Development of the intrinsic synaptic circuits of the inferior colliculus

下丘固有突触回路的发育

• 批准号: 10464327
• 负责人: Karl Kandler
• 金额: $ 59.22万
• 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/10464327
• 关键词: Acoustics; Address; Affect; Auditory; Axon; Cell Nucleus; 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; Slice; 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，也是大脑皮质下的主要整合中枢。 听觉通路。IC中的神经元被调节到特定的光谱-时间特征，并参与 通信声音和语音的处理。异常的声音诱发或自发的IC活动 与许多中枢听力障碍有关，包括言语知觉受损， 听力过敏症和耳鸣。中枢神经元的频谱-时间调谐产生于多个神经元的整合 上行和下行输入以及兴奋性和抑制性内在突触的复杂网络 IC神经元之间的联系。虽然IC的外部输入的功能和组织正在变得 对突触的组织、生理和发育的了解日益加深 IC的内在连接是有限的，阻碍了对其在IC功能中的潜在作用的深入了解。为了填满这个 为了解决知识差距问题，我们建议解决三个具体目标。在目标1中，我们将检验以下假设 IC核(CNIC)包含两个独立的、在功能上不同的局部网络，这些网络由盘状网络产生 和星状细胞。我们进一步假设，这些网络的分化发生在听力发作之后。 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 笼养谷氨酸扫描光刺激定位CNIC内的神经元 单突触连接到对照组小鼠和小鼠脑片中已识别的CNIC神经元 在脉冲白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 假设两种固有CNIC的突触连接的生理特性是不同的 他们的成熟依赖于正常的听觉体验。我们将通过以下方式解决此问题 对照小鼠和有病史小鼠脑片中已识别神经元的同步全细胞记录 不正常的听觉体验。在目标3中，我们将检验异常声音诱发的单个单位的假设 有异常听觉体验史的小鼠CNIC的反应反映了异常的内在反应 关系。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 在清醒对照组小鼠和有GABA型中枢神经元病病史的小鼠中鉴定出谷氨酸和GABA能CNIC神经元 异常听觉体验及其与体内观察到的变化和内在网络变化的相关性 具有体外特征的。拟议项目的结果将为本组织提供新的见解， 突触生理学、CNIC固有回路的发展及其在声音受损中的可能作用 在CNIC处理。这一新信息将对理解 CNIC导致中枢性听力障碍的产生，这种听力障碍通常在儿童中观察到 患有传导性听力损失。