Tinnitus, the perception of phantom sound, is often a debilitating condition that affects many millions of people. Little is known, however, about the molecules that participate in the induction of tinnitus. In brain slices containing the dorsal cochlear nucleus, we reveal a tinnitus-specific increase in the spontaneous firing rate of principal neurons (hyperactivity). This hyperactivity is observed only in noise-exposed mice that develop tinnitus and only in the dorsal cochlear nucleus regions that are sensitive to high frequency sounds. We show that a reduction in Kv7.2/3 channel activity is essential for tinnitus induction and for the tinnitus-specific hyperactivity. This reduction is due to a shift in the voltage dependence of Kv7 channel activation to more positive voltages. Our in vivo studies demonstrate that a pharmacological manipulation that shifts the voltage dependence of Kv7 to more negative voltages prevents the development of tinnitus. Together, our studies provide an important link between the biophysical properties of the Kv7 channel and the generation of tinnitus. Moreover, our findings point to previously unknown biological targets for designing therapeutic drugs that may prevent the development of tinnitus in humans.potassium channels | excitability | auditory brainstem | phantom perception T innitus is a common auditory disorder that is often the result of extreme sound exposure. An estimated 5-15% of the population experiences chronic tinnitus, with many millions of those sufferers disabled by this condition (1-3). With an even higher prevalence of chronic tinnitus in recent war veterans (4), the personal and financial costs of tinnitus have expanded dramatically. Despite the high prevalence of tinnitus, the neuronal mechanisms that mediate the initiation (induction) and the maintenance (expression) of the disorder remain poorly understood. As a result there is no generally accepted treatment, cure, or preventive method for tinnitus.Tinnitus is usually initiated by noise-induced cochlear damage that causes hair cell loss, ganglion cell degeneration, and reduced auditory nerve input to the central auditory system (5). Decreased peripheral input leads to pathogenic neuronal plasticity that results in subcortical hyperexcitability, increased neural synchrony, cortical reorganization, and ultimately stimulusindependent perception of sound (5-13). However, little is known about the plasticity mechanisms that initiate tinnitus. Elucidation of these mechanisms will lead to the development of drugs and therapies that can be applied soon after the acoustic trauma, thus preventing tinnitus from becoming permanent and irreversible.The dorsal cochlear nucleus (DCN) is an auditory brainstem nucleus that is indispensable to the induction of tinnitus: ablation of the DCN before noise exposure prevents the induction of tinnitus (14). Consistent with its key role in tinnitus generation, the DCN is a site where robust tinnitus-related neuronal plasticity has been identified (15). Studies in animal models of ...

Stereopsis is a ubiquitous feature of primate mammalian vision, but little is known about if and how rodents such as mice use stereoscopic vision. We used random dot stereograms to test for stereopsis in male and female mice, and they were able to discriminate near from far surfaces over a range of disparities, with diminishing performance for small and large binocular disparities. Based on two-photon measurements of disparity tuning, the range of disparities represented in the visual cortex aligns with the behavior and covers a broad range of disparities. When we examined their binocular eye movements, we found that, unlike primates, mice did not systematically vary relative eye positions or use vergence eye movements when presented with different disparities. Nonetheless, the representation of disparity tuning was wide enough to capture stereoscopic information over a range of potential vergence angles. Although mice share fundamental characteristics of stereoscopic vision with primates and carnivores, their lack of disparity-dependent vergence eye movements and wide neuronal representation suggests that they may use a distinct strategy for stereopsis.

A central transformation that occurs within mammalian visual cortex is the change from linear, polarity-sensitive responses to nonlinear, polarity-insensitive responses. These neurons are classically labelled as either simple or complex, respectively, on the basis of their response linearity ( Skottun et al., 1991 ). While the difference between cell classes is clear when the stimulus strength is high, reducing stimulus strength diminishes the differences between the cell types and causes some complex cells to respond as simple cells ( Crowder et al., 2007 ; van Kleef et al., 2010 ; Hietanen et al., 2013 ). To understand the synaptic basis for this shift in behavior, we used in vivo whole-cell recordings while systematically shifting stimulus contrast. We find systematic shifts in the degree of complex cell responses in mouse primary visual cortex (V1) at the subthreshold level, demonstrating that synaptic inputs change in concert with the shifts in response linearity and that the change in response linearity is not simply due to the threshold nonlinearity. These shifts are consistent with a visual cortex model in which the recurrent amplification acts as a critical component in the generation of complex cell responses ( Chance et al., 1999 ).

We stabilize the dynamic visual world on our retina by moving our eyes in response to motion signals. Coordinated movements between the two eyes are characterized by version when both eyes move in the same direction and vergence when the two eyes move differently. Vergence eye movements have been proposed to be important for tracking objects in three dimensions and may be elicited in primates by both differences in the spatial signals, or disparity, or by differences in the motion that the two eyes receive. These vergence eye movements require the integration of left and right eye inputs, but it remains unclear which neural circuits are responsible for the integration that leads to these eye movements. To address this issue, we measured vergence eye movements in mice using a stereoscopic stimulus that is known to elicit vergence eye movements in primates. We found that the primary signal that drives vergence eye movements is the difference in motion presented to each eye, whereas spatial disparity cues had little impact on vergence. We also found that the vergence eye movements we observed in mice were not affected by silencing visual cortex, or by manipulations that disrupt the normal development of binocularity in visual cortex. Instead, we demonstrate that right and left eye motion cues in rodents could be described by a summation of motion signals that occurs outside of the visual cortex.

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