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Auditory experience drives neural circuit refinement during windows of heightened brain plasticity, but little is known about the genetic regulation of this developmental process. The primary auditory cortex (A1) of mice exhibits a critical period for thalamocortical connectivity between postnatal days P12 and P15, during which tone exposure alters the tonotopic topography of A1. We hypothesized that a coordinated, multicellular transcriptional program governs this window for patterning of the auditory cortex. To generate a robust multicellular map of gene expression, we performed droplet-based, single-nucleus RNA sequencing (snRNA-seq) of A1 across three developmental time points (P10, P15, and P20) spanning the tonotopic critical period. We also tone-reared mice (7 kHz pips) during the 3-d critical period and collected A1 at P15 and P20. We identified and profiled both neuronal (glutamatergic and GABAergic) and nonneuronal (oligodendrocytes, microglia, astrocytes, and endothelial) cell types. By comparing normal- and tone-reared mice, we found hundreds of genes across cell types showing altered expression as a result of sensory manipulation during the critical period. Functional voltage-sensitive dye imaging confirmed GABA circuit function determines critical period onset, while Nogo receptor signaling is required for its closure. We further uncovered previously unknown effects of developmental tone exposure on trajectories of gene expression in interneurons, as well as candidate genes that might execute tonotopic plasticity. Our single-nucleus transcriptomic resource of developing auditory cortex is thus a powerful discovery platform with which to identify mediators of tonotopic plasticity.

We have previously reported evidence that Nogo-A activation of Nogo-receptor 1 (NgR1) can drive axonal dystrophy during the neurological progression of experimental autoimmune encephalomyelitis (EAE). However, the B-cell activating factor (BAFF/BlyS) may also be an important ligand of NgR during neuroinflammation. In the current study we define that NgR1 and its homologs may contribute to immune cell signaling during EAE. Meningeal B-cells expressing NgR1 and NgR3 were identified within the lumbosacral spinal cords of ngr1 +/+ EAE-induced mice at clinical score 1. Furthermore, increased secretion of immunoglobulins that bound to central nervous system myelin were shown to be generated from isolated NgR1- and NgR3-expressing B-cells of ngr1 +/+ EAE-induced mice. In vitro BAFF stimulation of NgR1- and NgR3-expressing B cells, directed them into the cell cycle DNA synthesis phase. However, when we antagonized BAFF signaling by co-incubation with recombinant BAFF-R, NgR1-Fc, or NgR3 peptides, the B cells remained in the G0/G1 phase. The data suggest that B cells express NgR1 and NgR3 during EAE, being localized to infiltrates of the meninges and that their regulation is governed by BAFF signaling.

Objective: This study systematically investigated the effects and molecular mechanisms of Baishaoluoshi Decoction (BD) on synaptic plasticity in rats with post‐stroke spasticity (PSS). Methods A rat model of PSS was established using middle cerebral artery occlusion. Behavioral assessments, including modified neurological severity scores, rotarod tests, and the Modified Ashworth Scale, were employed. Synaptic ultrastructure was analyzed using transmission electron microscopy (TEM). The molecular mechanisms were explored using immunofluorescence and western blot analyses to evaluate protein expression (Nogo‐A, Nogo receptor (NgR), RhoA, Collapsin Response Mediator Protein 2 (CRMP2), and AGG) and NgR/Olig2 colocalization. BD was also tested in combination with the NgR antagonist NEP1‐40. Results BD significantly ameliorated the neurological deficits, prolonged rotarod fall latency, and reduced spasticity. TEM revealed that BD restored the synaptic ultrastructure in the peri‐infarct regions by increasing postsynaptic density (PSD) thickness and length, and narrowing synaptic clefts. BD downregulates synaptic‐plasticity‐related proteins (Nogo‐A, NgR, RhoA, AGG, and CRMP2) and attenuates oligodendrocyte‐mediated inhibitory signaling via reduced NgR/Olig2 co‐localization. BD combined with NEP1‐40 exhibits synergistic therapeutic efficacy. Conclusion BD alleviates PSS by enhancing synaptic plasticity and suppressing inhibitory signaling through multitarget modulation of neuron–glia interactions. These findings highlight BD as a promising therapeutic intervention for PSS, which is supported by molecular evidence of its effects on synaptic remodeling and functional recovery. Baishaoluoshi Decoction alleviates post‐stroke spasticity by downregulating inhibitory proteins (Nogo‐A/NgR) in the peri‐infarct brain region and reducing NgR/Olig2 co‐localization in oligodendrocytes, thereby enhancing synaptic plasticity.

Nogo-66 receptor 1 (NgR1) binds a variety of structurally dissimilar ligands in the adult central nervous system to inhibit axon extension. Disruption of ligand binding to NgR1 and subsequent signaling can improve neuron outgrowth, making NgR1 an important therapeutic target for diverse neurological conditions such as spinal crush injuries and Alzheimer’s disease. Human NgR1 serves as a receptor for mammalian orthoreovirus (reovirus), but the mechanism of virus–receptor engagement is unknown. To elucidate how NgR1 mediates cell binding and entry of reovirus, we defined the affinity of interaction between virus and receptor, determined the structure of the virus–receptor complex, and identified residues in the receptor required for virus binding and infection. These studies revealed that central NgR1 surfaces form a bridge between two copies of viral capsid protein σ3, establishing that σ3 serves as a receptor ligand for reovirus. This unusual binding interface produces high-avidity interactions between virus and receptor to prime early entry steps. These studies refine models of reovirus cell-attachment and highlight the evolution of viruses to engage multiple receptors using distinct capsid components.

Background Nogo-A and its putative receptor NgR are considered to be among the inhibitors of axonal regeneration in the CNS. However, few studies so far have addressed the issue of local NgR complex multilateral localization within inflammation in an MS mouse model of autoimmune demyelination. Methods Chronic experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice. Analyses were performed on acute (days 18–22) and chronic (day 50) time points and compared to controls. The temporal and spatial expression of the Nogo receptor complex (NgR and coreceptors) was studied at the spinal cord using epifluorescent and confocal microscopy or real-time PCR. Data are expressed as cells/mm 2 , as mean % ± SEM, or as arbitrary units of integrated density. Results Animals developed a moderate to severe EAE without mortality, followed by a progressive, chronic clinical course. NgR complex spatial expression varied during the main time points of EAE. NgR with coreceptors LINGO-1 and TROY was increased in the spinal cord in the acute phase whereas LINGO-1 and p75 signal seemed to be dominant in the chronic phase, respectively. NgR was detected on gray matter NeuN + neurons of the spinal cord, within the white matter inflammatory foci (14.2 ± 4.3 % NgR + inflammatory cells), and found to be colocalized with GAP-43 + axonal growth cones while no β-TubIII + , SMI-32 + , or APP + axons were found as NgR + . Among the NgR + inflammatory cells, 75.6 ± 9.0 % were microglial/macrophages (lectin + ), 49.6 ± 14.2 % expressed CD68 (phagocytic ED1 + cells), and no cells were Mac-3 + . Of these macrophages/monocytes, only Arginase-1 + /NgR + but not iNOS + /NgR + were present in lesions both in acute and chronic phases. Conclusions Our data describe in detail the expression of the Nogo receptor complex within the autoimmune inflammatory foci and suggest a possible immune action for NgR apart from the established inhibitory one on axonal growth. Its expression by inflammatory macrophages/monocytes could signify a possible role of these cells on axonal guidance and clearance of the lesioned area during inflammatory demyelination.

Nogo receptor-1 (NgR1) and its ligands inhibit neuronal plasticity and limit functional recovery after brain damage such as ischemic stroke. We have previously shown that lateral olfactory tract usher substance (LOTUS) antagonizes NgR1-mediated signaling. Here, we investigated whether LOTUS enhances neuronal plasticity and functional recovery after brain focal ischemia in adult mice. Focal ischemic infarcts were induced in wild-type and LOTUS-overexpressing transgenic mice via middle cerebral artery occlusion. Endogenous LOTUS expression was increased in brain and cervical spinal cord of the contralateral side of ischemia in the chronic phase after brain ischemia. LOTUS overexpression accelerated midline-crossing axonal sprouting from the contralateral side to the ipsilateral side of ischemia in the medullar reticular formation and gray matter of denervated cervical spinal cord. Importantly, LOTUS overexpression improved neurological score highly correlated with laterality ratio of corticoreticular fibers of the medulla oblongata, indicating that LOTUS overexpression may overcome the inhibitory environment induced by NgR1 signaling for damaged motor pathway reconstruction after ischemic stroke. Thus, our data suggest that LOTUS overexpression accelerates neuronal plasticity in the brainstem and cervical spinal cord after stroke and LOTUS administration is useful for future therapeutic strategies.

Background Alzheimer’s disease is characterized by progressive accumulation of β-amyloid (Aβ)-containing amyloid plaques, and microglia play a critical role in internalization and degradation of Aβ. Our previous research confirmed that Nogo-66 binding to Nogo receptors (NgR) expressed on microglia inhibits cell adhesion and migration in vitro. Methods The adhesion and migration of microglia isolated from WT and APP/PS1 mice from different ages were measured by adhesion assays and transwells. After NEP1-40 (a competitive antagonist of Nogo/NgR pathway) was intracerebroventricularly administered via mini-osmotic pumps for 2 months in APP/PS1 transgenic mice, microglial recruitment toward Aβ deposits and CD36 expression were determined. Results In this paper, we found that aging led to a reduction of microglia adhesion and migration to fAβ 1–42 in WT and APP/PS1 mice. The adhesion and migration of microglia to fAβ 1–42 were downregulated by the Nogo, which was mediated by NgR, and the increased inhibitory effects of the Nogo could be observed in aged mice. Moreover, Rho GTPases contributed to the effects of the Nogo on adhesion and migration of microglia to fAβ 1–42 by regulating cytoskeleton arrangement. Furthermore, blocking the Nogo/NgR pathway enhanced recruitment of microglia toward Aβ deposits and expression of CD36 in APP/PS1 mice. Conclusion Taken together, Nogo/NgR pathway could take part in Aβ pathology in AD by modulating microglial adhesion and migration to Aβ and the Nogo/NgR pathway might be an important target for treating AD.

The aim of this study was to evaluate the neuroprotective effect of tanshinone IIA (TSA) on focal cerebral ischemia in rats and to investigate whether it was associated with Nogo-A/NgR1/RhoA/Rho-associated protein kinase 2 (ROCKII)/myosin light chain (MLC) signaling. In this study, focal cerebral ischemia animal model was used. Neurological deficit scores and infarction volume were investigated to evaluate the neuroprotection of TSA. Hematoxylin-eosin staining, Nissl staining, and immunofluorescence staining were conducted to detect ischemic changes in brain tissue and changes in neurofilament protein 200 (NF200) and growth-associated protein-43 (GAP-43) expression, respectively. Western blotting and qRT-PCR analyses were used to detect the expression levels of NF200, GAP-43 and Nogo-A/NgR1/RhoA/ROCKII/MLC pathway-related signaling molecules. TSA treatment can improve the survival rate of rats, reduce the neurological score and infarct volume, and reduce neuron damage. In addition, TSA also increased axon length and enhanced expression of NF200 and GAP-43. Importantly, TSA significantly attenuated the expression of Nogo-A, NgR1, RhoA, ROCKII, and p-MLC, and thus inhibiting the activation of this signaling pathway. TSA promoted axonal regeneration by inhibiting the Nogo-A/NgR1/RhoA/ROCKII/MLC signaling pathway, thereby exerting neuroprotective effects in cerebral ischemia rats, which provided support for the clinical application of TSA in stroke treatment.

BAI1, BAI2, and BAI3 (for ‘Brain-specific Angiogenesis Inhibitor-1, -2, and -3’) are adhesion-GPCRs implicated in neuronal development. The precise roles of individual BAIs remain unclear. BAIs interact with two sets of ligands, secreted C1ql proteins and membrane-bound RTN4R proteins (a.k.a. NoGo receptors), but which of these ligands regulate specific functions of BAIs is incompletely understood. To address these key questions, we here systematically examine the functions of the three BAIs in neuronal development using hippocampal neuron-glia cultures, genetic knockouts, and rescue experiments. In a direct comparison, we demonstrate that deletions of BAI1 or BAI3, but not of BAI2, increase axonal and dendritic arborizations but decrease excitatory synapse formation, while inhibitory synapse formation remains unaffected. Since biochemical and cellular assays reveal that only BAI3 binds to both RTN4Rs and C1qls, we analyzed the role of these two ligands in controlling BAI3 functions using rescue experiments. We find that RTN4R-binding to BAI3 is essential for restricting axonal and dendritic arborizations and for enabling excitatory synapse formation, whereas C1ql-binding to BAI3 is only required for synapse organization as monitored in hippocampal neuron-glia cultures. Thus, BAI1 and BAI3 perform diverse functions that shape multiple facets of neuronal development and that require their interaction with RTN4Rs. This study shows that the deletions of BAI1 and BAI3, but not of BAI2, enhance axonal and dendritic growth while reducing excitatory synapse formation in murine mixed neuron-glia cultures. BAI3's interaction with specific ligands is crucial for these processes, highlighting its key role in neuronal development.

The recovery process from traumatic brain injury (TBI) is significantly impeded by inhibitors such as Nogo-A, myelin associated glycoprotein, and oligodendrocyte myelin glycoprotein, which exert an impact on the regeneration and repair of neuronal axons through their binding to Nogo-66 receptor 1 (NgR1). Recent research findings have revealed that NgR1 signaling may play a pivotal role in various seizure mechanisms, including the regulation of synaptic plasticity and migration of neural precursor cells. In this study, wild type (WT) and NgR1 knockout (KO) mice were utilized to establish craniocerebral injury models, while pentylenetetrazol (PTZ) was employed to induce seizures in both groups of mice following TBI. The results revealed that NgR1 KO mice exhibited heightened levels of neuronal electrical activity, along with elevated seizure scores compared to WT controls. Immunofluorescence staining demonstrated an increase in the number of excitatory synapses (P <  0.001) and a decrease in inhibitory synaptic density (P <  0.001) in NgR1 KO mice. Furthermore, the NgR1 KO model mice also displayed an augmentation in the number of presynaptic vesicles (P <  0.001), a narrowing of the synaptic gap (P <  0.001), and an elongation of the synaptic active region (P <  0.001). Our findings have demonstrated that in the previous single cognition of NgR1 inhibition in nerve function repair following TBI, revealing the potential risks associated with inhibiting NgR1 activity in nerve function repair following TBI, and providing a new perspective for understanding the role of NgR1 in the nervous system.