Elevated Dnah11 Expression in Hippocampal CaMKII Neurons Impairs Memory via Disrupted Synaptic Plasticity in a Mouse Model of Noise-induced Hidden Hearing Loss

Although traditional noise-induced hearing loss (NIHL) has been widely investigated, the cognitive effects of noise-induced hidden hearing loss (NIHHL), particularly its impact on memory, remain poorly understood. The Dnah11 gene, which encodes a dynein motor protein involved in synaptic development, may play a role in NIHHL-related cognitive impairment. We aimed to investigate whether NIHHL induces memory impairment and explore the role of Dnah11 expression in this process. Behavioral experiments identified the peak of memory impairment at 1 month following noise exposure. To elucidate molecular changes, hippocampal gene expression was analyzed using transcriptomic sequencing, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and immunofluorescence. RNA sequencing revealed significant Dnah11 upregulation, with immunofluorescence confirming DNAH11 overexpression in hyperactivated CaMKII-positive excitatory neurons. Stereotaxic injection of recombinant adeno-associated virus (rAAV) vectors to knock down hippocampal Dnah11 expression improved memory performance in NIHHL mice without improving hearing loss. This cognitive improvement was accompanied by partial restoration of synaptic plasticity-related proteins, including SYN and PSD95. These findings indicate that Dnah11 upregulation in hippocampal excitatory neurons contributes to NIHHL-induced cognitive dysfunction, and targeting Dnah11 may offer a therapeutic strategy for memory impairment associated with hidden hearing loss. Overall design: To identify genes associated with NIHHL-induced memory impairment, we performed transcriptomic sequencing of hippocampal tissues from NIHHL and CON mice 1 month post-induction.Subsequently, RNA-seq data from the CON and NIHHL groups were analyzed to identify genes associated with learning or memory using GO enrichment analysis. Additionally,KEGG pathway enrichment analysis was conducted to identify genes linked to neurodegeneration diseases. The intersection of GO and KEGG analyses facilitated the identification of differential genes.