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，多巴胺能内耳传出系统是上调下 环境条件引起的声损伤，有一个主要的差距，在知识内部 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 社会沟通的背景。本申请的总体目标是确定激素和 声学信号是多巴胺神经支配可塑性的基础，它在内耳中合成， 转，影响初级听觉处理和编码的社会发声。平鳍见习鱼， 也许这类工作中最强大的模型具有揭示监管的巨大潜力， 多巴胺能内耳传出神经在社会交往中的作用重要的是，自然 女性外周听觉系统（包括其多巴胺能传出神经）的异常可塑性 海军军官学校的学生，似乎反映了人类听力损失和注意力的状况。中央 一种假说认为，内耳的多巴胺能系统是由内部状态的变化调节的， 循环激素和多巴胺的局部合成可以通过社会声学刺激来调节。这 这一假设得到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 多巴胺能神经传递中的多巴胺诱导的变化和2）表征多巴胺 合成和代谢后暴露于社会的声音信号。第一个目的是传播性的水平， 类固醇和褪黑激素将被实验性地操纵，并且多巴胺神经支配、多巴胺 将测量内耳中的受体基因表达和多巴胺合成和代谢。为 第二个目标是，当暴露在空气中时，将测量雌性内耳中局部多巴胺合成的变化。 男性广告呼叫和响应和注意社会声音刺激时。拟议 我们认为，该项目是创新的，因为它代表了对现状的实质性偏离， 采用简单但功能强大的非哺乳动物脊椎动物模型系统， 在外周听觉敏感性增强编码的社会声学信号，和多巴胺输入到内部 耳朵在调节听觉灵敏度的这种变化中起作用。这一贡献将是巨大的，因为它 将确定调节多巴胺新的生物学功能的生理和环境条件， 周边听觉系统：增加了对社会声学信号的检测。重要的是，我们的结果可以 在自然和行为相关的背景下解释内耳多巴胺调制的功能 这是迄今为止哺乳动物研究中所缺乏的。最终，这些发现有可能提供见解， 了解周期（月经）或激素下降（衰老）如何与听力敏感度的变化有关， 注意力以及大脑疾病，如ASD和ADHD，其中定向和检测社会 听觉线索严重受损

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.