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.

项目摘要 在所有感觉系统中，外围感觉器官损伤都会导致补偿性皮质可塑性支持 知名能力的显着恢复。在听觉系统中，听觉的神经输入到 人工耳蜗损伤，声音诱发的皮质活性或什至 增强。这种恢复是由于对不幸的听觉输入的皮质灵敏度（增益）提高。虽然这个 可塑性不支持由神经元射击的精确时机编码的声音处理的功能， 作为复杂的声音歧视，它提供了明显的声音检测恢复。一个主要差距 知识是缺乏确切的机制，该机制解释了如何实现和分发这种可塑性 在潜水员的兴奋性和抑制性皮质神经元，突触和电路上。在这里，我们提出了一种策略， 恢复皮质声音的合作，时间依赖性，细胞类型和突触特异性可塑性程序 加工。我们研究的结果将使该领域达到新的理解皮质水平 外周器官损伤后的可塑性，并会激发及时的细胞特异性治疗的发展 以及康复范式和治疗方法，可以进一步增强听力丧失后的感知的恢复 并减轻与大脑可塑性相关疾病的发展，例如Hyper Acusis和Tinnitus。 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 协调和协作计划，以实现皮质恢复。皮质神经元的主要类别包括 在子类中表达的血管活性肠道肽（VIP），生长抑素（SOM）和白细胞蛋白（PV） 以及脑内脑（IT），层（L）5个锥体区（PT）和L6皮质丘脑（CT）PNS。基于我们 初步结果，我们建议：1）PV是网络“稳定器”； 2）VIP是调节的“推动者” SOM活动； 3）SOM是允许高PN增益的“调节剂”。在细胞和合成水平上， 我们提出，在人工耳蜗损害后不久：4）PV和PT暴露了内在令人兴奋的减少； 5）CTS 表现出内在令人兴奋的增加； 6）丘脑突触输入到深皮层的深层层 CT/PT等于CT优势。总体而言，我们提出的研究和假设提供了实验 探测多个皮质神经元子类如何恢复外周输入后皮质加工的平台 损失（目标1和3）。结合目标2和3，我们提出的研究将确定基本的内在 （AIM 2）和突触机制（AIM 3）介导这种可塑性。

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