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Brain organoid technology has revolutionized the ability to model human neurodevelopment in vitro. However, current techniques remain limited by their reliance on simplified endothelial cell populations. Multi‐Region Brain Organoids (MRBOs) are engineered that integrate cerebral, mid/hindbrain, and complex endothelial organoids into one structure. Unlike earlier approaches based on isolated Human Umbilical Vein Endothelial Cells, the endothelial organoids contain diverse vascular cell types, including progenitors, mature endothelial cells, pericytes, proliferating angiogenic cells, and stromal cells. The strategy employs sequential modulation of key developmental pathways to generate individual organoids, followed by optimized fusion conditions that maintain regional identities while supporting cellular integration. Single‐nucleus RNA sequencing reveals that MRBOs develop discrete neural populations specific to each brain region alongside specialized endothelial populations that establish paracrine signaling networks. Integration analysis with human fetal brain data shows that MRBOs contribute to 80% of cellular clusters found in human fetal brain tissue (Carnegie stages 12–16). CellChat analysis identifies 13 previously uncharacterized endothelial‐neural signaling interactions. Endothelial‐derived factors are uncovered that support intermediate progenitor populations during hindbrain development, but not cerebral development, revealing a role for endothelial populations in regional brain patterning. This platform enables matching of multiple developmental regions while incorporating endothelial components, providing opportunities for studying neurodevelopmental disorders with disrupted neural‐endothelial interactions. Multi‐Region Brain Organoids combine cerebral, mid/hindbrain, and endothelial components into an advanced 3D model capturing 80% of fetal brain cellular diversity. This platform reveals essential endothelial‐neural signaling networks that maintain region‐specific intermediate progenitors during hindbrain development. With improved functional integration and early blood‐brain barrier formation, these organoids enable investigation of neurodevelopmental disorders with vascular involvement across multiple brain regions.

Introduction: Peppermint essential oil (PEO) and its main component, menthol, are used in Western and Eastern traditional medicine for their anti‐spasmodic, anti‐septic, or anti‐pruritic properties. Although topical application of PEO exhibits anti‐pruritic efficacy, the effects of PEO inhalation on itch sensation and pruritic behavior remain unclear. We aimed to determine whether PEO inhalation alleviates pruritus and itch‐responsive neural activity in the brains of mice with hapten‐induced dermatitis under acute stress conditions. Methods: Forty‐one female BALB/c mice were randomly assigned to six experimental groups. Twenty‐nine mice were subjected to oxazolone (OXA)‐induced dermatitis through an initial sensitization followed by three rounds of topical application of OXA every other day. During the final OXA application, twenty‐two mice were exposed to restraint stress for 2 h. Sixteen mice were subjected to the inhalation of 2.5% PEO. The total duration of scratching bouts and the number of c‐Fos‐positive cells in the parabrachial nucleus, central amygdala, periaqueductal gray, and ventral tegmental area were quantified. Results: PEO inhalation reduced the duration of scratching behavior induced by the combination of repeated OXA application and acute restraint stress. The c‐Fos‐positive cell number in the tested brain regions, except the ventral tegmental area, was positively correlated with the pruritic response. PEO inhalation alleviates OXA‐ or stress‐induced pruritus by modulating neuronal activity in itch‐related brain regions. Conclusion: Acute restraint stress exacerbates itch, and PEO inhalation alleviates the stress‐associated aggravation of pruritus caused by OXA‐induced dermatitis, which is associated with the modulation of neuronal activity in itch‐related brain regions. Acute restraint stress increased the total duration of scratching behavior in mice regardless of whether dermatitis is present. The number of c‐Fos‐positive cells correlated with pruritic responses. Inhalation of peppermint essential oil alleviated OXA‐induced pruritus under stress conditions and increased the number of c‐Fos‐positive cells in the itch‐responsive brain region.

Glial cell line-derived neurotrophic factor (GDNF) plays a critical role in neuronal survival and function. GDNF has two major splice variants in the brain, α-pro-GDNF and β-pro-GDNF, and both isoforms have strong neuroprotective effects on dopamine neurons. However, the expression of the GDNF splice variants in dopaminergic neurons in the brain remains unclear. Therefore, in this study, we investigated the mRNA and protein expression of α- and β-pro-GDNF in the mouse brain by real-time quantitative polymerase chain reaction, using splice variant-specific primers, and western blot analysis. At the mRNA level, β-pro-GDNF expression was significantly greater than that of α-pro-GDNF in the mouse brain. In contrast, at the protein level, α-pro-GDNF expression was markedly greater than that of β-pro-GDNF. To clarify the mechanism underlying this inverse relationship in mRNA and protein expression levels of the GDNF splice variants, we analyzed the expression of sorting protein-related receptor with A-type repeats (SorLA) by real-time quantitative polymerase chain reaction. At the mRNA level, SorLA was positively associated with β-pro-GDNF expression, but not with α-pro-GDNF expression. This suggests that the differential expression of α- and β-pro-GDNF in the mouse brain is related to SorLA expression. As a sorting protein, SorLA could contribute to the inverse relationship among the mRNA and protein levels of the GDNF isoforms. This study was approved by the Animal Ethics Committee of Xuzhou Medical University, China on July 14, 2016.

Optoelectronic neuromodulation has transformed neuroscience research and holds great promise for treating neurological disorders. However, conventional optoelectronic methods rely on ultraviolet/visible light, which poorly penetrates tissue and typically necessitates surgically implanted optical fibers for deep‐brain stimulation. Here, a heterostructure is presented that integrates near‐infrared (NIR)‐excitable upconversion nanoparticles (UCNPs) and broadband‐absorbing CsPbBr3 perovskite quantum dots (QDs). This nanostructure converts deeply penetrating 980 nm NIR light into localized electrical stimuli, enabling immediate and precise modulation of neuronal activity without implants. In vitro, NIR illumination of this heterostructure reliably increases the firing rate of wild‐type dopaminergic (DA) neurons in acute brain slices. Importantly, in vivo, transcranial NIR stimulation of the heterostructure in the secondary motor cortex (M2) and ventral tegmental area (VTA) modulates neuronal activity, triggers turning behavior, and promotes dopamine release. Moreover, it exhibits negligible neuroinflammation and structural stability in brain tissue over at least four weeks. By integrating a stable heterostructure for efficient NIR‐driven photocurrent generation, the method offers a non‐genetic, minimally invasive platform for precise neuromodulation in wild‐type animals. The Single‐Nanostructured Optoelectronic Vehicle for neuromodulation Activation (SNOVA) establishes a paradigm for non‐genetic, implant‐free neuromodulation. By integrating NIR‐excitable UCNPs with broadband‐absorbing perovskite QDs, SNOVA efficiently converts deeply penetrating light into localized electric fields that modulate neuronal ion dynamics, trigger behavioral responses, and enable precise, minimally invasive deep‐brain modulation.

Identifying the relations among different regions of the brain is vital for a better understanding of how the brain functions. While a large number of studies have investigated the neuroanatomical and neurochemical connections among brain structures, their specific findings are found in publications scattered over a large number of years and different types of publications. Text mining techniques have provided the means to extract specific types of information from a large number of publications with the aim of presenting a larger, if not necessarily an exhaustive picture. By using natural language processing techniques, the present paper aims to identify connectivity relations among brain regions in general and relations relevant to the paraventricular nucleus of the thalamus (PVT) in particular. We introduce a linguistically motivated approach based on patterns defined over the constituency and dependency parse trees of sentences. Besides the presence of a relation between a pair of brain regions, the proposed method also identifies the directionality of the relation, which enables the creation and analysis of a directional brain region connectivity graph. The approach is evaluated over the manually annotated data sets of the WhiteText Project. In addition, as a case study, the method is applied to extract and analyze the connectivity graph of PVT, which is an important brain region that is considered to influence many functions ranging from arousal, motivation, and drug-seeking behavior to attention. The results of the PVT connectivity graph show that PVT may be a new target of research in mood assessment.

Reference brains are indispensable tools in human brain mapping, enabling integration of multimodal data into an anatomically realistic standard space. Available reference brains, however, are restricted to the macroscopic scale and do not provide information on the functionally important microscopic dimension. We created an ultrahigh-resolution three-dimensional (3D) model of a human brain at nearly cellular resolution of 20 micrometers, based on the reconstruction of 7404 histological sections. \"BigBrain\" is a free, publicly available tool that provides considerable neuroanatomical insight into the human brain, thereby allowing the extraction of microscopic data for modeling and simulation. BigBrain enables testing of hypotheses on optimal path lengths between interconnected cortical regions or on spatial organization of genetic patterning, redefining the traditional neuroanatomy maps such as those of Brodmann and von Economo.

The neural circuits responsible for animal behavior remain largely unknown. We summarize new methods and present the circuitry of a large fraction of the brain of the fruit fly Drosophila melanogaster . Improved methods include new procedures to prepare, image, align, segment, find synapses in, and proofread such large data sets. We define cell types, refine computational compartments, and provide an exhaustive atlas of cell examples and types, many of them novel. We provide detailed circuits consisting of neurons and their chemical synapses for most of the central brain. We make the data public and simplify access, reducing the effort needed to answer circuit questions, and provide procedures linking the neurons defined by our analysis with genetic reagents. Biologically, we examine distributions of connection strengths, neural motifs on different scales, electrical consequences of compartmentalization, and evidence that maximizing packing density is an important criterion in the evolution of the fly’s brain. Animal brains of all sizes, from the smallest to the largest, work in broadly similar ways. Studying the brain of any one animal in depth can thus reveal the general principles behind the workings of all brains. The fruit fly Drosophila is a popular choice for such research. With about 100,000 neurons – compared to some 86 billion in humans – the fly brain is small enough to study at the level of individual cells. But it nevertheless supports a range of complex behaviors, including navigation, courtship and learning. Thanks to decades of research, scientists now have a good understanding of which parts of the fruit fly brain support particular behaviors. But exactly how they do this is often unclear. This is because previous studies showing the connections between cells only covered small areas of the brain. This is like trying to understand a novel when all you can see is a few isolated paragraphs. To solve this problem, Scheffer, Xu, Januszewski, Lu, Takemura, Hayworth, Huang, Shinomiya et al. prepared the first complete map of the entire central region of the fruit fly brain. The central brain consists of approximately 25,000 neurons and around 20 million connections. To prepare the map – or connectome – the brain was cut into very thin 8nm slices and photographed with an electron microscope. A three-dimensional map of the neurons and connections in the brain was then reconstructed from these images using machine learning algorithms. Finally, Scheffer et al. used the new connectome to obtain further insights into the circuits that support specific fruit fly behaviors. The central brain connectome is freely available online for anyone to access. When used in combination with existing methods, the map will make it easier to understand how the fly brain works, and how and why it can fail to work correctly. Many of these findings will likely apply to larger brains, including our own. In the long run, studying the fly connectome may therefore lead to a better understanding of the human brain and its disorders. Performing a similar analysis on the brain of a small mammal, by scaling up the methods here, will be a likely next step along this path.

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

Periventricular injury is frequently noted as one aspect of severe traumatic brain injury (TBI) and the presence of the ventricles has been hypothesized to be a primary pathogenesis associated with the prevalence of periventricular injury in patients with TBI. Although substantial endeavors have been made to elucidate the potential mechanism, a thorough explanation for this hypothesis appears lacking. In this study, a three-dimensional (3D) finite element (FE) model of the human head with an accurate representation of the cerebral ventricles is developed accounting for the fluid properties of the intraventricular cerebrospinal fluid (CSF) as well as its interaction with the brain. An additional model is developed by replacing the intraventricular CSF with a substitute with brain material. Both models are subjected to rotational accelerations with magnitudes suspected to induce severe diffuse axonal injury. The results reveal that the presence of the ventricles leads to increased strain in the periventricular region, providing a plausible explanation for the vulnerability of the periventricular region. In addition, the strain-exacerbation effect associated with the presence of the ventricles is also noted in the paraventricular region, although less pronounced than that in the periventricular region. The current study advances the understanding of the periventricular injury mechanism as well as the detrimental effects that the ventricles exert on the periventricular and paraventricular brain tissue.

Neurodevelopmental disorders of genetic origin delay the acquisition of normal abilities and cause disabling phenotypes. Nevertheless, spontaneous attenuation and even complete amelioration of symptoms in early childhood and adolescence can occur in many disorders, suggesting that brain circuits possess an intrinsic capacity to overcome the deficits arising from some germline mutations. We examined the molecular composition of almost a trillion excitatory synapses on a brain-wide scale between birth and adulthood in mice carrying a mutation in the homeobox transcription factor Pax6 , a neurodevelopmental disorder model. Pax6 haploinsufficiency had no impact on total synapse number at any age. By contrast, the molecular composition of excitatory synapses, the postnatal expansion of synapse diversity and the acquisition of normal synaptome architecture were delayed in all brain regions, interfering with networks and electrophysiological simulations of cognitive functions. Specific excitatory synapse types and subtypes were affected in two key developmental age-windows. These phenotypes were reversed within 2-3 weeks of onset, restoring synapse diversity and synaptome architecture to the normal developmental trajectory. Synapse subtypes with rapid protein turnover mediated the synaptome remodeling. This brain-wide capacity for remodeling of synapse molecular composition to recover and maintain the developmental trajectory of synaptome architecture may help confer resilience to neurodevelopmental genetic disorders. Brain-wide mapping of synapse molecular composition in Pax6 mutant mice shows remodelling and restoration of synaptome architecture during development, a possible means of conferring resilience to genetic disorders.