SummaryLarge numbers of brain regions are active during behaviors. A high-resolution, brain-wide activity map could identify brain regions involved in specific behaviors. We have developed functional ultrasound imaging to record whole-brain activity in behaving mice at a resolution of ∼100 μm. We detected 87 active brain regions during visual stimulation that evoked the optokinetic reflex, a visuomotor behavior that stabilizes the gaze both horizontally and vertically. Using a genetic mouse model of congenital nystagmus incapable of generating the horizontal reflex, we identified a subset of regions whose activity was reflex dependent. By blocking eye motion in control animals, we further separated regions whose activity depended on the reflex’s motor output. Remarkably, all reflex-dependent but eye motion-independent regions were located in the thalamus. Our work identifies functional modules of brain regions involved in sensorimotor integration and provides an experimental approach to monitor whole-brain activity of mice in normal and disease states.

SUMMARYThe accessory olfactory system controls social and sexual interactions in mice that are crucial for survival. Vomeronasal sensory neurons (VSNs) form synapses with dendrites of second order neurons in glomeruli of the accessory olfactory bulb (AOB). Axons of VSNs expressing the same vomeronasal receptor coalesce into multiple glomeruli within spatially conserved regions of the AOB. Here we examine the role of the Kirrel family of transmembrane proteins in the coalescence of VSN axons within the AOB. We find that Kirrel2 and Kirrel3 are differentially expressed in subpopulations of VSNs and that their expression is regulated by activity. Although Kirrel3 expression is not required for early axonal guidance events, such as fasciculation of the vomeronasal tract and segregation of apical and basal VSN axons in the AOB, it is necessary for proper coalescence of axons into glomeruli. Ablation of Kirrel3 expression results in disorganization of the glomerular layer of the posterior AOB and formation of fewer, larger glomeruli. Furthermore, Kirrel3 −/− mice display a loss of male-male aggression in a resident-intruder assay. Taken together, our results indicate that differential expression of Kirrels on vomeronasal axons generates a molecular code that dictates their proper coalescence into glomeruli within the AOB.

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Sensory systems enable us to encode a clear representation of our environment in the nervous system by spatially organizing sensory stimuli being received. The organization of neural circuitry to form a map of sensory activation is critical for the interpretation of these sensory stimuli. In rodents, social communication relies strongly on the detection of chemosignals by the vomeronasal system, which regulates a wide array of behaviours, including mate recognition, reproduction, and aggression. The binding of these chemosignals to receptors on vomeronasal sensory neurons leads to activation of second-order neurons within glomeruli of the accessory olfactory bulb. Here, vomeronasal receptor activation by a stimulus is organized into maps of glomerular activation that represent phenotypic qualities of the stimuli detected. Genetic, electrophysiological and imaging studies have shed light on the principles underlying cell connectivity and sensory map formation in the vomeronasal system, and have revealed important differences in sensory coding between the vomeronasal and main olfactory system. In this review, we summarize the key factors and mechanisms that dictate circuit formation and sensory coding logic in the vomeronasal system, emphasizing differences with the main olfactory system. Furthermore, we discuss how detection of chemosignals by the vomeronasal system regulates social behaviour in mice, specifically aggression.

The accessory olfactory system controls social and sexual behaviours in mice, both of which are critical for their survival. Vomeronasal sensory neuron (VSN) axons form synapses with mitral cell dendrites in glomeruli of the accessory olfactory bulb (AOB). Axons of VSNs expressing the same vomeronasal receptor (VR) converge into multiple glomeruli within spatially conserved regions of the AOB. Here, we have examined the role of the cell adhesion molecule Kirrel2 in the formation of glomeruli within the AOB. We find that Kirrel2 expression is dispensable for early axonal guidance events, such as fasciculation of the vomeronasal tract and segregation of apical and basal VSN axons into the anterior and posterior regions of the AOB, but is necessary for glomeruli formation. Specific ablation of Kirrel2 expression in VSN axons results in the disorganization of the glomerular layer of the posterior AOB and in the formation of fewer and larger glomeruli. Furthermore, simultaneous ablation of Kirrel2 and Kirrel3 expression leads to a loss of morphologically identifiable glomeruli in the AOB, reduced excitatory synapse numbers, and larger presynaptic terminals. Taken together, our results demonstrate that Kirrel2 and Kirrel3 are essential for the formation of glomeruli and suggest they contribute to synaptogenesis in the AOB.

Cellular interactions are key for the differentiation of distinct cell types within developing epithelia, yet the molecular mechanisms engaged in these interactions remain poorly understood. In the developing olfactory epithelium (OE), neural stem/progenitor cells give rise to odorant-detecting olfactory receptor neurons (ORNs) and glial-like sustentacular (SUS) cells. Here, we show in mice that the transmembrane receptor neogenin (NEO1) and its membranebound ligand RGMB control the balance of neurons and glial cells produced in the OE. In this layered epithelium, neogenin is expressed in progenitor cells, while RGMB is restricted to adjacent newly born ORNs. Ablation of Rgmb via gene-targeting increases the number of dividing progenitor cells in the OE and leads to supernumerary SUS cells. Neogenin loss-of-function phenocopies these effects observed in Rgmb −/− mice, supporting the proposal that RGMB-neogenin signaling regulates progenitor cell numbers and SUS cell production. Interestingly, Neo1−/− mice also exhibit increased apoptosis of ORNs, implicating additional ligands in the neogenin-dependent survival of ORNs. Thus, our results indicate that RGMB-neogenin-mediated cellcell interactions between newly born neurons and progenitor cells control the ratio of glia and neurons produced in the OE.

The formation of olfactory maps in the olfactory bulb (OB) is crucial for the control of innate and learned mouse behaviors. Olfactory sensory neurons (OSNs) expressing a specific odorant receptor project axons into spatially conserved glomeruli within the OB and synapse onto mitral cell dendrites. Combinatorial expression of members of the Kirrel family of cell adhesion molecules has been proposed to regulate OSN axonal coalescence; however, loss-of-function experiments have yet to establish their requirement in this process. We examined projections of several OSN populations in mice that lacked either Kirrel2 alone, or both Kirrel2 and Kirrel3. Our results show that Kirrel2 and Kirrel3 are dispensable for the coalescence of MOR1-3-expressing OSN axons to the most dorsal region (DI) of the OB. In contrast, loss of Kirrel2 caused MOR174-9-and M72-expressing OSN axons, projecting to the DII region, to target ectopic glomeruli. Our loss-of-function approach demonstrates that Kirrel2 is required for axonal coalescence in subsets of OSNs that project axons to the DII region and reveals that Kirrel2/3independent mechanisms also control OSN axonal coalescence in certain regions of the OB.

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