NSF-IOS-BSF:Influence of neuronal zinc homeostasis on cortical responses to sound

NSF-IOS-BSF：神经元锌稳态对皮质对声音反应的影响

• 批准号: 1655480
• 负责人: Elias Aizenman
• 金额: $ 124万
• 依托单位: University of Pittsburgh
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1655480&HistoricalAwards=false
• 关键词: NSF; IOS; BSF; Influence; neuronal

In the auditory system, as sound properties of the auditory environment change, auditory cells in the brain adjust their dynamic range of their responses to match changing background noise. This type of adaptation to sound is extremely important for brain auditory processing, for it provides a mechanism for allowing us to focus on specific sounds in the presence of variable background sound levels. However, the mechanisms underlying this adaptation remain unknown. This project will establish a previously unknown link between the metal zinc in the brain and control of auditory processing in the cerebral cortex of the brain. Thus, findings from this project will advance understanding about mechanisms of adaptations of sound processing and create a new framework for approaching and interpreting the role of the auditory system in the processing of sound. This joint NSF/BSF project will establish a joint US-Israel student exchange program as well as target underserved student populations both in Israel and the US and train them in problem-solving at behavioral, neural and molecular levels of analysis. Broad dissemination of the work will be made possible by active engagement with the International Society for Zinc Biology through a variety of activities.Zinc is packaged into glutamatergic vesicles by the ZnT3 zinc transporter, and released from synaptic terminals in an activity-dependent manner. Although the basic principles underlying zinc neurotransmission have begun to be deciphered, the sensory stimuli leading to the modulation of zinc signaling as well as the role of zinc in regulating sensory processing remain unknown. The central hypothesis of this project is that sound dependent changes in zinc signaling in the auditory cortex play a role in the sound level adaptation of neuronal input-output functions to match the prevailing stimulus intensity of the acoustic environment. This project aims to: i. Identify the consequences of experience-dependent plasticity of zinc-mediated modulation on input-output functions and receptive fields of layers 2/3 auditory cortical neurons in vivo, and ii. Establish the cellular and molecular mechanisms mediating the experience-dependent alterations in zinc-dependent auditory cortical processing. These studies will thus provide the first analysis of regulation of neuronal zinc and its effects on auditory processing, at the molecular, cellular and systems levels.

在听觉系统中，随着听觉环境的声音特性发生变化，大脑中的听觉细胞会调整其响应的动态范围以匹配不断变化的背景噪声。这种对声音的适应对于大脑听觉处理极其重要，因为它提供了一种机制，使我们能够在背景声音水平可变的情况下专注于特定的声音。然而，这种适应的机制仍然未知。该项目将在大脑中的金属锌与大脑皮层的听觉处理控制之间建立以前未知的联系。因此，该项目的研究结果将促进对声音处理适应机制的理解，并为接近和解释听觉系统在声音处理中的作用创建一个新的框架。这个 NSF/BSF 联合项目将建立一个美国-以色列联合学生交流计划，并针对以色列和美国服务不足的学生群体，培训他们在行为、神经和分子分析水平上解决问题。通过积极参与国际锌生物学学会的各种活动，将有可能实现这项工作的广泛传播。锌被 ZnT3 锌转运蛋白包装到谷氨酸囊泡中，并以活动依赖性方式从突触末端释放。尽管锌神经传递的基本原理已开始被破译，但导致锌信号传导调节的感觉刺激以及锌在调节感觉处理中的作用仍然未知。该项目的中心假设是，听觉皮层中锌信号传导的声音依赖性变化在神经元输入输出功能的声级适应中发挥作用，以匹配声学环境的主要刺激强度。 该项目的目的是：确定锌介导的调节的经验依赖性可塑性对体内 2/3 层听觉皮层神经元的输入输出功能和感受野的影响，以及 ii。建立介导锌依赖性听觉皮层处理中经验依赖性改变的细胞和分子机制。 因此，这些研究将在分子、细胞和系统水平上首次分析神经元锌的调节及其对听觉处理的影响。

项目成果

The ZIP3 Zinc Transporter Is Localized to Mossy Fiber Terminals and Is Required for Kainate-Induced Degeneration of CA3 Neurons

ZIP3 锌转运蛋白定位于苔藓纤维末端，是红藻氨酸诱导的 CA3 神经元变性所必需的

• DOI: 10.1523/jneurosci.0908-21.2022
• 发表时间: 2022-03
• 期刊: The Journal of Neuroscience
• 作者: Bogdanovic, Milos;Asraf, Hila;Gottesman, Noa;Sekler, Israel;Aizenman, Elias;Hershfinkel, Michal
• 通讯作者: Hershfinkel, Michal

Neuromodulatory Mechanisms Underlying Contrast Gain Control in Mouse Auditory Cortex

小鼠听觉皮层对比度增益控制的神经调节机制

• DOI: 10.1523/jneurosci.2054-21.2022
• 发表时间: 2022-07
• 期刊: The Journal of Neuroscience
• 作者: Cody, Patrick A.;Tzounopoulos, Thanos
• 通讯作者: Tzounopoulos, Thanos

The Function and Regulation of Zinc in the Brain

锌在大脑中的功能和调节

• DOI: 10.1016/j.neuroscience.2021.01.010
• 发表时间: 2021-03-01
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Krall RF;Tzounopoulos T;Aizenman E
• 通讯作者: Aizenman E

Synaptic zinc inhibition of NMDA receptors depends on the association of GluN2A with the zinc transporter ZnT1

NMDA 受体的突触锌抑制取决于 GluN2A 与锌转运蛋白 ZnT1 的关联

• DOI: 10.1126/sciadv.abb1515
• 发表时间: 2020-07
• 期刊: Science Advances
• 影响因子: 13.6
• 作者: Krall, Rebecca F.;Moutal, Aubin;Phillips, Matthew B.;Asraf, Hila;Johnson, Jon W.;Khanna, Rajesh;Hershfinkel, Michal;Aizenman, Elias;Tzounopoulos, Thanos
• 通讯作者: Tzounopoulos, Thanos

Fine Control of Sound Frequency Tuning and Frequency Discrimination Acuity by Synaptic Zinc Signaling in Mouse Auditory Cortex

小鼠听觉皮层突触锌信号传导对声音频率调谐和频率辨别敏锐度的精细控制

• DOI: 10.1523/jneurosci.1339-18.2018
• 发表时间: 2019-01
• 期刊: The Journal of Neuroscience
• 作者: Kumar, Manoj;Xiong, Shanshan;Tzounopoulos, Thanos;Anderson, Charles T.
• 通讯作者: Anderson, Charles T.