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Shenqi pill (SQP), a famous traditional Chinese medicine (TCM) herbal formula derived from Jinguiyaolue (Synopsis of Prescriptions of the Golden Chamber), has long been used to treat kidney yang deficiency syndrome. According to the TCM treatment principle that the liver and kidney are homologies, the clinical use of SQP in the treatment of nonalcoholic steatohepatitis (NASH) has achieved a good effect. However, the active targeted genes and underlying mechanism remain unclear. In this study, we aimed to explore the treatment mechanism of SQP in NASH rats, which may further contribute to the in-depth exploration of SQP in clinical applications. Network pharmacology analysis was used to screen the target genes of SQP for NASH treatment based on public databases. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and protein–protein interaction (PPI) analysis were used to search for crucial target genes and mechanisms. UPLC–MS/MS was used to verify the active compounds of the SQP screened. The hepatic pathology and biochemical indicators of rats were used to judge the modeling results and the curative effect of SQP. Western blotting and qRT–PCR were used to verify the expression of crucial target genes at the protein and RNA levels, respectively. Network pharmacology analysis and bioinformatics analysis showed that PTGS2, JUN, MYC, and CDKN1A might be crucial target genes in the primary mechanism of SQP in treating NASH and improving the inflammatory response. The UPLC–MS/MS results confirmed that the hub active compound, quercetin, screened out through the TCMSP database, is indeed present in SQP. Hepatic injury and lipid metabolism indicators of NASH rats were significantly improved after SQP treatment. The results of WB and qRT–PCR showed that the expression of PTGS2, JUN, MYC, and CDKN1A was higher in NASH rats than in normal rats and decreased after SQP treatment. The expression of inflammatory cytokines (IL-1β, IL-6, TNF-α) was reduced after SQP treatment, which confirmed that SQP could improve hepatic inflammation in rats. These results suggested that SQP could ameliorate NASH in rats, and that quercetin may be the critical active compound that exerts the therapeutic effect.

The purinergic signaling molecule adenosine (Ado) modulates many physiological and pathological functions in the brain. However, the exact source of extracellular Ado remains controversial. Here, utilizing a newly optimized genetically encoded GPCR-Activation-Based Ado fluorescent sensor (GRAB Ado ), we discovered that the neuronal activity–induced extracellular Ado elevation is due to direct Ado release from somatodendritic compartments of neurons, rather than from the axonal terminals, in the hippocampus. Pharmacological and genetic manipulations reveal that the Ado release depends on equilibrative nucleoside transporters but not the conventional vesicular release mechanisms. Compared with the fast-vesicular glutamate release, the Ado release is slow (~40 s) and requires calcium influx through L-type calcium channels. Thus, this study reveals an activity-dependent second-to-minute local Ado release from the somatodendritic compartments of neurons, potentially serving modulatory functions as a retrograde signal.

Licking behavior is important for water intake. The deep mesencephalic nucleus (DpMe) has been implicated in instinctive behaviors. However, whether the DpMe is involved in licking behavior and the precise neural circuit behind this behavior remains unknown. Here, we found that the activity of the DpMe decreased during water intake. Inhibition of vesicular glutamate transporter 2-positive (VGLUT2(+)) neurons in the DpMe resulted in increased water intake. Somatostatin-expressing (SST(+)), but not protein kinase C-δ-expressing (PKC-δ(+)), GABAergic neurons in the central amygdala (CeA) preferentially innervated DpMe VGLUT2(+) neurons. The SST(+) neurons in the CeA projecting to the DpMe were activated at the onset of licking behavior. Activation of these CeA SST(+) GABAergic neurons, but not PKC-δ(+) GABAergic neurons, projecting to the DpMe was sufficient to induce licking behavior and promote water intake. These findings redefine the roles of the DpMe and reveal a novel CeA(SST)–DpMe(VGLUT2) circuit that regulates licking behavior and promotes water intake. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12264-021-00817-2.

GABABreceptors in habenula cholinergic neurons mediate strong presynaptic excitation and control aversive memory expression. K+channel tetramerization domain (KCTD) proteins are key interacting partners of GABABreceptors; it remains unclear whether and how KCTDs contribute to GABABexcitatory signaling. Here, we show that KCTD8 and KCTD12 in these neurons facilitate the GABABreceptors expression in axonal terminals and contribute to presynaptic excitation by GABABreceptors. Genetically knocking outKCTD8/12/16orKCTD8/12, but not other combinations of the threeKCTDisoforms, substantially reduced GABABreceptors–mediated potentiation of glutamate release and presynaptic Ca2+entry in response to axonal stimulation, whereas they had no effect on GABAB-mediated inhibition in the somata of cholinergic neurons within the habenulo–interpeduncular pathway in mice of either sex. The physiological phenotypes were associated with a significant decrease in the GABABexpression within the axonal terminals but not the somata. Overexpressing either KCTD8 or KCTD12 in theKCTD8/12/16triple knock-out mice reversed the changes in axonal GABABexpression and presynaptic excitation. In mice lacking the KCTDs, aversion-predicting cues produced stronger neuronal activation in the interpeduncular nucleus, and the infusion of GABABagonist in this nucleus produced a weaker effect on fear extinction. Collectively, our results reveal isoform-specific roles of KCTD proteins in enriching the axonal expression of GABABreceptors, facilitating their presynaptic signaling, and modulating aversion-related memory processes.SIGNIFICANCE STATEMENTGABABreceptors represent the principal inhibitory neurotransmitter receptor, but they mediate strong presynaptic excitation in the habenulo–interpeduncular pathway and modulate aversion memory expression. KCTD proteins are integral constituents of GABABreceptors. By analyzing the physiological, neuroanatomical, and behavioral phenotypes of multiple KCTD knock-out mouse lines, we show that KCTD8 and KCTD12 facilitate the axonal expression and hence presynaptic excitation of GABABreceptors in habenula cholinergic neurons and control cued-aversion memory formation and expression in the habenulo–interpeduncular pathway. These results expand the physiological and behavioral functions of KCTDs in modulating the brain neural circuits.

Rubus chingii Hu (Chinese Raspberry), known as Fu-Pen-Zi in Chinese, a woody perennial plant of the genus Rubus in the Rosaceae family, has specific nutritional and medicinal values, which is considered food-medicine herb in China for thousands of years to treat impotence, premature ejaculation, enuresis, frequent urination, and other diseases. This review aims to summarize recent advances in the bioactive components, pharmacological effects, and drug development and utilization of Rubus chingii Hu, hoping to provide useful support for its further research and clinical application. The bioactive components in Rubus chingii Hu contain mainly terpenoids, flavonoids, alkaloids, phenolic acids, polysaccharides, and steroids. The main pharmacological effects are their anti-oxidant, anti-inflammatory, and anti-tumor capacity on human health. Rubus chingii Hu is a very valuable food-medicine herb. The development of Rubus chingii Hu–related drugs is relatively single, which is limited to traditional Chinese medicine and prescriptions. Therefore, it is vital to pay interest to Rubus chingii Hu and its bioactive components in the future and extend its scientific application.

Oxytocin (OT), a peptide hormone and neuromodulator, is involved in diverse physiological and pathophysiological processes in the central nervous system and the periphery. However, the regulation and functional sequences of spatial OT release in the brain remain poorly understood. We describe a genetically encoded G-protein-coupled receptor activation-based (GRAB) OT sensor called GRAB

Microglial abnormalities may contribute to neurodevelopmental disorders. PTEN is implicated as a susceptibility gene for autism spectrum disorders and its germline ablation in mice causes behavioral abnormalities. Here we find postnatal PTEN deletion in microglia causes deficits in sociability and novel object recognition test. Mutant mice harbor markedly more activated microglia that manifest enhanced phagocytosis. Interestingly, two-week postponement of microglia PTEN ablation leads to no social interaction defects, even though mutant microglia remain abnormal in adult animals. Disturbed neurodevelopment caused by early PTEN deletion in microglia is characterized by insufficient VGLUT1 protein in synaptosomes, likely a consequence of enhanced removal by microglia. In correlation, in vitro acute slice recordings demonstrate weakened synaptic inputs to layer 5 pyramidal neurons in the developing cortex. Therefore, microglial PTEN safeguards integrity of neural substrates underlying sociability in a developmentally determined manner.

Monosynaptic viral tracers are essential tools for dissecting neuronal connectomes and for targeted delivery of molecular sensors and effectors. Viral toxicity and complex multi-injection protocols are major limiting application barriers. To overcome these barriers, we developed an anterograde monosynaptic H129Amp tracer system based on HSV-1 strain H129. The H129Amp tracer system consists of two components: an H129-dTK-T2-pacFlox helper which assists H129Amp tracer’s propagation and transneuronal monosynaptic transmission. The shared viral features of tracer/helper allow for simultaneous single-injection and subsequent high expression efficiency from multiple-copy of expression cassettes in H129Amp tracer. These improvements of H129Amp tracer system shorten experiment duration from 28-day to 5-day for fast-bright monosynaptic tracing. The lack of toxic viral genes in the H129Amp tracer minimizes toxicity in postsynaptic neurons, thus offering the potential for functional anterograde mapping and long-term tracer delivery of genetic payloads. The H129Amp tracer system is a powerful tracing tool for revealing neuronal connectomes.

Gut microbiota (GM) dysbiosis and bile acid (BA) metabolism disorder play an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Probiotics had a beneficial effect on NAFLD, but further study is needed to explore probiotics as a potential therapeutic agent to NAFLD. The aim of this study was to investigate the regulatory effect of probiotics on gut microbiota in NAFLD rats and to explore the possible mechanism of probiotics regulating the bile acid receptor farnesoid X receptor/growth factor 15 (FXR/FGF15) signaling pathway in rats. We established a rat model of NAFLD fed with a high-fat diet (HFD) for 14 weeks, which was given different interventions (312 mg/kg/day probiotics or 10 mg/kg/day atorvastatin) from the 7th week. Serum lipids and total bile acids (TBA) were biochemically determined; hepatic steatosis and lipid accumulation were evaluated with HE staining. The expression levels of FXR, FGF15 mRNA, and protein in rat liver were detected. 16S rDNA was used to detect the changes of gut microbiota in rats. Compared with the HFD group, probiotics and atorvastatin significantly reduced serum lipids and TBA levels. And probiotics increased dramatically the expression of FXR, FGF15 mRNA, and protein in the liver. But there were no significant changes in the atorvastatin group. Probiotics and atorvastatin can upregulate the diversity of gut microbiota and downregulate the abundance of pathogenic bacteria in NAFLD model rats. In summary, probiotics alleviated NAFLD in HFD rats via the gut microbiota/FXR/FGF15 signaling pathway.

Microglial abnormalities may contribute to neurodevelopmental disorders. PTEN is implicated as a susceptibility gene for autism spectrum disorders and its germline ablation in mice causes behavioral abnormalities. Here we find postnatal PTEN deletion in microglia causes deficits in sociability and novel object recognition test. Mutant mice harbor markedly more activated microglia that manifest enhanced phagocytosis. Interestingly, two-week postponement of microglia PTEN ablation leads to no social interaction defects, even though mutant microglia remain abnormal in adult animals. Disturbed neurodevelopment caused by early PTEN deletion in microglia is characterized by insufficient VGLUT1 protein in synaptosomes, likely a consequence of enhanced removal by microglia. In correlation

Transition metal carbides show remarkable catalysis for MgH2, and the addition of carbon materials can attach excellent cycling stability. In this paper, Mg-doped with transition metal carbides (TiC) and graphene (G) composite (denoted as Mg–TiC–G) is designed to assess the influence of TiC and graphene on the hydrogen storage performance of MgH2. The as-prepared Mg–TiC–G samples showed favorable dehydrogenation kinetics compared to the pristine Mg system. After adding TiC and graphene, the dehydrogenation activation energy of MgH2 decreases from 128.4 to 111.2 kJ mol−1. The peak desorption temperature of MgH2 doped with TiC and graphene is 326.5 °C, which is 26.3 °C lower than the pure Mg. The improved dehydrogenation performance of Mg–TiC–G composites is attributed to synergistic effects between catalysis and confinement.

Alterations in internal states, such as elevated arousal level and increased anxiety or fear, triggered by alerting environmental cues are required for behavioral state transitions promoting survival. However, the specific brain region that plays an interfacing role between alerting stimuli and internal states remains to be identified. Here, we report that the medial sector of the auditory thalamus (ATm), which consists of a group of non-lemniscal thalamic nuclei, can fulfill this function. VGluT2-expressing ATm (ATmVGluT2+) neurons receive direct and strong inputs from both visual and auditory midbrain regions, and project to multiple downstream structures critically involved in brain state regulation. Their activity was correlated with, and indispensable for, both blue light- and sound-induced NREM sleep-to-Wake transition, and their arousing effects were mainly mediated by, but not limited to, the temporal association cortices. ATmVGluT2+ neuron activation in awake behaving mice induced pupil dilation and behavioral responses suggestive of anxiety. Blocking the neurotransmitter release of ATmVGluT2+ neurons receiving auditory inputs selectively abolished loud noise-triggered escape behavior but not locomotion. Thus, the ATm is an interface in mouse brain that can transform alerting environmental cues into internal arousal and emotional state alterations that promote survival.

The capability to selectively and precisely modulate neural activities represents a powerful tool for neuroscience research and clinical therapeutics. Traditional electrical stimulations associate with bulky and tethered implants, and optogenetic methods rely on genetic modification for cell targeting. Here, we report an optoelectronic, non-genetic strategy for exciting and inhibiting neural activities, accomplished by bioresorbable, thin-film silicon (Si) diodes. Under illumination, these devices establish polarity-dependent, positive or negative voltages at the semiconductor/solution interface. Such photovoltaic signals enable deterministic depolarization and hyperpolarization of cultured neurons, upregulating and downregulating intracellular calcium dynamics in vitro. Furthermore, flexible, thin-film Si based devices mounted on the nerve tissue selectively activate and silence in vivo activities, both in the peripheral nerve and the brain. Finally, these Si membranes naturally dissolve within the animal body. Such a Si-based material and device platform offers broad potential for biomedical applications.

A scaled plane-strain shaking table test was conducted in this study to investigate the seismic performance of a Geosynthetic Reinforced Soil-Integrated Bridge System (GRS-IBS) with a full-length bridge beam resting on two GRS abutments at opposite ends subjected to earthquake motions in the longitudinal direction. This study examined the effects of different combinations of reinforcement stiffness J and spacing Sv on the seismic performance of the GRS-IBS. Test results show that reducing the reinforcement spacing was more beneficial to minimize the seismic effect on the GRS abutment as compared to increasing the reinforcement stiffness. The seismic inertial forces acted on the top of two side GRS abutments interacted with each other through the bridge beam, which led to close peak acceleration amplitudes at the locations near the bridge beam. Overall, the GRS-IBS did not experience obvious structure failure and significant displacements during and after shaking. Shaking in the longitudinal direction of the bridge beam increased the vertical stress in the reinforced soil zone. The maximum tensile forces in the upper and lower geogrid layers due to shaking happened under the center of the beam seat and at the abutment facing respectively.

Brain-to-brain interfaces (BtBIs) hold exciting potentials for direct communication between individual brains. However, technical challenges often limit their performance in rapid information transfer. Here, we demonstrate an optical brain-to-brain interface that transmits information regarding locomotor speed from one mouse to another and allows precise, real-time control of locomotion across animals with high information transfer rate. We found that the activity of the genetically identified neuromedin B (NMB) neurons within the nucleus incertus (NI) precisely predicts and critically controls locomotor speed. By optically recording Ca2+ signals from the NI of a “Master” mouse and converting them to patterned optogenetic stimulations of the NI of an “Avatar” mouse, the BtBI directed the Avatar mice to closely mimic the locomotion of their Masters with information transfer rate about two orders of magnitude higher than previous BtBIs. These results thus provide proof-of-concept that optical BtBIs can rapidly transmit neural information and control dynamic behaviors across individuals.

G

Gq-coupled receptors regulate numerous physiological processes by activating enzymes and inducing intracellular Ca2+ signals. There is a strong need for an optogenetic tool that enables powerful experimental control over Gq signaling. Here, we present chicken opsin 5 (cOpn5) as the long sought-after, single-component optogenetic tool that mediates ultra-sensitive optical control of intracellular Gq signaling with high temporal and spatial resolution. Expressing cOpn5 in mammalian cells enables blue light-triggered, Gq-dependent Ca2+ release from intracellular stores and protein kinase C activation. Strong Ca2+ transients were evoked by brief light pulses of merely 10 ms duration and at 3 orders lower light intensity of that for common optogenetic tools. Photostimulation of cOpn5-expressing cells at the subcellular and single-cell levels generated intracellular and intercellular Ca2+ wave propagation, respectively, thus demonstrating the high spatial precision of cOpn5 optogenetics. The cOpn5-mediated optogenetics could also be applied to activate neurons and control animal behavior in a circuit-dependent manner. We further revealed that optogenetic activation of cOpn5-expressing astrocytes induced massive ATP release and modulation neuronal activation in the brain of awake, behaving mice. cOpn5 optogenetics may find broad applications in studying the mechanisms and functional relevance of Gq signaling in both non-excitable cells and excitable cells in all major organ systems.

As a peptide hormone and neuromodulator, oxytocin (OT) plays a critical role in a variety of physiological and pathophysiological processes in both the central nervous system and the periphery. However, the processes that regulate spatial OT release in the brain remain enigmatic. Here, we developed a genetically encoded GPCR activation-based (GRAB) OT sensor called GRABOT1.0. Using this sensor, we directly visualized stimulation-induced OT release from specific compartments of OT neurons in acute brain slices, and discovered that N-type calcium channels predominantly mediate axonal OT release, while L-type calcium channels mediate somatodendritic OT release. In addition, we found that components in the fusion machinery of OT release differ between axon terminals versus somata and dendrites. Finally, we demonstrated the sensor responses to the activation of OT neurons in various brain regions in vivo and revealed region specific OT release during male courtship behavior. Taken together, these results provide key insights regarding the role of compartmental OT release in the control of physiological and behavioral functions.

The ventral pallidum (VP) integrates reward signals to regulate cognitive, emotional, and motor processes associated with motivational salience. Previous studies have revealed that the VP projects axons to many cortical and subcortical structures. However, descriptions of the neuronal morphologies and projection patterns of the VP neurons at the single neuron level are lacking, thus hindering the understanding of the wiring diagram of the VP. In this study, we used recently developed progress in robust sparse labeling and fluorescence micro-optical sectioning tomography imaging system (fMOST) to label mediodorsal thalamus-projecting neurons in the VP and obtain high-resolution whole-brain imaging data. Based on these data, we reconstructed VP neurons and classified them into three types according to their fiber projection patterns. We systematically compared the axonal density in various downstream centers and analyzed the soma distribution and dendritic morphologies of the various subtypes at the single neuron level. Our study thus provides a detailed characterization of the morphological features of VP neurons, laying a foundation for exploring the neural circuit organization underlying the important behavioral functions of VP.

The brain-computer interface can create a connection between the central nervous system of a human or animal and an external device to exchange information. We designed a complete set of brain-computer interface collection components Neurochat Series, using the latest 3D printing technology and high-precision CNC to reduce the complexity of production, while ensuring the collection effect, reducing the time for electrode production. With the help of Neurochat series, the signal collection from brain waves to local field potentials and neuron spikes is realized, which is very suitable for obtaining EEG information data in animal experiments.

Geosynthetic-reinforced soil-integrated bridge system (GRS-IBS) has obtained wide popularity recently. Despite of the abundant research on the behavior of GRS-IBS under static loading, its dynamic performance has not been investigated well, especially for the whole GRS-IBS structure. In this paper, a numerical model in finite element DBLEAVES program was built to simulate the seismic response of GRS-IBS, which was based on the experimental study performed on the whole GRS-IBS with bridge beam resting on the two opposite directional abutments. The applicability and accuracy of the GRS-IBS model was verified by the measured accelerations, lateral facing displacements, and reinforcement tensile forces. Then a variable-amplitude harmonic ground motion record was adopted for relevant parameter analysis. Both experimental and numerical results showed that smaller reinforcement spacing led to smaller lateral facing displacements and tensile forces. Besides, it was found that an increase in earthquake wave frequency and bridge span would induce the increase of acceleration response, lateral facing displacement, and tensile force in reinforcement. The necessity of the whole GRS-IBS model was suggested in the related experimental studies by the significant differences of lateral facing displacement and tensile force of reinforcement among different bridge spans.

As the resident immune cells in the central nervous system (CNS), microglia orchestrate immune responses and dynamically sculpt neural circuits in the CNS. Microglial dysfunction and mutations of microglia-specific genes have been implicated in many diseases of the CNS. Developing effective and safe vehicles for transgene delivery into microglia will facilitate the studies of microglia biology and microglia-associated disease mechanisms. Here, we report the discovery of adeno-associated virus (AAV) variants that mediate efficient in vitro and in vivo microglial transduction via directed evolution of the AAV capsid protein. These AAV-cMG and AAV-MG variants are capable of delivering various genetic payloads into microglia with high efficiency, and enable sufficient transgene expression to support fluorescent labeling, Ca

Neural activities can be modulated by leveraging light-responsive nanomaterials as interfaces for exerting photothermal, photoelectrochemical or photocapacitive effects on neurons or neural tissues. Here we show that bioresorbable thin-film monocrystalline silicon pn diodes can be used to optoelectronically excite or inhibit neural activities by establishing polarity-dependent positive or negative photovoltages at the semiconductor/solution interface. Under laser illumination, the silicon-diode optoelectronic interfaces allowed for the deterministic depolarization or hyperpolarization of cultured neurons as well as the upregulated or downregulated intracellular calcium dynamics. The optoelectronic interfaces can also be mounted on nerve tissue to activate or silence neural activities in peripheral and central nervous tissues, as we show in mice with exposed sciatic nerves and somatosensory cortices. Bioresorbable silicon-based optoelectronic thin films that selectively excite or inhibit neural tissue may find advantageous biomedical applicability.

The medial prefrontal cortex (mPFC) contains populations of GABAergic interneurons that play different roles in cognition and emotion. Their local and long-range inputs are incompletely understood. We used monosynaptic rabies viral tracers in combination with fluorescence micro-optical sectioning tomography to generate a whole-brain atlas of direct long-range inputs to GABAergic interneurons in the mPFC of male mice. We discovered that three subtypes of GABAergic interneurons in two areas of the mPFC are innervated by same upstream areas. Input from subcortical upstream areas includes cholinergic neurons from the basal forebrain and serotonergic neurons (which co-release glutamate) from the raphe nuclei. Reconstruction of single-neuron morphology revealed novel substantia innominata-anteromedial thalamic nucleus-mPFC and striatum-anteromedial thalamic nucleus-mPFC circuits. Based on the projection logic of individual neurons, we classified cortical and hippocampal input neurons into several types. This atlas provides the anatomical foundation for understanding the functional organization of the mPFC.

Fiber photometry is a sensitive and easy way to detect changes in fluorescent signals. The combination of fiber photometry with various fluorescent biomarkers has substantially advanced neuroscience research over the last decade. Despite the wide use of fiber photometry in biomedical fields, the lack of a detailed and comprehensive protocol has limited progress and sometimes complicated the interpretation of data. Here, we describe detailed procedures of fiber photometry for the long-term monitoring of neuronal activity in freely-behaving animals, including surgery, apparatus setup, data collection, and analysis.

Sensorimotor transformation, a process that converts sensory stimuli into motor actions, is critical for the brain to initiate behaviors. Although the circuitry involved in sensorimotor transformation has been well delineated, the molecular logic behind this process remains poorly understood. Here, we performed high-throughput and circuit-specific single-cell transcriptomic analyses of neurons in the superior colliculus (SC), a midbrain structure implicated in early sensorimotor transformation. We found that SC neurons in distinct laminae expressed discrete marker genes. Of particular interest, Cbln2 and Pitx2 were key markers that define glutamatergic projection neurons in the optic nerve (Op) and intermediate gray (InG) layers, respectively. The Cbln2+ neurons responded to visual stimuli mimicking cruising predators, while the Pitx2+ neurons encoded prey-derived vibrissal tactile cues. By forming distinct input and output connections with other brain areas, these neuronal subtypes independently mediated behaviors of predator avoidance and prey capture. Our results reveal that, in the midbrain, sensorimotor transformation for different behaviors may be performed by separate circuit modules that are molecularly defined by distinct transcriptomic codes.

Excessive alcohol intake is a direct cause of alcoholic liver disease (ALD). ALD usually manifests as fatty liver in the initial stage and then develops into alcoholic hepatitis (ASH), fibrosis and cirrhosis. Severe alcoholism induces extensive hepatocyte death, liver failure, and even hepatocellular carcinoma (HCC). Currently, there are few effective clinical means to treat ALD, except for abstinence. Natural compounds are a class of compounds extracted from herbs with an explicit chemical structure. Several natural compounds, such as silymarin, quercetin, hesperidin, and berberine, have been shown to have curative effects on ALD without side effects. In this review, we pay particular attention to natural compounds and developing clinical drugs based on natural compounds for ALD, with the aim of providing a potential treatment for ALD.

The striatum participates in numerous important behaviors. Its principal projection neurons use GABA and peptides as neurotransmitters and interact extensively with interneurons, including cholinergic interneurons (ChIs) that are tonically active. Dissecting the interactions between projection neurons and ChIs is important for uncovering the role and mechanisms of the striatal microcircuits. Here, by combining several optogenetic tools with cell type-specific electrophysiological recordings, we uncovered direct electrical coupling between D1-type projection neurons and ChIs, in addition to the chemical transmission between these two major cell types. Optogenetic stimulation or inhibition led to bilateral current exchanges between D1 neurons and ChIs, which can be abolished by gap junction blockers. We further confirmed the presence of gap junctions through paired electrophysiological recordings and dye microinjections. Finally, we found that activating D1 neurons promotes basal activity of ChIs via gap junctions. Collectively, these results reveal the coexistence of the chemical synapse and gap junctions between D1 neurons and ChIs, which contributes to maintaining the tonically active firing patterns of ChIs.

The precise control of neural activities at both cellular and circuit levels reveals significant impacts on the fundamental neuroscience explorations and medical applications. Optogenetic methods provide efficient cell-specific modulations, and the ability of simultaneous neural activation and inhibition in the same brain region of freely moving animals is highly desirable and being actively researched. Here we report bidirectional neuronal activity manipulation accomplished by a wireless, dual-color optogenetic probe in synergy with the co-expression of two spectrally distinct opsins (ChrimsonR and stGtACR2) in a rodent model. Based on vertically assembled, thin-film microscale light-emitting diodes (micro-LEDs) with a lateral dimension of 125 × 180 µm2 on flexible substrates, the dual-color probe shows colocalized red and blue emissions and allows chronic in vivo operations with desirable biocompatibilities. In addition, we discover that neurons co-expressing the two opsins can be deterministically evoked or silenced under red or blue irradiations. Implanted in behaving mice, the wirelessly controlled dual-color probe interferes with dopaminergic neurons in the ventral tegmental area (VTA), increasing or decreasing dopamine levels with colocalized red and blue stimulations. Such bidirectional regulations further generate rewarding and aversive behaviors of freely moving mice in a place preference test and interrogate social interactions among multiple mice. The technologies established here will create numerous opportunities and profound implications for brain research.

With the continuous improvement of living standards but the lack of exercise, aging-associated metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD) are becoming a lingering dark cloud over society. Studies have found that metabolic disorders are near related to glucose, lipid metabolism, and cellular aging. Fibroblast growth factor 21 (FGF21), a member of the FGFs family, efficiently regulates the homeostasis of metabolism and cellular aging. By activating autophagy genes and improving inflammation, FGF21 indirectly delays cellular aging and directly exerts anti-aging effects by regulating aging genes. FGF21 can also regulate glucose and lipid metabolism by controlling metabolism-related genes, such as adipose triglyceride lipase (ATGL) and acetyl-CoA carboxylase (ACC1). Because FGF21 can regulate metabolism and cellular aging simultaneously, FGF21 analogs and FGF21 receptor agonists are gradually being valued and could become a treatment approach for aging-associated metabolic diseases. However, the mechanism by which FGF21 achieves curative effects is still not known. This review aims to interpret the interactive influence between FGF21, aging, and metabolic diseases and delineate the pharmacology of FGF21, providing theoretical support for further research on FGF21.

Dopamine (DA) neurons of the dorsal raphe nucleus (DRN) were traditionally viewed as an extension of the ventral tegmental area (VTA) DA population. While the VTA DA population is known to play important roles in reward processing, emerging evidence now supports the view that DRN DA neurons are a specialized midbrain DA subsystem that performs distinct functions in parallel to the VTA DA population. Recent studies have shed new light on the roles of DRN DA neurons in encoding incentive salience and in regulating memory expression and arousal. Here, we review recent findings using mouse models about the physiology and behavioral functions of DRN DA neurons, highlight the engagement of DRN DA neurons and their upstream circuits in opioid addiction, and discuss emerging lines of investigation that reveal multifaceted heterogeneity among DRN DA neurons.

The brain serotonin systems participate in numerous aspects of reward processing, although it remains elusive how exactly serotonin signals regulate neural computation and reward-related behavior. The application of optogenetics and imaging techniques during the last decade has provided many insights. Here, we review recent progress on the organization and physiology of the dorsal raphe serotonin neurons and the relationships between their activity and behavioral functions in the context of reward processing. We also discuss several interesting theories on serotonin's function and how these theories may be reconciled by the possibility that serotonin, acting in synergy with coreleased glutamate, tracks and calculates the so-called beneficialness of the current state to guide an animal's behavior in dynamic environments.

The purinergic signaling molecule adenosine (Ado) modulates many physiological and pathological brain functions,but its spatiotemporal release dynamics in the brain remains largely unknown. We developed a genetically encoded GPCR-Activation–Based Ado sensor (GRABAdo) in which Ado-induced changes in the human A2A receptor are reflected by fluorescence increases. This GRABAdo revealed that neuronal activity-induced extracellular Ado elevation was due to direct Ado release from somatodendritic regions of the neuron, requiring calcium influx through L-type calcium channels, rather than the degradation of extracellular ATP. The Ado release was slow (∼30 s) and depended on equilibrative nucleoside transporters (ENTs) rather than conventional vesicular release mechanisms. Thus, GRABAdo reveals an activity-dependent slow Ado release from somatodendritic region of the neuron, potentially serving modulating functions as a retrograde signal.

Recording and interrogating brain activities using optical methods have become emerging technologies in neuroscience. Traditional tools for optogenetic stimulation in the deep brain are mostly based on implantable fibers, imposing constraints on the animal movement. Recently developed microscale light-emitting diodes (micro-LEDs), which can be wirelessly operated, serve as injectable light sources that directly interact with neural systems. Here, we exploit a wirelessly controlled, implantable system for optogenetic studies in behaving animals. Thin-film indium gallium nitride (InGaN)-based blue micro-LEDs transferred onto flexible probes are injected into the animal brain and optically activate channelrhodopsin-2 expressing neurons. A customized circuit module with a battery is employed to modulate the micro-LED, which is remotely controlled at a distance up to 50mvia 2.4-GHz radio frequency communications. The systems are implemented on freely moving mice, and demonstrate optogenetic modulation of locomotive behaviors in vivo. Moreover, independent and synchronous control of multiple animals is accomplished with the communication unit in the design circuit. The proposed system provides the potential for advanced optical neural interfaces and offers solutions to study complicated animal behaviors in neuroscience research.

We developed a dual-adeno-associated-virus expression system that enables strong and sparse labeling of individual neurons with cell-type and projection specificity. We demonstrated its utility for whole-brain reconstruction of midbrain dopamine neurons and striatum-projecting cortical neurons. We further extended the labeling method for rapid reconstruction in cleared thick brain sections and simultaneous dual-color labeling. This labeling system may facilitate the process of generating mesoscale single-neuron projectomes of mammalian brains. An AAV-based platform achieves sparse yet bright labeling of neurons with cell-type specificity. This technology will facilitate the reconstruction of neurons in the mouse brain.

The neurotransmitter acetylcholine (ACh) regulates a diverse array of physiological processes throughout the body. Despite its importance, cholinergic transmission in the majority of tissues and organs remains poorly understood owing primarily to the limitations of available ACh-monitoring techniques. We developed a family of ACh sensors (GACh) based on G-protein-coupled receptors that has the sensitivity, specificity, signal-to-noise ratio, kinetics and photostability suitable for monitoring ACh signals in vitro and in vivo. GACh sensors were validated with transfection, viral and/or transgenic expression in a dozen types of neuronal and non-neuronal cells prepared from multiple animal species. In all preparations, GACh sensors selectively responded to exogenous and/or endogenous ACh with robust fluorescence signals that were captured by epifluorescence, confocal, and/or two-photon microscopy. Moreover, analysis of endogenous ACh release revealed firing-pattern-dependent release and restricted volume transmission, resolving two long-standing questions about central cholinergic transmission. Thus, GACh sensors provide a user-friendly, broadly applicable tool for monitoring cholinergic transmission underlying diverse biological processes.

Optical upconversion that converts infrared light into visible light is of significant interest for broad applications in biomedicine, imaging, and displays. Conventional upconversion materials rely on nonlinear light-matter interactions, exhibit incidence-dependent efficiencies, and require high-power excitation. We report an infrared-to-visible upconversion strategy based on fully integrated microscale optoelectronic devices. These thin-film, ultraminiaturized devices realize near-infrared (∼810 nm) to visible [630 nm (red) or 590 nm (yellow)] upconversion that is linearly dependent on incoherent, low-power excitation, with a quantum yield of ∼1.5%. Additional features of this upconversion design include broadband absorption, wide-emission spectral tunability, and fast dynamics. Encapsulated, freestanding devices are transferred onto heterogeneous substrates and show desirable biocompatibilities within biological fluids and tissues. These microscale devices are implanted in behaving animals, with in vitro and in vivo experiments demonstrating their utility for optogenetic neuromodulation. This approach provides a versatile route to achieve upconversion throughout the entire visible spectral range at lower power and higher efficiency than has previously been possible.

Immunosignal hybridization chain reaction (isHCR) combines antibody-antigen interactions with hybridization chain reaction (HCR) technology, which results in amplification of immunofluorescence signals by up to two to three orders of magnitude with low background. isHCR's highly modular and easily adaptable design enables the technique to be applied broadly, and we further optimized its use in multiplexed imaging and in state-of-the-art tissue expansion and clearing techniques.

Brain-to-brain interfaces (BtBIs) hold exciting potentials for direct communication between individual brains. However, technical challenges often limit their performance in rapid information transfer. Here, we demonstrate an optical brain-to-brain interface that transmits information regarding locomotor speed from one mouse to another and allows precise, real-time control of locomotion across animals with high information transfer rate. We found that the activity of the genetically identified neuromedin B (NMB) neurons within the nucleus incertus (NI) precisely predicts and critically controls locomotor speed. By optically recording Ca

Inflammatory bowel disease (IBD) is a chronic, inflammatory, and autoimmune disorder. The pathogenesis of IBD is not yet clear. Studies have shown that the imbalance between T helper 17 (Th17) and regulatory T (Treg) cells, which differentiate from CD4+ T cells, contributes to IBD. Th17 cells promote tissue inflammation, and Treg cells suppress autoimmunity in IBD. Therefore, Th17/Treg cell balance is crucial. Some regulatory factors affecting the production and maintenance of these cells are also important for the proper regulation of the Th17/Treg balance; these factors include T cell receptor (TCR) signaling, costimulatory signals, cytokine signaling, bile acid metabolites, and the intestinal microbiota. This article focuses on our understanding of the function and role of the balance between Th17/Treg cells in IBD and these regulatory factors and their clinical significance in IBD.