The role of Netrin-1 in semicircular canal morphogenesis

The vestibular system of the inner ear detects head position using three orthogonally oriented semicircular canals. Vestibular function relies on precise canal shape and orientation, and slight changes can cause vestibular defects. Canals are sculpted from pouches that protrude from the otic vesicle, the simple sphere of epithelium that forms the inner ear. In the center of each pouch, a "fusion plate" forms where cells lose their epithelial morphology and the basement membrane breaks down. The opposing layers of the fusion plate intercalate and are subsequently removed, creating a canal. Proper fusion depends on Netrin-1, which regulates basement membrane breakdown during fusion in mice, although the underlying molecular mechanism is unknown. This dissertation describes our work to better understand the cellular effects of Netrin-1 during canal formation. Although vestibular apparatus structure is shared among species, some developmental events that lead to this structure differ. For example, while fusion plate basement membrane breakdown is conserved, apoptosis is required for fusion in chicks, but not in mice. We used gain-of-function approaches to determine the main cellular effect of Netrin-1 during fusion in chicks and mice. We show that overexpression of Netrin-1 in chicks prevents canal fusion from occurring normally by interfering with apoptosis. On the other hand, we show that ectopic expression of Netrin-1 in mice using a conditional expression allele causes excessive fusion, resulting in canal truncation. This suggests that Netrin-1 may play divergent roles during canal morphogenesis in chicks and mice. To determine if Netrin-1 regulates the basement membrane in other contexts, we created a Netrin-1 conditional null allele. This was necessary because existing Netrin-1 mutants express residual Netrin-1 protein, which could be sufficient to rescue basement membrane defects in other tissues, and because existing mutants die shortly after birth, preventing postnatal analysis. Complete loss of Netrin-1 protein in our newly generated mice does not cause more severe defects in fusion compared to existing Netrin-1 hypomorphs, suggesting that residual Netrin-1 protein does not affect the basement membrane during fusion in Netrin-1 hypomorphs. Future work will determine if complete loss of Netrin-1 affects basement membrane integrity in other tissues

Cooperation of different neuronal systems during hand sign recognition.

Hand signs with symbolic meaning can often be utilized more successfully than words to communicate an intention; however, the underlying brain mechanisms are undefined. The present study using magnetoencephalography (MEG) demonstrates that the primary visual, mirror neuron, social recognition and object recognition systems are involved in hand sign recognition. MEG detected well-orchestrated multiple brain regional electrical activity among these neuronal systems. During the assessment of the meaning of hand signs, the inferior parietal, superior temporal sulcus (STS) and inferior occipitotemporal regions were simultaneously activated. These three regions showed similar time courses in their electrical activity, suggesting that they work together during hand sign recognition by integrating information in the ventral and dorsal pathways through the STS. The results also demonstrated marked right hemispheric predominance, suggesting that hand expression is processed in a manner similar to that in which social signs, such as facial expressions, are processed

A Gata3–Mafb transcriptional network directs post-synaptic differentiation in synapses specialized for hearing

Information flow through neural circuits is determined by the nature of the synapses linking the subtypes of neurons. How neurons acquire features distinct to each synapse remains unknown. We show that the transcription factor Mafb drives the formation of auditory ribbon synapses, which are specialized for rapid transmission from hair cells to spiral ganglion neurons (SGNs). Mafb acts in SGNs to drive differentiation of the large postsynaptic density (PSD) characteristic of the ribbon synapse. In Mafb mutant mice, SGNs fail to develop normal PSDs, leading to reduced synapse number and impaired auditory responses. Conversely, increased Mafb accelerates synaptogenesis. Moreover, Mafb is responsible for executing one branch of the SGN differentiation program orchestrated by the Gata3 transcriptional network. Remarkably, restoration of Mafb rescues the synapse defect in Gata3 mutants. Hence, Mafb is a powerful regulator of cell-type specific features of auditory synaptogenesis that offers a new entry point for treating hearing loss. DOI: http://dx.doi.org/10.7554/eLife.01341.00

Spatio-Temporal Dynamics of Human Intention Understanding in Temporo-Parietal Cortex: A Combined EEG/fMRI Repetition Suppression Paradigm

Inferring the intentions of other people from their actions recruits an inferior fronto-parietal action observation network as well as a putative social network that includes the posterior superior temporal sulcus (STS). However, the functional dynamics within and among these networks remains unclear. Here we used functional magnetic resonance imaging (fMRI) and high-density electroencephalogram (EEG), with a repetition suppression design, to assess the spatio-temporal dynamics of decoding intentions. Suppression of fMRI activity to the repetition of the same intention was observed in inferior frontal lobe, anterior intraparietal sulcus (aIPS), and right STS. EEG global field power was reduced with repeated intentions at an early (starting at 60 ms) and a later (∼330 ms) period after the onset of a hand-on-object encounter. Source localization during these two intervals involved right STS and aIPS regions highly consistent with RS effects observed with fMRI. These results reveal the dynamic involvement of temporal and parietal networks at multiple stages during the intention decoding and without a strict segregation of intention decoding between these networks

“Biological Geometry Perception”: Visual Discrimination of Eccentricity Is Related to Individual Motor Preferences

In the continuum between a stroke and a circle including all possible ellipses, some eccentricities seem more “biologically preferred” than others by the motor system, probably because they imply less demanding coordination patterns. Based on the idea that biological motion perception relies on knowledge of the laws that govern the motor system, we investigated whether motorically preferential and non-preferential eccentricities are visually discriminated differently. In contrast with previous studies that were interested in the effect of kinematic/time features of movements on their visual perception, we focused on geometric/spatial features, and therefore used a static visual display.In a dual-task paradigm, participants visually discriminated 13 static ellipses of various eccentricities while performing a finger-thumb opposition sequence with either the dominant or the non-dominant hand. Our assumption was that because the movements used to trace ellipses are strongly lateralized, a motor task performed with the dominant hand should affect the simultaneous visual discrimination more strongly. We found that visual discrimination was not affected when the motor task was performed by the non-dominant hand. Conversely, it was impaired when the motor task was performed with the dominant hand, but only for the ellipses that we defined as preferred by the motor system, based on an assessment of individual preferences during an independent graphomotor task.Visual discrimination of ellipses depends on the state of the motor neural networks controlling the dominant hand, but only when their eccentricity is “biologically preferred”. Importantly, this effect emerges on the basis of a static display, suggesting that what we call “biological geometry”, i.e., geometric features resulting from preferential movements is relevant information for the visual processing of bidimensional shapes

Excitability of the Primary Motor Cortex Increases More Strongly with Slow- than with Normal-Speed Presentation of Actions

Introduction: The aim of the present study was to investigate how the speed of observed action affects the excitability of the primary motor cortex (M1), as assessed by the size of motor evoked potentials (MEPs) induced by transcranial magnetic stimulation (TMS). Copyright:Methods: Eighteen healthy subjects watched a video clip of a person catching a ball, played at three different speeds (normal-, half-, and quarter-speed). MEPs were induced by TMS when the model\u27s hand had opened to the widest extent just before catching the ball ("open") and when the model had just caught the ball ("catch"). These two events were locked to specific frames of the video clip ("phases"), rather than occurring at specific absolute times, so that they could easily be compared across different speeds. MEPs were recorded from the thenar (TH) and abductor digiti minimi (ADM) muscles of the right hand.Results: The MEP amplitudes were higher when the subjects watched the video clip at low speed than when they watched the clip at normal speed. A repeated-measures ANOVA, with the factor VIDEO-SPEED, showed significant main effects. Bonferroni\u27s post hoc test showed that the following MEP amplitude differences were significant: TH, normal vs. quarter; ADM, normal vs. half; and ADM, normal vs. quarter. Paired t-tests showed that the significant MEP amplitude differences between TMS phases under each speed condition were TH, "catch" higher than "open" at quarter speed; ADM, "catch" higher than "open" at half speed.Conclusions: These results indicate that the excitability of M1 was higher when the observed action was played at low speed. Our findings suggest that the action observation system became more active when the subjects observed the video clip at low speed, because the subjects could then recognize the elements of action and intention in others

Multilateral Subsidy Games. CEPR Discussion Paper No. 6479

This paper examines the rationale for multilateral agreements to limit investment subsidies. The welfare ranking of symmetric multilateral subsidy games is shown to depend on whether or not investment levels are "friendly", raising rival profits in total, and/or strategic complements, raising rival profits at the margin. In both Cournot and Bertrand competition, when spillovers are low and competition is intense (because goods are close substitutes), national welfare- maximizing governments will over-subsidize investment, and banning subsidies would improve welfare. When spillovers are high, national governments under-subsidize from a global welfare perspective, but the subsidy game is welfare superior to non-intervention

Cochlear structure and patterning is normal in <i>Lrig1^−/−</i>;<i>Lrig2^−/−</i> double mutants but cochlear innervation is disrupted.

<p>(A–C) Cochlear tissue from adult animals was immunostained and then imaged as a flat-mount by confocal microscopy. In controls (A), neurofilament (NF)-positive neurites from both afferent and efferent neurons align in distinct radial bundles. Efferent projections also travel non-radially along the length of the cochlea in the inner spiral bundle (ISB) (bracket in A). The regular spacing normally found between these axonal bundles (A, arrowheads) is disrupted in <i>Lrig1^−/−</i>;<i>Lrig2^−/−</i> double mutants (C, arrowheads). In addition, the ISB is reduced (brackets). Innervation was grossly normal in <i>Lrig1^−/−;Lrig2^+/−</i> animals. (D–F) Efferent axons and their terminals were visualized by staining for Choline acetyltransferase (ChAT) (D–F and D′–F′) and synaptophysin (Syp) (D″–F″). High power images of the boxed regions illustrate the obvious reduction in efferent innervation in double mutants (F′, F″) compared to controls (D′, D″). <i>Lrig1^−/−;Lrig2^+/−</i> animals showed an intermediate effect (E′, E″). ISB = inner spiral bundle, oC = organ of Corti, sg = spiral ganglion. See <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003824#pgen.1003824.s004" target="_blank">Figure S4</a> for images of additional genotypes. (A–F) Scale bar = 50 µm. (D′–F″) Scale bar = 10 µm.</p

Paintfill analysis reveals inner ear morphological defects in <i>Lrig</i> mutants.

<p>Inner ear morphology was assessed blind to genotype in animals with all possible combinations of <i>Lrig1</i> and <i>Lrig3</i> mutant alleles. “n” corresponds to the total number of ears that were scored for each genotype. Columns indicate the number of ears of each genotype that showed defects in the lateral canal, posterior canal, or saccule/utricle, with the percent of total ears examined in parentheses. Novel phenotypes were observed only in <i>Lrig1^−/−;Lrig3^−/−</i> double mutant animals.</p