Stimulus Timing-Dependent Plasticity in Dorsal Cochlear Nucleus Is Altered in Tinnitus

Abstract

Tinnitus and cochlear damage have been associated with changes in somatosensory-auditory integration and plasticity in the dorsal cochlear nucleus (DCN). Recently, we demonstrated in vivo that DCN bimodal plasticity is stimulus timing-dependent, with Hebbian and anti-Hebbian timing rules that reflect in vitro spike timing-dependent plasticity. In this in vivo study, we assessed the stimulus timing dependence of bimodal plasticity in a tinnitus model. Guinea pigs were exposed to a narrowband noise that produced a temporary elevation of auditory brainstem response thresholds. A total of 60% of the guinea pigs developed tinnitus as indicated by gap-induced prepulse inhibition of the acoustic startle. After noise exposure and tinnitus induction, stimulus timing-dependent plasticity was measured by comparing responses to sound before and after paired somatosensory and auditory stimulation presented with varying intervals and orders. In comparison with Sham and noise-exposed animals that did not develop tinnitus, timing rules in verified tinnitus animals were more likely to be anti-Hebbian and broader for those bimodal intervals in which the neural activity showed enhancement. Furthermore, units from exposed animals with tinnitus were more weakly suppressed than either Sham animals or exposed animals without tinnitus. The broadened timing rules in the enhancement phase in animals with tinnitus, and in the suppressive phase in exposed animals without tinnitus was in contrast to narrow, Hebbian-like timing rules in Sham animals. These findings implicate alterations in DCN bimodal spike timing-dependent plasticity as underlying mechanisms in tinnitus, opening the way for a therapeutic target.

Bimodal stimulus timing-dependent plasticity in primary auditory cortex is altered after noise exposure with and without tinnitus

“…Somatosensory-auditory bimodal stimulation results in long-lasting changes in neural firing rates in DCN (Dehmel et al 2012b) that are stimulus timing dependent (Koehler and Shore, 2013a), consistent with in vitro results showing spike timing-dependent plasticity (STDP) at parallel-fiber synapses (Tzounopoulos et al 2004). Furthermore, application of noise overexposure leading to tinnitus altered the stimulus timing-dependent rules from Hebbian to anti-Hebbian, with broader windows of enhancement than in sham-controls or noise-exposed animals without tinnitus (Koehler and Shore 2013b). These data implicate alterations in DCN bimodal STDP as an underlying mechanism in tinnitus generation.…”

“…Somatosensory convergence with auditory neurons as early in the pathway as the dorsal cochlear nucleus (DCN; Kanold and Young 2001;Shore 2005;Zhou et al 2007) is a potential etiology for tinnitus following noise exposure (Dehmel et al 2012b;Kaltenbach and McCaslin 1996;Koehler et al 2011;Koehler and Shore 2013b). Somatosensory-auditory bimodal stimulation results in long-lasting changes in neural firing rates in DCN (Dehmel et al 2012b) that are stimulus timing dependent (Koehler and Shore, 2013a), consistent with in vitro results showing spike timing-dependent plasticity (STDP) at parallel-fiber synapses (Tzounopoulos et al 2004).…”

“…The present study tested the hypothesis that stimulus timingdependent plasticity as observed in DCN (Koehler and Shore 2013a) following bimodal stimulation is also observed in A1, and that it is modified following noise damage (Koehler and Shore 2013b). In A1, bimodal stimulation in sham-animals resulted in stimulus timing-dependent responses similar to those in DCN.…”

“…Experiments were performed on mature, female pigmented guinea pigs (n ϭ 16; 250 -350 g; Elm Hill colony). The guinea pigs used in this study were the same animals used in a recently published report (Koehler and Shore 2013b), in which electrodes were simultaneously placed in A1 and DCN. All procedures were performed in accordance with the National Institutes of Health Guidelines for the Use and Care of Laboratory Animals and approved by the University of Michigan Committee on the Use and Care of Animals (UCUCA).…”

Effects of Unilateral Acoustic Trauma on Tinnitus-Related Spontaneous Activity in the Inferior Colliculus

“…According to the hyperactivity model of tinnitus, neurons in the central auditory system respond to the weakened input of a sound-damaged cochlea by down-regulating inhibitory connections (Moller 2007;Middleton et al 2011;Wang et al 2011) and enhancing membrane excitability (Dong et al 2010;Pilati et al 2012;Koehler and Shore 2013;Li et al 2013). This "rebalancing" may raise spontaneous activity (i.e., activity in the absence of sound) to levels that impart a false perception of sound stimulation (Chen and Jastreboff 1995; Kaltenbach and Afman 2000;.…”