Interocular velocity cues elicit vergence eye movements in mice.

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 as version when both eyes move in the same direction and vergence when the two eyes move in opposite directions. Vergence eye movements are necessary to track objects in three dimensions. In primates they can be elicited by intraocular differences in either spatial signals (disparity) or velocity, requiring the integration of left and right eye inputs. Whether mice are capable of similar behaviors is not known. To address this issue, we measured vergence eye movements in mice using a stereoscopic stimulus known to elicit vergence eye movements in primates. We found that mice also exhibit vergence eye movements, although at a low gain and that the primary driver of these vergence eye movements is interocular motion. Spatial disparity cues alone are ineffective. We also found that the vergence eye movements we observed in mice were robust to silencing visual cortex and to manipulations that disrupt the normal development of binocularity in visual cortex. A sublinear combination of motor commands driven by monocular signals is sufficient to account for our results.NEW & NOTEWORTHY The visual system integrates signals from the left and right eye to generate a representation of the world in depth. The binocular integration of signals may be observed from the coordinated vergence eye movements elicited by object motion in depth. We explored the circuits and signals responsible for these vergence eye movements in rodent and find these vergence eye movements are generated by a comparison of the motion and not spatial visual signals.

Mice Discriminate Stereoscopic Surfaces Without Fixating in Depth.

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.SIGNIFICANCE STATEMENT Binocular vision allows us to derive depth information by comparing right and left eye information. We characterized binocular integration in mice because tools exist in these animals to dissect the underlying neural circuitry for binocular vision. Using random dot stereograms, we find that behavior and disparity tuning in the visual cortex share fundamental characteristics with primates, but we did not observe any evidence of disparity-dependent changes in vergence angle. We propose that mice use a distinct strategy of stereopsis compared with primates by using a broad range of disparities to encode depth over a large field of view and to compensate for nonstereoscopic changes in vergence angle that arise during natural behavior.

Synaptic Basis for Contrast-Dependent Shifts in Functional Identity in Mouse V1.

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).

Anti-osteogenic function of a LIM-homeodomain transcription factor LMX1B is essential to early patterning of the calvaria.

The calvaria (upper part of the skull) is made of plates of bone and fibrous joints (sutures and fontanelles), and the proper balance and organization of these components are crucial to normal development of the calvaria. In a mouse embryo, the calvaria develops from a layer of head mesenchyme that surrounds the brain from shortly after mid-gestation. The mesenchyme just above the eye (supra-orbital mesenchyme, SOM) generates ossification centers for the bones, which then grow toward the apex gradually. In contrast, the mesenchyme apical to SOM (early migrating mesenchyme, EMM), including the area at the vertex, does not generate an ossification center. As a result, the dorsal midline of the head is occupied by sutures and fontanelles at birth. To date, the molecular basis for this regional difference in developmental programs is unknown. The current study provides vital insights into the genetic regulation of calvarial patterning. First, we showed that osteogenic signals were active in both EMM and SOM during normal development, which suggested the presence of an anti-osteogenic factor in EMM to counter the effect of these signals. Subsequently, we identified Lmx1b as an anti-osteogenic gene that was expressed in EMM but not in SOM. Furthermore, head mesenchyme-specific deletion of Lmx1b resulted in heterotopic ossification from EMM at the vertex, and craniosynostosis affecting multiple sutures. Conversely, forced expression of Lmx1b in SOM was sufficient to inhibit osteogenic specification. Therefore, we conclude that Lmx1b plays a key role as an anti-osteogenic factor in patterning the head mesenchyme into areas with different osteogenic competence. In turn, this patterning event is crucial to generating the proper organization of the bones and soft tissue joints of the calvaria.

Neural crest-specific deletion of Ldb1 leads to cleft secondary palate with impaired palatal shelf elevation.

BACKGROUND: LIM domain binding protein 1 (LDB1) is a transcriptional co-factor, which interacts with multiple transcription factors and other proteins containing LIM domains. Complete inactivation of Ldb1 in mice resulted in early embryonic lethality with severe patterning defects during gastrulation. Tissue-specific deletions using a conditional knockout allele revealed additional roles of Ldb1 in the development of the central nervous system, hematopoietic system, and limbs. The goal of the current study was to determine the importance of Ldb1 function during craniofacial development in mouse embryos. RESULTS: We generated tissue-specific Ldb1 mutants using Wnt1-Cre, which causes deletion of a floxed allele in the neural crest; neural crest-derived cells contribute to most of the mesenchyme of the developing face. All examined Wnt1-Cre;Ldb1(fl/-) mutants suffered from cleft secondary palate. Therefore, we performed a series of experiments to investigate how Ldb1 regulated palate development. First, we examined the expression of Ldb1 during normal development, and found that Ldb1 was expressed broadly in the palatal mesenchyme during early stages of palate development. Second, we compared the morphology of the developing palate in control and Ldb1 mutant embryos using sections. We found that the mutant palatal shelves had abnormally blunt appearance, and failed to elevate above the tongue at the posterior domain. An in vitro head culture experiment indicated that the elevation defect was not due to interference by the tongue. Finally, in the Ldb1 mutant palatal shelves, cell proliferation was abnormal in the anterior, and the expression of Wnt5a, Pax9 and Osr2, which regulate palatal shelf elevation, was also altered. CONCLUSIONS: The function of Ldb1 in the neural crest-derived palatal mesenchyme is essential for normal morphogenesis of the secondary palate.

Pathogenic plasticity of Kv7.2/3 channel activity is essential for the induction of tinnitus.

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.