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脑源性神经营养因子信号在发育中的端脑中控制着海马齿状回的形成,并调节与恐惧相关的行为。

Bone morphogenetic protein signaling in the developing telencephalon controls formation of the hippocampal dentate gyrus and modifies fear-related behavior.

机构信息

Department of Neurobiology, University of Chicago, Chicago, Illinois 60637, USA.

出版信息

J Neurosci. 2010 May 5;30(18):6291-301. doi: 10.1523/JNEUROSCI.0550-10.2010.

Abstract

The cortical hem is an embryonic signaling center that generates bone morphogenetic proteins (BMPs) and acts as an organizer for the hippocampus. The role of BMP signaling in hippocampal neurogenesis, however, has not been established. We therefore generated mice that were deficient in Bmpr1b constitutively, and deficient in Bmpr1a conditionally in the dorsal telencephalon. In double mutant male and female mice, the dentate gyrus (DG) was dramatically smaller than in control mice, reflecting decreased production of granule neurons at the peak period of DG neurogenesis. Additionally, the pool of cells that generates new DG neurons throughout life was reduced, commensurate with the smaller size of the DG. Effects of diminished BMP signaling on the cortical hem were at least partly responsible for these defects in DG development. Reduction of the DG and its major extrinsic output to CA3 raised the possibility that the DG was functionally compromised. We therefore looked for behavioral deficits in double mutants and found that the mice were less responsive to fear- or anxiety-provoking stimuli, whether the association of the stimulus with fear or anxiety was learned or innate. Given that no anatomical defects appeared in the double mutant telencephalon outside the DG, our observations support a growing literature that implicates the hippocampus in circuitry mediating fear and anxiety. Our results additionally indicate a requirement for BMP signaling in generating the dorsalmost neuronal lineage of the telencephalon, DG granule neurons, and in the development of the stem cell niche that makes neurons in the adult hippocampus.

摘要

皮质边缘是一个胚胎信号中心,能产生骨形态发生蛋白(BMPs),并作为海马的组织者。然而,BMP 信号在海马神经发生中的作用尚未确定。因此,我们生成了 Bmpr1b 持续缺失和 Bmpr1a 条件性缺失的背侧端脑的小鼠。在双突变雄性和雌性小鼠中,齿状回(DG)明显小于对照组小鼠,反映出 DG 神经发生高峰期颗粒神经元生成减少。此外,产生新 DG 神经元的细胞池减少,与 DG 变小相符。减少的 BMP 信号对皮质边缘的影响至少部分导致了 DG 发育缺陷。DG 及其对 CA3 的主要外向输出减少,这增加了 DG 功能受损的可能性。因此,我们在双突变体中寻找行为缺陷,发现小鼠对恐惧或焦虑刺激的反应性降低,无论刺激与恐惧或焦虑的关联是学习的还是先天的。鉴于除 DG 之外,双突变体端脑中没有出现任何解剖缺陷,我们的观察结果支持越来越多的文献表明海马参与了调节恐惧和焦虑的电路。我们的结果还表明,BMP 信号在产生端脑最背侧的神经元谱系、DG 颗粒神经元以及成年海马中的神经元干细胞龛的发育中是必需的。

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