GABA and NPY Signaling Interact to Shape Inhibition in the Auditory Tectothalamic Pathway

摘要 抑制对听觉信号的处理有着至关重要的影响，几乎影响到听觉的各个方面。下腔 在丘脑（IC）中，抑制作用塑造了神经元对听觉线索的反应，这些听觉线索对语言和 发声处理，包括频率调谐曲线和频率调制的方向选择性 (FM)清扫。此外，突触抑制减弱是年龄相关性听力损失的一个关键特征。则IC将 被认为是中枢听觉通路的枢纽，尽管抑制在IC中起着至关重要的作用， γ-氨基丁酸能抑制的潜在机制仍不清楚。我们的理解中存在这种差距 因为已经证明难以鉴定IC中不同的GABA能神经元类型。我们最近克服了 通过鉴定神经肽Y（NPY）表达作为一类新的抑制性成分的标志物， IC中的神经元NPY神经元是GABA能神经元，具有星状形态并投射到听觉丘脑 （MG）.此外，我们发现，NPY信号转导抑制了一个大家族的IC神经递质的兴奋性。 表达NPY Y1受体（Y1 R）的神经元。在这个建议中，我将研究潜在的机制， IC中的NPY信号传导以及NPY和GABA的共同释放如何影响体内听觉处理。整体 本研究的目的是确定NPY和GABA信号如何从一类确定的IC GABA能 神经元影响Y1 R神经元以形成听觉中的频率调谐和FM扫描方向选择性 顶盖丘脑通路我将进一步确定增强NPY信号是否能改善听觉系统的功能， 在小鼠衰老模型中被破坏的IC和MG中的加工。为了实现这些目标，我将使用 体外和体内电生理学，结合药理学，化学遗传学和光遗传学。 目标1将在K99阶段实现。我将联合收割机体外电生理学与药理学相结合 和光遗传学电路映射，以确定GABA和NPY信号如何相互作用以调节神经元的兴奋性。 的IC。 目标2将在K99阶段执行。我将在体内记录IC-MG途径，同时使用 药理学、化学遗传学和光遗传学来调节NPY和GABA能信号传导。这一目标将 确定神经肽Y信号如何塑造神经元的音调感受野和调频扫描方向选择性， IC和MG。 在目标3中，在R 00阶段，我将联合收割机与我在K99阶段学到的技能结合起来 在电生理学和病毒道示踪研究如何NPY和Y1 R神经元相互作用， MG中的突触后活动。我将进一步确定这个回路中的兴奋-抑制相互作用 在小鼠衰老模型中受到影响。这项研究将提供一个机械的理解，如何不同的 GABA能神经元的亚型与IC中的神经肽信号相互作用，以形成听觉计算。 顶盖丘脑通路

Abstract Inhibition critically shapes auditory signal processing, impacting nearly every aspect of hearing. In the inferior colliculus (IC), inhibition shapes how neurons respond to auditory cues that are essential for speech and vocalization processing, including frequency tuning curves and directional selectivity for frequency modulated (FM) sweeps. In addition, diminished synaptic inhibition is a critical feature in age-related hearing loss. The IC is considered the hub of the central auditory pathway, and despite the crucial role of inhibition in the IC, the cellular mechanisms underlying GABAergic inhibition remain largely unknown. This gap in our understanding exists because it has been proven difficult to identify distinct GABAergic neuron types in the IC. We recently overcame this problem by identifying Neuropeptide Y (NPY) expression as a marker for a novel class of inhibitory principal neurons in the IC. NPY neurons are GABAergic, have a stellate morphology and project to the auditory thalamus (MG). In addition, we found that NPY signaling dampens the excitability of a large family of IC glutamatergic neurons that express the NPY Y1 receptor (Y1R). In this proposal, I will investigate the mechanisms underlying NPY signaling in the IC and how the co-release of NPY and GABA affects auditory processing in vivo. The overall objective of this research is to determine how NPY and GABA signaling from a defined class of IC GABAergic neurons influence Y1R neurons to shape frequency tuning and FM sweep direction selectivity in the auditory tectothalamic pathway. I will further determine whether augmenting NPY signaling improves features of auditory processing in the IC and MG that are disrupted in a mouse model of aging. To pursue these objectives, I will use in vitro and in vivo electrophysiology, combined with pharmacology, chemogenetics and optogenetics. Aim 1 will be accomplished during the K99 phase. I will combine in vitro electrophysiology with pharmacology and optogenetic circuit mapping to determine how GABA and NPY signaling interact to modulate excitability in the IC. Aim 2 will be performed during the K99 phase. I will make in vivo recordings in the IC-MG pathway while using pharmacology, chemogenetics and optogenetics to modulate NPY and GABAergic signaling. This aim will determine how NPY signaling shapes the tonal receptive fields and FM sweep direction selectivity of neurons in the IC and MG. In Aim 3, during the R00 phase, I will combine the skills I have learned during the K99 phase with my background in electrophysiology and viral tract tracing to investigate how NPY and Y1R neurons interact to shape postsynaptic activity in the MG. I will further determine how excitatory-inhibitory interactions in this circuit are affected in a mouse model of aging. This research will provide a mechanistic understanding of how a distinct subtype of GABAergic neuron interacts with neuropeptide signaling in the IC to shape auditory computations in the tectothalamic pathway.