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Transcriptional-profile changes in the medial geniculate body after noise-induced tinnitus.

ABSTRACT: Tinnitus is a disturbing condition defined as the occurrence of acoustic hallucinations with no actual sound. Although the mechanisms underlying tinnitus have been explored extensively, the pathophysiology of the disease is not completely understood. Moreover, genes and potential treatment targets related to auditory hallucinations remain unknown. In this study, we examined transcriptional-profile changes in the medial geniculate body after noise-induced tinnitus in rats by performing RNA sequencing and validated differentially expressed genes via quantitative polymerase chain reaction analysis. The rat model of tinnitus was established by analyzing startle behavior based on gap-pre-pulse inhibition of acoustic startles. We identified 87 differently expressed genes, of which 40 were upregulated and 47 were downregulated. Pathway-enrichment analysis revealed that the differentially enriched genes in the tinnitus group were associated with pathway terms, such as coronavirus disease COVID-19, neuroactive ligand-receptor interaction. Protein-protein-interaction networks were established, and two hub genes (Rpl7a and AC136661.1) were identified among the selected genes. Further studies focusing on targeting and modulating these genes are required for developing potential treatments for noise-induced tinnitus in patients.

SUBMITTER: Liu P

PROVIDER: S-EPMC10984379 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Transcriptional-profile changes in the medial geniculate body after noise-induced tinnitus.

Liu Peng P Xue Xinmiao X Zhang Chi C Zhou Hanwen H Ding Zhiwei Z Wang Li L Jiang Yuke Y Shen Wei-Dong WD Yang Shiming S Wang Fangyuan F

Experimental biology and medicine (Maywood, N.J.) 20240318

Tinnitus is a disturbing condition defined as the occurrence of acoustic hallucinations with no actual sound. Although the mechanisms underlying tinnitus have been explored extensively, the pathophysiology of the disease is not completely understood. Moreover, genes and potential treatment targets related to auditory hallucinations remain unknown. In this study, we examined transcriptional-profile changes in the medial geniculate body after noise-induced tinnitus in rats by performing RNA sequen ...[more]

PMID: 38562529

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Project description:IntroductionTinnitus is a prevalent and disabling condition characterized by the perception of sound in the absence of external acoustic stimuli. The hyperactivity of the auditory pathway is a crucial factor in the development of tinnitus. This study aims to examine genetic expression variations in the dorsal cochlear nucleus (DCN) and inferior colliculus (IC) following the onset of tinnitus using transcriptomic analysis. The goal is to investigate the relationship between hyperactivity in the DCN and IC.MethodsTo confirm the presence of tinnitus behavior, we utilized the gap pre-pulse inhibition of the acoustic startle (GPIAS) response paradigm. In addition, we conducted auditory brainstem response (ABR) tests to determine the baseline hearing thresholds, and repeated the test one week after subjecting the rats to noise exposure (8-16 kHz, 126 dBHL, 2 h). Samples of tissue were collected from the DCN and IC in both the tinnitus and non-tinnitus groups of rats. We employed RNA sequencing and quantitative PCR techniques to analyze the changes in gene expression between these two groups. This allowed us to identify any specific genes or gene pathways that may be associated with the development or maintenance of tinnitus in the DCN and IC.ResultsOur results demonstrated tinnitus-like behavior in rats exposed to noise, as evidenced by GPIAS measurements. We identified 61 upregulated genes and 189 downregulated genes in the DCN, along with 396 upregulated genes and 195 downregulated genes in the IC. Enrichment analysis of the DCN revealed the involvement of ion transmembrane transport regulation, synaptic transmission, and negative regulation of neuron apoptotic processes in the development of tinnitus. In the IC, the enrichment analysis indicated that glutamatergic synapses and neuroactive ligand-receptor interaction pathways may significantly contribute to the process of tinnitus development. Additionally, protein-protein interaction (PPI) networks were constructed, and 9 hub genes were selected based on their betweenness centrality rank in the DCN and IC, respectively.ConclusionsOur findings reveal enrichment of differential expressed genes (DEGs) associated with pathways linked to alterations in neuronal excitability within the DCN and IC when comparing the tinnitus group to the non-tinnitus group. This indicates an increased trend in neuronal excitability within both the DCN and IC in the tinnitus model rats. Additionally, the enriched signaling pathways within the DCN related to changes in synaptic plasticity suggest that the excitability changes may propagate to IC.New and noteworthyOur findings reveal gene expression alterations in neuronal excitability within the DCN and IC when comparing the tinnitus group to the non-tinnitus group at the transcriptome level. Additionally, the enriched signaling pathways related to changes in synaptic plasticity in the differentially expressed genes within the DCN suggest that the excitability changes may propagate to IC.

Project description:BACKGROUND:The phenomenon of short-term tinnitus suppression by different forms of acoustic stimulation is referred to as residual inhibition (RI). RI can be triggered in the majority of tinnitus cases and was found to be depending on the used intensity, length or types of sounds. Past research already stressed the impact of noise stimulation as well as the superiority of amplitude modulated (AM) pure tones at the individual tinnitus frequency for RI in tonal tinnitus. Recently a novel approach for the determination of noise-like tinnitus characteristics was proposed. OBJECTIVES:The aim of the present study was to investigate whether in participants with noise-like tinnitus RI can be increased by AM noise stimuli according to the individual tinnitus frequency range. METHODS:For this purpose the individual tinnitus characteristics (noise-like and tonal tinnitus) of 29 people affected by tinnitus (mean age = 55.59, 7 females, mean tinnitus duration = 159.97 months) were assessed via customizable noise-band matching. The objective was to generate bandpass filtered stimuli according to the individual tinnitus sound (individualized bandpass filtered [IBP] sounds). Subsequently, various stimuli differing in bandpass filtering and AM were tested with respect to their potential to induce RI. Participants were acoustically stimulated with 7 different types of stimuli for 3 min each and had to rate the loudness of their tinnitus after each stimuli. RESULTS:Results indicate a general efficacy of noise stimuli for the temporary suppression of tinnitus, but no significant differences between AM and unmodulated IBP. Significantly better effects were observed for the subgroup with noise-like tinnitus (n = 14), especially directly after stimulation offset. CONCLUSIONS:The study at hand provides further insights in potential mechanisms behind RI for different types of tinnitus. Beyond that, derived principles may qualify for new or extend current tinnitus sound therapies.

Project description:BackgroundThe dorsal cochlear nucleus (DCN) is a region known to integrate somatosensory and auditory inputs and is identified as a potential key structure in the generation of phantom sound perception, especially noise-induced tinnitus. Yet, how altered homeostatic plasticity of the DCN induces and maintains the sensation of tinnitus is not clear. Here, we chemogenetically decrease activity of a subgroup of DCN neurons, Ca2+/Calmodulin kinase 2 α (CaMKII α)-positive DCN neurons, using Gi-coupled human M4 Designer Receptors Exclusively Activated by Designer Drugs (hM4Di DREADDs), to investigate their role in noise-induced tinnitus.ResultsMice were exposed to loud noise (9-11kHz, 90dBSPL, 1h, followed by 2h of silence), and auditory brainstem responses (ABRs) and gap prepulse inhibition of acoustic startle (GPIAS) were recorded 2 days before and 2 weeks after noise exposure to identify animals with a significantly decreased inhibition of startle, indicating tinnitus but without permanent hearing loss. Neuronal activity of CaMKII α+ neurons expressing hM4Di in the DCN was lowered by administration of clozapine-N-oxide (CNO). We found that acutely decreasing firing rate of CaMKII α+ DCN units decrease tinnitus-like responses (p = 3e -3, n = 11 mice), compared to the control group that showed no improvement in GPIAS (control virus; CaMKII α-YFP + CNO, p = 0.696, n = 7 mice). Extracellular recordings confirmed CNO to decrease unit firing frequency of CaMKII α-hM4Di+ mice and alter best frequency and tuning width of response to sound. However, these effects were not seen if CNO had been previously administered during the noise exposure (n = 6 experimental and 6 control mice).ConclusionWe found that lowering DCN activity in mice displaying tinnitus-related behavior reduces tinnitus, but lowering DCN activity during noise exposure does not prevent noise-induced tinnitus. Our results suggest that CaMKII α-positive cells in the DCN are not crucial for tinnitus induction but play a significant role in maintaining tinnitus perception in mice.

Dataset Information

Transcriptional-profile changes in the medial geniculate body after noise-induced tinnitus.

Publications

Transcriptional-profile changes in the medial geniculate body after noise-induced tinnitus.

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