Axotomy-induced synaptic stripping modulates survival and axon regeneration of injured motoneurons. Celsr2 is supposed to mediate homophilic interactions of neighboring cells during development, and its role in synaptic stripping remains unknow. In a model of brachial plexus avulsion, Celsr2 knockout improved functional recovery, motoneuron survival, and axon regeneration. Celsr2 was indicated to express in spinal motoneurons, excitatory and inhibitory interneurons, astrocytes, and a subset of oligodendrocytes using Celsr2LacZ mice. Double immunostaining showed that the coverage of inhibitory and excitatory vesicles on injured motoneurons were remarkably reduced after injury, whereas more inhibitory vesicles were maintained in Celsr2-/- mutants than control mice. In the ultrastructure, the density of inhibitory F-boutons on injured motoneurons was higher in Celsr2-/- mutants than controls. Conditional knockout of Celsr2 in astrocytes or oligodendrocytes showed the similar axotomy-induced synaptic withdrawal to the control. RNAseq of injured spinal samples identified 12 MHC I molecules with significant changes between Celsr2-/- and control mice. After injury, expression of MHC I surrounding injured motoneurons was increased, particularly high in Celsr2-/- mutants. In conclusion, Celsr2 knockout enhances MHC I signaling, alleviates inhibitory synaptic stripping cell-autonomously, and contributes to motoneuron survival and regeneration, and Celsr2 is a potential target for neural repair.

The aggregation of TAR DNA binding protein 43 kDa (TDP-43) is related to different neurodegenerative diseases, which leads to microglial activation and neuronal loss. The molecular mechanism driving neuronal death by reactive microglia, however, has not been completely resolved. In this study, we generated a mouse model by overexpressing mutant human TDP-43 (M337V) in the primary motor cortex, leading to prominent motor-learning deficits. In vivo 2-photon imaging shows an active approach of microglia toward parvalbumin interneurons, resulting in disrupted cortical excitatory-inhibitory balance. Proteomics studies suggest that activation of the complement pathway induces microglial activity. To develop an early interventional strategy, treadmill exercise successfully prevents the deterioration of motor dysfunction under enhanced adipocytic release of clusterin to block the complement pathway. These results demonstrate a previously unrecognized pathway by which TDP-43 induces cortical deficits and provide additional insights for the mechanistic explanation of exercise training in disease intervention.

Innate social investigation behaviors are critical for animal survival and are regulated by both neural circuits and neuroendocrine factors. Our understanding of how neuropeptides regulate social interest, however, is incomplete at the current stage. In this study, we identified the expression of secretin (SCT) in a subpopulation of excitatory neurons in the basolateral amygdala. With distinct molecular and physiological features, BLASCT+ cells projected to the medial prefrontal cortex and were necessary and sufficient for promoting social investigation behaviors, whilst other basolateral amygdala neurons were anxiogenic and antagonized social behaviors. Moreover, the exogenous application of secretin effectively promoted social interest in both healthy and autism spectrum disorder model mice. These results collectively demonstrate a previously unrecognized group of amygdala neurons for mediating social behaviors and suggest promising strategies for social deficits.

Light plays an essential role in psychobiological and psychophysiological processes, such as alertness. The alerting effect is influenced by light characteristics and the timing of interventions. This meta-analysis is the first to systematically review the effect of light intervention on alertness and to discuss the optimal protocol for light intervention. In this meta-analysis, registered at PROSPERO (Registration ID: CRD42020181485), we conducted a systematic search of the Web of Science, PubMed, and PsycINFO databases for studies published in English prior to August 2021. The outcomes included both subjective and objective alertness. Subgroup analyses considered a variety of factors, such as wavelength, correlated color temperature (CCT), light illuminance, and timing of interventions (daytime, night-time, or all day). Twenty-seven crossover studies and two parallel-group studies were included in this meta-analysis, with a total of 1210 healthy participants (636 (52%) male, mean age 25.62 years). The results revealed that light intervention had a positive effect on both subjective alertness (standardized mean difference (SMD) = -0.28, 95% confidence interval (CI): -0.49 to -0.06, P = 0.01) and objective alertness in healthy subjects (SMD = -0.34, 95% CI: -0.68 to -0.01, P = 0.04). The subgroup analysis revealed that cold light was better than warm light in improving subjective alertness (SMD = -0.37, 95% CI: -0.65 to -0.10, P = 0.007, I2 = 26%) and objective alertness (SMD = -0.36, 95% CI: -0.66 to -0.07, P = 0.02, I2 = 0). Both daytime (SMD = -0.22, 95% CI: -0.37 to -0.07, P = 0.005, I2 = 74%) and night-time (SMD = -0.32, 95% CI: -0.61 to -0.02, P = 0.04, I2 = 0) light exposure improved subjective alertness. The results of this meta-analysis and systematic review indicate that light exposure is associated with significant improvement in subjective and objective alertness. In addition, light exposure with a higher CCT was more effective in improving alertness than light exposure with a lower CCT. Our results also suggest that both daytime and night-time light exposure can improve subjective alertness.

Acupuncture is a medical treatment that has been widely practiced in China for over 3000 years, yet the neural mechanisms of acupuncture are not fully understood. We hypothesized that neurons and astrocytes act independently and synergistically under acupuncture stimulation. To investigate this, we used two-photon in vivo calcium recording to observe the effects of acupuncture stimulation at ST36 (Zusanli) in mice. Acupuncture stimulation in peripheral acupoints potentiated calcium signals of pyramidal neurons and astrocytes in the somatosensory cortex and resulted in late-onset calcium transients in astrocytes. Chemogenetic inhibition of neurons augmented the astrocytic activity. These findings suggest that acupuncture activates neuronal and astrocytic activity in the somatosensory cortex and provide evidence for the involvement of both neurons and astrocytes in acupuncture treatment.

Epilepsy frequently leads to cognitive dysfunction and approaches to treatment remain limited. Although regular exercise effectively improves learning and memory functions across multiple neurological diseases, its application in patients with epilepsy remains controversial. Here, we adopted a 14-day treadmill-exercise paradigm in a pilocarpine injection-induced mouse model of epilepsy. Cognitive assays confirmed the improvement of object and spatial memory after endurance training, and electrophysiological studies revealed the maintenance of hippocampal plasticity as a result of physical exercise. Investigations of the mechanisms underlying this effect revealed that exercise protected parvalbumin interneurons, probably via the suppression of neuroinflammation and improved integrity of blood-brain barrier. In summary, this work identified a previously unknown mechanism through which exercise improves cognitive rehabilitation in epilepsy.

Minimal hepatic encephalopathy (MHE) is characterized as cognitive deficits including memory and learning dysfunctions after liver injuries or hepatic diseases. Our understandings of neurological mechanisms of MHE-associated cognitive syndromes, however, are far from complete. In the current study we generated a mouse MHE model by repetitive administrations of thioacetamide (TAA), which induced hyperammonemia plus elevated proinflammatory cytokines in both the general circulation and motor cortex. MHE mice presented prominent motor learning deficits, which were associated with excess dendritic spine pruning in the motor cortex under 2-photon in vivo microscopy. The pharmaceutical blockade of glucocorticoid receptor or suppression of its biosynthesis further rescued motor learning deficits and synaptic protein loss. Moreover, MHE mice presented microglial activation, which can be alleviated after glucocorticoid pathway inhibition. In sum, our data demonstrates corticosterone-induced microglial activation, synaptic over-pruning and motor learning impairments in MHE, providing new insights for MHE pathogenesis and potential targets of clinical interventions.

Our previous studies showed that mutant mice with congenital absence of the corticospinal tract (CST) undergo spontaneous remodeling of motor networks to partially compensate for absent CST function. Here, we asked whether voluntary wheel running could further improve locomotor plasticity in CST-deficient mice. Adult mutant mice were randomly allocated to a "runners" group with free access to a wheel, or a "non-runners" group with no access to a wheel. In comparison with non-runners, there was a significant motor improvement including fine movement, grip strength, decreased footslip errors in runners after 8-week training, which was supported by the elevated amplitude of electromyography recording and increased neuromuscular junctions in the biceps. In runners, terminal ramifications of monoaminergic and rubrospinal descending axons were significantly increased in spinal segments after 12 weeks of exercise compared to non-runners. 5-ethynyl-2'-deoxyuridine (EDU) labeling showed that proliferating cells, 90% of which were Olig2-positive oligodendrocyte progenitors, were 4.8-fold more abundant in runners than in non-runners. In 8-week runners, RNAseq analysis of spinal samples identified 404 genes up-regulated and 398 genes down-regulated, and 69 differently expressed genes involved in signal transduction, among which the NF-κB, PI3K-Akt and cyclic AMP (cAMP) signaling were three top pathways. Twelve-week training induced a significant elevation of postsynaptic density protein 95 (PSD95), synaptophysin 38 and myelin basic protein (MBP), but not of brain derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and insulin like growth factor-1 (IGF-1). Thus, locomotor training activates multiple signaling pathways, contributes to neural plasticity and functional improvement, and might palliate locomotor deficits in patients.

Our group has shown that the polysaccharides extracted from Lycium barbarum (LBP) are neuroprotective for retinal ganglion cells (RGCs) in different animal models. Protecting RGCs from secondary degeneration is a promising direction for therapy in glaucoma management. The complete optic nerve transection (CONT) model can be used to study primary degeneration of RGCs, while the partial optic nerve transection (PONT) model can be used to study secondary degeneration of RGCs because primary degeneration of RGCs and secondary degeneration can be separated in location in the same retina in this model; in other situations, these types of degeneration can be difficult to distinguish. In order to examine which kind of degeneration LBP could delay, both CONT and PONT models were used in this study. Rats were fed with LBP or vehicle daily from 7 days before surgery until sacrifice at different time-points and the surviving numbers of RGCs were evaluated. The expression of several proteins related to inflammation, oxidative stress, and the c-jun N-terminal kinase (JNK) pathways were detected with Western-blot analysis. LBP did not delay primary degeneration of RGCs after either CONT or PONT, but it did delay secondary degeneration of RGCs after PONT. We found that LBP appeared to exert these protective effects by inhibiting oxidative stress and the JNK/c-jun pathway and by transiently increasing production of insulin-like growth factor-1 (IGF-1). This study suggests that LBP can delay secondary degeneration of RGCs and this effect may be linked to inhibition of oxidative stress and the JNK/c-jun pathway in the retina.

Lycium barbarum polysaccharides (LBP) are major bioactive constituents of wolfberry which possess several pharmacological effects such as antioxidant and immunomodulatory activities. We aimed to evaluate how LBP attenuated the hepatic injury in a non-alcoholic steatohepatitis (NASH) methionine-choline deficient (MCD) mouse model. NASH was induced in C57BL/6N mice by feeding with MCD diet for 6 weeks. During the experiments, 1 mg/kg LBP was intragastrically fed on a daily basis with or without MCD diet lasting from the 4th to 6th week. Control and vehicle-control (LBP + PBS) were fed with a regular animal chow. LBP significantly ameliorated NASH-induced injuries, including the increase of serum ALT and AST levels, hepatic oxidative stress, fibrosis, inflammation, and apoptosis. The hepatoprotective effects of LBP were accompanied by the attenuation of thioredoxin interacting protein, nod-like receptor protein 3/6 (NLRP3/6) and reduced NF-κB (nuclear factor-kappa B) activity. Vehicle LBP fed mice showed no adverse effect on the liver. In conclusion, the suppression of the NLRP3/6 inflammasome pathway and NF-κB activation may partly contribute to the reduction of the hepatic injury during the progression of NASH by therapeutic LBP treatment.

Neurobiological investigation of heroin revealed that abusers of this highly addictive substance show dysregulation in brain circuits for reward processing and cognitive control. Psychologically, personality traits related to reward processing and cognitive control differed between heroin abusers and non-abusers. Yet, there is no direct evidence on the relationship between these neurobiological and psychological findings on heroin abusers, and whether such relationship is altered in these abusers. The present study filled this research gap by integrating findings obtained via magnetic resonance imaging (structural volume and resting-state functional connectivity) and self-reported personality trait measures (Zuckerman׳s Sensation Seeking Scale and Barratt Impulsivity Scale) on 33 abstinent heroin users and 30 matched healthy controls. The key finding is a negative relationship between high sensation seeking tendency and midbrain structural volume in the heroin users. Importantly, there was stronger coupling between the midbrain and ventromedial prefrontal cortex and weaker coupling between the midbrain and dorsolateral prefrontal cortex in heroin users. Our findings offer significant insight into the neural underpinning of sensation seeking in heroin users. Importantly, the data shed light on a novel relationship between the mesolimbic-prefrontal pathway of the reward system and the high sensation seeking personality trait in heroin abusers.

Systemic Lupus Erythematosus (SLE) is an autoimmune disease which is characterised by elevated levels of autoantibodies and cytokines in the body. Via alteration of the regulation of inflammation, damage to different organ systems, including the central nervous system (CNS), was found in SLE patients. Patients diagnosed with SLE were reported to suffer from different kinds of psychiatric signs and symptoms. As neurogenesis has been suggested to be a potential key player of psychiatric symptoms and emotional behavior disturbances, this study aims to investigate whether neurogenesis is altered in an animal model of SLE. Also, neuroinflammation was studied.

Despite the obvious clinical interest, our understanding of how developmental mechanisms are redeployed during degeneration and regeneration after brain and spinal cord injuries remains quite rudimentary. In animal models of spinal cord injury, although spontaneous regeneration of descending axons is limited, compensation by intact corticospinal axons, descending tracts from the brainstem, and local intrinsic spinal networks all contribute to the recovery of motor function. Here, we investigated spontaneous motor compensation and plasticity that occur in the absence of corticospinal tract, using Celsr3|Emx1 mice in which the corticospinal tract is completely and specifically absent as a consequence of Celsr3 inactivation in the cortex. Mutant mice had no paresis, but displayed hyperactivity in open-field, and a reduction in skilled movements in food pellet manipulation tests. The number of spinal motoneurons was reduced and their terminal arbors at neuromuscular junctions were atrophic, which was reflected in electromyography deficits. Rubrospinal projections, calretinin-positive propriospinal projections, afferent innervation of motoneurons by calretinin-positive segmental interneurons, and terminal ramifications of monoaminergic projections were significantly increased. Contrary to control animals, mutants also developed a severe and persistent disability of forelimb use following the section of the rubrospinal tract at the C4 spinal level. These observations demonstrate for the first time that the congenital absence of the corticospinal tract induces spontaneous plasticity, both at the level of the motor spinal cord and in descending monoaminergic and rubrospinal projections. Such compensatory mechanisms could be recruited in case of brain or spinal cord lesion or degeneration.

Induced pluripotent stem cells (iPSCs) hold promise for the treatment of motoneuron diseases because of their distinct features including pluripotency, self-derivation and potential ability to differentiate into motoneurons. However, it is still unknown whether human iPSC-derived motoneurons can functionally innervate target muscles in vivo, which is the definitive sign of successful cell therapy for motoneuron diseases. In the present study, we demonstrated that human iPSCs derived from mesenchymal cells of the umbilical cord possessed a high yield in neural differentiation. Using a chemically-defined in vitro system, human iPSCs efficiently differentiated into motoneurons which displayed typical morphology, expressed specific molecules, and generated repetitive trains of action potentials. When transplanted into the injured musculocutaneous nerve of rats, they survived robustly, extended axons along the nerve, and formed functional connections with the target muscle (biceps brachii), thereby protecting the muscle from atrophy. Our study provides evidence for the first time that human iPSC-derived motoneurons are truly functional not only in vitro but also in vivo, and they have potential for stem cell-based therapies for motoneuron diseases.

Hemangioendothelioma (HE) is a type of angiomatous lesions that features endothelial cell proliferation. Understanding the mechanisms orchestrating HE angiogenesis can provide therapeutic insights. It has been shown that platelets can support normal and malignant endothelial cells during angiogenesis. Using the mouse endothelial-derived EOMA cell line as a model of HE, we explored the regulatory effect of platelets. We found that platelets stimulated EOMA proliferation but did not mitigate apoptosis. Furthermore, direct platelet-EOMA cell contact was required and the proliferation was mediated via integrin β3/Akt signaling in EOMA cells. SiRNA knockdown of integrin β3 and inhibition of Akt activity significantly abolished platelet-induced EOMA cell proliferation in vitro and tumor development in vivo. These results provide a new mechanism by which platelets support HE progression and suggest integrin β3 as a potential target to treat HE.

Rapidly approaching objects indicating threats can induce defensive response through activating a subcortical pathway comprising superior colliculus (SC), lateral posterior nucleus (LP), and basolateral amygdala (BLA). Abnormal defensive response has been reported in autism, and impaired synaptic connections could be the underlying mechanism. Whether the SC-LP-BLA pathway processes looming stimuli abnormally in autism is not clear. Here, we found that looming-evoked defensive response is impaired in a subgroup of the valproic acid (VPA) mouse model of autism. By combining the conventional neurotracer and transneuronal rabies virus tracing techniques, we demonstrated that synaptic connections in the SC-LP-BLA pathway were abnormal in VPA mice whose looming-evoked defensive responses were absent. Importantly, we further translated the finding to children with autism and observed that they did not present looming-evoked defensive response. Furthermore, the findings of the DTI with the probabilistic tractography showed that the structural connections of SC-pulvinar-amygdala in autism children were weak. The pulvinar is parallel to the LP in a mouse. Because looming-evoked defensive response is innate in humans and emerges much earlier than do social and language functions, the absence of defensive response could be an earlier sign of autism in children.

Animals promote their survival by avoiding rapidly approaching objects that indicate threats. In mice, looming-evoked defensive responses are triggered by the superior colliculus (SC) which receives direct retinal inputs. However, the specific neural circuits that begin in the retina and mediate this important behaviour remain unclear. Here we identify a subset of retinal ganglion cells (RGCs) that controls mouse looming-evoked defensive responses through axonal collaterals to the dorsal raphe nucleus (DRN) and SC. Looming signals transmitted by DRN-projecting RGCs activate DRN GABAergic neurons that in turn inhibit serotoninergic neurons. Moreover, activation of DRN serotoninergic neurons reduces looming-evoked defensive behaviours. Thus, a dedicated population of RGCs signals rapidly approaching visual threats and their input to the DRN controls a serotonergic self-gating mechanism that regulates innate defensive responses. Our study provides new insights into how the DRN and SC work in concert to extract and translate visual threats into defensive behavioural responses.

The severe shortage of donor liver organs requires the development of alternative methods to provide transplantable liver tissues such as stem cell-derived organoids. Despite several studies describing the generation of vascularized and functional liver tissues, none have succeeded in assembling human liver buds containing hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs). Here, we report a reproducible, easy-to-follow, and comprehensive self-assembly protocol to generate three-dimensional (3D) human liver buds from naïve mesenchymal stem cells (MSCs), MSC-derived hepatocytes, and HSC- and LSEC-like cells. By optimizing the ratio between these different cell lineages, the cell mixture self-assembled into 3D human liver buds within 72 h in vitro, and exhibited similar characteristics with early-stage murine liver buds. In a murine model of acute liver failure, the mesenteric transplantation of self-assembled human liver buds effectively rescued animal death, and triggered hepatic ameliorative effects that were better than the ones observed after splenic transplantation of human hepatocytes or naïve MSCs. In addition, transplanted human liver buds underwent maturation during injury alleviation, after which they exhibited a gene expression profile signature similar to the one of adult human livers. Collectively, our protocol provides a promising new approach for the in vitro construction of functional 3D human liver buds from multiple human MSC-derived hepatic cell lineages; this new technique would be useful for clinical transplantation and regenerative medicine research.

Our past researches suggested that L. barbarum exhibits direct neuroprotective and immune regulatory effects on the central nervous system, which are highly related to the events involved in the spinal cord injury, but not yet been investigated. Immune responses play an important role in the development of the pathology after secondary injury, particularly the M1 and M2 types of macrophage, on which special emphasis was laid in this study.

The active component of Wolfberry (Lycium barbarum), lycium barbarum polysaccharides (LBP), has been shown to be neuroprotective to retinal ganglion cells (RGCs) against ocular hypertension (OH). Aiming to study whether this neuroprotection is mediated via modulating immune cells in the retina, we used multiphoton confocal microscopy to investigate morphological changes of microglia in whole-mounted retinas. Retinas under OH displayed slightly activated microglia. One to 100 mg/kg LBP exerted the best neuroprotection and elicited moderately activated microglia in the inner retina with ramified appearance but thicker and focally enlarged processes. Intravitreous injection of bacterial endotoxin lipopolysaccharide (LPS) decreased the survival of RGCs at 4 weeks, and the activated microglia exhibited amoeboid appearance as fully activated phenotype. When activation of microglia was attenuated by intravitreous injection of macrophage/microglia inhibitory factor, protective effect of 10 mg/kg LBP was attenuated. The results implicated that neuroprotective effects of LBP were partly due to modulating the activation of microglia.[This corrects the article on p. in vol. .].