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Protein knockdown using the auxin-inducible degron (AID) technology is useful to study protein function in living cells because it induces rapid depletion, which makes it possible to observe an immediate phenotype. However, the current AID system has two major drawbacks: leaky degradation and the requirement for a high dose of auxin. These negative features make it difficult to control precisely the expression level of a protein of interest in living cells and to apply this method to mice. Here, we overcome these problems by taking advantage of a bump-and-hole approach to establish the AID version 2 (AID2) system. AID2, which employs an OsTIR1(F74G) mutant and a ligand, 5-Ph-IAA, shows no detectable leaky degradation, requires a 670-times lower ligand concentration, and achieves even quicker degradation than the conventional AID. We demonstrate successful generation of human cell mutants for genes that were previously difficult to deal with, and show that AID2 achieves rapid target depletion not only in yeast and mammalian cells, but also in mice. Auxin-inducible degron systems can be leaky and require high doses of auxin. Here the authors establish AID2 which uses an OsTIR1 mutant and the ligand 5-Ph-IAA to overcome these problems and establish AID-mediated target depletion in mice.

Olfactory neurons respond to various odorants according to which olfactory receptors, of many, they express. During development, axons from olfactory neurons that express the same olfactory receptor converge to share the same glomeruli. Nakashima et al. now show that, in mice, the neurons build these connections according to shared patterns of activity. When the olfactory receptor is triggered, it causes its cell not simply to fire but to fire in specific patterns. Neurons that speak the same code end up connected at the same glomerulus. Science , this issue p. eaaw5030 The temporal pattern of neuronal firing rather than its synchronicity refines olfactory codes in the brain. Neural circuits emerge through the interplay of genetic programming and activity-dependent processes. During the development of the mouse olfactory map, axons segregate into distinct glomeruli in an olfactory receptor (OR)–dependent manner. ORs generate a combinatorial code of axon-sorting molecules whose expression is regulated by neural activity. However, it remains unclear how neural activity induces OR-specific expression patterns of axon-sorting molecules. We found that the temporal patterns of spontaneous neuronal spikes were not spatially organized but were correlated with the OR types. Receptor substitution experiments demonstrated that ORs determine spontaneous activity patterns. Moreover, optogenetically differentiated patterns of neuronal activity induced specific expression of the corresponding axon-sorting molecules and regulated axonal segregation. Thus, OR-dependent temporal patterns of spontaneous activity play instructive roles in generating the combinatorial code of axon-sorting molecules during olfactory map formation.

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.

In open-skill sports such as soccer, the environment surrounding players is rapidly changing. Therefore, players are required to process a large amount of external information and take appropriate actions in a very short period. Executive functions (EFs)-the cognitive control processes that regulate thoughts and action-are needed for high performance in soccer. In this study, we measured the EFs of young soccer players aged 8-11 years, who were applying for admission to an elite youth program of a Japanese Football League club. We found that even though admission was determined by the soccer performance of the players, significant differences were observed between players who were approved and those who were not approved into the program. Soccer players who had been approved into the program got higher scores in general EFs tests than those who had been rejected. Our results proposed that measuring EFs provides coaches with another objective way to assess the performance levels of soccer players.

In the mouse olfactory system, odorants are detected by ~1,000 different odorant receptors (ORs) produced by olfactory sensory neurons (OSNs). Each OSN expresses only one functional OR species, which is referred to as the “one neuron–one receptor” rule. Furthermore, OSN axons bearing the same OR converge to a specific projection site in the olfactory bulb (OB) forming a glomerular structure, i.e., the “one glomerulus–one receptor” rule. Based on these basic rules, binding signals of odorants detected by OSNs are converted to topographic information of activated glomeruli in the OB. During development, the glomerular map is formed by the combination of two genetically programmed processes: one is OR-independent projection along the dorsal–ventral axis, and the other is OR-dependent projection along the anterior-posterior axis. The map is further refined in an activity-dependent manner during the neonatal period. Here, we summarize recent progress of neural map formation in the mouse olfactory system.

The brain constructs spatially organized sensory maps to represent sensory information. The formation of sensory maps has traditionally been thought to depend on synchronous neuronal activity. However, recent evidence from the olfactory system suggests that cell type-specific temporal patterns of spontaneous activity play an instructive role in shaping the olfactory glomerular map. These findings challenge traditional views and highlight the importance of investigating the spatiotemporal dynamics of neural activity to understand the development of complex neural circuits. This review discusses the implications of new findings in the olfactory system and outlines future research directions.

Caspases are known to mediate neuronal apoptosis during brain development. However, here we show that nonapoptotic activation of caspase-3 at presynapses drives microglial synaptic phagocytosis. Real-time observation and spatiotemporal manipulation of synaptic caspase-3 in the newly established, mouse-derived culture system demonstrate that increased neuronal activity triggers localized presynaptic caspase-3 activation, facilitating synaptic tagging by complements. High-resolution live imaging reveals that caspase-3 activation promotes synapse-selective complement-dependent microglial phagocytosis without axonal shearing. Furthermore, activity-dependent caspase-3 activation at inhibitory presynapses induces microglial phagocytosis in mice and increases seizure susceptibility. This increased susceptibility is reversed by genetic depletion of microglial complement receptors. Thus, localized, nonapoptotic caspase activity guides complement-dependent microglial synaptic phagocytosis and remodels neuronal circuits. Caspases are known to mediate neuronal apoptosis during brain development. Here authors demonstrate a role for nonapoptotic caspase-3 activation in neurons with elevated activity, in the promotion of C1q deposition and synaptic phagocytosis by microglia.

[This corrects the article DOI: 10.1371/journal.pone.0201871.].

Interactions between the prefrontal cortex and the thalamus are critical for cognitive processing, including working memory and attention. Specifically, theta oscillations in the anterior cingulate cortex (ACC) and mediodorsal thalamic nucleus (MDT) during cognitive tasks are associated with persistent neural activity during working memory; however, the cellular mechanisms underlying the theta oscillations remain unclear. Using targeted patch-clamp recordings combined with neuronal projection identification in rats, we demonstrate that there is a subcircuit of monosynaptically interconnected ACC and MDT neurons to form a positive feedback loop. Synaptic transmission from the ACC to the MDT exhibits short-term facilitation, particularly within the theta frequency range. Moreover, MDT-projecting ACC neurons display a membrane potential resonance at theta frequencies. The results show that the ACC-MDT pathway exhibits synaptic facilitation and membrane resonance preferentially at theta frequencies, indicating that the circuit is tuned to theta dynamics. Anterior cingulate cortical neurons exhibit membrane resonance at theta frequencies, and their synaptic transmission to the mediodorsal thalamic nucleus shows facilitation at theta frequencies.

Odour information induces various innate responses that are critical to the survival of the individual and for the species. An axon guidance molecule, Neuropilin 2 (Nrp2), is known to mediate targeting of olfactory sensory neurons (primary neurons), to the posteroventral main olfactory bulb (PV MOB) in mice. Here we report that Nrp2-positive (Nrp2 + ) mitral cells (MCs, second-order neurons) play crucial roles in transmitting attractive social signals from the PV MOB to the anterior part of medial amygdala (MeA). Semaphorin 3F, a repulsive ligand to Nrp2, regulates both migration of Nrp2 + MCs to the PV MOB and their axonal projection to the anterior MeA. In the MC-specific Nrp2 knockout mice, circuit formation of Nrp2 + MCs and odour-induced attractive social responses are impaired. In utero , electroporation demonstrates that activation of the Nrp2 gene in MCs is sufficient to instruct their circuit formation from the PV MOB to the anterior MeA. Neuropilin 2 (Nrp2) is expressed by a subset of mitral cells in the postero-ventral olfactory bulb in mice. Here the authors show that Nrp2 is sufficient to instruct mitral cell targeting to the anterior part of medial amygdala that modulates olfactory-driven attractive social behaviour.