The role of activity in auditory system development

活动在听觉系统发育中的作用

• 批准号: 7595072
• 负责人: DWIGHT E BERGLES
• 金额: $ 17.62万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-26 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7595072
• 关键词: AMPA Receptors; ATP Receptors; Acoustic Nerve; Action Potentials; Age; Auditory; Auditory system; Brain; Cells; Cochlea; Cochlear nucleus; Computer Systems Development; Connexins; Data; Dendrites; Exhibits; Fire - disasters; Frequencies; Gap Junctions; Genes; Goals; Growth; Hearing; Human; Inner Hair Cells; Lead; Length; Maps; Measures; Mediating; Methodology; Molecular Genetics; Mutation; Nerve Fibers; Neurons; Optics; Organ; Pattern; Peripheral; Physiological; Play; Proteins; Purinergic P2 Receptors; Purinoceptor; Rattus; Receptor Activation; Role; Sensory; Signal Transduction; Supporting Cell; Suramin; Temperature; Testing; Tinnitus; deafness; extracellular; ganglion cell; in vivo; insight; postsynaptic; public health relevance; pyridoxal phosphate-6-azophenyl-2' ,4' -disulfonic acid; receptor; research study; sensory system; sound; spiral ganglion

DESCRIPTION (provided by applicant): Spontaneous activity in developing sensory systems has been shown to be important for the growth and survival of projection neurons and may help to refine and stabilize sensory maps in the brain. Recent in vivo studies indicate that bursts of action potentials occur in afferent spiral ganglion neurons prior to the onset of hearing; however the mechanisms responsible for generating this activity have not been determined. Our preliminary studies indicate that inner hair cells (IHCs) in the developing cochlea are periodically depolarized by ATP that is released spontaneously from neighboring supporting cells. These ATP-dependent depolarizations can trigger Ca2+ action potentials in IHCs, suggesting that extracellular ATP may be responsible for initiating activity in auditory nerve fibers. Here, we propose to test the hypothesis that `spontaneous' activity in primary afferent spiral ganglion neurons prior to the onset of hearing requires purinergic receptor activation. We will use cochlear explant cultures prepared from prehearing rats to characterize the patterns of spontaneous activity that occur in spiral ganglion neurons, and determine whether this activity is dependent on ATP receptors and requires gap junctions/hemichannels. In addition, we will examine the firing patterns of spiral ganglion neurons in vivo, by making extracellular recordings from these neurons in prehearing rats. To test whether the in vivo firing of spiral ganglion neurons is mediated by ATP, we will infuse P2 receptor antagonists into the cochlea while recording extracellular action potentials from these neurons. These experiments seek to define the patterns of activity carried by auditory nerve fibers during the prehearing period and determine if this activity is mediated by the release of ATP within the cochlea. Ultimately, the data gained from these mechanistic studies will enable us manipulate this activity in vivo to determine the specific role that activity plays in auditory system development. PUBLIC HEALTH RELEVANCE: This proposal seeks to determine the mechanisms responsible for initiating sensory-independent activity in auditory nerves before the onset of hearing. As our preliminary findings suggest that ATP release from supporting cells may play an important role in the initiation of this activity, these studies may yield new insight into how mutations in gap junctions and other supporting cell-associated genes result in deafness. Furthermore, our experiments may have direct relevance to human conditions where sound in perceived in the absence of sensory input, such as peripheral tinnitus.

描述（由申请人提供）：已证明感觉系统发育中的自发活动对于投射神经元的生长和存活很重要，并且可能有助于完善和稳定大脑中的感觉图。最近的体内研究表明，在听力出现之前，传入螺旋神经节神经元中会发生动作电位的爆发；然而，负责产生这种活动的机制尚未确定。我们的初步研究表明，发育中的耳蜗中的内毛细胞 (IHC) 会被邻近支持细胞自发释放的 ATP 周期性去极化。这些 ATP 依赖性去极化可以触发 IHC 中的 Ca2+ 动作电位，表明细胞外 ATP 可能负责启动听觉神经纤维的活动。在这里，我们建议检验以下假设：初级传入螺旋神经节神经元在听力出现之前的“自发”活动需要嘌呤能受体激活。我们将使用从预听大鼠制备的耳蜗外植体培养物来表征螺旋神经节神经元中发生的自发活动模式，并确定该活动是否依赖于 ATP 受体以及是否需要间隙连接/半通道。此外，我们将通过在预听大鼠中对螺旋神经节神经元进行细胞外记录来检查体内螺旋神经节神经元的放电模式。为了测试体内螺旋神经节神经元的放电是否由 ATP 介导，我们将 P2 受体拮抗剂注入耳蜗，同时记录这些神经元的细胞外动作电位。这些实验旨在确定听觉神经纤维在预听期间的活动模式，并确定该活动是否由耳蜗内 ATP 的释放介导。最终，从这些机制研究中获得的数据将使我们能够在体内操纵这种活动，以确定该活动在听觉系统发育中发挥的具体作用。公共健康相关性：该提案旨在确定在听力出现之前启动听觉神经中感觉独立活动的机制。我们的初步研究结果表明，支持细胞释放的 ATP 可能在该活动的启动中发挥重要作用，因此这些研究可能会对间隙连接和其他支持细胞相关基因的突变如何导致耳聋产生新的见解。此外，我们的实验可能与人类在没有感觉输入的情况下感知声音的情况有直接关系，例如周围性耳鸣。