Hormonal and acoustic regulation of the dopaminergic auditory efferent system: improving detection of social acoustic signals at the level of the inner ear

虽然有充分的证据表明，在 导致声音创伤的环境条件，对内部环境的认识存在很大差距。 该系统的调节器及其在正常听力条件下的功能意义，特别是在 社会交流的语境。此应用程序的总体目标是确定荷尔蒙和 内耳中的多巴胺神经及其合成的可塑性的声学信号，在 反过来，会影响社会发声的初级听觉处理和编码。普莱芬恩海军学员鱼， 也许这类工作最可靠的模型具有揭示监管和 多巴胺能内耳传出神经在社会交流中的作用。重要的是，自然 以及女性外周听觉系统(包括其多巴胺能传出神经)的非凡可塑性 海军学员，似乎反映了人类听力损失和注意力丧失的情况。中环 假说认为，内耳的多巴胺能系统是由内部状态的变化通过 循环中的荷尔蒙和多巴胺的局部合成可以受到社会声音刺激的调节。这 假设得到了初步数据的有力支持，将通过以下两个具体目标进行检验：1)测量 激素诱导的多巴胺能神经传递的变化和2)多巴胺的变化特征 接触社会声音信号后的合成和新陈代谢。第一个目标是循环的性行为水平 类固醇和褪黑素将被实验操纵并改变多巴胺的神经支配、多巴胺 将测量内耳中受体基因的表达以及多巴胺的合成和代谢。对于 第二个目的是测量女性暴露后内耳局部多巴胺合成的变化。 对于男性广告呼叫，以及在响应和关注社会声音刺激时。建议数 我们认为，项目是创新的，因为它代表了对现状的实质性改变， 使用简单但强大的非哺乳动物脊椎动物模型系统，其中激素驱动的 在外周，听觉敏感性增强了社会声音信号的编码，并将多巴胺输入到内部 耳朵在调节这种听觉敏感度的变化中起着重要作用。这一贡献将是重大的，因为它 将确定调节多巴胺的一种新的生物学功能的生理和环境条件 外周听觉系统：增加对社会声音信号的检测。重要的是，我们的结果可能 在自然和行为相关的背景下解释内耳的多巴胺调节功能 到目前为止，在哺乳动物研究中还没有这一点。归根结底，这些发现有可能提供见解 周期(月经)或荷尔蒙下降(衰老)如何与听力敏感度和 注意以及诸如ASD和ADHD等脑部疾病，在这些疾病中，社交定向和检测 听觉信号严重受损。

While there is ample evidence that the dopaminergic inner ear efferent system is upregulated under environmental conditions that induce acoustic trauma, there is a major gap in knowledge about internal regulators of this system and its functional significance under normal hearing conditions, especially in the context of social communication. The overall objective of this application is to determine the hormonal and acoustic signals that underlie the plasticity of dopamine innervation and its synthesis in the inner ear, which, in turn, affects primary auditory processing and encoding of social vocalizations. The plainfin midshipman fish, perhaps the most robust model for this kind of work has the enormous potential of uncovering regulation and function of dopaminergic inner ear efferents in the context of social communication. Importantly, the natural and extraordinary plasticity of the peripheral auditory system (including its dopaminergic efferents) in female midshipman, appears to mirror conditions reflective of human hearing loss and attention. The central hypothesis is that the dopaminergic system of the inner ear is regulated by changes in internal state via circulating hormones and local synthesis of dopamine can be modulated by social acoustic stimuli. This hypothesis, strongly supported by preliminary data, will be tested by the following two specifc aims: 1) Measure hormone-induced changes in dopaminergic neurotransmission and 2) Characterize changes in dopamine synthesis and metabolism after exposure to social acoustic signals. For the first aim circulating levels of sex steroids and melatonin will be experimentally manipulated and changes in dopamine innervation, dopamine receptor gene expression and dopamine synthesis and metabolism in the inner ear will be measured. For the second aim, changes in local dopamine synthesis in the inner ear of females will be measured when exposed to male advertisement calls and when responding and attending to social acoustic stimuli. The proposed project is innovative, in our opinion, because it represents a substantive departure from the status quo by employing a simple but powerful, non-mammalian vertebrate model system where hormone-driven increases in periphery auditory sensitivity enhance encoding of social acoustic signals, and dopamine input to the inner ear plays a role in mediating this change in auditory sensitivity. This contribution will be significant because it will identify physiological and environmental conditions that regulate a novel biological function for dopamine in the peripheral auditory system: increased detection of social-acoustic signals. Importantly, our results could interpret the function of dopamine modulation of the inner ear in a natural and behaviorally relevant context that is absent in mammalian studies thus far. Ultimately, these findings have the potential to provide insights into how cycling (menstrual) or decline in hormones (aging) may be linked to changes in hearing sensitivity and attention as well as brain diseases such as ASD and ADHD where orientation to and detection of social auditory cues is severely impaired.