Synaptic modulation in the dorsal cochlear nucleus : a biological substrate of tinnitus

Acoustic over exposure (AOE) triggers hearing loss alongside a decreased excitability in the dorsal cochlear nucleus (DCN) within 3 to 5 days post exposure. On a longer time scale (from 6 weeks onwards) AOE can also generate phantom auditory perceptions known as tinnitus alongside a spontaneous hyperactivity in the DCN. The delayed onset of this hyperactivity relative to the early onset of hearing loss and decreased excitability suggests intermediate plastic changes in the DCN that remain to be identified. The first aim of this thesis was to identify in vitro, AOE-induced changes in synaptic plasticity within the DCN that could underlie the subsequent development of tinnitus. The second aim was to identify means of reversing the in vitro changes in synaptic plasticity triggered by AOE. The final aim was to test whether reversing the identified AOE-induced changes in synaptic plasticity could prevent the onset of tinnitus. Wistar rats were exposed to a loud (110 dB SPL) single tone (15 kHz) for a period of 9 hours (AOE protocol). Auditory brainstem response recordings performed 3 to 5 days later showed a significant increase of the rat’s hearing threshold for frequencies above 8 kHz. Field potential recordings of auditory nerve compound action potentials revealed a decreased amplitude and conduction velocity which was confirmed using computational modelling studies. Whole cell recordings of auditory nerve evoked excitatory post synaptic currents (EPSCs) revealed a decrease in EPSC amplitudes after AOE due to a decreased number of release sites. Field potential recordings of parallel fibre evoked activity performed 3 to 5 days following AOE showed that AOE prevented the induction of long term potentiation (LTP) otherwise observed at multisensory DCN synapses. Whole cell recordings of parallel fibre evoked EPSCs in fusiform cells revealed this to be due to an increased release probability after AOE. Perfusion of D-AP5 (an NMDA receptor antagonist) promoted the induction of LTP otherwise deficient after AOE. Perfusion of D-AP5 or elevating the concentration of magnesium in the extracellular medium decreased the release probability after AOE. Based on these findings, subsets of rats were placed on a high magnesium diet (in combination with magnesium injections) immediately after AOE. This reduced the behavioural evidence of tinnitus measured as deficits in silent gap detection. In conclusion, following AOE, the absence of LTP induction in the DCN due to an increased release probability constitutes an in vitro deficit prior to the later onset of tinnitus. Decreasing release probability at DCN multisensory synapses after AOE allowed AOE induced tinnitus to be targeted and reversed in an animal model.