Development of the intrinsic synaptic circuits of the inferior colliculus

下丘固有突触回路的发育

• 批准号: 10569562
• 负责人: Karl Kandler
• 金额: $ 57.55万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-08 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569562
• 关键词: Acoustics; Address; Affect; Auditory; Axon; Cell Nucleus; Cell Shape; Cells; Cellular Morphology; Characteristics; Child; Childhood; Chronic; Communication; Conductive hearing loss; Development; Exhibits; Exposure to; Functional disorder; Generations; Glutamates; Hearing; Hyperacusis; Impairment; In Vitro; Inferior Colliculus; Knowledge; Lasers; Location; Maps; Midbrain structure; Morphology; Mus; Neurons; Neurotransmitter Receptor; Noise; Otitis Media with Effusion; Pattern; Physiologic pulse; Physiological; Physiology; Play; Probability; Process; Property; Recording of previous events; Research; Role; Scanning; Shapes; Slice; Sound Localization; Speech; Speech Perception; Stimulus; Synapses; Synaptic plasticity; Testing; Tinnitus; Whole-Cell Recordings; auditory pathway; auditory processing; awake; cell type; developmental plasticity; experience; hearing impairment; in vivo; insight; neural circuit; neuronal circuitry; novel; optogenetics; patch clamp; preference; presynaptic; response; sound; spatiotemporal; stellate cell

Project Summary The auditory midbrain (inferior colliculus, IC) is a hub and a major subcortical integration center in the central auditory pathway. Neurons in the IC are tuned to specific spectro-temporal features and are involved in the processing of communication sounds and speech. Abnormal sound-evoked or spontaneous IC activity has been associated with numerous central hearing dysfunctions including impaired speech perception, hyperacusis, and tinnitus. The spectro-temporal tuning of IC neurons arises from the integration of a multitude of ascending and descending inputs and an elaborated network of excitatory and inhibitory intrinsic synaptic connections between IC neurons. While the function and organization of external inputs to the IC are becoming increasingly understood, current understanding of the organization, physiology, and development of synaptic connections intrinsic to the IC is limited, hampering insight into their potential roles in IC function. To fill this knowledge gap, we propose to address three specific Aims. In Aim 1 we will test the hypothesis that the central nucleus of the IC (CNIC) contains two separate, functionally distinct, local networks arising from disc-shaped and stellate cells. We further hypothesize that the differentiation of these networks occurs after hearing onset requires normal patterns or levels of sound-evoked activity. To address these hypotheses, we will use laser scanning photostimulation with caged glutamate to map the location of neurons in the CNIC that monosynaptically connect to identified CNIC neurons in slices from control mice and from mice that were reared in pulsed white noise or have experienced temporary conductive hearing loss. In Aim 2 we will test the hypothesis that the physiological properties of synaptic connections are distinct between the two intrinsic CNIC networks and that their maturation depends on normal auditory experience. We will address this using simultaneous whole-cell recordings from identified neurons in slices from control mice and mice with a history of abnormal auditory experience. In Aim 3 we will test the hypothesis that abnormal sound-evoked single unit responses in the CNIC of mice with a history of abnormal auditory experience reflect abnormal intrinsic connections. We will address this by characterizing spectro-temporal responses properties of optogenetically identified glutamatergic and GABAergic CNIC neurons in awake control mice and mice with a history of abnormal auditory experience and correlate the changes observed in in-vivo with changes in intrinsic networks characterized in-vitro. Results from the proposed project will provided novel insight into the organization, synaptic physiology, and development of intrinsic CNIC circuits and their possible role in impaired sound processing in the CNIC. This new information will be valuable for understanding the circuit changes in the CNIC that contribute to the generation of central hearing deficits that are commonly observed in children that suffered from conductive hearing loss.

项目摘要 听觉中脑（下丘，IC）是中枢神经系统的中枢和主要的皮质下整合中心。 听觉通路IC中的神经元被调谐到特定的频谱-时间特征，并参与了神经元的活动。 处理通信声音和语音。异常的声音诱发或自发的IC活动， 与包括言语感知受损在内的许多中枢听力障碍有关， 听觉过敏和耳鸣IC神经元的频谱-时间调谐来自于大量 以及兴奋性和抑制性内在突触的复杂网络 IC神经元之间的连接。虽然对IC的外部输入的功能和组织正在变得 越来越多的理解，目前的理解的组织，生理学，和发展的突触 IC固有的连接是有限的，阻碍了对它们在IC功能中的潜在作用的洞察。填补这一 知识差距，我们建议解决三个具体目标。在目标1中，我们将检验中央 IC的核心（CNIC）包含两个独立的，功能不同的，局部网络，由盘状 和星状细胞。我们进一步假设这些网络的分化发生在听力开始后 需要正常的声音诱发活动模式或水平。为了解决这些假设，我们将使用激光 用笼状谷氨酸扫描光刺激以绘制CNIC中神经元的位置， 单突触连接到来自对照小鼠和来自 在脉冲白色噪声中长大或经历过暂时性传导性听力损失。在目标2中，我们将测试 这一假说认为突触连接的生理特性在两种内在CNIC之间是不同的， 网络，它们的成熟取决于正常的听觉体验。我们将使用 来自对照小鼠和有病史小鼠切片中已鉴定神经元的同步全细胞记录 异常的听觉体验在目标3中，我们将测试异常声音诱发的单个单位的假设， 具有异常听觉经历史的小鼠的CNIC中的反应反映了异常的内在 连接.我们将通过表征光遗传学的光谱-时间响应特性来解决这个问题。 在清醒的对照小鼠和有糖尿病史的小鼠中鉴定出多巴胺能和GABA能CNIC神经元。 异常的听觉体验，并将体内观察到的变化与内在网络的变化相关联 体外表征。拟议项目的结果将为该组织提供新的见解， 突触生理学，和内在CNIC回路的发展及其在受损声音中的可能作用 在CNIC中处理。这些新的信息对于理解电路的变化是有价值的， CNIC导致中枢性听力缺陷，这在儿童中常见， 患有传导性听力损失