Coding in Auditory Neurons: Effects of Amino Acids

听觉神经元的编码：氨基酸的作用

• 批准号: 9026275
• 负责人: Donald M. Caspary
• 金额: $ 52.22万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-08-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9026275
• 关键词: Acetylcholine; Acoustics; Acute; Affect; Affinity; Age; Age-Years; Aging; Agonist; Amino Acids; Animals; Area; Arousal; Attention; Auditory; Auditory area; Autoradiography; Award; Binding; Biological Assay; Brain Stem; Cell Nucleus; Cell physiology; Cholinergic Receptors; Code; Cognitive; Complex; Confocal Microscopy; Data; Development; Disease; Dorsal; Drosophila acetylcholine receptor alpha-subunit; Elderly; Environment; Glutamates; Grant; Health; Hearing; Hippocampus (Brain); Human; Immunohistochemistry; Immunoprecipitation; In Vitro; Individual; Inferior Colliculus; Label; Lead; Learning; Ligands; Location; Medial geniculate body; Mediating; Mental Depression; Modeling; Nature; Neurons; Neurotransmitters; Nicotinic Receptors; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiology; Play; Population; Presbycusis; Process; Property; Rattus; Reporting; Resources; Role; Sensory; Signal Transduction; Slice; Societies; Speech; Stimulus; Stream; Structure; Synapses; System; Thalamic structure; Time; United States; Withdrawal; age related; aged; auditory nuclei; awake; basal forebrain; cell type; cholinergic; cholinergic neuron; density; directed attention; drug development; gamma-Aminobutyric Acid; improved; in vivo; middle age; mind control; neurotransmission; novel; patch clamp; postsynaptic; presynaptic; radioligand; receptor; receptor function; response; social; sound; voltage clamp; young adult

 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.

 描述（由适用提供）：与年龄相关的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，老年人经常很难理解言语，这可能会导致社会活动和抑郁症的撤离。老年人还显示出在复杂的听觉环境中参加语音的能力的定义。衰老的研究表明，老年人可以通过使用注意力和认知资源来降级临时信息，因此他们可以保持语音理解。在上一个赠款期间完成的研究详细介绍了可能支撑声学信息编码的年轻和老年丘脑皮质回路的受体抑制作用的构成和功能。这些研究使用醒着的大鼠中位数基因体（MGB）的体外切片记录和体内记录，发现MGB和听觉皮层中GABAA受体的化妆，功能和药理学的显着变化。在年轻人中，难以理解的言语和新颖的刺激导致 从包括听觉皮层和海马在内的皮质区域发送的下游信号激活了脑干胆碱能唤醒/注意电路。反过来，脑干胆碱能神经元 项目到包括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建立重要刺激的显着性方面起着至关重要的作用。在MGB中发现了高水平的烟碱胆碱能受体（NACHR），但有关其亚基组成，MGB电路中的位置以及衰老如何影响这些系统还有很多待了解。人类和大鼠在整个丘脑中显示出一个关键NACHR亚基的年龄相关的30+％损失。我们的初步MGB分析支持并扩展这些发现。这些数据首次表明，NACHR的亚基构成的显着变化，导致接收器亲和力与年龄相关的损失。初步贴片钳切片数据显示，支持这种与年龄相关的亲和力损失的突触前和后NACHR反应减少了。体外和体内方法将：SA1。在年轻成人MGB的主要细分和细胞类型中表征异源NACHR：1A）药理学，亚基组成和位置以及1B）生理学和细胞位置。 SA2。表征了MGB中主要细分和细胞类型的NACHR中与年龄相关的变化：2A）药理学，亚基组成和位置以及2B）生理学和细胞位置。 SA3。 3A）确定在加工新颖的，暂时丰富的刺激中发生的与年龄相关的变化，这些变化是从清醒动物中的MGB单位记录的。 3B）离子遗嘱研究将检查NACHR激动剂和拮抗剂对这些临时反应特性的影响。了解与衰老相关的药理和功能性NACHR变化将为选择性药物疗法的发展提供信息，这可能会减轻与年龄相关的语音理解的丧失。