Mutation of Npr2 leads to blurred tonotopic organization of central auditory circuits in mice.
Mutation of Npr2 leads to blurred tonotopic organization of central auditory circuits in mice.
复制标题
DOI：
10.1371/journal.pgen.1004823
复制
发表时间：
2014-12
期刊：
影响因子：
4.5
通讯作者：
Goodrich LV
中科院分区：
文献类型：
--
作者：
Lu CC;Cao XJ;Wright S;Ma L;Oertel D;Goodrich LV
音调是听觉系统的基本组织特征。声音由螺旋神经节神经元（SGN）中的电活动的空间和时间模式编码，并且经由音调有序的过程从耳蜗通过第八神经传输到耳蜗核。在到达脑干后，SGN轴突以定型模式分叉，其中一个分支支配前腹侧耳蜗核（aVCN）中的靶神经元，另一个支配后腹侧和背侧耳蜗核（pVCN和DCN）中的靶神经元。每个分支都是音调拓扑组织的，从而沿着沿着多个并行通路系统地分布声学信息以用于在脑干中处理。在受体鸟苷酸环化酶Npr2突变的小鼠中，这种空间组织被破坏。外周SGN过程似乎正常，但中央SGN过程未能分叉，并且在它们离开听神经时紊乱。在耳蜗核内，SGN终支的色调组织模糊，aVCN神经支配不足，SGN输入到靶神经元的会聚减少。耳蜗核内的电路tonotopy也退化，揭示了从DCN到VCN的tuberculoventral细胞投影的地形图的变化。尽管如此，Npr2突变SGN轴突能够以正常的灵敏度和时间传递声学信息，如VCN神经元的听觉脑干反应和电生理记录所揭示的。虽然信号传输的大多数特征是正常的，但在对一连串电击的反应中观察到间歇性故障，这可能是由于Npr2突变传入纤维中分支点的动作电位传导故障。我们的研究结果表明，Npr2是必要的典型的中央听觉回路的精确的空间组织，但信号仍然传输与正常的时间，和突变小鼠可以听到，即使有这些缺陷。数以百万计的人患有使人衰弱的听力缺陷，从完全无法检测声音到神经系统编码声音的方式发生更微妙的变化。许多形式的耳聋是由于基因突变损害了毛细胞的发育或功能，毛细胞负责将声音转化为可由大脑处理的电信号。携带这些突变的小鼠和人类都无法通过标准的听力测试。相比之下，人们对中枢听觉处理障碍的遗传基础知之甚少，这种疾病定义不清，难以诊断，因为这些患者仍然可以检测到声音。通过发现小鼠中枢听觉回路正常布线所需的基因，我们可以研究回路水平的变化如何影响回路功能，从而提高我们对中枢听觉处理障碍的理解。在这里，我们表明，利钠肽受体Npr2需要建立在小鼠中枢听觉系统的频率图。令人惊讶的是，尽管电路组织发生了巨大变化，但Npr2突变小鼠仍然能够以正常的灵敏度和时间对声音做出反应，这强调了需要更好的听力诊断方法。
Tonotopy is a fundamental organizational feature of the auditory system. Sounds are encoded by the spatial and temporal patterns of electrical activity in spiral ganglion neurons (SGNs) and are transmitted via tonotopically ordered processes from the cochlea through the eighth nerve to the cochlear nuclei. Upon reaching the brainstem, SGN axons bifurcate in a stereotyped pattern, innervating target neurons in the anteroventral cochlear nucleus (aVCN) with one branch and in the posteroventral and dorsal cochlear nuclei (pVCN and DCN) with the other. Each branch is tonotopically organized, thereby distributing acoustic information systematically along multiple parallel pathways for processing in the brainstem. In mice with a mutation in the receptor guanylyl cyclase Npr2, this spatial organization is disrupted. Peripheral SGN processes appear normal, but central SGN processes fail to bifurcate and are disorganized as they exit the auditory nerve. Within the cochlear nuclei, the tonotopic organization of the SGN terminal arbors is blurred and the aVCN is underinnervated with a reduced convergence of SGN inputs onto target neurons. The tonotopy of circuitry within the cochlear nuclei is also degraded, as revealed by changes in the topographic mapping of tuberculoventral cell projections from DCN to VCN. Nonetheless, Npr2 mutant SGN axons are able to transmit acoustic information with normal sensitivity and timing, as revealed by auditory brainstem responses and electrophysiological recordings from VCN neurons. Although most features of signal transmission are normal, intermittent failures were observed in responses to trains of shocks, likely due to a failure in action potential conduction at branch points in Npr2 mutant afferent fibers. Our results show that Npr2 is necessary for the precise spatial organization typical of central auditory circuits, but that signals are still transmitted with normal timing, and that mutant mice can hear even with these deficits. Millions of people suffer from debilitating hearing defects, ranging from a complete inability to detect sound to more subtle changes in how sounds are encoded by the nervous system. Many forms of deafness are due to mutations in genes that impair the development or function of hair cells, which are responsible for changing sound into electrical signals that can be processed by the brain. Both mice and humans carrying these mutations fail standard hearing tests. In contrast, very little is known about the genetic basis of central auditory processing disorders, which are poorly defined and difficult to diagnose, since these patients can still detect sounds. By finding genes that are required for the normal wiring of central auditory circuits in mice, we can investigate how changes at the circuit level affect circuit function and therefore improve our understanding of central auditory processing disorders. Here, we show that the natriuretic peptide receptor Npr2 is required to establish frequency maps in the mouse central auditory system. Surprisingly, despite a dramatic change in circuit organization, Npr2 mutant mice are still able to respond to sounds with normal sensitivity and timing, underscoring the need for better hearing diagnostic methods in mice as in humans.
登录
查看更多内容
影响因子：
2.5
作者：
BLACKBURN, CC;SACHS, MB
通讯作者：
SACHS, MB
影响因子：
3.3
作者：
CANT, NB;MOREST, DK
通讯作者：
MOREST, DK
影响因子：
3.7
作者：
Lauer, Amanda M.;Connelly, Catherine J.;Ryugo, David K.
通讯作者：
Ryugo, David K.
影响因子：
5.7
作者：
Clandinin, Thomas R.;Feldheim, David A.
通讯作者：
Feldheim, David A.
影响因子：
3
作者：
Clause, Amanda;Tuan Nguyen;Kandler, Karl
通讯作者：
Kandler, Karl