Activation of the GABAergic neural circuit in salicylate-induced tinnitus: from the inferior colliculus to the medial geniculate body.

Abstract

Objective: This study aimed to investigate the regulatory functions of gamma-aminobutyric acid (GABA)ergic neural circuits from the inferior colliculus (IC) to the medial geniculate body (MGB) in salicylate-induced tinnitus.

Methods.: Mice were treated with salicylate to induce tinnitus, and tinnitus-like behaviors were evaluated via gap prepulse inhibition of acoustic startle. Using combined viral tracing methodologies, we identified and mapped the pathways and connections from the IC to the MGB. Moreover, we used Gq-coupled human M3 designer receptors exclusively activated by designer drugs (DREADDs) and Gi-coupled human M4 DREADDs, allowing targeted control of GABAergic neurons through excitation or suppression in the IC and MGB regions. Following the administration of Clozapine N-oxide, which can bind to the abovementioned specific receptors, we modulated these neural circuits to assess their impact on tinnitus severity in a mouse model.

Results.: Our results indicated that mice exposed to salicylate exhibited tinnitus-like behavior. GABAergic neurons projecting retrogradely from the MGB to the IC are mainly concentrated in the external nucleus of the IC. After the administration of Clozapine N-oxide, the chemogenetic activation of IC-MGB GABAergic neurons aggravated salicylate-induced tinnitus. Our study revealed that activation of GABAergic neurons between the IC and MGB was effective in inducing tinnitus perception, even in the absence of salicylate. However, chemogenetic inhibition of the IC-MGB GABAergic circuit did not reverse salicylate-induced tinnitus.

Conclusion.: This finding suggests that activation of the IC-MGB GABAergic neural circuit may contribute to tinnitus generation, but through a mechanism that is distinct from salicylate-induced tinnitus. This study provided novel insights into the mechanisms underlying tinnitus.