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

摘要 抑制关键地塑造了听觉信号处理，几乎影响到听力的方方面面。在劣势中 丘(IC)，抑制塑造神经元如何对听觉线索做出反应，听觉线索对语音和 发声处理，包括调频曲线和调频方向选择 (FM)扫掠。此外，突触抑制减弱是年龄相关性听力损失的一个重要特征。这个IC是 被认为是中枢听觉通路的枢纽，尽管抑制在IC中起着关键作用，但细胞 GABA能抑制的机制在很大程度上仍不清楚。我们理解上的这种差距是存在的 因为已经证明很难在IC中识别不同的GABA能神经元类型。我们最近克服了 通过确定神经肽Y(NPY)的表达作为一类新的抑制性主体的标记来解决这个问题 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 (毫克)。此外，我们还发现NPY信号抑制了IC谷氨酸能大家族的兴奋性 表达NPY Y1受体(Y1R)的神经元。在这项提案中，我将调查潜在的机制 在IC中的NPY信号以及NPY和GABA的共同释放如何影响体内的听觉处理。整体而言 这项研究的目的是确定NPY和GABA信号是如何从一类确定的IC GABA能 神经元影响听觉中Y1R神经元的频率调谐和调频方向选择 顶盖丘脑通路。我将进一步确定增强NPY信号是否改善听觉功能 在衰老的小鼠模型中，IC和MG中的处理被中断。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。我将把体外电生理学和药理学结合起来 以及光遗传电路图以确定GABA和NPY信号如何相互作用来调节兴奋性。 集成电路。 目标2将在K99阶段进行。我将在IC-MG通路中进行活体记录，同时使用 药理学、化学遗传学和光遗传学调节NPY和GABA能信号。这一目标将 确定NPY信号如何塑造神经元的音调感受野和FM扫描方向选择性 IC和MG。 在目标3中，在R00阶段，我将把我在K99阶段学到的技能与我的背景相结合 在电生理学和病毒道示踪中研究NPY和Y1R神经元如何相互作用形成 MG的突触后活动。我将进一步确定这个回路中的兴奋-抑制相互作用是如何 在衰老的小鼠模型中受到影响。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塑造听觉计算 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.