Synaptic, Cellular and Circuit Mechanisms of Cortical Plasticity after Cochlear Damage

耳蜗损伤后皮质可塑性的突触、细胞和电路机制

• 批准号: 10623300
• 负责人: Thanos Tzounopoulos
• 金额: $ 62.87万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-03 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623300
• 关键词: Acoustic Nerve; Area; Auditory; Auditory Perception; Auditory area; Auditory system; Biophysics; Brain; Brain Stem; Cells; Cochlea; Communication; Complex; Conscious; Detection; Development; Discrimination; Disease; Electrophysiology (science); Esthesia; Exhibits; Health; Hyperacusis; In Vitro; Interneurons; Ion Channel; Knowledge; Mediating; Mission; Mus; Neurons; Noise-Induced Hearing Loss; Organ; Parvalbumins; Pathway interactions; Perception; Peripheral; Pharmacotherapy; Property; Pyramidal Tracts; Recovery; Research; Role; Schizophrenia; Sensory; Somatostatin; Synapses; System; Testing; Thalamic structure; Time; Tinnitus; United States National Institutes of Health; Vasoactive Intestinal Peptide; auditory thalamus; awake; cell type; disability; hearing impairment; imaging study; improved; in vivo; in vivo two-photon imaging; neuronal circuitry; novel; painful neuropathy; pharmacologic; programs; rehabilitation paradigm; sensory cortex; sensory system; sound; two photon microscopy

PROJECT SUMMARY In all sensory systems, peripheral sensory organ damage leads to compensatory cortical plasticity that supports a remarkable recovery of perceptual capabilities. In the auditory system, while auditory nerve input to the brainstem is significantly reduced after cochlear damage, sound-evoked cortical activity is maintained or even enhanced. This recovery is due to increased cortical sensitivity (gain) to the spared auditory input. Although this plasticity does not support features of sound processing encoded by the precise timing of neuronal firing, such as complex sound discrimination, it provides a remarkable recovery of sound detection. A major gap in knowledge is the lack of a precise mechanism that explains how this plasticity is implemented and distributed over the diverse excitatory and inhibitory cortical neurons, synapses and circuits. Here we propose a strategic, cooperative, time-dependent, cell type- and synapse-specific plasticity program that restores cortical sound processing. The results from our studies will advance the field to a new level of understanding regarding cortical plasticity after peripheral organ damage, and will inspire the development of well-timed, cell-specific treatments and rehabilitative paradigms and cures that may further enhance the recovery of perception after hearing loss, and mitigate the development of brain plasticity-related disorders, such as hyperacusis and tinnitus. Cortical principal neurons (PN) and interneurons (IN) are very diverse and thus capable of supporting a coordinated and collaborative plan for achieving cortical recovery. The major classes of cortical neurons include vasoactive intestinal-peptide (VIP), somatostatin (SOM) and parvalbumin (PV) expressing IN sub-classes, as well as intratelencephalic (IT), layer (L) 5 pyramidal tract (PT), and L6 corticothalamic (CT) PNs. Based on our preliminary results, we propose that: 1) PVs are the network “stabilizers”; 2) VIPs are the “enablers” that regulate SOM activity; and 3) SOMs are the “modulators” that allow for high PN gain. At the cellular and synaptic level, we propose that soon after cochlear damage: 4) PVs and PTs exhibit a decrease in intrinsic excitability; 5) CTs exhibit an increase in intrinsic excitability; and 6) thalamic synaptic input to deep cortical layers is shifted from CT/PT equivalent to CT dominant. Overall, our proposed research and hypotheses provide an experimental platform to probe how multiple cortical neuronal sub-classes restore cortical processing after peripheral input loss (Aims 1 and 3). In combination with Aims 2 and 3, our proposed studies will determine the underlying intrinsic (Aim 2) and synaptic mechanisms (Aim 3) that mediate this plasticity.

项目概要 在所有感觉系统中，周围感觉器官损伤会导致补偿性皮质可塑性，从而支持 听觉系统的感知能力显着恢复，同时听觉神经的输入。 耳蜗损伤后脑干明显减少，声音诱发的皮层活动得以维持甚至 这种恢复是由于皮质对备用审计员输入的敏感性（增益）增加。 可塑性不支持由神经放电的精确计时编码的声音处理特征，例如 作为复杂的声音辨别，它提供了声音检测恢复方面的一个重大差距。 知识是缺乏一个精确的机制来解释这种可塑性是如何实现和分配的 在这里，我们提出了一种策略性的、 合作性的、时间依赖性的、细胞类型和突触特异性的可塑性程序，可恢复皮质声音 我们的研究结果将推动该领域对皮质的理解达到一个新的水平。 外周器官损伤后的可塑性，并将激发适时的细胞特异性治疗的发展 以及可以进一步增强听力损失后知觉恢复的康复范例和治疗方法， 并减轻大脑可塑性相关疾病的发展，例如听觉过敏和耳鸣。 皮质主神经元 (PN) 和中间神经元 (IN) 非常多样化，因此能够支持 实现皮质恢复的协调和协作计划 皮质神经元的主要类别包括 血管活性肠肽 (VIP)、生长抑素 (SOM) 和小白蛋白 (PV) 表达 IN 亚类，如 以及端脑内 (IT)、第 5 层锥体束 (PT) 和 L6 皮质丘脑 (CT) PN。 初步结果，我们建议：1）PV是网络“稳定器”；2）VIP是监管的“推动者”； SOM 活性；3) SOM 是在细胞和突触水平上实现高 PN 增益的“调节剂”。 我们认为，耳蜗损伤后不久：4) PV 和 PT 表现出内在兴奋性下降；5) CT 6) 丘脑突触输入到深层皮质层的转移从 CT/PT 相当于 CT 主导 总体而言，我们提出的研究和假设提供了实验。 探索多个皮质神经子类如何在外周输入后恢复皮质处理的平台 结合目标 2 和 3，我们提出的研究将确定潜在的内在损失。 （目标 2）和调节这种可塑性的突触机制（目标 3）。

项目成果

A CRE/DRE dual recombinase transgenic mouse reveals synaptic zinc-mediated thalamocortical neuromodulation.

• DOI: 10.1126/sciadv.adf3525
• 发表时间: 2023-06-09
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Kouvaros, Stylianos;Bizup, Brandon;Solis, Oscar;Kumar, Manoj;Ventriglia, Emilya;Curry, Fallon P.;Michaelides, Michael;Tzounopoulos, Thanos
• 通讯作者: Tzounopoulos, Thanos

Cell-type-specific plasticity of inhibitory interneurons in the rehabilitation of auditory cortex after peripheral damage.

• DOI: 10.1038/s41467-023-39732-7
• 发表时间: 2023-07-13
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Kumar M;Handy G;Kouvaros S;Zhao Y;Brinson LL;Wei E;Bizup B;Doiron B;Tzounopoulos T
• 通讯作者: Tzounopoulos T