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

项目摘要 在发育的关键期，听觉剥夺可引起整个大脑皮层沿着的持续性变化。 听觉神经轴，以及初级听觉皮层下游的大脑区域。其中一个脑区， 纹状体，与听觉皮层形成一个兴奋回路，驱动决策。最近，我发现 短暂的发育性HL导致兴奋性突触强度的持续变化，抑制性突触强度的持续变化 突触强度和细胞放电特性。这些变化涉及 介导长时程增强的受体。因此，康复后仍然存在的行为障碍 可能部分是由于皮质纹状体兴奋性长期表达的变化， 增强（eLTP）。这个提议的核心假设是听觉联想 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 表达沿着听觉皮质纹状体回路。目的一是探讨NMDA受体和GABAA/B在脑缺血中的作用 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）在成年沙鼠的皮质纹状体脑切片中进行全细胞记录， 在eLTP诱导过程中存在NMDA或GABA受体阻滞剂，或2）通过输注NMDA或GABA 在听觉辨别训练期间，通过微插管将阻断剂直接注入皮层或纹状体。瞄准二 将评估学习诱导的皮层和纹状体神经和突触特性的变化如何促进 任务获取期间的eLTP。这将通过1）使用ACx L5的体外全细胞记录来实现 或纹状体来测量学习诱导的NMDA和GABA受体功能的变化以及它们如何改变 听觉辨别学习过程中eLTP表达的可能性或2）通过使用体内 来自ACx L5或纹状体的电生理记录，以测量神经放电率的变化， 模式与听觉辨别学习过程中eLTP体内测量值的增加相关。目的 三个人会问，发育中的HL如何诱导突触强度或神经放电的设定点的变化， 皮质纹状体回路的沿着特性影响听觉学习过程中eLTP的表达。这将是 通过1）使用来自成年动物的ACx L5或纹状体的体外全细胞记录， 经历了发育性HL，以测量HL诱导的突触强度设定点变化如何影响 在听觉辨别学习过程中驱动eLTP表达的学习诱导的变化或2）通过使用 来自ACx L5或成年动物纹状体的体内电生理记录， 发展HL测量HL诱导的神经放电特性的变化如何影响学习诱导的 在听觉辨别学习中驱动LTP的变化。总之，这一提议将揭示HL- 诱导的细胞和突触特性的变化沿着皮质纹状体回路， 学习引起的细胞和突触特性的变化，促进听觉学习。

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.