2 mRNA在海马表达增加，在前额叶皮层和杏仁核表达减少（Fig 3）。虽然在脑内某些区域活动增强，在另一些区域活动减弱，但总体效果是减轻焦虑。
      进一步研究发现，无论是喂养鼠李糖乳杆菌还是不添加益生菌膳食的小鼠在迷走神经切除后，神经系统的化学物质及小鼠行为并未发生明显变化（Fig 4），提示迷走神经在细菌调节肠-脑轴中起作用。
      这一研究再次证明了肠道细菌在肠-脑轴中的重要作用，提示益生菌在小鼠焦虑和抑郁中有一定作用，为异常情绪的治疗提供新思路。本研究最后还提出，不能排除与压力性精神病相关的其它的神经递质和神经肽在其中的作用（如5-羟色胺、去甲肾上腺素、谷氨酸盐、肾上腺皮质激素释放激素等），今后的研究应该关注一下鼠李糖乳杆菌与上述物质的关系。

Fig. 1. Effect of L. rhamnosus (JB-1) administration on behavior and stress-induced levels of corticosterone. (A) Stress-induced hyperthermia (SIH). There were no significant differences between L. rhamnosus (JB-1)-fed (n = 16) and broth-fed animals (n = 20). Elevated plus maze (EPM). Mice fed with the Lactobacillus (n = 16) entered significantly more times (***P < 0.001) into the open arms of the EPM apparatus in comparison with broth-fed mice (n = 20). (C) Forced swim test (FST). Animals fed with L. rhamnosus (JB-1) (n = 8) spent less time immobile (**P < 0.01) compared with broth-fed mice (n = 8). (B) Effect of L. rhamnosus (JB-1) on fear-related behaviors. On day 1, analysis revealed no differences in the learning curves between L. rhamnosus (JB-1)-fed mice (n = 16) and broth-fed control animals (n = 20). On day 2 (memory testing), L. rhamnosus (JB-1) treated animals displayed an enhanced memory towards cues (represented by the white boxes underneath the x axis. **P< 0.01 for cue no. 5 and *P < 0.05 for cue no. 6) and context (represented by the grey boxes underneath the x axis.*P < 0.05 for context 6). On day 3 (memory extinction), no differences were observed between the two treatment groups. (C) Effect of L. rhamnosus (JB-1)administration on stress-induced levels of corticosterone. Stress-induced corticosterone was measured in plasma 30 min after FST. Stress-induced levels ofcorticosterone are significantly lower in L. rhamnosus (JB-1)-fed mice compared with broth fed control animals (###P < 0.001).

Fig. 2. Effect of L. rhamnosus (JB-1) administration on central GABAB1b Mrna expression. Mice fed with L. rhamnosus (JB-1) (n = 6) had higher levels of GABAB1b mRNA in the cingulate 1 (CG1) (A) and prelimbic (PrL) (B) cortices in comparison with broth fed control mice (n = 6). However, no differences between the two groups were observed in the infralimbic (IL) cortex (C). On the other hand, L. rhamnosus (JB-1) fed animals showed reduced levels of GABAB1b mRNA in the basolateral amygdala (BLA) (D), central amygdala (CeA) (E), locus coeruleus (LC) (F), dentate gyrus (DG) (G), cornus ammonis region 3 (CA3) (H), and cornus ammonis region 1 (CA1) (I) in comparison with broth fed mice.Values represent pixel density (*P < 0.05; **P < 0.01; ***P < 0.001).

Fig. 3. Effect of L. rhamnosus (JB-1) administration on central GABAAα2 mRNA expression. Mice fed with L. rhamnosus (JB-1) (n = 6) had lower levelsof GABAAα2 mRNA in CG1 (A) PrL (B), and IL (C) cortices. In addition, GABAAα2 mRNA was also reduced in the BLA (D) and CeA (E) of L. rhamnosus (JB-1) fed mice in comparison with broth fed animals. No differences in GABAAα2 mRNA between the two groups were observed in the LC (F). On the contrary, GABAAα2 mRNA is increased in the DG (G) of L. rhamnosus (JB-1) fed animals in comparison with broth control mice, but no differences were observed in CA3 (H) and CA1 (I). Values represent pixel density (*P < 0.05; ***P < 0.001).