Targeted inhibition of the BDNF/AKT/mTOR pathway in the inferior colliculus ameliorates salicylate-induced tinnitus in rats.

Tinnitus refers to the perception of sound in the absence of an external acoustic source. It affects approximately 14% of the global adult population, with 20% of affected individuals experiencing comorbid anxiety and depression, imposing a significant socioeconomic burden. Although its pathological mechanisms remain incompletely elucidated, the predominant hypothesis posits that tinnitus arises from interactions between peripheral auditory damage and compensatory central plasticity. Peripheral auditory insults (e.g., cochlear hair cell dysfunction) trigger neuronal hyperexcitability in the central auditory pathway, including the inferior colliculus (IC), thalamus, and auditory cortex. This hyperexcitability is closely associated with enhanced glutamatergic signaling, reduced γ-aminobutyric acid (GABA)-ergic inhibition, and neuroinflammation. In recent years, brain-derived neurotrophic factor (BDNF) and its role in regulating synaptic plasticity have become an increasing focus in tinnitus research. BDNF activates tropomyosin receptor kinase B (TrkB) and downstream PI3K/AKT/mTOR signaling, playing a pivotal role in neuronal survival, synaptic remodeling, and excitation-inhibition balance. In auditory injury models, noise exposure or ototoxic agents induce aberrant BDNF upregulation in the spiral ganglion and IC, enhancing synaptic transmission efficiency and promoting central neuronal hyperexcitability. Notably, hyperactivation of the AKT/mTOR pathway—a hub integrating metabolic and trophic signals—facilitates synthesis of synaptic proteins (e.g., PSD-95, synapsin I), potentiates glutamatergic synaptic efficacy, and suppresses GABAergic interneuron activity, thereby disrupting neural network excitation-inhibition equilibrium. This imbalance is strongly linked to tinnitus chronicity and shares commonality with pathologies like epilepsy and neurodegeneration. Furthermore, recent evidence indicates that microglial activation amplifies neuroinflammation via a BDNF-TNF-α positive feedback loop, suggesting that glia-neuron crosstalk sustains central hyperexcitability in tinnitus. The mTOR pathway is a master regulator of protein synthesis-dependent synaptic plasticity, which is critical for neural circuit adaptation in the central auditory system. Although mTOR also functions in the peripheral auditory system, its role in central auditory plasticity—and particularly its dysregulation in conditions such as tinnitus—has attracted increasing attention. Pharmacological inhibition of mTOR with rapamycin can alleviate certain auditory pathologies, but it remains unclear whether this therapeutic effect involves normalizing maladaptive plasticity within central hubs like the inferior colliculus.