PDF(Pubmed)
Abstract：
Functional magnetic resonance imaging (fMRI) suggests that the hypoxic ventilatory response is facilitated by the AMP-activated protein kinase (AMPK), not at the carotid bodies, but within a subnucleus (Bregma -7.5 to -7.1 mm) of the nucleus tractus solitarius that exhibits right-sided bilateral asymmetry. Here, we map this subnucleus using cFos expression as a surrogate for neuronal activation and mice in which the genes encoding the AMPK-α1 (Prkaa1) and AMPK-α2 (Prkaa2) catalytic subunits were deleted in catecholaminergic cells by Cre expression via the tyrosine hydroxylase promoter. Comparative analysis of brainstem sections, relative to controls, revealed that AMPK-α1/α2 deletion inhibited, with right-sided bilateral asymmetry, cFos expression in and thus activation of a neuronal cluster that partially spanned three interconnected anatomical nuclei adjacent to the area postrema: SolDL (Bregma -7.44 mm to -7.48 mm), SolDM (Bregma -7.44 mm to -7.48 mm) and SubP (Bregma -7.48 mm to -7.56 mm). This approximates the volume identified by fMRI. Moreover, these nuclei are known to be in receipt of carotid body afferent inputs, and catecholaminergic neurons of SubP and SolDL innervate aspects of the ventrolateral medulla responsible for respiratory rhythmogenesis. Accordingly, AMPK-α1/α2 deletion attenuated hypoxia-evoked increases in minute ventilation (normalised to metabolism), reductions in expiration time, and increases sigh frequency, but increased apnoea frequency during hypoxia. The metabolic response to hypoxia in AMPK-α1/α2 knockout mice and the brainstem and spinal cord catecholamine levels were equivalent to controls. We conclude that within the brainstem an AMPK-dependent, hypoxia-responsive subnucleus partially spans SubP, SolDM and SolDL, namely SubSol-HIe, and is critical to coordination of active expiration, the hypoxic ventilatory response and defence against apnoea.
摘要：
功能磁共振成像（fMRI）表明，AMP激活的蛋白激酶（AMPK）促进了低氧通气反应，不是颈动脉体，但是在孤束核的亚核（Bregma-7.5至-7.1mm）内，表现出右侧双侧不对称。这里,我们使用cFos表达作为神经元激活的替代，并在小鼠中通过Cre表达在儿茶酚胺能细胞中删除了编码AMPK-α1（Prkaa1）和AMPK-α2（Prkaa2）催化亚基的基因。酪氨酸羟化酶启动子。脑干切片的比较分析，相对于控件，显示AMPK-α1/α2缺失抑制，由于右侧的双边不对称，cFos表达并因此激活了神经元簇，该神经元簇部分地跨越了邻近区域的三个相互连接的解剖核：SolDL（Bregma-7.44mm至-7.48mm），SolDM(Bregma-7.44mm至-7.48mm)和SubP(Bregma-7.48mm至-7.56mm)。这近似于由fMRI识别的体积。此外，已知这些细胞核接收颈动脉体传入输入，SubP和SolDL的儿茶酚胺能神经元支配负责呼吸节律发生的腹外侧延髓。因此，AMPK-α1/α2缺失减弱了低氧诱发的微小通气增加（代谢正常化），到期时间的减少，增加叹息频率，但缺氧时呼吸暂停频率增加。AMPK-α1/α2敲除小鼠对缺氧的代谢反应以及脑干和脊髓儿茶酚胺水平与对照组相当。我们得出结论，在脑干内AMPK依赖性，缺氧反应性亚核部分跨越SubP，SolDM和SolDL,即SubSol-HIe,对于主动到期的协调至关重要，低氧通气反应和预防呼吸暂停。
