Coding in Auditory Neurons: Effects of Amino Acids

 描述（由申请人提供）：听力损失是一种复杂的疾病，影响至少30-50%的65岁或以上的美国人口。在公共场合，老年人经常难以理解言语，这可能导致退出社交活动和抑郁症。老年人在复杂的听觉环境中注意言语的能力也有缺陷。老龄化研究表明，老年人可以保持言语理解，因为他们的年龄，尽管退化的时间信息上升，通过使用注意力和认知资源。在上一个资助期完成的研究详细说明了年轻和老年丘脑皮层回路中介导抑制的受体的组成和功能，这些受体可能是声学信息编码的基础。这些研究使用清醒大鼠内侧膝状体（MGB）的体外切片记录和体内记录，发现MGB和听觉皮层中GABAA受体的组成、功能和药理学发生了显著的年龄相关变化。在年轻的成年人中，难以理解的语言和新颖的刺激导致 下游信号从皮质区发送，包括听觉皮质和海马，以激活脑干胆碱能唤醒/注意回路。脑干胆碱能神经元 投射到听觉结构，包括MGB。在感觉丘脑中，神经递质乙酰胆碱在唤醒注意力和建立重要刺激的显著性方面起着关键作用。在MGB中发现了高水平的烟碱胆碱能受体（nAChR），但关于它们的亚基组成、在MGB回路中的位置以及衰老如何影响这些系统，还有很多东西有待了解。人类和大鼠在整个丘脑中表现出30%以上的一个关键nAChR亚基的年龄相关损失。我们初步的MGB检测支持并扩展了这些发现。这些数据表明，第一次，存在显着的年龄相关的变化，亚基组成的nAChRs导致年龄相关的损失受体亲和力。初步膜片钳切片数据显示，突触前和突触后nAChR反应减少，支持这种与年龄相关的亲和力丧失。体外和体内方法将：SA 1。通过：1A）药理学、亚基组成和位置，以及1B）生理学和细胞位置，表征非成体MGB的主要亚类和细胞类型中的异聚nAChR。SA 2.通过：2A）药理学、亚基组成和位置，以及2B）生理学和细胞位置，表征MGB中主要亚群和细胞类型的nAChR中发生的年龄相关变化。SA 3. 3A）确定在处理从清醒动物的MGB单元记录的新颖的、时间丰富的刺激时发生的年龄相关的变化。3B）离子电渗研究将检查nAChR激动剂和拮抗剂对这些时间响应性质的影响。了解与衰老相关的药理学和功能性nAChR变化将为选择性药物治疗的发展提供信息，这些药物治疗可以改善与年龄相关的言语理解能力丧失。

 DESCRIPTION (provided by applicant): Age-related hearing loss is a complex disorder affecting at least 30-50% of the United States population aged 65 or older. In public settings, seniors frequently have difficulty understanding speech, which can lead to withdrawal from social activities and depression. Elderly individuals also show deficits in their ability to attendto speech in complex auditory environments. Aging studies suggest that the elderly can maintain speech understanding as they age despite degraded ascending temporal information by using attentional and cognitive resources. Studies completed during the previous grant period detailed the makeup and function of receptors mediating inhibition in young and aged thalamocortical circuits likely to underpin coding of acoustic information. Using in vitro slice recordings and in vivo recordings from awake rat medial geniculate body (MGB), these studies found significant age-related changes in the makeup, function, and pharmacology of GABAA receptors in MGB and in auditory cortex. In young adults, difficult-to-understand speech and novel stimuli result in downstream signals sent from cortical areas, including auditory cortex and hippocampus, to activate brainstem cholinergic arousal/attentional circuits. In turn, brainstem cholinergic neurons project to auditory structures including MGB. In sensory thalamus, the neurotransmitter acetylcholine plays a critical role in waking attention and in establishing the salience of important stimuli. High levels of nicotinic cholinergic receptors (nAChRs) are found in MGB, yet much remains to be learned about their subunit composition, location within MGB circuits and how aging impacts these systems. Humans and rats show a 30+% age-related loss of one key nAChR subunit in whole thalamus. Our preliminary MGB assays support and extend these findings. These data suggest, for the first time, the presence of significant age-related changes in the subunit makeup of nAChRs resulting in an age-related loss in receptor affinity. Preliminary patch-clamp slice data show reduced pre- and postsynaptic nAChR responses supporting this age-related loss in affinity. In vitro and in vivo approaches will: SA1. Characterize heteromeric nAChRs in the major subdivisions and cell types of young-adult MGB via: 1A) pharmacology, subunit composition and location, and 1B) physiology and cellular location. SA2. Characterize age-related changes that occur in nAChRs for the major subdivisions and cell types in MGB via: 2A) pharmacology, subunit composition and location, and 2B) physiology and cellular location. SA3. 3A) Determine age-related changes that occur in processing novel, temporally rich stimuli recorded from MGB units in awake animals. 3B) Iontophoretic studies will examine the impact of nAChR agonist and antagonists on these temporal responses properties. Understanding pharmacologic and functional nAChR changes associated with aging would inform development of selective pharmacotherapy that could ameliorate age-related loss of speech understanding.