MicroRNAs Related to Cognitive Impairment After Hearing Loss.

OBJECTIVES: Our research group has previously demonstrated that hearing loss might be a risk factor for synaptic loss within the hippocampus and impairment of cognition using an animal model of Alzheimer disease. In this study, after inducing hearing loss in a rat model of Alzheimer disease, the associations of various microRNAs (miRNAs) with cognitive impairment were investigated. METHODS: Rats were divided randomly into two experimental groups: the control group, which underwent sham surgery and subthreshold amyloid-ß infusion and the deaf group, which underwent bilateral cochlear ablation and subthreshold amyloid-ß infusion. All rats completed several cognitive function assessments 11 weeks after surgery, including the object-in-place task (OPT), the novel object recognition task (NOR), the object location task (OLT), and the Y-maze test. After the rats completed these tests, hippocampus tissue samples were assessed using miRNA microarrays. Candidate miRNAs were selected based on the results and then validated with quantitative reverse transcriptionpolymerase chain reaction (qRT-PCR) analyses. RESULTS: The deaf group showed considerably lower scores on the OPT, OLT, and Y-maze test than the control group. The microarray analysis revealed that miR-29b-3p, -30e-5p, -153-3p, -376a-3p, -598-3p, -652-5p, and -873-3p were candidate miRNAs, and qRT-PCR showed significantly higher levels of miR-376a-3p and miR-598-3p in the deaf group. CONCLUSION: These results indicate that miR-376a-3p and miR-598-3p were related to cognitive impairment after hearing loss.

Axonal sprouting in the dorsal cochlear nucleus affects gap­prepulse inhibition following noise exposure.

One of the primary theories of the pathogenesis of tinnitus involves maladaptive auditory­somatosensory plasticity in the dorsal cochlear nucleus (DCN), which is assumed to be due to axonal sprouting. Although a disrupted balance between auditory and somatosensory inputs may occur following hearing damage and may induce tinnitus, examination of this phenomenon employed a model of hearing damage that does not account for the causal relationship between these changes and tinnitus. The present study aimed to investigate changes in auditory­somatosensory innervation and the role that axonal sprouting serves in this process by comparing results between animals with and without tinnitus. Rats were exposed to a noise­inducing temporary threshold shift and were subsequently divided into tinnitus and non­tinnitus groups based on the results of gap prepulse inhibition of the acoustic startle reflex. DCNs were collected from rats divided into three sub­groups according to the number of weeks (1, 2 or 3) following noise exposure, and the protein levels of vesicular glutamate transporter 1 (VGLUT1), which is associated with auditory input to the DCN, and VGLUT2, which is in turn primarily associated with somatosensory inputs, were assessed. In addition, factors related to axonal sprouting, including growth­associated protein 43 (GAP43), postsynaptic density protein 95, synaptophysin, α­thalassemia/mental retardation syndrome X­linked homolog (ATRX), growth differentiation factor 10 (GDF10), and leucine­rich repeat and immunoglobulin domain­containing 1, were measured by western blot analyses. Compared to the non­tinnitus group, the tinnitus group exhibited a significant decrease in VGLUT1 at 1 week and a significant increase in VGLUT2 at 3 weeks post­exposure. In addition, rats in the tinnitus group exhibited significant increases in GAP43 and GDF10 protein expression levels in their DCN at 3 weeks following noise exposure. Results from the present study provided further evidence that changes in the neural input distribution to the DCN may cause tinnitus and that axonal sprouting underlies these alterations.