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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.

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.

We have previously reported that a 2.1-kb homology (H) sequence, conserved between mouse and human, regulates the odorant receptor (OR) gene MOR28 in transgenic mice. Here, we narrowed down the essential sequences of the H to a core of 124 bp by using a transient expression system in zebrafish embryos. Transgenic experiments in mice demonstrated that the core-H sequence is sufficient to endow expression of the MOR28 minigene. Deletion and mutation analyses of the core-H region revealed two homeodomain sequences to be essential for the H enhancer activity. Targeted deletion of the core-H abolished expression of three proximal OR genes, MOR28, MOR10, and MOR83, in cis, indicating the presence of another locus control region/enhancer in the downstream region, that regulates four distal OR genes in the same MOR28 cluster. In the heterozygous mice, the H⁻ phenotype of the mutant allele was not rescued by the wild-type H⁺ allele in trans.

The olfactory piriform cortex is thought to participate in olfactory associative memory. Like the hippocampus, which is essential for episodic memory, it belongs to an evolutionally conserved paleocortex and comprises a three-layered cortical structure. During slow-wave sleep, the olfactory piriform cortex becomes less responsive to external odor stimuli and instead displays sharp wave (SPW) activity similar to that observed in the hippocampus. Neural activity patterns during hippocampal SPW have been intensively studied in terms of memory consolidation; however, little is known about the activity patterns of olfactory cortical neurons during olfactory cortex sharp waves (OC-SPWs). In this study, we recorded multi-unit neural activities in the anterior piriform cortex in urethane-anesthetized mice. We found that the activity patterns of olfactory cortical neurons during OC-SPWs were non-randomly organized. Individual olfactory cortical neurons varied in the timings of their peak firing rates during OC-SPW events. Moreover, specific pairs of olfactory cortical neurons were more frequently activated together than expected by chance. On the basis of these observations, we speculate that coordinated activation of specific subsets of olfactory cortical neurons repeats during OC-SPWs, thereby facilitating synaptic plasticity underlying the consolidation of olfactory associative memories.

Genetic manipulation of protein levels is a promising approach to identify the function of a specific protein in living organisms. Previous studies demonstrated that the auxin-inducible degron (AID) strategy provides rapid and reversible degradation of various proteins in fungi and mammalian mitotic cells. In this study, we employed this technology to postmitotic neurons to address whether the AID system could be applied to the nervous system. Using adeno-associated viruses, we simultaneously introduced EGFP fused with an AID tag, and an F-box family protein, TIR1 from Oryza sativa (OsTIR1) into hippocampal neurons. In dissociated hippocampal neurons, EGFP fluorescence signals rapidly decreased when adding a plant hormone, auxin. Further, auxin-induced EGFP degradation was also observed in hippocampal acute slices. Taken together, these results open the door for neuroscientists to manipulate protein expression levels by the AID-system in a temporally-controlled manner.

The tryptophan and kynurenine pathway is well-known to play an important role in nervous, endocrine, and immune systems, as well as in the development of inflammatory diseases. It has been documented that some kynurenine metabolites are considered to have anti-oxidative, anti-inflammatory, and/or neuroprotective properties. Importantly, many of these kynurenine metabolites may possess immune-regulatory properties that could alleviate the inflammation response. The abnormal activation of the tryptophan and kynurenine pathway might be involved in the pathophysiological process of various immune-related diseases, such as inflammatory bowel disease, cardiovascular disease, osteoporosis, and/or polycystic ovary syndrome. Interestingly, kynurenine metabolites may be involved in the brain memory system and/or intricate immunity via the modulation of glial function. In the further deliberation of this concept with engram, the roles of gut microbiota could lead to the development of remarkable treatments for the prevention of and/or the therapeutics for various intractable immune-related diseases.

Postprandial hyperglycemia is a risk factor not only for diabetes mellitus, but also arteriosclerosis. Therefore, controlling the rapid postprandial increase in blood glucose levels is necessary. This study aimed to develop a mulberry leaf and water chestnut husk tea and investigate its effect on postprandial blood glucose levels. We measured the polyphenols and 1-deoxynojirimycin contents as well as antioxidant activity of mulberry leaf and water chestnut husk tea in an in vitro experiment. The effect of the tea on postprandial blood glucose levels in 30 participants with borderline diabetes was investigated in a randomized, double-blind, placebo-controlled crossover comparison study. The 1-deoxynojirimycin and total polyphenol contents in the tea (test food, 3g) were 10.2±0.8 and 61.3±1.4 mg, respectively. The test food showed higher antioxidant activity than the placebo food. Compared with those in the placebo group, blood glucose levels in the test group significantly decreased 30 and 60 min after eating rice. Additionally, insulin was significantly lower at all time points (30, 60, 90, and 120 min after rice consumption). The mulberry leaves and water chestnut mix tea may be an effective beverage to reduce insulin secretion and prevent rapid increases in blood glucose levels in patients with borderline diabetes.

The endolymphatic sac is a small sac-shaped organ at the end of the membranous labyrinth of the inner ear. The endolymphatic sac absorbs the endolymph, in which the ion balance is crucial for inner ear homeostasis. Of the three sections of the endolymphatic sac, the intermediate portion is the center of endolymph absorption, particularly sodium transport, and is thought to be regulated by aldosterone. Disorders of the endolymphatic sac may cause an excess of endolymph (endolymphatic hydrops), a histological observation in Meniere’s disease. A low-salt diet is an effective treatment for Meniere’s disease, and is based on the assumption that the absorption of endolymph in the endolymphatic sac abates endolymphatic hydrops through a physiological increase in aldosterone level. However, the molecular basis of endolymph absorption in each portion of the endolymphatic sac is largely unknown because of difficulties in gene expression analysis, resulting from its small size and intricate structure. The present study combined reverse transcription-quantitative polymerase chain reaction and laser capture microdissection techniques to analyze the difference of gene expression of the aldosterone-controlled epithelial Na+ channel, thiazide-sensitive Na+-Cl− cotransporter, and Na+, K+-ATPase genes in the three individual portions of the endolymphatic sac in a rat model. A low-salt diet increased the expression of aldosterone-controlled ion transporters, particularly in the intermediate portion of the endolymphatic sac. Our findings will contribute to the understanding of the physiological function of the endolymphatic sac and the pathophysiology of Meniere’s disease.

A intermediate multidomain state and large crystallographic tilting of 1.78° for the ( hh 0) pc planes of a (001) pc -oriented single-domain Mn-doped BiFeO 3 (BFMO) thin film were found when an electric field was applied along the [110] pc direction. The anomalous crystallographic tilting was caused by ferroelastic domain switching of the 109° domain switching. In addition, ferroelastic domain switching occurred via an intermediate multidomain state. To investigate these switching dynamics under an electric field, we used in situ fluorescent X-ray induced Kossel line pattern measurements with synchrotron radiation. In addition, in situ inverse X-ray fluorescence holography (XFH) experiments revealed that atomic displacement occurred under an applied electric field. We attributed the atomic displacement to crystallographic tilting induced by a converse piezoelectric effect. Our findings provide important insights for the design of piezoelectric and ferroelectric materials and devices.