Decreasing dorsal cochlear nucleus activity ameliorates noise-induced tinnitus perception in mice

• Published in: BMC biology 2022-05, Vol.20 (1), p.102-102, Article 102
• Main Authors: Malfatti, Thawann, Ciralli, Barbara, Hilscher, Markus M, Leao, Richardson N, Leao, Katarina E
• Format: Article
• Language: English
• Subjects: Animals; Auditory perception; Background noise; Brain stem; Ca2+/calmodulin-dependent protein kinase II; Calcium ions; Calcium-binding protein; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calmodulin; Chemogenetics; Clozapine; Cochlea; Cochlear nuclei; Cochlear Nucleus - physiology; Development and progression; Dorsal cochlear nucleus; Evoked Potentials, Auditory, Brain Stem - physiology; Firing rate; GPIAS; Hearing loss; Hearing protection; Homeostatic plasticity; Kinases; Mice; Neural transmission; Neurological research; Neurons; Noise; Noise levels; Perception; Physiological aspects; Psychological aspects; Sensation; Sound; Subgroups; Tinnitus; Tinnitus - etiology; Unit recording; Viruses
• ISSN: 1741-7007; 1741-7007
• DOI: 10.1186/s12915-022-01288-1

The 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, Ca /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. Mice 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). We 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.