Stimulus-timing-dependent modifications of rate-level functions in animals with and without tinnitus.

Tinnitus has been associated with enhanced central gain manifested by increased spontaneous activity and sound-evoked firing rates of principal neurons at various stations of the auditory pathway. Yet, the mechanisms leading to these modifications are not well understood. In a recent in vivo study, we demonstrated that stimulus-timing-dependent bimodal plasticity mediates modifications of spontaneous and tone-evoked responses of fusiform cells in the dorsal cochlear nucleus (DCN) of the guinea pig. Fusiform cells from sham animals showed primarily Hebbian learning rules while noise-exposed animals showed primarily anti-Hebbian rules, with broadened profiles for the animals with behaviorally verified tinnitus (Koehler SD, Shore SE. J Neurosci 33: 19647-19656, 2013a). In the present study we show that well-timed bimodal stimulation induces alterations in the rate-level functions (RLFs) of fusiform cells. The RLF gains and maximum amplitudes show Hebbian modifications in sham and no-tinnitus animals but anti-Hebbian modifications in noise-exposed animals with evidence for tinnitus. These findings suggest that stimulus-timing bimodal plasticity produced by the DCN circuitry is a contributing mechanism to enhanced central gain associated with tinnitus.

Stefanescu RA ，Koehler SD ，Shore SE 《-》

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

Central auditory circuits are influenced by the somatosensory system, a relationship that may underlie tinnitus generation. In the guinea pig dorsal cochlear nucleus (DCN), pairing spinal trigeminal nucleus (Sp5) stimulation with tones at specific intervals and orders facilitated or suppressed subsequent tone-evoked neural responses, reflecting spike timing-dependent plasticity (STDP). Furthermore, after noise-induced tinnitus, bimodal responses in DCN were shifted from Hebbian to anti-Hebbian timing rules with less discrete temporal windows, suggesting a role for bimodal plasticity in tinnitus. Here, we aimed to determine if multisensory STDP principles like those in DCN also exist in primary auditory cortex (A1), and whether they change following noise-induced tinnitus. Tone-evoked and spontaneous neural responses were recorded before and 15 min after bimodal stimulation in which the intervals and orders of auditory-somatosensory stimuli were randomized. Tone-evoked and spontaneous firing rates were influenced by the interval and order of the bimodal stimuli, and in sham-controls Hebbian-like timing rules predominated as was seen in DCN. In noise-exposed animals with and without tinnitus, timing rules shifted away from those found in sham-controls to more anti-Hebbian rules. Only those animals with evidence of tinnitus showed increased spontaneous firing rates, a purported neurophysiological correlate of tinnitus in A1. Together, these findings suggest that bimodal plasticity is also evident in A1 following noise damage and may have implications for tinnitus generation and therapeutic intervention across the central auditory circuit.

Basura GJ ，Koehler SD ，Shore SE 《-》

Muscarinic acetylcholine receptors control baseline activity and Hebbian stimulus timing-dependent plasticity in fusiform cells of the dorsal cochlear nucleus.

Cholinergic modulation contributes to adaptive sensory processing by controlling spontaneous and stimulus-evoked neural activity and long-term synaptic plasticity. In the dorsal cochlear nucleus (DCN), in vitro activation of muscarinic acetylcholine receptors (mAChRs) alters the spontaneous activity of DCN neurons and interacts with N-methyl-d-aspartate (NMDA) and endocannabinoid receptors to modulate the plasticity of parallel fiber synapses onto fusiform cells by converting Hebbian long-term potentiation to anti-Hebbian long-term depression. Because noise exposure and tinnitus are known to increase spontaneous activity in fusiform cells as well as alter stimulus timing-dependent plasticity (StTDP), it is important to understand the contribution of mAChRs to in vivo spontaneous activity and plasticity in fusiform cells. In the present study, we blocked mAChRs actions by infusing atropine, a mAChR antagonist, into the DCN fusiform cell layer in normal hearing guinea pigs. Atropine delivery leads to decreased spontaneous firing rates and increased synchronization of fusiform cell spiking activity. Consistent with StTDP alterations observed in tinnitus animals, atropine infusion induced a dominant pattern of inversion of StTDP mean population learning rule from a Hebbian to an anti-Hebbian profile. Units preserving their initial Hebbian learning rules shifted toward more excitatory changes in StTDP, whereas units with initial suppressive learning rules transitioned toward a Hebbian profile. Together, these results implicate muscarinic cholinergic modulation as a factor in controlling in vivo fusiform cell baseline activity and plasticity, suggesting a central role in the maladaptive plasticity associated with tinnitus pathology.NEW & NOTEWORTHY This study is the first to use a novel method of atropine infusion directly into the fusiform cell layer of the dorsal cochlear nucleus coupled with simultaneous recordings of neural activity to clarify the contribution of muscarinic acetylcholine receptors (mAChRs) to in vivo fusiform cell baseline activity and auditory-somatosensory plasticity. We have determined that blocking the mAChRs increases the synchronization of spiking activity across the fusiform cell population and induces a dominant pattern of inversion in their stimulus timing-dependent plasticity. These modifications are consistent with similar changes established in previous tinnitus studies, suggesting that mAChRs might have a critical contribution in mediating the maladaptive alterations associated with tinnitus pathology. Blocking mAChRs also resulted in decreased fusiform cell spontaneous firing rates, which is in contrast with their tinnitus hyperactivity, suggesting that changes in the interactions between the cholinergic and GABAergic systems might also be an underlying factor in tinnitus pathology.

Stefanescu RA ，Shore SE 《-》

Stimulus timing-dependent plasticity in dorsal cochlear nucleus is altered in tinnitus.

Koehler SD ，Shore SE 《-》

NMDA Receptors Mediate Stimulus-Timing-Dependent Plasticity and Neural Synchrony in the Dorsal Cochlear Nucleus.

Stefanescu RA ，Shore SE 《Frontiers in Neural Circuits》