Social experience in adolescence shapes prefrontal cortex structure and function in adulthood.

During adolescence, the prefrontal cortex (PFC) undergoes dramatic reorganization. PFC development is profoundly influenced by the social environment, disruptions to which may prime the emergence of psychopathology across the lifespan. We investigated the neurobehavioral consequences of isolation experienced in adolescence in mice, and in particular, the long-term consequences that were detectable even despite normalization of the social milieu. Isolation produced biases toward habit-like behavior at the expense of flexible goal seeking, plus anhedonic-like reward deficits. Behavioral phenomena were accompanied by neuronal dendritic spine over-abundance and hyper-excitability in the ventromedial PFC (vmPFC), which was necessary for the expression of isolation-induced habits and sufficient to trigger behavioral inflexibility in socially reared controls. Isolation activated cytoskeletal regulatory pathways otherwise suppressed during adolescence, such that repression of constituent elements prevented long-term isolation-induced neurosequelae. Altogether, our findings unveil an adolescent critical period and multi-model mechanism by which social experiences facilitate prefrontal cortical maturation.

Neuronal Ensembles in the Amygdala Allow Social Information to Motivate Later Decisions.

Social experiences carry tremendous weight in our decision-making, even when social partners are not present. To determine mechanisms, we trained female mice to respond for two food reinforcers. Then, one food was paired with a novel conspecific. Mice later favored the conspecific-associated food, even in the absence of the conspecific. Chemogenetically silencing projections from the prelimbic subregion (PL) of the medial prefrontal cortex to the basolateral amygdala (BLA) obstructed this preference while leaving social discrimination intact, indicating that these projections are necessary for socially driven choice. Further, mice that performed the task had greater densities of dendritic spines on excitatory BLA neurons relative to mice that did not. We next induced chemogenetic receptors in cells active during social interactions-when mice were encoding information that impacted later behavior. BLA neurons stimulated by social experience were necessary for mice to later favor rewards associated with social conspecifics but not make other choices. This profile contrasted with that of PL neurons stimulated by social experience, which were necessary for choice behavior in social and nonsocial contexts alike. The PL may convey a generalized signal allowing mice to favor particular rewards, while units in the BLA process more specialized information, together supporting choice motivated by social information.

Analysis of the Efficacy and Safety of Coronary Catheterization through Distal Transradial Access: A Single-Center Data.

Background and Aims: The distal transradial access (dTRA) is a new puncture site for coronary catheterization. We sought to evaluate the feasibility, safety, and complication rates of using the dTRA for cardiac catheterization in Chinese patients. Methods: A total of 263 consecutive patients who underwent catheterization through the dTRA were enrolled. The primary endpoint of the study was the rate of conversion to another access site due to the impossibility of successful artery puncture or intubation. Secondary safety endpoints were the rates of bleeding-related complications and nerve disorders. Results: Among 263 patients, the puncture success rate was 96.2% (253/263). Eleven patients were successfully punctured, but the guide wire was difficult to advance. One patient had intubation failure, and the success rate of intubation was 91.6% (241/263). Two hundred thirty-three patients underwent puncture via the right dTRA, 5 patients underwent puncture via the left dTRA, and 3 patients underwent puncture via the bilateral dTRA. A total of 158 (65.6%) patients underwent coronary angiography, and 83 (34.4%) patients underwent percutaneous coronary intervention. After the procedure, only 2 (0.8%) patients had mild bleeding at the puncture site, 2 (0.8%) had a forearm hematoma, and no patient had a nerve disorder. Conclusions: DTRA has a low incidence of complications, making it a safe and effective technique for cardiac catheterization.

Developmental pyrethroid exposure causes a neurodevelopmental disorder phenotype in mice.

Neurodevelopmental disorders (NDDs) are a widespread and growing public health challenge, affecting as many as 17% of children in the United States. Recent epidemiological studies have implicated ambient exposure to pyrethroid pesticides during pregnancy in the risk for NDDs in the unborn child. Using a litter-based, independent discovery-replication cohort design, we exposed mouse dams orally during pregnancy and lactation to the Environmental Protection Agency's reference pyrethroid, deltamethrin, at 3 mg/kg, a concentration well below the benchmark dose used for regulatory guidance. The resulting offspring were tested using behavioral and molecular methods targeting behavioral phenotypes relevant to autism and NDD, as well as changes to the striatal dopamine system. Low-dose developmental exposure to the pyrethroid deltamethrin (DPE) decreased pup vocalizations, increased repetitive behaviors, and impaired both fear conditioning and operant conditioning. Compared with control mice, DPE mice had greater total striatal dopamine, dopamine metabolites, and stimulated dopamine release, but no difference in vesicular dopamine capacity or protein markers of dopamine vesicles. Dopamine transporter protein levels were increased in DPE mice, but not temporal dopamine reuptake. Striatal medium spiny neurons showed changes in electrophysiological properties consistent with a compensatory decrease in neuronal excitability. Combined with previous findings, these results implicate DPE as a direct cause of an NDD-relevant behavioral phenotype and striatal dopamine dysfunction in mice and implicate the cytosolic compartment as the location of excess striatal dopamine.

Predominance of Escherichia-Shigella in Gut Microbiome and Its Potential Correlation with Elevated Level of Plasma Tumor Necrosis Factor Alpha in Patients with Tuberculous Meningitis.

Tuberculous meningitis (TBM), the most lethal and disabling form of tuberculosis (TB), may be related to gut microbiota composition, warranting further study. Here we systematically compared gut microbiota compositions and blood cytokine profiles of TBM patients, pulmonary TB patients, and healthy controls. Notably, the significant gut microbiota dysbiosis observed in TBM patients was associated with markedly high proportions of Escherichia-Shigella species as well as increased blood levels of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). Next, we obtained a fecal bacterial isolate from a TBM patient and administered it via oral gavage to mice in order to develop a murine gut microbiota dysbiosis model for use in exploring mechanisms underlying the observed relationship between gut microbial dysbiosis and TBM. Thereafter, cells of commensal Escherichia coli (E. coli) were isolated and administered to model mice by gavage and then mice were inoculated with Mycobacterium tuberculosis (M. tuberculosis). Subsequently, these mice exhibited increased blood TNF-α levels accompanied by downregulated expression of tight junction protein claudin-5, increased brain tissue bacterial burden, and elevated central nervous system inflammation relative to corresponding indicators in controls administered PBS by gavage. Thus, our results demonstrated that a signature dysbiotic gut microbiome profile containing a high proportion of E. coli was potentially associated with an increased circulating TNF-α level in TBM patients. Collectively, these results suggest that modulation of dysbiotic gut microbiota holds promise as a new strategy for preventing or alleviating TBM. IMPORTANCE As the most severe form of tuberculosis, the pathogenesis of tuberculous meningitis (TBM) is still unclear. Gut microbiota dysbiosis plays an important role in a variety of central nervous system diseases. However, the relationship between gut microbiota and TBM has not been identified. In our study, significant dysbiosis in gut microbiota composition with a high proportion of E. coli and increased levels of TNF-α in plasma was noted in TBM patients. A commensal E. coli was isolated and shown to increase the plasma level of TNF-α and downregulate brain tight junction protein claudin-5 in the murine model. Gavage administration of E. coli aggravated the bacterial burden and increased the inflammatory responses in the central nervous system after M. tuberculosis infection. Dysbiosis of gut microbiota may be a promising therapeutic target and biomarker for TBM prevention or treatment.

Social incentivization of instrumental choice in mice requires amygdala-prelimbic cortex-nucleus accumbens connectivity.

Social experiences influence decision making, including decision making lacking explicit social content, yet mechanistic factors are unclear. We developed a new procedure, social incentivization of future choice (SIFC). Female mice are trained to nose poke for equally-preferred foods, then one food is paired with a novel conspecific, and the other with a novel object. Mice later respond more for the conspecific-associated food. Thus, prior social experience incentivizes later instrumental choice. SIFC is pervasive, occurring following multiple types of social experiences, and is not attributable to warmth or olfactory cues alone. SIFC requires the prelimbic prefrontal cortex (PL), but not the neighboring orbitofrontal cortex. Further, inputs from the basolateral amygdala to the PL and outputs to the nucleus accumbens are necessary for SIFC, but not memory for a conspecific. Basolateral amygdala→PL connections may signal the salience of social information, leading to the prioritization of coincident rewards via PL→nucleus accumbens outputs.

Social experience alters oxytocinergic modulation in the nucleus accumbens of female prairie voles.

Social relationships are dynamic and evolve with shared and personal experiences. Whether the functional role of social neuromodulators also evolves with experience to shape the trajectory of relationships is unknown. We utilized pair bonding in the socially monogamous prairie vole as an example of socio-sexual experience that dramatically alters behaviors displayed toward other individuals. We investigated oxytocin-dependent modulation of excitatory synaptic transmission in the nucleus accumbens as a function of pair-bonding status. We found that an oxytocin receptor agonist decreases the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in sexually naive virgin, but not pair-bonded, female voles, while it increases the amplitude of electrically evoked EPSCs in paired voles, but not in virgins. This oxytocin-induced potentiation of synaptic transmission relies on the de novo coupling between oxytocin receptor signaling and endocannabinoid receptor type 1 (CB1) receptor signaling in pair-bonded voles. Blocking CB1 receptors after pair-bond formation increases the occurrence of a specific form of social rejection-defensive upright response-that is displayed toward the partner, but not toward a novel individual. Altogether, our results demonstrate that oxytocin's action in the nucleus accumbens is changed through social experience in a way that regulates the trajectory of social interactions as the relationship with the partner unfolds, potentially promoting the maintenance of a pair bond by inhibiting aggressive responses. These results provide a mechanism by which social experience and context shift oxytocinergic signaling to impact neural and behavioral responses to social cues.

Ghrelin infusion into the basolateral amygdala suppresses CTA memory formation in rats via the PI3K/Akt/mTOR and PLC/PKC signaling pathways.

Ghrelin is a circulating orexigenic hormone that promotes feeding behavior and regulates metabolism in humans and rodents. We previously reported that local infusion of ghrelin into the basolateral amygdala (BLA) blocked memory acquisition for conditioned taste aversion (CTA) by activating growth hormone secretagogue receptor 1a. In this study, we further explored the underlying mechanism and signaling pathways mediating ghrelin modulation of CTA memory in rats. Pharmacological agents targeting distinct signaling pathways were infused into the BLA during conditioning. We showed that preadministration of the PI3K inhibitor LY294002 abolished the repressive effect of ghrelin on CTA memory. Moreover, LY294002 pretreatment prevented ghrelin from inhibiting Arc and zif268 mRNA expression in the BLA triggered by CTA memory retrieval. Preadministration of rapamycin eliminated the repressive effect of ghrelin, while Gsk3 inhibitors failed to mimic ghrelin's effect. In addition, PLC and PKC inhibitors microinfused in the BLA blocked ghrelin's repression of CTA acquisition. These results demonstrate that ghrelin signaling in the BLA shapes CTA memory via the PI3K/Akt/mTOR and PLC/PKC pathways. We conducted in vivo multichannel recordings from mouse BLA neurons and found that microinjection of ghrelin (20 µM) suppressed intrinsic excitability. By means of whole-cell recordings from rat brain slices, we showed that bath application of ghrelin (200 nM) had no effect on basal synaptic transmission or synaptic plasticity of BLA pyramidal neurons. Together, this study reveals the mechanism underlying ghrelin-induced interference with CTA memory acquisition in rats, i.e., suppression of intrinsic excitability of BLA principal neurons via the PI3K/Akt/mTOR and PLC/PKC pathways.

Elevated Natural Killer Cell-Mediated Cytotoxicity Is Associated with Cavity Formation in Pulmonary Tuberculosis Patients.

Cavitation is a major pathological feature of pulmonary tuberculosis (TB). The study is aimed at investigating the mechanism of natural killer (NK) cells participating the cavity formation during Mycobacterium tuberculosis (MTB) infection. Human peripheral blood samples were donated by pulmonary TB patients with cavity or not. Real-time quantitative PCR and enzyme-linked immunosorbent assay were performed to analyze the expression of cytokines secreted by NK cells. And the cytotoxicity of NK cells was compared between two groups. Our data showed that NK cells were more abundant in cohorts of cavity. Increased abundance of granzyme A and granzyme B was observed in culture supernatants of NK cells isolated from cavitary TB patients, which also resulted in a higher level of nonviable MTB-infected monocytes. Our data firstly demonstrates that NK cells participate in cavity formation in pulmonary TB patients. The elevated level and increased cytotoxicity of NK cells accelerate the cavitary formulation.

Increased Expression of IL-10 in Peripheral Blood Mononuclear Cells Correlates with Negative Interferon-γ Release Assay Results in Culture-Confirmed Tuberculosis Patients.

INTRODUCTION: Interferon-γ release assays (IGRAs) can have high false-negative rates for active tuberculosis (TB) cases. Here we investigated factors, including potential anti-inflammatory mechanisms, that contributed to false-negative IGRA results. METHODS: We established two cohorts. In the first cohort, we reviewed IGRA results for confirmed TB cases diagnosed in our hospital in 2018. Cases with false-negative IGRA results were analysed to identify factors contributing to false-negative results. In the second cohort, we prospectively studied IL-10 expression levels in peripheral blood mononuclear cells (PBMCs) of IGRAs-positive and IGRAs-negative TB cases after antigenic stimulation to correlate IL-10 expression with IGRAs results. RESULTS: Of 1232 culture-confirmed TB cases, 1124 produced true-positive IGRA results and 108 had false-negative IGRA results. Multivariate logistic regression analysis identified glucocorticoid use and extrapulmonary TB as independent risk factors for false-negative IGRA results. Notably, IL-10 expression of the IGRA-negative group was significantly up-regulated as compared to that of the IGRA-positive group. The average cell supernatant IL-10 concentration of the IGRA-negative group was 4.77 pg/mL, a value that was statistically greater than the IGRA-positive group concentration (1.47 pg/mL, P = 0.007). After PBMCs pretreatment with BRD6989 (to enhance IL-10 secretion), average IFN-γ concentrations in cell supernatants from the IGRA-positive group significantly decreased from 59.73 pg/mL to 33.79 pg/mL (P = 0.011). By contrast, addition of AS101 (to inhibit IL-10 secretion) to false-negative group PBMCs led to an increase of average IFN-γ concentration in cell supernatants from 19.01 pg/mL to 45.10 pg/mL (P = 0.030), a result that was inversely correlated with IL-10 concentration. CONCLUSION: Our data demonstrate that increased IL-10 secretion by PBMCs is inversely correlated with IGRA assay results in culture-confirmed TB patients. Glucocorticoids use and extrapulmonary TB are significantly associated with false-negative IGRA results. Combination testing to measure IL-10 secretion and IFN-γ release is recommended to improve IGRAs specificity.

Rarity of rpoB Mutations Outside the Rifampicin Resistance-Determining Region of Mycobacterium tuberculosis Isolates from Patients Responding Poorly to First-Line Tuberculosis Regimens in Beijing, China: A Retrospective Study.

BACKGROUND: Early and accurate diagnosis of rifampicin (RIF)-resistant Mycobacterium tuberculosis (MTB) is essential for controlling community spread of drug-resistant tuberculosis (TB). In order to discover mutations residing outside the rifampicin resistance-determining region (RRDR) of the MTB rpoB gene, we conducted this retrospective study. METHODS: We retrospectively screened patient records to obtain Xpert MTB/RIF assay results for patients who received care at the Beijing Chest Hospital from 2016 to 2019 in order to identify subjects who met study selection criteria. Stored frozen patient isolates were cultured, harvested, and then subjected to drug susceptibility testing. Concurrently, entire rpoB gene DNA of each isolate was amplified and then sequenced to reveal rpoB mutations. RESULTS: Overall, 104 RIF-susceptible tuberculosis patients who were tested using the Xpert MTB/RIF assay also had poor first-line regimen treatment responses. Isolates obtained from these cases included 101 MTB isolates that possessed wild-type rpoB allelic profiles, as demonstrated using Sanger sequencing. However, sequences from the other three isolates confirmed that rpoB of one isolate harbored a mutation encoding the amino acid substitution Ile491Phe and that rpoB genes of two isolates contained a mutation encoding the amino acid substitution Ser450Leu. CONCLUSION: Our data demonstrated that mutations found outside the RRDR of MTB rpoB are rare in Beijing, China, indicating that World Health Organization-approved molecular diagnostics are generally suitable for diagnosing RIF resistance.

Neovascularization and tissue regeneration by endothelial progenitor cells in ischemic stroke.

Endothelial progenitor cells (EPCs) are immature endothelial cells (ECs) capable of proliferating and differentiating into mature ECs. These progenitor cells migrate from bone marrow (BM) after vascular injury to ischemic areas, where they participate in the repair of injured endothelium and new blood vessel formation. EPCs also secrete a series of protective cytokines and growth factors that support cell survival and tissue regeneration. Thus, EPCs provide novel and promising potential therapies to treat vascular disease, including ischemic stroke. However, EPCs are tightly regulated during the process of vascular repair and regeneration by numerous endogenous cytokines that are associated closely with the therapeutic efficacy of the progenitor cells. The regenerative capacity of EPCs also is affected by a range of exogenous factors and drugs as well as vascular risk factors. Understanding the functional properties of EPCs and the factors related to their regenerative capacity will facilitate better use of these progenitor cells in treating vascular disease. Here, we review the current knowledge of EPCs in cerebral neovascularization and tissue regeneration after cerebral ischemia and the factors associated with their regenerative function to better understand the underlying mechanisms and provide more effective strategies for the use of EPCs in treating ischemic stroke.

Incerto-thalamic modulation of fear via GABA and dopamine.

Fear generalization and deficits in extinction learning are debilitating dimensions of Post-Traumatic Stress Disorder (PTSD). Most understanding of the neurobiology underlying these dimensions comes from studies of cortical and limbic brain regions. While thalamic and subthalamic regions have been implicated in modulating fear, the potential for incerto-thalamic pathways to suppress fear generalization and rescue deficits in extinction recall remains unexplored. We first used patch-clamp electrophysiology to examine functional connections between the subthalamic zona incerta and thalamic reuniens (RE). Optogenetic stimulation of GABAergic ZI → RE cell terminals in vitro induced inhibitory post-synaptic currents (IPSCs) in the RE. We then combined high-intensity discriminative auditory fear conditioning with cell-type-specific and projection-specific optogenetics in mice to assess functional roles of GABAergic ZI → RE cell projections in modulating fear generalization and extinction recall. In addition, we used a similar approach to test the possibility of fear generalization and extinction recall being modulated by a smaller subset of GABAergic ZI → RE cells, the A13 dopaminergic cell population. Optogenetic stimulation of GABAergic ZI → RE cell terminals attenuated fear generalization and enhanced extinction recall. In contrast, optogenetic stimulation of dopaminergic ZI → RE cell terminals had no effect on fear generalization but enhanced extinction recall in a dopamine receptor D1-dependent manner. Our findings shed new light on the neuroanatomy and neurochemistry of ZI-located cells that contribute to adaptive fear by increasing the precision and extinction of learned associations. In so doing, these data reveal novel neuroanatomical substrates that could be therapeutically targeted for treatment of PTSD.

Magnesium-Based Whitlockite Bone Mineral Promotes Neural and Osteogenic Activities.

Nerves spread throughout human bone minerals and play an important role in regulating osteogenic homeostasis. However, whether the distributive nerves can sense bone minerals and the role of bone minerals in nerve outgrowth are still unclear. We hypothesized that a natural magnesium-containing bone mineral, whitlockite (WH), the second most abundant bone mineral in the human body, could simultaneously promote both osteogenic and neural activities. To verify the hypothesis, both WH and hydroxyapatite (HAP) nanoparticles were synthesized, and their characterization was completed by Fourier-transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD). The effect of WH on neural differentiation of mesenchymal stem cells (MSCs) and neural progenitor cells (NPCs) in 2D and 3D culture was examined by immunostaining and quantitative real-time polymerase chain reaction (qRT-PCR). The secretion of calcitonin gene-related polypeptide (CGRP) was examined by enzyme-linked immunosorbent assay (ELISA). The neural and osteogenic differentiation in a preosteoblasts and NPCs coculture system was examined by immunostaining and qRT-PCR. The results showed that WH promotes the gene and protein expression of neuronal specific marker (MAP-2 and ßIII-tubulin) in 2D and 3D culture systems. In addition, the neurite length in the WH group was significantly longer than in other groups. Furthermore, both neural differentiation and osteogenic differentiation were simultaneously enhanced in the WH group in the coculture system. Thus, this study demonstrated the simultaneous stimulatory effect of WH bone mineral on neural and osteogenic activities, which provided WH as a valuable material for bone regeneration.

Urokinase-Type Plasminogen Activator Protects Cerebral Cortical Neurons from Soluble Aß-Induced Synaptic Damage.

Soluble amyloid ß (Aß)-induced synaptic dysfunction is an early event in the pathogenesis of Alzheimer's disease (AD) that precedes the deposition of insoluble Aß and correlates with the development of cognitive deficits better than the number of plaques. The mammalian plasminogen activation (PA) system catalyzes the generation of plasmin via two activators: tissue-type (tPA) and urokinase-type (uPA). A dysfunctional tPA-plasmin system causes defective proteolytic degradation of Aß plaques in advanced stages of AD. In contrast, it is unknown whether uPA and its receptor (uPAR) contribute to the pathogenesis of this disease. Neuronal cadherin (NCAD) plays a pivotal role in the formation of synapses and dendritic branches, and Aß decreases its expression in cerebral cortical neurons. Here we show that neuronal uPA protects the synapse from the harmful effects of soluble Aß. However, Aß-induced inactivation of the eukaryotic initiation factor 2α halts the transcription of uPA mRNA, leaving unopposed the deleterious effects of Aß on the synapse. In line with these observations, the synaptic abundance of uPA, but not uPAR, is decreased in the frontal cortex of AD patients and 5xFAD mice, and in cerebral cortical neurons incubated with soluble Aß. We found that uPA treatment increases the synaptic expression of NCAD by a uPAR-mediated plasmin-independent mechanism, and that uPA-induced formation of NCAD dimers protects the synapse from the harmful effects of soluble Aß oligomers. These data indicate that Aß-induced decrease in the synaptic abundance of uPA contributes to the development of synaptic damage in the early stages of AD.SIGNIFICANCE STATEMENT Soluble amyloid ß (Aß)-induced synaptic dysfunction is an early event in the pathogenesis of cognitive deficits in Alzheimer's disease (AD). We found that neuronal urokinase-type (uPA) protects the synapse from the deleterious effects of soluble Aß. However, Aß-induced inactivation of the eukaryotic initiation factor 2α decreases the synaptic abundance of uPA, leaving unopposed the harmful effects of Aß on the synapse. In line with these observations, the synaptic expression of uPA is decreased in the frontal cortex of AD brains and 5xFAD mice, and uPA treatment abrogates the deleterious effects of Aß on the synapse. These results unveil a novel mechanism of Aß-induced synaptic dysfunction in AD patients, and indicate that recombinant uPA is a potential therapeutic strategy to protect the synapse before the development of irreversible brain damage.

Modulation of fear generalization by the zona incerta.

Fear expressed toward threat-associated stimuli is an adaptive behavioral response. In contrast, the generalization of fear responses toward nonthreatening cues is a maladaptive and debilitating dimension of trauma- and anxiety-related disorders. Expressing fear to appropriate stimuli and suppressing fear generalization require integration of relevant sensory information and motor output. While thalamic and subthalamic brain regions play important roles in sensorimotor integration, very little is known about the contribution of these regions to the phenomenon of fear generalization. In this study, we sought to determine whether fear generalization could be modulated by the zona incerta (ZI), a subthalamic brain region that influences sensory discrimination, defensive responses, and retrieval of fear memories. To do so, we combined differential intensity-based auditory fear conditioning protocols in mice with C-FOS immunohistochemistry and designer receptors exclusively activated by designer drugs (DREADDs)-based manipulation of neuronal activity in the ZI. C-FOS immunohistochemistry revealed an inverse relationship between ZI activation and fear generalization: The ZI was less active in animals that generalized fear. In agreement with this relationship, chemogenetic inhibition of the ZI resulted in fear generalization, while chemogenetic activation of the ZI suppressed fear generalization. Furthermore, targeted stimulation of GABAergic cells in the ZI reduced fear generalization. To conclude, our data suggest that stimulation of the ZI could be used to treat fear generalization in the context of trauma- and anxiety-related disorders.

Chronic stress induces cell type-selective transcriptomic and electrophysiological changes in the bed nucleus of the stria terminalis.

Distinct regions and cell types in the anterolateral group of the bed nucleus of the stria terminalis (BNSTALG) act to modulate anxiety in opposing ways. A history of chronic stress increases anxiety-like behavior with lasting electrophysiological effects on the BNSTALG. However, the opposing circuits within the BNSTALG suggest that stress may have differential effects on the individual cell types that comprise these circuits to shift the balance to favor anxiogenesis. Yet, the effects of stress are generally examined by treating all neurons within a particular region of the BNST as a homogenoeus population. We used patch-clamp electrophysiology and single-cell quantitative reverse transcriptase PCR (scRT-PCR) to determine how chronic shock stress (CSS) affects electrophysiological and neurochemical properties of Type I, Type II, and Type III neurons in the BNSTALG. We report that CSS resulted in changes in the input resistance, time constant, action potential waveform, and firing rate of Type III but not Type I or II neurons. Additionally, only the Type III neurons exhibited an increase in Crf mRNA and a decrease in striatal-enriched protein tyrosine phosphatase (Ptpn5) mRNA after CSS. In contrast, only non-Type III cells showed a reduction in calcium-permeable AMPA receptor (CP-AMPAR) current and changes in mRNA expression of genes encoding AMPA receptor subunits after CSS. Importantly, none of the effects of CSS observed were seen in all cell types. Our results suggest that Type III neurons play a unique role in the BNSTALG circuit and represent a population of CRF neurons particularly sensitive to chronic stress.

Rho-kinase inhibition has antidepressant-like efficacy and expedites dendritic spine pruning in adolescent mice.

Adolescence represents a critical period of neurodevelopment, defined by structural and synaptic pruning within the prefrontal cortex. While characteristic of typical development, this structural instability may open a window of vulnerability to developing neuropsychiatric disorders, including depression. Thus, therapeutic interventions that support or expedite neural remodeling in adolescence may be advantageous. Here, we inhibited the neuronally-expressed cytoskeletal regulatory factor Rho-kinase (ROCK), focusing primarily on the clinically-viable ROCK inhibitor fasudil. ROCK inhibition had rapid antidepressant-like effects in adolescent mice, and its efficacy was comparable to ketamine and fluoxetine. It also modified levels of the antidepressant-related signaling factors, tropomyosin/tyrosine receptor kinase B and Akt, as well as the postsynaptic marker PSD-95, in the ventromedial prefrontal cortex (vmPFC). Meanwhile, adolescent-typical dendritic spine pruning on excitatory pyramidal neurons in the vmPFC was expedited. Further, vmPFC-specific shRNA-mediated reduction of ROCK2, the dominant ROCK isoform in the brain, had antidepressant-like consequences. We cautiously suggest that ROCK inhibitors may have therapeutic potential for adolescent-onset depression.

Treatment with IL-19 improves locomotor functional recovery after contusion trauma to the spinal cord.

BACKGROUND AND PURPOSE: IL-19 skews the immune response towards a Th2 type and appears to stimulate angiogenesis. In the current study, we tested if IL-19 treatment could reduce secondary injury and improve functional recovery after contusion spinal cord injury (SCI). EXPERIMENTAL APPROACH: Firstly, mice were given a moderate-severe thoracic SCI at the T9-10 level and expression of IL-19 and its receptor was measured in the injured spinal cord. Then SCI mice were treated with mouse recombinant IL-19 and its blocking antibody to investigate the therapeutic effect of IL-19. KEY RESULTS: Protein expression of IL-19 and its receptor IL-20R1 and IL-20R2 was up-regulated in the injured spinal cord of mice. IL-19 treatment promoted the recovery of locomotor function dose-dependently and reduced loss of motor neurons and microglial and glial activation following SCI. Treatment of SCI mice with IL-19 attenuated macrophage accumulation, reduced protein levels of TNF-α and CCL2 and promoted Th2 response and M2 macrophage activation in the injured region. Treatment of SCI mice with IL-19 promoted angiogenesis through up-regulating VEGF in the injured region. Treatment of SCI mice with IL-19 up-regulated HO-1 expression and decreased oxidative stress in the injured region. The beneficial effect of IL-19 was abolished by coadministration of the blocking antibody. Additionally, IL-19 deficiency in mice delayed the recovery of locomotor function following SCI. CONCLUSIONS AND IMPLICATIONS: IL-19 treatment reduced secondary injuries and improved locomotor functional recovery after contusion SCI, through diverse mechanisms including immune cell polarization, angiogenesis and anti-oxidative responses.

Association of vitamin D receptor BsmI rs1544410 and ApaI rs7975232 polymorphisms with susceptibility to adolescent idiopathic scoliosis: A systematic review and meta-analysis.

BACKGROUND: AIS is the most common spinal deformity disease, yet its etiology remains uncertain. Significant associations have been found between AIS risk and vitamin D receptor (VDR) gene polymorphisms; however, some of these results are controversial. The aim of this study was to determine whether VDR BsmI rs1544410 and ApaI rs7975232 polymorphisms are correlated with AIS. METHODS: Databases, including PubMed, EMBASE, Web of Science, the Cochrane Library, the Chinese Biomedical Literature Database, and the Wanfang Database, were systematically searched, and eligible case-control studies that explored the association of VDR (BsmI and ApaI) and the susceptibility to AIS were selected. The pooled odds ratio (OR) with 95% confidence interval (95% CI) was calculated to assess the associations, and subgroup meta-analyses were performed according to the ethnicity of the study population. RESULTS: A total of 5 studies with 717 cases and 554 controls fulfilled the inclusion criteria after assessment by 2 reviewers. Generally, significant correlations were found between the BsmI polymorphism and AIS risk in overall populations and in Asian populations (overall population: B vs b: OR = 2.12, 95% CI = 1.21-3.75, P = .009; BB vs bb: OR = 3.38, 95% CI = 1.08-10.57, P = .036; Bb vs bb: OR = 2.50, 95% CI = 1.29-4.82, P = .006; BB/Bb vs bb: OR = 2.71, 95% CI = 1.31-5.63, P = .007; Asian population: B vs b: OR = 2.42, 95% CI = 1.27-4.61, P = .007; BB vs bb: OR = 4.09, 95% CI = 1.03-16.22, P = .045; Bb vs bb: OR =  2.94, 95% CI = 1.42-6.10, P = .004; BB/Bb vs bb: OR = 3.23, 95% CI = 1.42-7.35, P = .005). There was no significant association observed in Caucasian populations (all P > .05). With regard to the ApaI polymorphism, we found that it significantly decreased the risk of AIS (Aa vs AA: OR = 0.43, 95% CI = 0.24-0.77, P = .004; Aa/aa vs AA: OR = 0.52, 95% CI = 0.30-0.91, P = .023); however, we could not draw a definitive conclusion for Caucasian populations, as no studies have been conducted in this group to determine the role of the VDR ApaI polymorphism in AIS etiology and development. CONCLUSION: VDR BsmI was significantly associated with AIS susceptibility in the overall and Asian populations, while the VDR ApaI polymorphism only played a key role in AIS etiology and development in Asian populations.