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Structural elucidation and molecular scrutiny of cerebral vasculature is crucial for understanding the functions and diseases of the brain. Here, we introduce SeeNet, a method for near-complete three-dimensional visualization of cerebral vascular networks with high signal-to-noise ratios compatible with molecular phenotyping. SeeNet employs perfusion of a multifunctional crosslinker, vascular casting by temperature-controlled polymerization of hybrid hydrogels, and a bile salt-based tissue-clearing technique optimized for observation of vascular connectivity. SeeNet is capable of whole-brain visualization of molecularly characterized cerebral vasculatures at the single-microvessel level. Moreover, SeeNet reveals a hitherto unidentified vascular pathway bridging cerebral and hippocampal vessels, thus serving as a potential tool to evaluate the connectivity of cerebral vasculature. Structural and molecular elucidation of cerebrovascular network is promising for understanding energy supply system in the brain. Here, the authors describe labeling and tissue clearing techniques that visualize the whole-brain vasculature in a molecularly characterizable manner.

Hippocampal sharp wave (SW)/ripple complexes are thought to contribute to memory consolidation. Previous studies suggest that behavioral rewards facilitate SW occurrence in vivo. However, little is known about the precise mechanism underlying this enhancement. Here, we examined the effect of dopaminergic neuromodulation on spontaneously occurring SWs in acute hippocampal slices. Local field potentials were recorded from the CA1 region. A brief (1 min) treatment with dopamine led to a persistent increase in the event frequency and the magnitude of SWs. This effect lasted at least for our recording period of 45 min and did not occur in the presence of a dopamine D1/D5 receptor antagonist. Functional multineuron calcium imaging revealed that dopamine-induced SW augmentation was associated with an enriched repertoire of the firing patterns in SW events, whereas the overall tendency of individual neurons to participate in SWs and the mean number of cells participating in a single SW were maintained. Therefore, dopaminergic activation is likely to reorganize cell assemblies during SWs.

Sharp wave-ripple complexes (SW-Rs), a transient form of high-frequency field oscillations observed in the hippocampus, are thought to mediate memory consolidation. They are initiated mainly in hippocampal CA3 area and propagate to the entorhinal cortex through the subiculum; however, little is known about how SW-Rs are initiated and propagate. Here, we used functional multineuronal calcium imaging to monitor SW-R-relevant neuronal activity from the subiculum at single-cell resolution. An unexpected finding was that a subset of subicular neurons was activated immediately before hippocampal SW-Rs. The SW-R-preceding activity was not abolished by surgical lesion of the CA1-to-subiculum projection and thus, it probably arose from entorhinal inputs. Therefore, SW-Rs are likely to be triggered by entorhinal-to-CA3/CA1 inputs. Moreover, the subiculum is not merely a passive intermediate region that SW-Rs pass through, but rather, it seems to contribute to an active modification of neural information related to SW-Rs.

Introduction Combination treatment with fingolimod (FTY720) plus pathogenic antigen is thought to prevent glucose‐6‐phosphate isomerase (GPI)325‐339‐induced arthritis progression by effective induction of immune tolerance. Here, we examined the efficacy of this combination treatment on remission maintenance. Methods GPI325‐339‐induced arthritis mice were treated for 5 days with FTY720 (1.0 mg/kg, p.o.) alone, GPI325–339 (10 μg/mouse, i.v.) alone, or with the FTY720 plus GPI325‐339 combination. In some experiments, mice were resensitized with GPI325‐339. Results Following resensitization with GPI325‐339, combination‐treated mice exhibited neither severe relapse nor elevated lymphocyte infiltration in joints. Neither anti‐human nor mouse GPI325‐339 antibody levels were correlated with clinical symptoms. This suggests that combination treatment prevents relapse following resensitization via regulation of pathogenic antigen‐specific T cells. The proportion of regulatory T (Treg) cells in inguinal lymph nodes was increased post treatment in the FTY720 alone and FTY720 plus GPI325‐339 groups. In contrast, the proportion of glucocorticoid‐induced tumor necrosis factor receptor‐family‐related gene/protein (GITR)+ non‐Treg cells was increased only in combination‐treated mice. Furthermore, GITR+ non‐Treg cells, which were induced by the combination treatment in vivo, possess suppressive activity and high ability to produce interleukin (IL)‐10. Conclusion GITR+ non‐Treg cells might play a key role in relapse prevention following resensitization. Thus, this combination treatment might establish immune tolerance by induction of GITR+ non‐Treg cells. In this study, we demonstrated that the combination treatment with fingolimod (FTY720) plus pathogenic antigen (glucose‐6‐phosphate isomerase (GPI)325‐339) could induce and maintain remission of GPI325‐339‐induced arthritis. GITR+CD25−CD4+ cells, which constitute the anergic population, might prevent relapse following resensitization via high level production of IL‐10; the GITR+ non‐Treg cells that were induced by the combination treatment might play a key role in the establishment of tolerance.