Noise trauma-induced auditory processing deficits and anxiety

Hearing is integral to human life, playing crucial roles in safety, communication, social interaction, and overall well-being. Noise exposure significantly contributes to the prevalence of hearing loss, which impacts 19.5-21.2% of the global population. Current treatments for noise trauma-induced hearing loss and tinnitus lack FDA-approved medications, with existing therapies often being insufficient. Moreover, hearing deficits are associated with increased anxiety, yet the molecular mechanisms linking noise-induced auditory processing deficits and anxiety are poorly understood. The aim of this project is to examine the roles of parvalbumin-expressing (PV) interneurons and tumor necrosis factor alpha (TNF-α) receptors in noise-induced auditory processing deficits and anxiety. For this purpose; behavioral, molecular, and electrophysiological approaches were utilized using a transgenic mouse model (PVcre/TdTomato+). Noise-exposed mice showed reduced locomotor activity and exploration in anxiety-related behavioral tests and auditory processing deficits in acoustic startle response-based tests. Our findings reveal distinct roles of TNFR1 (Tumor Necrosis Factor Receptor 1) and TNFR2 (Tumor Necrosis Factor Receptor 2) signaling in the ventral hippocampus (vHPC) and primary auditory cortex (AI). TNFR1 signaling exacerbates, while TNFR2 signaling mitigates, noise trauma-induced auditory processing deficits and anxiety. Noise-induced deficits and their impact on the vHPC were dependent on TNF signaling, with TNFR1 knockdown ameliorating deficits by preventing PV neuron loss in the AI. Additionally, the knockdown of TNFR1 in PV neurons in the AI reduced noise trauma-induced auditory processing deficits, preserving auditory function. Conversely, the knockdown of TNFR2 disrupted neuroprotective signaling, leading to microglial deramification. Furthermore, TNF-α signaling modulated synaptic transmission, with the knockdown of TNFR1 protecting against noise-induced synaptic changes, while the knockdown of TNFR2 exacerbated synaptic alterations. This thesis project elucidates the differential roles of TNFR1 and TNFR2 in noise-induced auditory and anxiety-related deficits, providing insights into potential therapeutic targets for mitigating the adverse effects of noise trauma.