The impact of transient developmental HL on corticostriatal eLTP expression during auditory learning.

听觉学习过程中瞬时发育性 HL 对皮质纹状体 eLTP 表达的影响。

• 批准号: 10320528
• 负责人: Todd M. Mowery
• 金额: $ 24.1万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320528
• 关键词: impact; transient; developmental; HL; corticostriatal

PROJECT SUMMARY Auditory deprivation during the critical period of development can induce persistent changes along the entire auditory neuraxis, as well as, brain regions downstream of primary auditory cortex. One such brain region, the striatum, forms an excitatory circuit with the auditory cortex that drives decision-making. Recently, I have found that transient developmental HL leads to persistent changes in the excitatory synaptic strength, inhibitory synaptic strength, and cellular firing properties of gerbil auditory corticostriatal neurons. These changes involve receptors that mediate long-term potentiation. Thus the behavioral impairments that remain after recovery from developmental HL could in part be due to changes in the corticostriatal expression of excitatory long-term potentiation (eLTP) during task acquisition. The core hypothesis of this proposal is that auditory associative learning delay in HL subjects is caused by NMDA and GABA receptor mediated disruptions to eLTP expression along the auditory corticostriatal circuit. Aim one will assess how NMDA receptor and GABAA/B receptor function contributes to eLTP expression and auditory learning in the cortex and striatum. This will be accomplished by 1) carrying out whole-cell recording from corticostriatal brain slices in adult gerbils in the presence of NMDA or GABA receptor blockers during the induction of eLTP or 2) by infusing NMDA or GABA blockers directly into the cortex or striatum via micro cannula during auditory discrimination training. Aim two will assess how learning-induced changes to neural and synaptic properties in the cortex and striatum promote eLTP during task acquisition. This will be accomplished by 1) using in vitro whole-cell recordings from ACx L5 or striatum to measure the learning-induced changes to NMDA and GABA receptor function and how they alter the probability of eLTP expression during auditory discrimination learning or 2) by using in vivo electrophysiological recordings from ACx L5 or striatum to measure how changes to neural firing rates and patterns are correlated with increases in in vivo measures of eLTP during auditory discrimination learning. Aim three will ask how developmental HL-induced changes to the set point of synaptic strength or neural firing properties along the corticostriatal circuit affect eLTP expression during auditory learning. This will be accomplished by 1) using in vitro whole-cell recordings from ACx L5 or striatum of adult animals that experienced developmental HL to measure how the HL-induced changes to synaptic strength set points impact the learning-induced changes that drive eLTP expression during auditory discrimination learning or 2) by using in vivo electrophysiological recordings from ACx L5 or striatum of adult animals that experienced developmental HL to measure how HL-induced changes to neural firing properties impact the learning-induced changes that drive LTP during auditory discrimination learning. Together, this proposal will reveal how HL- induced changes to cellular and synaptic properties along the corticostriatal circuit interact with the learning-induced changes to cellular and synaptic properties that promote auditory learning.

项目摘要 在关键时期，听觉剥夺会导致整个过程中的持续变化 听觉神经以及主要听觉皮层下游的大脑区域。一个大脑区域，一个 纹状体，形成一个带有听觉皮层的兴奋回路，可驱动决策。最近，我发现了 瞬时发育HL导致兴奋性突触强度，抑制性的持续变化 Gerbil听觉皮层神经元的突触强度和细胞发射特性。这些变化涉及 介导长期增强的受体。因此，恢复后仍然存在的行为障碍 从发育中的HL可能部分是由于兴奋性长期的皮质纹状体表达的变化 在任务采集期间的增强（ELTP）。该提议的核心假设是听觉关联 HL受试者的学习延迟是由NMDA和GABA受体介导的ELTP中断引起的 沿听觉皮质纹状体电路的表达。 AIM ONE将评估NMDA受体和GABAA/B如何 受体功能有助于皮质和纹状体中的ELTP表达和听觉学习。这将是 通过1）从成年晶状体的皮质纹状体脑切片中进行全细胞记录完成 通过注入NMDA或GABA，在诱导ELTP期间存在NMDA或GABA受体阻滞剂 在听觉歧视训练期间，通过微套管直接进入皮质或纹状体。瞄准两个 将评估学习诱导的皮质和纹状体中神经和突触特性的变化 任务采集期间的ELTP。这将通过1）使用ACX L5的体外全细胞记录来完成 或纹状体测量学习引起的NMDA和GABA受体功能的变化以及它们如何改变 在听觉歧视学习过程中ELTP表达的概率或2）使用体内 来自ACX L5或纹状体的电生理记录，以衡量如何改变神经发射率和 模式与听觉歧视学习过程中ELTP的体内测量值的增加相关。目的 三个会询问发育性HL引起的突触强度或神经射击的设定点的变化 沿皮质纹状体电路的性质会影响听觉学习过程中的ELTP表达。这将是 通过1）使用ACX L5或成年动物纹状体的体外全细胞记录完成 经验丰富的发育HL，以衡量HL诱导的变化如何变化突触强度设定点影响 学习引起的变化在听觉歧视学习过程中推动ELTP表达的变化或2）使用 来自ACX L5或成年动物纹状体的体内电生理记录 发育性HL衡量HL诱导的神经发射特性的变化如何影响学习诱导的 在听觉歧视学习过程中更改LTP的变化。该提议在一起将揭示如何 沿皮质纹状体回路对细胞和突触特性的诱导变化与 学习引起的对促进听觉学习的细胞和突触特性的变化。