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

项目总结 在发育的关键时期，听觉剥夺会导致整个大脑的持续变化 听神经轴，以及初级听觉皮质下游的脑区。一个这样的大脑区域，即 纹状体与驱动决策的听觉皮质形成兴奋回路。最近，我发现 短暂性发育性HL导致兴奋性突触强度的持续性变化，抑制性 沙土鼠听皮层纹状体神经元的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 发育性HL的部分原因可能是兴奋性长时程皮质纹状体表达的变化 任务习得过程中的增强(ELTP)。这一提议的核心假设是听觉联想 NMDA和GABA受体介导的ELTP干扰导致HL患者学习延迟 沿听觉皮质纹状体环路的表达。目的一将评估NMDA受体和GABAA/B如何 受体功能参与了大脑皮层和纹状体的ELTP表达和听觉学习。这将是 通过1)对成年沙土鼠皮质纹状体脑片进行全细胞记录 在ELTP诱导过程中NMDA或GABA受体阻滞剂的存在，或2)通过输注NMDA或GABA 在听觉辨别训练中，阻滞剂通过微型插管直接进入皮质或纹状体。目标二 将评估学习诱导的皮质和纹状体神经和突触特性的变化如何促进 任务习得过程中的英语学习策略。这将通过1)使用来自ACX L5的体外全细胞记录来实现 或纹状体测量学习诱导的NMDA和GABA受体功能的变化以及它们是如何变化的 ELTP在听觉辨别学习中表达的概率或2)在体内使用 来自ACX L5或纹状体的电生理记录，以测量神经放电率和 在听觉辨别学习过程中，模式与体内ELTP测量的增加相关。目标 三个问题是：发育中的HL如何引起突触强度或神经放电的设定点的变化 皮层纹状体回路的特性会影响听觉学习过程中ELTP的表达。这将是 通过1)使用来自ACX L5或成年动物纹状体的体外全细胞记录来完成 体验发育性HL以衡量HL诱导的突触强度设定点的变化如何影响 在听觉辨别学习中驱动ELTP表达的学习诱导的变化或2)通过使用 成年动物ACX L5或纹状体的在体电生理记录 发育性HL测量HL诱导的神经放电特性的变化如何影响学习诱导 在听觉辨别学习过程中驱动LTP的变化。综上所述，这项提案将揭示HL- 沿皮质纹状体回路的细胞和突触特性的诱导变化与 学习诱导的细胞和突触特性的变化，从而促进听觉学习。

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.