Central Gain Dysregulation as a Reversible Over‑Consolidation Layer in Age‑Related Hearing Loss

Hypothesis

Age‑related hearing loss comprises two sequential layers: an irreversible peripheral decay of spiral ganglion neurons and stria vascularis, and a reversible central over‑consolidation manifested as maladaptive gain increase in the auditory midbrain and cortex. The central layer reflects a shift in the brain’s prediction‑error weighting that suppresses surprise, leading to rigidity that exacerbates temporal processing deficits beyond what peripheral loss predicts.

Mechanistic Insight

Peripheral synaptopathy reduces afferent drive, prompting homeostatic up‑regulation of excitatory synaptic strength in the inferior colliculus (IC) and auditory cortex. Simultaneously, age‑related decline in GABAergic inhibition—documented in cortical layers II/III [6]—removes the counter‑balance that normally prevents runaway excitation. The net effect is a hyper‑responsive circuit that over‑fits to existing sound statistics, treating novel temporal cues as noise and thereby reducing perceptual flexibility. This mirrors the “over‑consolidation” idea: the system has over‑optimized its internal model and now resists updating it with new evidence.

Novel Prediction

If central over‑consolidation drives the functional hearing deficit, then restoring the excitation/inhibition (E/I) balance in the IC should improve temporal resolution and speech‑in‑noise performance without altering peripheral SGN numbers or stria vascularis function.

Experimental Approach

1. Animal model – Use C57BL/6J mice aged 18‑24 mo, which exhibit presbycusis‑like SGN loss and stria vascularis decline [1][2].
2. Peripheral validation – Quantify SGN density (anti‑TuJ1) and stria vascularis Na⁺‑K⁺‑ATPase expression to confirm baseline decay [3].
3. Central manipulation – Deliver a GABA_A receptor positive allosteric modulator (e.g., low‑dose benzodiazepine) locally to the IC via micro‑dialysis, or optogenetically enhance parvalbumin‑positive interneuron activity.
4. Readouts –
   • Auditory brainstem response (ABR) wave I amplitude to confirm peripheral SGN input remains unchanged.
   • IC multi‑unit evoked potentials to measure gain change.
   • Behavioral gap‑detection and amplitude‑modulation discrimination tasks to assess temporal processing.
   • Speech‑in‑noise performance in a conditioned avoidance paradigm.
5. Control groups – Vehicle‑treated aged mice, young adult mice, and aged mice receiving a nonspecific excitatory modulator.

Falsifiable Outcome

• Support: Central GABAergic enhancement reduces IC evoked‑potential gain by ≥20 % relative to vehicle, improves gap‑detection thresholds by ≥15 %, and rescues speech‑in‑noise scores to within 10 % of young adult levels, while ABR wave I and stria vascularis markers remain unchanged.
• Refute: No significant improvement in temporal or speech‑in‑noise metrics despite verified central E/I shift, or peripheral measures worsen, indicating that central gain is not the limiting factor.

This framework directly tests whether the “over‑consolidation” of central auditory circuits is a reversible component of presbycusis, offering a mechanistic bridge between peripheral decay and functional hearing impairment.