Uncovering the Functional Effects of Neurotrophins in the Auditory Brainstem

揭示神经营养素对听觉脑干的功能影响

• 批准号: 10823506
• 负责人: Kristine McLellan
• 金额: $ 4.29万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10823506
• 关键词: Affect; Auditory; Auditory Brainstem Responses; Auditory Perceptual Disorders; Auditory system; Biological Assay; Biological Models; Birds; Brain Stem; Brain-Derived Neurotrophic Factor; Cell Nucleus; Cells; Characteristics; Chick; Chickens; Cochlear nucleus; Dendrites; Development; Developmental Process; Disease; Electrophysiology (science); Electroporation; Embryo; Embryonic Development; Event; Exhibits; Growth; Growth Factor; Hearing; Ion Channel; Ion Channel Gating; Knowledge; Link; Measurement; Measures; Mediating; Nervous System; Neurons; Pattern; Peripheral; Phenotype; Phosphotransferases; Potassium; Potassium Channel; Property; Proteins; Psychophysiology; Receptor Protein-Tyrosine Kinases; Regulation; Research; Research Proposals; Role; Signal Pathway; Signal Transduction; Signaling Protein; Sodium; Sodium Channel; Sound Localization; Structure; Synapses; System; Testing; Time; Tissues; Transfection; auditory pathway; auditory processing; auditory stimulus; binaural hearing; electric field; experimental study; hatching; hearing impairment; in vivo; inner ear development; neural; neural circuit; neuron development; neuronal excitability; neurotransmission; neurotrophic factor; patch clamp; receptor; response; sound; spatiotemporal; timeline; transmission process; voltage

PROJECT SUMMARY/ABSTRACT Neurotrophins are secreted signaling proteins that promote the growth and organization of developing neurons. Gradients of expression of the neurotrophin and its associated tyrosine receptor kinase (Trk) allow for spatiotemporally regulated signaling that promotes synapse strengthening and neuronal maturation. For example, Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is secreted within the developing avian auditory brainstem. Its receptor, tryrosine receptor kinase B (TrkB), is highly expressed early in embryonic development and systematically decreases to negligible amount by the time the embryo hatches. While neurotrophin signaling is essential to induce cellular and synaptic maturation in other neural tissues, its direct effects on the development and functionality of the central auditory system remains unknown. Temporal precision is essential for auditory brainstem neurons to accurately encode the complexities of sound. Therefore, the objective of this research proposal is to determine how neurotrophin signaling affects intrinsic ion channel properties responsible for establishing functional phenotypes for the roles they subserve: binaural hearing and sound localization. Specifically, I will investigate the role of the BDNF/TrkB signaling pathway on defining the intrinsic phenotype of auditory brainstem neurons. I will additionally test the importance of neurotrophin regulation on the development of mature and robust auditory brainstem signaling in response to sound. The central hypothesis of this research proposal is that altered neurotrophin signaling in the auditory brainstem will decrease the ability for auditory brainstem neurons to transmit information in a temporally reliable manner. In Aim 1 I will use patch clamp electrophysiology to determine the effects of aberrant neurotrophin signaling on the intrinsic properties of auditory brainstem neurons. In Aim 2 I will assess the functional ramifications of irregular neurotrophin signaling by measuring electrical field potentials from auditory brainstem structures. Collectively, this research will elucidate the importance of neurotrophin signaling at the cellular and systems level within the auditory brainstem, providing possible candidates for developmental signals that may be dysregulated in early central auditory-related disorders.

项目概要/摘要 神经营养素是分泌的信号蛋白，可促进发育中神经元的生长和组织。 神经营养蛋白及其相关酪氨酸受体激酶 (Trk) 的表达梯度允许 促进突触强化和神经元成熟的时空调节信号。为了 例如，脑源性神经营养因子（BDNF）是一种在发育中的鸟类体内分泌的神经营养蛋白 听觉脑干。其受体酪氨酸受体激酶 B (TrkB) 在胚胎早期高度表达 发育并在胚胎孵化时系统地减少到可以忽略不计的量。尽管 神经营养素信号传导对于诱导其他神经组织中的细胞和突触成熟至关重要，其直接作用 对中枢听觉系统发育和功能的影响仍不清楚。 时间精度对于听觉脑干神经元准确编码声音的复杂性至关重要。 因此，本研究计划的目的是确定神经营养蛋白信号传导如何影响内在离子 通道属性负责为其所服务的角色建立功能表型：双耳 听觉和声音定位。具体来说，我将研究 BDNF/TrkB 信号通路在 定义听觉脑干神经元的内在表型。我将另外测试的重要性 神经营养素对成熟和强大的听觉脑干信号发育的调节 声音。 该研究提案的中心假设是听觉脑干中神经营养蛋白信号的改变 会降低听觉脑干神经元以时间可靠的方式传输信息的能力。 在目标 1 中，我将使用膜片钳电生理学来确定异常神经营养蛋白信号传导对 听觉脑干神经元的内在特性。在目标 2 中，我将评估以下功能的影响： 通过测量听觉脑干结构的电场电位来测量不规则的神经营养素信号传导。 总的来说，这项研究将阐明神经营养素信号传导在细胞和系统水平上的重要性 在听觉脑干内，为可能失调的发育信号提供可能的候选者 早期中枢听觉相关疾病。