Rene Oliver Goral, Patricia W Lamb, Jerrel L Yakel
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引用次数: 0
Abstract
Acetylcholine (ACh) neurons in the central nervous system are required for the coordination of neural network activity during higher brain functions, such as attention, learning, and memory, as well as locomotion. Disturbed cholinergic signaling has been described in many neurodevelopmental and neurodegenerative disorders. Furthermore, cotransmission of other signaling molecules, such as glutamate and GABA, with ACh has been associated with essential roles in brain function or disease. However, it is unknown when ACh neurons become cholinergic during development. Thus, understanding the timeline of how the cholinergic system develops and becomes active in the healthy brain is a crucial part of understanding brain development. To study this, we used transgenic mice to selectively label ACh neurons with tdTomato. We imaged serial sectioned brains and generated whole-brain reconstructions at different time points during pre- and postnatal development. We found three crucial time windows-two in the prenatal and one in the postnatal brain-during which most ACh neuron populations become cholinergic in the brain. We also found that cholinergic gene expression is initiated in cortical ACh interneurons, while the cerebral cortex is innervated by cholinergic projection neurons from the basal forebrain. Taken together, we show that ACh neuron populations are present and become cholinergic before postnatal day 12, which is the onset of major sensory processes, such as hearing and vision. We conclude that the birth of ACh neurons and initiation of cholinergic gene expression are temporally separated during development but highly coordinated by brain anatomical structure.
中枢神经系统中的乙酰胆碱(ACh)神经元是协调高级大脑功能(如注意力、学习和记忆以及运动)过程中神经网络活动的必要条件。许多神经发育和神经退行性疾病都存在胆碱能信号传递紊乱的情况。此外,其他信号分子(如谷氨酸和 GABA)与 ACh 的共同传递也与在大脑功能或疾病中的重要作用有关。然而,人们还不知道 ACh 神经元在发育过程中何时变成胆碱能神经元。因此,了解胆碱能系统如何在健康大脑中发育和活跃的时间表是了解大脑发育的关键部分。为了研究这一点,我们利用转基因小鼠选择性地用tdTomato标记胆碱能神经元。我们对连续切片的大脑进行了成像,并在出生前和出生后发育的不同时间点生成了全脑重建图。我们发现了三个关键的时间窗口--两个在出生前,一个在出生后--在此期间,大脑中大多数 ACh 神经元群都会变成胆碱能神经元。我们还发现,胆碱能基因表达始于大脑皮层的 ACh 中间神经元,而大脑皮层则由来自前脑基底的胆碱能投射神经元支配。总之,我们的研究表明,ACh 神经元群在出生后第 12 天之前就已存在并成为胆碱能神经元,而出生后第 12 天正是听觉和视觉等主要感官过程的开始。我们的结论是,乙酰胆碱(ACh)神经元的诞生和胆碱能基因表达的启动在发育过程中时间上是分离的,但与大脑解剖结构高度协调。在神经发育障碍和智力障碍中观察到胆碱能信号传递紊乱。虽然人们已充分了解 ACh 释放在神经回路功能中的作用,但却不知道 ACh 神经元何时变成胆碱能神经元。我们对 ACh 神经元进行了标记,以研究发育中的大脑中 ACh 神经元何时成为胆碱能神经元,并对连续切片的大脑进行了重建。在这里,我们发现,ACh 神经元群在出生前后的三个时间窗口中开始具有胆碱能。乙酰胆碱能神经元是沿着大脑形成的尾柄方向形成的。在大脑皮层和海马中,ACh 神经元间的胆碱能基因表达激活与来自前脑基底的胆碱能神经支配相吻合。我们强调,大脑 ACh 神经元在 P12 之前就具有胆碱能,而 P12 是听觉和视觉等主要感官功能的起始阶段。
期刊介绍:
An open-access journal from the Society for Neuroscience, eNeuro publishes high-quality, broad-based, peer-reviewed research focused solely on the field of neuroscience. eNeuro embodies an emerging scientific vision that offers a new experience for authors and readers, all in support of the Society’s mission to advance understanding of the brain and nervous system.