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

GABA 和 NPY 信号相互作用形成听觉顶丘脑通路的抑制

• 批准号: 10369755
• 负责人: Marina Augusto Silveira
• 金额: $ 11.22万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369755
• 关键词: Affect; Aging; Animal Vocalization; Auditory; Brain region; Communication; Complex; Critical Pathways; Cues; Detection; Drug usage; Electrophysiology (science); Elements; Equilibrium; Family; Foundations; Frequencies; Glutamates; Goals; Hearing; In Vitro; Inferior Colliculus; Ipsilateral; Medial; Morphology; Mus; Neural Inhibition; Neuromodulator; Neurons; Neuropeptides; Neurotransmitters; Outcomes Research; Pathway interactions; Pharmacology; Phase; Population; Positioning Attribute; Presbycusis; Property; Research; Role; Shapes; Signal Transduction; Sound Localization; Speech; Synapses; Testing; Tetraodontidae; Thalamic structure; Viral; Work; aged; auditory pathway; auditory processing; auditory thalamus; experimental study; gamma-Aminobutyric Acid; improved; in vivo; molecular marker; mouse model; neural circuit; neuronal excitability; neuropeptide Y; neuropeptide Y-Y1 receptor; neuroregulation; novel; optogenetics; postsynaptic; public health relevance; receptive field; receptor; relating to nervous system; response; signal processing; skills; sound; speech processing; synaptic inhibition; therapeutic development; vocalization

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.

抽象的 抑制作用批判性地塑造了听觉信号处理，几乎影响了听力的各个方面。在下 Colliculus（IC），抑制作用塑造神经元如何应对对语音至关重要的听觉线索的反应 发声处理，包括频率调整曲线和频率调制的定向选择性 （FM）扫荡。此外，突触抑制减少是与年龄相关的听力损失的关键特征。 IC是 被认为是中央听觉途径的枢纽，尽管抑制在IC中至关重要，但细胞还是 GABA能抑制作用的机制在很大程度上尚不清楚。我们理解的差距存在 因为事实证明，很难在IC中识别出不同的GABA能神经元类型。我们最近克服了 通过将神经肽Y（NPY）表达识别为新型抑制性原则的标记来通过识别神经肽Y（NPY） IC中的神经元。 NPY神经元具有GABA能，具有星形的形态，并向听觉丘脑进行了项目 （mg）。此外，我们发现NPY信号传导抑制了大型IC谷氨酸能的兴奋性 表达NPY Y1受体（Y1R）的神经元。在此提案中，我将研究基本机制 IC中的NPY信号传导以及NPY和GABA的共用释放如何影响体内听觉处理。总体 这项研究的目的是确定NPY和GABA信号如何来自定义的IC GABA能类别 神经元影响Y1R神经元以塑造听觉中的频率调整和FM扫描方向选择性 构造河流途径。我将进一步确定增强NPY信号是否改善了听觉的功能 在小鼠衰老模型中破坏的IC和MG处理。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。 AIM 1将在K99阶段完成。我将在体外电生理学与药理学结合 和光遗传电路映射以确定GABA和NPY信号如何相互作用以调节兴奋性 IC。 AIM 2将在K99阶段执行。我将在使用IC-MG途径中的体内录制 药理学，化学遗传学和光遗传学调节NPY和GABA能信号传导。这个目标 确定NPY信号传导如何塑造音调接受场和FM扫描方向选择性的神经元的选择性 IC和MG。 在AIM 3中，在R00阶段，我将结合我在K99阶段学到的技能与背景 在电生理学和病毒道追踪中，研究NPY和Y1R神经元如何相互作用以形状 MG中突触后活性。我将进一步确定该电路中的兴奋性抑制作用如何 在老鼠衰老模型中受到影响。这项研究将提供对如何独特的机械理解 GABA能神经元的亚型与IC中的神经肽信号传导相互作用，以塑造听觉计算 构造河流途径。