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。

基本信息

批准号：
10376744
负责人：
Todd M. Mowery
金额：
$ 33.36万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
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/10376744
关键词：
Address Adult Affect Animals Auditory Auditory area Auditory system Behavior Behavioral Bicuculline Bilateral Bilateral Hearing Loss Brain Brain region Cannulas Cell physiology Cells Cerebrospinal Fluid Childhood Cognitive Conductive hearing loss Corpus striatum structure Decision Making Development Discrimination Discrimination Learning Ear Electrophysiology (science)GABA Receptor Gerbils Human Impairment Implant In Vitro Individual Infusion procedures Learning Long-Term Potentiation Measures Mediating Memory Methodology N-Methyl-D-Aspartate Receptors N-Methylaspartate Neuraxis Neurons Noise Pattern Physiology Play Probability Property Protocols documentation Pyramidal Cells Recovery Research Sensory Sensory Deprivation Slice Structure Synapses Training Treatment outcome Whole-Cell Recordings auditory deprivation auditory discrimination behavioral impairment classical conditioning critical period deprivation experience experimental study extracellular gamma-Aminobutyric Acid hearing impairment hippocampal pyramidal neuron implantation in vivo mature animal multi-electrode arrays normal hearing postnatal prevent receptor receptor function relating to nervous system

项目摘要

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.

项目概要发育关键时期的听觉剥夺会引起整个身体的持续变化听觉神经轴以及初级听觉皮层下游的大脑区域。其中一个这样的大脑区域，纹状体与听觉皮层形成兴奋回路，驱动决策。最近，我发现短暂的发育性 HL 会导致兴奋性突触强度、抑制性突触强度的持续变化沙鼠听觉皮质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 的变化可能部分归因于兴奋性长期皮质纹状体表达的变化任务获取期间的增强（eLTP）。该提案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 破坏引起的沿着听觉皮质纹状体回路表达。目标一将评估 NMDA 受体和 GABAA/B 如何受体功能有助于皮层和纹状体中的 eLTP 表达和听觉学习。这将是通过以下方式完成：1）对成年沙鼠的皮质纹状体脑切片进行全细胞记录在诱导 eLTP 期间存在 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，阻滞剂通过微插管直接进入皮层或纹状体。目标二将评估学习引起的皮质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。这将通过以下方式实现：1) 使用 ACx L5 的体外全细胞记录或纹状体来测量学习引起的 NMDA 和 GABA 受体功能的变化以及它们如何改变听觉辨别学习期间 eLTP 表达的概率或 2) 通过使用体内来自 ACx L5 或纹状体的电生理记录，用于测量神经放电率和纹状体的变化模式与听觉辨别学习期间 eLTP 体内测量的增加相关。目的三个人会问发育性 HL 如何引起突触强度或神经放电设定点的变化皮质纹状体回路的特性影响听觉学习过程中 eLTP 的表达。这将是 1) 使用成年动物 ACx L5 或纹状体的体外全细胞记录来完成经验丰富的发育 HL 来测量 HL 引起的突触强度设定点变化如何影响在听觉辨别学习期间驱动 eLTP 表达的学习引起的变化或 2) 通过使用来自成年动物 ACx L5 或纹状体的体内电生理记录发展性 HL 来衡量 HL 引起的神经放电特性变化如何影响学习引起的在听觉辨别学习过程中驱动 LTP 的变化。该提案将共同揭示 HL 如何- 沿着皮质纹状体回路引起的细胞和突触特性的变化与学习引起的细胞和突触特性的变化，促进听觉学习。