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Abstract Individuals’ continuous success in competitive interactions with conspecifics strongly affects their social hierarchy. Medial prefrontal cortex (mPFC) is the key brain region mediating both social competition and hierarchy. However, the molecular regulatory mechanisms underlying the neural ensemble in the mPFC remains unclear. Here, we demonstrate that in excitatory neurons of prelimbic cortex (PL), lncRNA Sera remodels the utilization of Pkm Exon9 and Exon10, resulting in a decrease in the Pkm1/2 ratio in highly competitive mice. By employing a tet-on/off system, we disrupt or rebuild the normal Pkm1/2 ratio by controlling the expression of Pkm2 in PL excitatory neurons. We find that long-term Pkm2 modulation induces timely competition alteration and hysteretic rank change, through phosphorylating the Ser845 site of GluA1. Together, this study uncovers a crucial role of lncRNA Sera/Pkm2 pathway in the transition of social competition to rank by remodeling neural ensemble in mPFC.

Minimizing toxicity of herpes simplex virus 1 (HSV) based tools for anterograde tracing is important for functional studies. Here the authors generate an anterograde monosynaptic tracer system based on HSV amplicon, which shows fast tracing, bright labeling, low toxicity, input-defined postsynaptic neurons’ anterograde monosynaptic tracing feature, and has potential for functional mapping.

The investigation of brain networks and neural circuits involves the crucial aspects of observing and modulating neurophysiological activity. Recently, opto-electrodes have emerged as an efficient tool for electrophysiological recording and optogenetic stimulation, which has greatly facilitated the analysis of neural coding. However, implantation and electrode weight control have posed significant challenges in achieving long-term and multi-regional brain recording and stimulation. To address this issue, we have developed a mold and custom-printed circuit board-based opto-electrode. We report successful opto-electrode placement and high-quality electrophysiological recordings from the default mode network (DMN) of the mouse brain. This novel opto-electrode facilitates synchronous recording and stimulation in multiple brain regions and holds promise for advancing future research on neural circuits and networks.

Abstract Dynamic change of mitochondrial morphology and distribution along neuronal branches are essential for neural circuitry formation and synaptic efficacy. However, the underlying mechanism remains elusive. We show here that Pink1 knockout (KO) mice display defective dendritic spine maturation, reduced axonal synaptic vesicles, abnormal synaptic connection, and attenuated long-term synaptic potentiation (LTP). Drp1 activation via S616 phosphorylation rescues deficits of spine maturation in Pink1 KO neurons. Notably, mice harboring a knockin (KI) phosphor-null Drp1 S616A recapitulate spine immaturity and synaptic abnormality identified in Pink1 KO mice. Chemical LTP (cLTP) induces Drp1S616 phosphorylation in a PINK1-dependent manner. Moreover, phosphor-mimetic Drp1S616D restores reduced dendritic spine localization of mitochondria in Pink1 KO neurons. Together, this study provides the first in vivo evidence of functional regulation of Drp1 by phosphorylation and suggests that PINK1-Drp1S616 phosphorylation coupling is essential for convergence between mitochondrial dynamics and neural circuitry formation and refinement.

Abstract Background Viral tracers are important tools for mapping brain connectomes. The feature of predominant anterograde transneuronal transmission offers herpes simplex virus-1 (HSV-1) strain H129 (HSV1-H129) as a promising candidate to be developed as anterograde viral tracers. In our earlier studies, we developed H129-derived anterograde polysynaptic tracers and TK deficient (H129-dTK) monosynaptic tracers. However, their broad application is limited by some intrinsic drawbacks of the H129-dTK tracers, such as low labeling intensity due to TK deficiency and potential retrograde labeling caused by axon terminal invasion. The glycoprotein K (gK) of HSV-1 plays important roles in virus entry, egress, and virus-induced cell fusion. Its deficiency severely disables virus egress and spread, while only slightly limits viral genome replication and expression of viral proteins. Therefore, we created a novel H129-derived anterograde monosynaptic tracer (H129-dgK) by targeting gK, which overcomes the limitations of H129-dTK. Methods Using our established platform and pipeline for developing viral tracers, we generated a novel tracer by deleting the gK gene from the H129-G4. The gK-deleted virus (H129-dgK-G4) was reconstituted and propagated in the Vero cell expressing wildtype H129 gK (gKwt) or the mutant gK (gKmut, A40V, C82S, M223I, L224V, V309M), respectively. Then the obtained viral tracers of gKmut pseudotyped and gKwt coated H129-dgK-G4 were tested in vitro and in vivo to characterize their tracing properties. Results H129-dgK-G4 expresses high levels of fluorescent proteins, eliminating the requirement of immunostaining for imaging detection. Compared to the TK deficient monosynaptic tracer H129-dTK-G4, H129-dgK-G4 labeled neurons with 1.76-fold stronger fluorescence intensity, and visualized 2.00-fold more postsynaptic neurons in the downstream brain regions. gKmut pseudotyping leads to a 77% decrease in retrograde labeling by reducing axon terminal invasion, and thus dramatically improves the anterograde-specific tracing of H129-dgK-G4. In addition, assisted by the AAV helper trans-complementarily expressing gKwt, H129-dgK-G4 allows for mapping monosynaptic connections and quantifying the circuit connectivity difference in the Alzheimer’s disease and control mouse brains. Conclusions gKmut pseudotyped H129-dgK-G4, a novel anterograde monosynaptic tracer, overcomes the limitations of H129-dTK tracers, and demonstrates desirable features of strong labeling intensity, high tracing efficiency, and improved anterograde specificity.

Abstract The third isoform of the Na+–Ca2+ exchanger (NCX3) is crucial for a physiological fine-tuning of the Ca2+ fluxes in excitable tissues. In this view, the NCX3 accounts for the aberrant Ca2+ influx seen during neuronal excitotoxicity, such as in Alzheimer’s disease (AD). However, little is known about NCX3 regulation and functional properties. Withania somnifera (L.) Dunal (W. somnifera), a traditional indigenous plant widely recognized for having numerous medicinal values, was undertaken to determine its potential therapeutic benefit against aggregated Aβ1–42-induced NCX3 dysregulation and the thereof cognition impairment in 5xFAD mice. The undertaken sourced dried roots of authenticated W. somnifera physicochemical compositional tests satisfied standards of pharmacognostic quality, and further phytochemical analysis of the roots methanol extract revealed the roots constitute several antioxidants. Following an intra-gastric gavage administration of synthesized W. somnifera roots methanolic extract from postnatal day 30 (P30) to P75, in vivo cognitional studies and then neurochemical examinations of the NCX3 expression level, Aβ plaque deposition, and antioxidant activities in the AD-associated brain regions of 4-month-old 5xFAD mice suggests that the oxidative stress normalizing effects of W. somnifera constituents, operating on the NCX3, may have a therapeutic role in the improvement of cognition in AD.

Abstract Background Aldh1a1 neurons are a subtype of gamma-aminobutyric acid (GABA) inhibitory neurons that use Aldh1a1 rather than glutamate decarboxylase (GAD) as an enzyme for synthesizing GABA transmitters. However, the behaviors and circuits of this newly identified subtype of inhibitory interneurons remain unknown. Methods We generated a mutant mouse line in which cyclization recombination enzyme (CRE) was expressed under the control of the Aldh1a1 promotor (Aldh1a1-CRE mice). Using this mutant strain of mice together with the heterozygous male Alzheimer’s disease (AD) related model mice (APPswe/PSEN1dE9, or AD mice) and a genetically modified retrograde and anterograde synaptic tracing strategy, we have studied a specific synaptic circuit of Aldh1a1 neurons with system-level function and disease progression in AD mice. Results We demonstrate that Aldh1a1 neurons encode delay of gratification that measures self-control skills in decision making by projecting inhibitory synapses directly onto excitatory glutamate neurons in the intermediate lateral septum (EGNIS) and receiving synaptic inputs from layer 5b pyramidal neurons in the medial prefrontal cortex (L5PN). L5PN → Aldh1a1 synaptic transmission undergoes long-term potentiation (LTP). Pathway specific inhibition by either genetic silencing presynaptic terminals or antagonizing postsynaptic receptors impairs delay of gratification, resulting in the impulsive behaviors. Further studies show that reconstitution of Aldh1a1-deficient neurons with the expression of exogenous Aldh1a1 (eAldh1a1) restores Aldh1a1 → EGNIS synaptic transmission and rescues the impulsive behaviors in AD mice. Conclusions These results not only identify a specific function and circuit of Aldh1a1 neurons but also provide a cellular point of entry to an important but understudied synaptic mechanism for the induction of impulsive behaviors at an early stage of AD.

Accumulating evidence suggests that gut microbiota as a critical mediator of gut-brain axis plays an important role in human health. Altered gut microbial profiles have been implicated in increasing the vulnerability of psychiatric disorders, such as autism, depression, and schizophrenia. However, the cellular and molecular mechanisms underlying the association remain unknown. Here, we modified the gut microbiome with antibiotics in newborn mice, and found that gut microbial alteration induced behavioral impairment by decreasing adult neurogenesis and long-term potentiation of synaptic transmission, and altering the gene expression profile in hippocampus. Reconstitution with normal gut flora produced therapeutic effects against both adult neurogenesis and behavioral deficits in the dysbiosis mice. Furthermore, our results show that circulating metabolites changes mediate the effect of gut dysbiosis on hippocampal plasticity and behavior outcomes. Elevating the serum 4-methylphenol, a small aromatic metabolite produced by gut bacteria, was found to induce autism spectrum disorder (ASD)-like behavior impairment and hippocampal dysfunction. Together our finding demonstrates that early-life gut dysbiosis and its correlated metabolites change contribute to hippocampal dysfunction and behavior impairment, hence highlight the potential microbiome-mediated therapies for treating psychiatric disorders.

Cholinergic neurons in the basal forebrain constitute a major source of cholinergic inputs to the forebrain, modulate diverse functions including sensory processing, memory and attention, and are vulnerable to Alzheimer's disease (AD). Recently, we classified cholinergic neurons into two distinct subpopulations; calbindin D28K-expressing (D28K+) versus D28K-lacking (D28K−) neurons. Yet, which of these two cholinergic subpopulations are selectively degenerated in AD and the molecular mechanisms underlying this selective degeneration remain unknown. Here, we reported a discovery that D28K+ neurons are selectively degenerated and this degeneration induces anxiety-like behaviors in the early stage of AD. Neuronal type specific deletion of NRADD effectively rescues D28K+ neuronal degeneration, whereas genetic introduction of exogenous NRADD causes D28K− neuronal loss. This gain- and loss-of-function study reveals a subtype specific degeneration of cholinergic neurons in the disease progression of AD and hence warrants a novel molecular target for AD therapy.

H doping can enhance the performance of ZnO thin-film transistors (TFTs) to a certain extent, and the design of double active layers is an effective way to further improve a device’s performance. However, there are few studies on the combination of these two strategies. We fabricated TFTs with ZnO:H (4 nm)/ZnO (20 nm) double active layers by magnetron sputtering at room temperature, and studied the effect of the hydrogen flow ratio on the devices’ performance. ZnO:H/ZnO-TFT has the best overall performance when H2/(Ar + H2) = 0.13% with a mobility of 12.10 cm2/Vs, an on/off current ratio of 2.32 × 107, a subthreshold swing of 0.67 V/Dec, and a threshold voltage of 1.68 V, which is significantly better than the performance of single active layer ZnO:H-TFTs. This exhibits that the transport mechanism of carriers in double active layer devices is more complicated. On one hand, increasing the hydrogen flow ratio can more effectively suppress the oxygen-related defect states, thus reducing the carrier scattering and increasing the carrier concentration. On the other hand, the energy band analysis shows that electrons accumulate at the interface of the ZnO layer close to the ZnO:H layer, providing an additional path for carrier transport. Our research exhibits that the combination of a simple hydrogen doping process and double active layer construction can achieve the fabrication of high-performance ZnO-based TFTs, and that the whole room temperature process also provides important reference value for the subsequent development of flexible devices.

Congenital cytomegalovirus (cCMV) infection is the leading infectious cause of neurodevelopmental disorders. However, the neuropathogenesis remains largely elusive due to a lack of informative animal models. In this study, we developed a congenital murine CMV (cMCMV) infection mouse model with high survival rate and long survival period that allowed long-term follow-up study of neurodevelopmental disorders. This model involves in utero intracranial injection and mimics many reported clinical manifestations of cCMV infection in infants, including growth restriction, hearing loss, and impaired cognitive and learning-memory abilities. We observed that abnormalities in MRI/CT neuroimaging were consistent with brain hemorrhage and loss of brain parenchyma, which was confirmed by pathological analysis. Neuropathological findings included ventriculomegaly and cortical atrophy associated with impaired proliferation and migration of neural progenitor cells in the developing brain at both embryonic and postnatal stages. Robust inflammatory responses during infection were shown by elevated inflammatory cytokine levels, leukocyte infiltration, and activation of microglia and astrocytes in the brain. Pathological analyses and CT neuroimaging revealed brain calcifications induced by cMCMV infection and cell death via pyroptosis. Furthermore, antiviral treatment with ganciclovir significantly improved neurological functions and mitigated brain damage as shown by CT neuroimaging. These results demonstrate that this model is suitable for investigation of mechanisms of infection-induced brain damage and long-term studies of neurodevelopmental disorders, including the development of interventions to limit CNS damage associated with cCMV infection.

Presently, the treatment options for ischemic stroke (IS) are limited due to the complicated pathological process of the disease. Chuanxiong Rhizome (CR), also known as Conioselinum anthriscoides “Chuanxiong” (rhizome), is the most widely used traditional Chinese medicine for treating stroke. This study aimed to uncover the key phytochemicals and biological functions of CR against IS through a network pharmacology approach combining with IS pathophysiology analysis. We employed permanent unilateral common carotid artery ligation to construct a mouse model of global cerebral ischemia and found that cerebral ischemia injuries were improved after 7 days of gavage treatment of CR (1,300 mg/kg/day). CR exerts protective effects on neurons mainly by acting on targets related to synaptic structure, synaptic function, neuronal survival and neuronal growth. A total of 18 phytochemicals from CR based on UHPLC-MS/MS that corresponded to 85 anti-IS targets. Coniferyl ferulate, neocnidilide and ferulic acid were identified as the key phytochemicals of CR against IS. Its brain protective effects involve anti-inflammatory, anti-oxidative stress, and anti-cell death activities and improves blood circulation. Additionally, the two most important synergistic effects of CR phytochemicals in treating IS are prevention of infection and regulation of blood pressure. In brain samples of Sham mice, L-tryptophan and vanillin were detected, while L-tryptophan, gallic acid, vanillin and cryptochlorogenic acid were detected in IS mice by UHPLC–MS/MS. Our findings provide a pathophysiology relevant pharmacological basis for further researches on IS therapeutic drugs.

We demonstrate the growth of ultra-thin (~5 nm) indium ytterbium oxide (In-Yb-O) thin film using a simple vacuum-free aqueous solution approach for the first time. The influences of Yb addition on the microstructural, chemical, optical, and electrical properties of In2O3 are well investigated. The analyses indicate that Yb dopant could suppress oxygen vacancy defects effectively owing to the lower standard electrode potential, lower electronegativity, and stronger metal-oxide bond strength than that of In. The optimized In-Yb-O thin-film transistors (TFTs) exhibit excellent electrical performance (mobility of 8 cm2/Vs and on/off ratio of ~108) and enhanced stability. The triumph of In-Yb-O TFTs is owing to the high quality In2O3 matrix, the remarkable suppressor of Yb, and the nanometer-thin and atomically smooth nature (RMS: ~0.26 nm) of channel layer. Therefore, the eco-friendly water-induced ultra-thin In-Yb-O channel provides an excellent opportunity for future large-scale and cost-effective electronic applications.

Thin-film transistors (TFTs) made of solution-processable transparent metal oxide semiconductors show great potential for use in emerging large-scale optoelectronics. However, current solution-processed metal oxide TFTs still suffer from relatively poor device performance, hindering their further advancement. In this work, we create a novel ultrathin crystalline indium–boron–oxide (In-B-O) channel layer for high-performance TFTs. We show that high-quality ultrathin (~10 nm) crystalline In-B-O with an atomically smooth nature (RMS: ~0.15 nm) could be grown from an aqueous solution via facile one-step spin-coating. The impacts of B doping on the physical, chemical and electrical properties of the In2O3 film are systematically investigated. The results show that B has large metal–oxide bond dissociation energy and high Lewis acid strength, which can suppress oxygen vacancy-/hydroxyl-related defects and alleviate dopant-induced carrier scattering, resulting in electrical performance improvement. The optimized In-B-O (10% B) TFTs based on SiO2/Si substrate demonstrate a mobility of ~8 cm2/(V s), an on/off current ratio of ~106 and a subthreshold swing of 0.86 V/dec. Furthermore, by introducing the water-processed high-K ZrO2 dielectric, the fully aqueous solution-grown In-B-O/ZrO2 TFTs exhibit excellent device performance, with a mobility of ~11 cm2/(V s), an on/off current of ~105, a subthreshold swing of 0.19 V/dec, a low operating voltage of 5 V and superior bias stress stability. Our research opens up new avenues for low-cost, large-area green oxide electronic devices with superior performance.

Black phosphorus (BP), a single elemental two-dimensional (2D) material with a sizable band gap, meets several critical material requirements in the development of future nanoelectronic applications. This work reports the ambipolar characteristics of few-layer BP, induced using 2D transparent hexagonal boron nitride (h-BN) capping. The 2D h-BN capping have several advantages over conventional Al2O3 capping in flexible and transparent 2D device applications. The h-BN capping technique was used to achieve an electron mobility in the BP devices of 73 cm2V−1s−1, thereby demonstrating n-type behavior. The ambipolar BP devices exhibited ultrafast photodetector behavior with a very high photoresponsivity of 1980 mA/W over the ultraviolet (UV), visible, and infrared (IR) spectral ranges. The h-BN capping process offers a feasible approach to fabricating n-type behavior BP semiconductors and high photoresponse BP photodetectors.

Sentinel-2 NDVI and surface reflectance time series have been widely used in various geoscience research, but the data is deteriorated or missing due to the cloud contamination, so it is necessary to reconstruct the Sentinel-2 NDVI and surface reflectance time series. At present, there are few studies on reconstructing the Sentinel-2 NDVI or surface reflectance time series, and these existing reconstruction methods have some shortcomings. We proposed a new method to reconstruct the Sentinel-2 NDVI and surface reflectance time series using the penalized least-square regression based on discrete cosine transform (DCT-PLS) method. This method iteratively identifies cloud-contaminated NDVI over NDVI time series from the Sentinel-2 surface reflectance data by adjusting the weights. The NDVI and surface reflectance time series are then reconstructed from cloud-free NDVI and surface reflectance using the adjusted weights as constraints. We have made some improvements to the DCT-PLS method. First, the traditional discrete cosine transformation (DCT) in the DCT-PLS method is matrix generated from discrete and equally spaced data, we reconfigured the DCT formulas to adapt for irregular interval time series, and optimized the control parameters N and s according to the typical vegetation samples in China. Second, the DCT-PLS method was deployed in the Google Earth Engine (GEE) platform for the efficiency and convenience of data users. We used the DCT-PLS method to reconstruct the Sentinel-2 NDVI time series and surface reflectance time series in the blue, green, red, and near infrared (NIR) bands in typical vegetation samples and the Zhangjiakou and Hangzhou study area. We found that this method performed better than the SG filter method in reconstructing the NDVI time series, and can identify and reconstruct the contaminated NDVI as well as surface reflectance with low root mean square error (RMSE) and high coefficient of determination (R2). However, in cases of a long range of cloud contamination, or above water surface, it may be necessary to increase the control parameter s for a more stable performance. The GEE code is freely available online and the link is in the conclusions of this article, researchers are welcome to use this method to generate cloudless Sentinel-2 NDVI and surface reflectance time series with 10 m spatial resolution, which is convenient for landcover classification and many other types of research.

As an important part of the Earth’s environmental system, sandy soils are particularly sensitive to changes in the climatic environment. As one of the four major desert regions in China, the MuUs desert has transformed from a desert to an oasis after more than half a century of ecological management. In this paper, we analyzed the spatial and temporal patterns of surface albedo, evapotranspiration, and fraction vegetation cover in the MuUs desert based on the Global Land Surface Satellite (GLASS) product with high spatial and temporal resolution and assessed the relationships between their variability and snow cover, air temperature, and precipitation. It is of great significance to understand the effect of desertification control and climate change after the conversion of land surface types in the MuUs region. The results show that the desertification control in the MuUs area has achieved remarkable results since 1982. The fraction vegetation coverage of the MuUs desert showed a significant increasing trend, with an interannual change rate of 1.32% each decade−1. The surface albedo of MuUs desert decreased significantly. Affected by vegetation and snow cover, it was lower in summer and higher in winter. The evapotranspiration showed a significant upward trend, higher in summer and lower in winter, which is significantly correlated with the changes in surface albedo, air temperature, and vegetation. In addition, the local-scale biophysical effects caused by vegetation change have influenced the climate of the MuUs region, manifested as the increase in precipitation and air temperature. In general, with the support of relevant policies and human construction projects, the overall ecological environment in the MuUs desert is developing in a good way.

IQSEC2 (aka BRAG1) is a guanine nucleotide exchange factor (GEF) highly enriched in synapses. As a top neurodevelopmental disorder risk gene, numerous mutations are identified in Iqsec2 in patients with intellectual disabilities accompanied by other developmental, neurological, and psychiatric symptoms, though with poorly understood underlying molecular mechanisms. The atomic structures of IQSECs, together with biochemical analysis, presented in this study reveal an autoinhibition and Ca2+- dependent allosteric activation mechanism for all IQSECs and rationalize how each identified Iqsec2 mutation can alter the structure and function of the enzyme. Transgenic mice modeling two pathogenic variants of Iqsec2 (R359C and Q801P), with one activating and the other inhibiting the GEF activity of the enzyme, recapitulate distinct clinical phenotypes in patients. Our study demonstrates that different mutations on one gene such as Iqsec2 can have distinct neurological phenotypes and accordingly will require different therapeutic strategies. [ABSTRACT FROM AUTHOR]