Protection and restoration of cochlear synapses from noise-induced synaptopathy in male and female mice

雄性和雌性小鼠噪音诱导的突触病对耳蜗突触的保护和恢复

基本信息

批准号：
10407992
负责人：
STEVEN H GREEN
金额：
$ 57.46万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10407992
关键词：
Affect Apical Auditory Auditory Brainstem Responses Auditory Threshold Brain Cell Nucleus Cell membrane Cells Ciliary Neurotrophic Factor Cochlea Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Estrogens Estrous Cycle Estrus Exposure to Female Future Gene Expression Genetic Transcription Genomics Glutamate Receptor Gonadal Steroid Hormones Hair Cells Histologic Hormones Human In Vitro Inner Hair Cells Longitudinal Studies Mediating Membrane Mifepristone Molecular Mus Natural regeneration Neurons Noise Nuclear Nuclear Receptors Peptides Performance Permeability Phase Phenotype Predisposition Progesterone Progesterone Receptors Protein Kinase Reagent Regenerative capacity Role Rolipram Sensory Sex Differences Signal Pathway Signal Transduction Synapses Testing Time Tinnitus Transcript Trauma cochlear synaptopathy excitotoxicity experimental study follow-up hearing impairment in vitro Model in vitro regeneration in vivo male neurotrophic factor noise exposure non-genomic novel therapeutic intervention phosphodiesterase IV prevent protein function receptor regenerative therapy restoration small molecule therapeutics sound speech in noise spiral ganglion therapeutic candidate therapeutic target tool transcriptome

项目摘要

Most spiral ganglion neurons (SGNs) make afferent synapses on the auditory sensory cells, the inner hair cells (IHCs), and convey auditory information to the brain. Noise damages cochlear afferent synapses even at sound levels too low to destroy hair cells. Noise-induced cochlear “synaptopathy” (NICS) is detectable by histological examination and counting of synapses and is also evident, noninvasively, as reduced auditory brainstem response (ABR) wave I amplitude. While synaptopathy does not detectably affect auditory thresholds, it may cause hearing impairments such as poorer speech-in-noise performance or tinnitus. In the course of investigating means to prevent NICS, we observed that female mice are significantly less susceptible than are males to NICS. Remarkably, female susceptibility varies with estrous cycle phase, with lowest susceptibility correlated with the estrous phase at which progesterone (P4) levels are highest (and estrogen lowest). In vitro experiments additionally show that a high level of P4 promotes rapid regeneration of synapses. These data showing sex differences in synaptopathy are the first to show that susceptibility varies through the estrous cycle and to show a protective role for P4. To follow up, our first aim is to determine whether a high level of steroid sex hormone does reduce NICS. To that end, we will experimentally manipulate levels of P4 and estrogen in male and female mice. We have further shown that, not only P4 but also the neurotrophic factor CNTF and agents that activate cyclic AMP (cAMP) signaling promote synaptic regeneration. The latter include compounds, such as rolipram, that can be administered systemically. P4, CNTF, and rolipram represent excellent reagents for investigating the role in vivo of cAMP in synapse regeneration and may also be candidate therapeutics for post-noise synapse regeneration therapy. However, cochlear synapses may lose their capacity for regeneration with time after damage and the timecourse may differ among the different agents promoting regeneration. Our second aim will determine how long after noise these agents, P4, CNTF, or cAMP, may be administered and still promote regeneration. Unlike the case for peptide neurotrophic factors, the molecular and cellular mechanism(s) by which progesterone or cAMP promote synapse regeneration remain obscure. Our third aim asks whether these factors function via genomic actions or via cytoplasmic targets or plasma membrane receptors – a necessary preliminary step for future detailed mechanistic studies of signaling pathways and possible transcriptome changes involved. For cAMP, the question is whether cAMP- dependent protein kinase enters the nucleus or remains a cytoplasmic signal, a question we successfully answered previously with respect to survival signaling. For progesterone, our preliminary studies suggest that a nuclear receptor is not involved so our focus will be on plasma membrane progesterone receptors.

大多数螺旋神经节神经元 (SGN) 在听觉感觉细胞（内毛细胞）上产生传入突触（IHC），并将听觉信息传递到大脑，即使在耳蜗传入突触。噪音水平太低而无法破坏毛细胞，可以通过噪音检测到耳蜗“突触病”（NICS）。组织学检查和突触计数也很明显，非侵入性地，听觉减少脑干反应（ABR）波 I 幅度，而突触病不会明显影响听觉。阈值，它可能会导致听力障碍，例如噪声中语音表现较差或耳鸣。在研究预防 NICS 的方法过程中，我们观察到雌性小鼠明显不易受影响值得注意的是，女性对 NICS 的敏感性随动情周期阶段的不同而变化，其中最低。易感性与孕激素 (P4) 水平最高（雌激素体外实验还表明，高水平的 P4 可以促进突触的快速再生。这些显示突触病性别差异的数据首次表明，易感性随性别的不同而变化。并表现出对发情周期的保护作用。跟进，我们的首要目的是确定是否高。类固醇性激素的水平确实会降低 NICS。为此，我们将通过实验控制 P4 的水平。我们进一步证明，不仅是 P4，还有神经营养性小鼠。 CNTF 因子和激活环 AMP (cAMP) 信号传导的药物可促进突触再生。包括可以全身施用的化合物，例如咯利普兰、CNTF和咯利普兰。代表了研究 cAMP 在突触再生中的体内作用的优秀试剂，也可能是噪声后突触再生疗法的候选疗法，然而，耳蜗突触可能会丢失。它们的再生能力随损坏后的时间而变化，并且不同的时间进程可能有所不同我们的第二个目标将确定这些药剂，P4，CNTF，噪音后多久，或 cAMP，可以被施用并且仍然促进再生，与肽神经营养因子的情况不同，黄体酮或 cAMP 促进突触再生的分子和细胞机制我们的第三个目标仍然不清楚，即这些因素是通过基因组作用还是通过细胞质发挥作用。靶标或质膜受体——未来详细机制研究的必要预备步骤对于 cAMP，问题是 cAMP 是否涉及信号通路和可能的转录组变化。依赖性蛋白激酶进入细胞核还是保持细胞质信号，这是我们成功解决的问题对于黄体酮，我们的初步研究表明，之前已经回答过。不涉及核受体，因此我们的重点将放在质膜孕酮受体上。