Coding in Auditory Neurons: Effects of Amino Acids

 描述(由申请人提供)：年龄相关性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，老年人经常有理解语言的困难，这可能导致退出社交活动和抑郁。老年人在复杂的听觉环境中说话的能力也表现出缺陷。衰老研究表明，老年人可以在他们变老的过程中保持对语言的理解，尽管通过使用注意力和认知资源来降低上升的时间信息。在之前的资助期间完成的研究详细介绍了在年轻和老年丘脑皮质回路中介导抑制的受体的组成和功能，这些受体可能为声音信息的编码奠定基础。使用体外切片记录和清醒大鼠内侧膝状体(MGB)的在体记录，这些研究发现MGB和听觉皮质中GABAA受体的组成、功能和药理随年龄发生显著变化。对于年轻人来说，难懂的语言和新奇的刺激会导致 从包括听觉皮质和海马体在内的皮质区域发出的下游信号，激活脑干胆碱能觉醒/注意回路。反过来，脑干胆碱能神经元 投射到包括MGB在内的听觉结构。在感觉丘脑中，神经递质乙酰胆碱在唤醒注意力和确定重要刺激的突出性方面发挥着关键作用。在MGB中发现了高水平的尼古丁胆碱能受体(NAChRs)，但关于它们的亚单位组成、MGB回路中的位置以及衰老如何影响这些系统，仍有许多有待了解。人类和大鼠显示，整个丘脑中一个关键的nAChR亚单位与年龄相关的30%以上的丢失。我们的初步MGB测试支持并扩展了这些发现。这些数据首次表明，nAChRs亚单位组成存在与年龄相关的显著变化，导致与年龄相关的受体亲和力丧失。初步的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：SA1。通过：1)药理、亚基组成和位置，以及1)生理和细胞定位，描述青壮年MGB主要亚基和细胞类型中的异构体nAChRs。SA2.通过以下几个方面描述MGB主要亚单位和细胞类型的nAChRs与年龄相关的变化：A)药理学、亚单位组成和位置，以及2B)生理和细胞位置。SA3.3a)确定在清醒动物中处理从MGB单位记录的新的、时间丰富的刺激时发生的与年龄相关的变化。3b)离子导入研究将考察nAChR激动剂和拮抗剂对这些时间反应特性的影响。了解与衰老相关的药理学和功能性nAChR的变化将有助于选择性药物治疗的发展，这种药物治疗可以改善与年龄相关的言语理解丧失。

 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.