Cell-specific Synaptic and Intrinsic Plasticity of Auditory Cortical Neurons after Noise Exposure

项目摘要/摘要 暴露在强声中可导致耳蜗毛细胞死亡和毛细胞与神经细胞之间突触的丧失。 听神经，这是导致大脑传入输入丧失的原因。虽然减少了投入，但由于 噪音暴露，可以预测会导致对声音的反应减少，它矛盾地增加了兴奋性 听觉皮质的反应。观察到的兴奋性反应的增加起到了适应功能，例如 这增加了对声音的反应，即使减少了来自听觉外周的输入，也有助于感知。 这种现象被称为听觉增益适应。小白蛋白(PV)神经元的减少- 对主神经元的介导性抑制被认为是获得适应的一种可能机制 噪音暴露。然而，噪声后听觉皮质的固有可塑性和突触可塑性的机制 暴露在危险中的人是未知的。我们初步的活体钙成像结果表明，PV神经元 增加他们在噪声暴露后对声音的反应增益，而听觉皮质切片结果显示 PV神经元静息膜电位的去极化。此外，这些可塑性变化发生在 PV神经元先于主神经元。通过确定PV的突触和内在可塑性机制 和主神经元，我们将理解似乎违反直觉的PV增益和内在增加是如何 兴奋性最终会导致噪声暴露后兴奋性收益增加。我的目标是检验这一假设 噪声暴露可诱导听觉皮质的可塑性，包括PV和主值随时间的增加 神经元的内在兴奋性，以及突触接触中突触的特异性变化。因此，通过利用 光遗传学、全细胞电生理学和活体听觉脑干反应(ABR)的结合 和失真产物耳声发射(DPOAE)测量，本提案旨在测试这一点 假设。此外，这项建议旨在调查噪声暴露条件，在这些条件下，塑性 发生，并以细胞和特定层的方式对塑性的时间过程进行详细的调查。 这一建议的结果将为噪声后成人听觉皮质的可塑性机制提供深入的见解。 曝光。这项提议的预期结果可能确定疾病的潜在治疗靶点。 与病理性的增益增加有关，如耳鸣和听觉过敏，并有助于我们理解 成人听皮层的可塑性。

Project Summary/Abstract Exposure to loud sound induces death of cochlear hair cells and loss of synapses between hair cells and the auditory nerve, which contribute to loss of afferent input to the brain. While a reduction of input, as a result of noise exposure, may be predicted to cause reduced responses to sound, it paradoxically increases excitatory responses in auditory cortex. The observed increase in excitatory responses serves an adaptive function, such that increased responsiveness to sound aids perception even with reduced input from the auditory periphery. This phenomenon has been termed auditory gain adaptation. A decrease in parvalbumin (PV) neuron- mediated inhibition to principal neurons has been suggested as a possible mechanism for gain adaptation after noise exposure. However, the mechanisms of intrinsic and synaptic plasticity in auditory cortex after noise exposure are unknown. Our preliminary, in vivo calcium imaging results, demonstrate that PV neurons increase their gain in response to sound after noise exposure, while auditory cortical slice results show a depolarization of the resting membrane potential of PV neurons. Furthermore, these plastic changes occur in PV neurons before principal neurons. By determining the synaptic and intrinsic mechanisms of plasticity of PV and principal neurons, we will understand how the seemingly counterintuitive increases in PV gain and intrinsic excitability ultimately result in increased excitatory gain after noise exposure. I aim to test the hypothesis that noise exposure induces plasticity in auditory cortex that involves time-dependent increases in PV and principal neuron intrinsic excitability, as well as synapse-specific changes in their synaptic contacts. Thus, by utilizing a combination of optogenetics, whole-cell electrophysiology, and in vivo Auditory Brainstem Response (ABR) and Distortion Product Otoacoustic Emission (DPOAE) measurements, this proposal aims to test this hypothesis. Furthermore, this proposal aims to investigate the noise exposure conditions in which plasticity occurs, and conduct a detailed investigation of the time course of plasticity in a cell and layer-specific manner. Results from this proposal will provide insight to the adult plasticity mechanisms of auditory cortex after noise exposure. The expected outcome of this proposal may identify potential therapeutic targets of disorders implicated in pathological increases of gain, such as tinnitus and hyperacusis, and aid our understanding of adult plasticity in auditory cortex.