Divergent roles of estrogen receptor subtypes in regulating estrogen-modulated colonic ion transports and epithelial repair.

Although it was described previously for estrogen (E2) regulation of intestinal epithelial Cl- and HCO3- secretion in sex difference, almost nothing is known about the roles of estrogen receptor (ER) subtypes in regulating E2-modulated epithelial ion transports and epithelial restitution. Here, we aimed to investigate ERα and ERß subtypes in the regulation of E2-modulated colonic epithelial HCO3- and Cl- secretion and epithelial restitution. Through physiological and biochemical studies, in combination of genetic knockdown, we showed that ERα attenuated female colonic Cl- secretion but promoted Ca2+-dependent HCO3- secretion via store-operated calcium entry (SOCE) mechanism in mice. However, ERß attenuated HCO3- secretion by inhibiting Ca2+via the SOCE and inhibiting cAMP via protein kinases. Moreover, ERα but not ERß promoted epithelial cell restitution via SOCE/Ca2+ signaling. ERα also enhanced cyclin D1, proliferating cell nuclear antigen, and ß-catenin expression in normal human colonic epithelial cells. All ERα-mediated biological effects could be attenuated by its selective antagonist and genetic knockdown. Finally, both ERα and ERß were expressed in human colonic epithelial cells and mouse colonic tissues. We therefore conclude that E2 modulates complex colonic epithelial HCO3- and Cl- secretion via ER subtype-dependent mechanisms and that ERα is specifically responsible for colonic epithelial regeneration. This study provides novel insights into the molecular mechanisms of how ERα and ERß subtypes orchestrate functional homeostasis of normal colonic epithelial cells.

Online and offline effects of parietal 10 Hz repetitive transcranial magnetic stimulation on working memory in healthy controls.

Parietal alpha activity shows a specific pattern of phasic changes during working memory. It decreases during the encoding and recall phases but increases during the maintenance phase. This study tested whether online rTMS delivered to the parietal cortex during the maintenance phase of a working memory task would increase alpha activity and hence improve working memory. Then, 46 healthy volunteers were randomly assigned to two groups to receive 3-day parietal 10 Hz online rTMS (either real or sham, 3600 pulses in total) that were time-locked to the maintenance phase of a spatial span task (180 trials in total). Behavioral performance on another spatial span task and EEG signals during a change detection task were recorded on the day before the first rTMS (pretest) and the day after the last rTMS (posttest). We found that rTMS improved performance on both online and offline spatial span tasks. For the offline change detection task, rTMS enhanced alpha activity within the maintenance phase and improved interference control of working memory at both behavioral (K score) and neural (contralateral delay activity) levels. These results suggested that rTMS with alpha frequency time-locked to the maintenance phase is a promising way to boost working memory.

Altered effective connectivity among face-processing systems in major depressive disorder.

BACKGROUND: Neuroimaging studies have revealed abnormal functional interaction during the processing of emotional faces in patients with major depressive disorder (MDD), thereby enhancing our comprehension of the pathophysiology of MDD. However, it is unclear whether there is abnormal directional interaction among face-processing systems in patients with MDD. METHODS: A group of patients with MDD and a healthy control group underwent a face-matching task during functional magnetic resonance imaging. Dynamic causal modelling (DCM) analysis was used to investigate effective connectivity between 7 regions in the face-processing systems. We used a Parametric Empirical Bayes model to compare effective connectivity between patients with MDD and controls. RESULTS: We included 48 patients and 44 healthy controls in our analyses. Both groups showed higher accuracy and faster reaction time in the shape-matching condition than in the face-matching condition. However, no significant behavioural or brain activation differences were found between the groups. Using DCM, we found that, compared with controls, patients with MDD showed decreased self-connection in the right dorsolateral prefrontal cortex (DLPFC), amygdala, and fusiform face area (FFA) across task conditions; increased intrinsic connectivity from the right amygdala to the bilateral DLPFC, right FFA, and left amygdala, suggesting an increased intrinsic connectivity centred in the amygdala in the right side of the face-processing systems; both increased and decreased positive intrinsic connectivity in the left side of the face-processing systems; and comparable task modulation effect on connectivity. LIMITATIONS: Our study did not include longitudinal neuroimaging data, and there was limited region of interest selection in the DCM analysis. CONCLUSION: Our findings provide evidence for a complex pattern of alterations in the face-processing systems in patients with MDD, potentially involving the right amygdala to a greater extent. The results confirm some previous findings and highlight the crucial role of the regions on both sides of face-processing systems in the pathophysiology of MDD.

Effects of working memory span training on top-down attentional asymmetry at both neural and behavioral levels.

The leftward asymmetry of the visual field and posterior brain regions, a feature of the normal attention process, can be strengthened by brain stimulation, e.g. administering alpha frequency stimulation to the left posterior cortex. However, whether it can be strengthened by cognitive training, especially with nonlateralized tasks, is unknown. We used a dataset from a 2-month-long randomized controlled trial and compared the control group with 2 training groups trained with backward or forward memory span tasks. A lateralized change detection task with varied memory loads was administered as the pre-, mid-, and post-tests with simultaneous electroencephalographic recording. Intrasubject response variability (IRV) and the alpha modulation index (MI) were calculated. Analysis of IRV showed more enhanced leftward attentional bias in the backward group than in the other groups. Consistently, analysis of MI found that its enhancements in the left hemisphere (but not the right hemisphere) of the backward group were significantly higher than those of the other groups. Further analysis revealed that left MI changes predicted left IRV improvement. All of these results indicated that backward memory span training enhanced leftward attentional asymmetry at both the behavioral and neural levels.

Effects of 12-week escitalopram treatment on resting-state functional connectivity of large-scale brain networks in major depressive disorder.

In this study, the effects of antidepressants on large-scale brain networks and the neural basis of individual differences in response were explored. A total of 41 patients with major depressive disorder (MDD) and 42 matched healthy controls (HCs) were scanned by resting-state functional magnetic resonance imaging separately at baseline and after a 12-week follow-up. The patients with MDD received escitalopram for 12 weeks. After treatment, patients were classified into those with MDD in remission [MDDr, endpoint 17-item Hamilton Depression Rating Scale (HAMD) total score ≤7] and those in nonremission (MDDnr). The human Brainnetome Atlas was used to define large-scale networks and compute within- and between-network resting-state functional connectivity (rsFC). Results showed the decreased subcortical network (SCN)-ventral attention network (VAN) connectivity at baseline increased in patients with MDD after 12-week treatment, and it was comparable with that of HCs. This change was only observed in patients with MDDr. However, the decreased within-network rsFC in SCN and default mode network (DMN) persisted in all patients with MDD, including those with MDDr and MDDnr, after treatment. The strength of SCN-VAN connectivity at baseline was significantly negatively correlated with the reduction rate of HAMD score in all patients with MDD. Thus, SCN-VAN connectivity may be an antidepressant target associated with depressive state changes and a predictor of treatment response to serotonin reuptake inhibitors. The within-network rsFC in SCN and DMN may reflect a trait-like abnormality in MDD. These findings provide further insights into the mechanism of antidepressants and their individual differences in response. The trial name is "Appropriate technology study of MDD diagnosis and treatment based on objective indicators and measurement" (URL: http://www.chictr.org.cn/showproj.aspx?proj=21377; registration number: ChiCTR-OOC-17012566).

Intermittent theta burst stimulation over the parietal cortex has a significant neural effect on working memory.

The crucial role of the parietal cortex in working memory (WM) storage has been identified by fMRI studies. However, it remains unknown whether repeated parietal intermittent theta-burst stimulation (iTBS) can improve WM. In this within-subject randomized controlled study, under the guidance of fMRI-identified parietal activation in the left hemisphere, 22 healthy adults received real and sham iTBS sessions (five consecutive days, 600 pulses per day for each session) with an interval of 9 months between the two sessions. Electroencephalography signals of each subject before and after both iTBS sessions were collected during a change detection task. Changes in contralateral delay activity (CDA) and K-score were then calculated to reflect neural and behavioral WM improvement. Repeated-measures ANOVA suggested that real iTBS increased CDA more than the sham one (p = .011 for iTBS effect). Further analysis showed that this effect was more significant in the left hemisphere than in the right hemisphere (p = .029 for the hemisphere-by-iTBS interaction effect). Pearson correlation analyses showed significant correlations for two conditions between CDA changes in the left hemisphere and K score changes (ps <.05). In terms of the behavioral results, significant K score changes after real iTBS were observed for two conditions, but a repeated-measures ANOVA showed a nonsignificant main effect of iTBS (p = .826). These results indicate that the current iTBS protocol is a promising way to improve WM capability based on the neural indicator (CDA) but further optimization is needed to produce a behavioral effect.

Neural representations of the amount and the delay time of reward in intertemporal decision making.

Numerous studies have examined the neural substrates of intertemporal decision-making, but few have systematically investigated separate neural representations of the two attributes of future rewards (i.e., the amount of the reward and the delay time). More importantly, no study has used the novel analytical method of representational connectivity analysis (RCA) to map the two dimensions' functional brain networks at the level of multivariate neural representations. This study independently manipulated the amount and delay time of rewards during an intertemporal decision task. Both univariate and multivariate pattern analyses showed that brain activity in the dorsomedial prefrontal cortex (DMPFC) and lateral frontal pole cortex (LFPC) was modulated by the amount of rewards, whereas brain activity in the DMPFC and dorsolateral prefrontal cortex (DLPFC) was modulated by the length of delay. Moreover, representational similarity analysis (RSA) revealed that even for the regions of the DMPFC that overlapped between the two dimensions, they manifested distinct neural activity patterns. In terms of individual differences, those with large delay discounting rates (k) showed greater DMPFC and LFPC activity as the amount of rewards increased but showed lower DMPFC and DLPFC activity as the delay time increased. Lastly, RCA suggested that the topological metrics (i.e., global and local efficiency) of the functional connectome subserving the delay time dimension inversely predicted individual discounting rate. These findings provide novel insights into neural representations of the two attributes in intertemporal decisions, and offer a new approach to construct task-based functional brain networks whose topological properties are related to impulsivity.

The VNTR of the AS3MT gene is associated with brain activations during a memory span task and their training-induced plasticity.

BACKGROUND: The Arsenic (+3 oxidation state) methyltransferase (AS3MT) gene has been identified as a top risk gene for schizophrenia in several large-scale genome-wide association studies. A variable number tandem repeat (VNTR) of this gene is the most significant expression quantitative trait locus, but its role in brain activity in vivo is still unknown. METHODS: We first performed a functional magnetic resonance imaging (fMRI) scan of 101 healthy subjects during a memory span task, trained all subjects on an adaptive memory span task for 1 month, and finally performed another fMRI scan after the training. After excluding subjects with excessive head movements for one or more scanning sessions, data from 93 subjects were included in the final analyses. RESULTS: The VNTR was significantly associated with both baseline brain activation and training-induced changes in multiple regions including the prefrontal cortex and the anterior and posterior cingulate cortex. Additionally, it was associated with baseline brain activation in the striatum and the parietal cortex. All these results were corrected based on the family-wise error rate method across the whole brain at the peak level. CONCLUSIONS: This study sheds light on the role of AS3MT gene variants in neural plasticity related to memory span training.

Resting-state functional connectivity of the amygdala subregions in unmedicated patients with obsessive-compulsive disorder before and after cognitive behavioural therapy.

BACKGROUND: Cognitive behavioural therapy (CBT) is considered an effective first-line treatment for obsessive-compulsive disorder (OCD). However, the neural basis of CBT for OCD has not yet been elucidated. The role of the amygdala in OCD and its functional coupling with the cerebral cortex have received increasing attention, and may provide new understanding of the neural basis of CBT for OCD. METHODS: We acquired baseline resting-state functional MRI (fMRI) scans from 45 unmedicated patients with OCD and 40 healthy controls; we then acquired another wave of resting-state fMRI scans from the patients with OCD after 12 weeks of CBT. We performed seed-based resting-state functional connectivity analyses of the amygdala subregions to examine changes in patients with OCD as a result of CBT. RESULTS: Compared to healthy controls, patients with OCD showed significantly increased resting-state functional connectivity at baseline between the left basolateral amygdala and the right middle frontal gyrus, and between the superficial amygdala and the right cuneus. In patients with OCD who responded to CBT, we found decreased resting-state functional connectivity after CBT between the amygdala subregions and the visual association cortices and increased resting-state functional connectivity between the amygdala subregions and the right inferior parietal lobe. Furthermore, these changes in resting-state functional connectivity were positively associated with changes in scores on the compulsion or obsession subscales of the Yale-Brown Obsessive-Compulsive Scale. LIMITATIONS: Because of the lack of a second scan for healthy controls after 12 weeks, our results may have been confounded by other variables. CONCLUSION: Our findings yield insights into the pathophysiology of OCD; they also reveal the potential neural changes elicited by CBT, and thus have implications for guiding effective treatment strategies with CBT for OCD.

ERP evidence for the effect of working memory span training on working memory maintenance: A randomized controlled trial.

There is a lot of debate in the literature with regards to whether the effects of working memory span training generalize to working memory tasks that are different from the trained task, however, there is little evidence to date supporting this idea. The present randomized controlled trial included 80 undergraduate students who were randomly assigned to either the experimental group (N = 40) or the control group (N = 40) in order to receive a working memory span intervention for 20 sessions over the course of 4 weeks. Brain electrophysiological signals during a dot pattern expectancy (DPX) task and a change detection task were recorded both before and after the intervention. The amplitudes of characteristic event-related potential (ERP) components reflecting working memory maintenance capability during the delay period of both tasks (i.e., the contingent negative variation or CNV, derived from the DPX task, and the contralateral delay activity or CDA, derived from the change detection task) were used as the primary outcome measures. Our data indicated that the intervention resulted in specific changes in both, the CNV and the CDA, suggesting that working memory span training generalized to working memory maintenance processes as observed in working memory tasks that were different from the trained task. We conclude that working memory span training might serve as a useful tool to improve working memory maintenance capability. Trial Registration: Chinese Clinical Trial Registry (chiCTR-INR-17011728).

Effect of rs1063843 in the CAMKK2 gene on the dorsolateral prefrontal cortex.

Recently, a single nucleotide polymorphism (SNP) in the CAMKK2 gene (rs1063843) was found to be associated with lower expression of the gene in the dorsolateral prefrontal cortex (DLPFC) and with schizophrenia (SCZ) and deficits in working memory and executive function. However, the brain mechanism underlying this association is poorly understood. A functional magnetic resonance imaging (fMRI) study (N = 84 healthy volunteers) involving multiple cognitive tasks, including a Stroop task (to measure attentional executive control), an N-back task (to measure working memory), and a delay discounting task (to measure decision making) to identify the brain regions affected by rs1063843 was performed. Across all three tasks, it was found that carriers of the risk allele consistently exhibited increased activation of the left DLPFC. In addition, the risk allele carriers also exhibited increased activation of the right DLPFC and the left cerebellum during the Stroop task and of the left caudate nucleus during the N-back task. These findings helped to elucidate the role of CAMKK2 in cognitive functions and in the etiology of SCZ. Hum Brain Mapp 37:2398-2406, 2016. © 2016 Wiley Periodicals, Inc.

The ANK3 gene and facial affect processing: An ERP study.

ANK3 is one of the most promising candidate genes for bipolar disorder (BD). A polymorphism (rs10994336) within the ANK3 gene has been associated with BD in at least three genome-wide association studies of BD [McGuffin et al., 2003; Kieseppä, 2004; Edvardsen et al., 2008]. Because facial affect processing is disrupted in patients with BD, the current study aimed to explore whether the BD risk alleles are associated with the N170, an early event-related potential (ERP) component related to facial affect processing. We collected data from two independent samples of healthy individuals (Ns = 83 and 82, respectively) to test the association between rs10994336 and an early event-related potential (ERP) component (N170) that is sensitive to facial affect processing. Repeated-measures analysis of covariance in both samples consistently revealed significant main effects of rs10994336 genotype (Sample I: F (1, 72) = 7.24, P = 0.009; Sample II: F (1, 69) = 11.81, P = 0.001), but no significant interaction of genotype × electrodes (Ps > 0.05) or genotype × emotional conditions (Ps > 0.05). These results suggested that rs10994336 was linked to early ERP component reflecting facial structural encoding during facial affect processing. These results shed new light on the brain mechanism of this risk SNP and associated disorders such as BD. © 2016 Wiley Periodicals, Inc.

Contribution of resting-state functional connectivity of the subgenual anterior cingulate to prediction of antidepressant efficacy in patients with major depressive disorder.

This study investigated how resting-state functional connectivity (rsFC) of the subgenual anterior cingulate cortex (sgACC) predicts antidepressant response in patients with major depressive disorder (MDD). Eighty-seven medication-free MDD patients underwent baseline resting-state functional MRI scans. After 12 weeks of escitalopram treatment, patients were classified into remission depression (RD, n = 42) and nonremission depression (NRD, n = 45) groups. We conducted two analyses: a voxel-wise rsFC analysis using sgACC as a seed to identify group differences, and a prediction model based on the sgACC rsFC map to predict treatment efficacy. Haufe transformation was used to interpret the predictive rsFC features. The RD group showed significantly higher rsFC between the sgACC and regions in the fronto-parietal network (FPN), including the bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral inferior parietal lobule (IPL), compared to the NRD group. These sgACC rsFC measures correlated positively with symptom improvement. Baseline sgACC rsFC also significantly predicted treatment response after 12 weeks, with a mean accuracy of 72.64% (p < 0.001), mean area under the curve of 0.74 (p < 0.001), mean specificity of 0.82, and mean sensitivity of 0.70 in 10-fold cross-validation. The predictive voxels were mainly within the FPN. The rsFC between the sgACC and FPN is a valuable predictor of antidepressant response in MDD patients. These findings enhance our understanding of the neurobiological mechanisms underlying treatment response and could help inform personalized treatment strategies for MDD.

Zinc pyrithione ameliorates colitis in mice by interacting on intestinal epithelial TRPA1 and TRPV4 channels.

AIMS: Although zinc pyrithione (ZPT) has been studied as topical antimicrobial and cosmetic consumer products, little is known about its pharmacological actions in gastrointestinal (GI) health and inflammation. Our aims were to investigate the effects of ZPT on transient receptor potential (TRP) channels and Ca2+ signaling in intestinal epithelial cells (IECs) and its therapeutic potential for colitis. MAIN METHODS: Digital Ca2+ imaging and patch-clamp electrophysiology were performed on human colonic epithelial cells (HCoEpiC) and rat small intestinal epithelial cells (IEC-6). The transcription levels of proinflammatory cytokines such as IL-1ß were detected by RTq-PCR. Dextran sulfate sodium (DSS) was used to induce colitis in mice. KEY FINDINGS: ZPT dose-dependently induced Ca2+ signaling and membrane currents in IECs, which were attenuated by selective blockers of transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 4 (TRPV4) channels, respectively. Interestingly, Ca2+ entry via TRPA1 channels inhibited the activity of TRPV4 channels in HCoEpiC, but not vice versa. ZPT significantly promoted migration of IECs by activating TRPA1 and TRPV4 channels. ZPT reversed lipopolysaccharides (LPS)-induced changes in mRNA expression of TRPA1 and TRPV4. Moreover, ZPT decreased mRNA levels of pro-inflammatory factors promoted by LPS in HCoEpiC, which were restored by selective TRPA1 blocker. In whole animal studies in vivo, ZPT significantly ameliorated DSS-induced body weight loss, colon shortening and increases in stool score, serum calprotectin and lactic acid (LD) in mouse model of colitis. SIGNIFICANCE: ZPT exerts anti-colitic action likely by anti-inflammation and pro-mucosal healing through TRP channels in IECs. The present study not only expands pharmacology spectrum of ZPT in GI tract, but also repurposes it to a potential drug for colitis therapy.

Interaction between BDNF Val66Met polymorphism and mismatch negativity for working memory capacity in schizophrenia.

Both the brain-derived neurotrophic factor (BDNF) valine (Val)/methionine (Met) polymorphism and mismatch negativity (MMN) amplitude are reportedly linked to working memory impairments in schizophrenia. However, there is evident scarcity of research aimed at exploring the relationships among the three factors. In this secondary analysis of a randomized, controlled, double-blind trial, we investigated these relationships. The trial assessed the efficacy of transcranial direct current stimulation for enhancing working memory in clinically stable schizophrenia patients, who were randomly divided into three groups: dorsolateral prefrontal cortex stimulation, posterior parietal cortex stimulation, and sham stimulation groups. Transcranial direct current stimulation was administered concurrently with a working memory task over five days. We assessed the BDNF genotype, MMN amplitude, working memory capacity, and interference control subdomains. These assessments were conducted at baseline with 54 patients and followed up post-intervention with 48 patients. Compared to BDNF Met-carriers, Val homozygotes exhibited fewer positive and general symptoms and increased working memory capacity at baseline. A correlation between MMN amplitude and working memory capacity was noted only in BDNF Val homozygotes. The correlations were significantly different in the two BDNF genotype groups. Furthermore, in the intervention group that showed significant improvement in MMN amplitude, BDNF Val homozygotes exhibited greater enhancement in working memory capacity than Met-carriers. This study provides in vivo evidence for the interaction between MMN and BDNF Val/Met polymorphism for working memory capacity. As MMN has been considered a biomarker of N-methyl-D-aspartate receptor (NMDAR) function, these data shed light on the complex interactions between BDNF and NMDAR in terms of working memory in schizophrenia.

Effects of escitalopram therapy on effective connectivity among core brain networks in major depressive disorder.

BACKGROUND: Patients with major depressive disorder (MDD) have abnormal functional interaction among large-scale brain networks, indicated by aberrant effective connectivity of the default mode network (DMN), salience network (SN), and dorsal attention network (DAN). However, it remains unclear whether antidepressants can normalize the altered effective connectivity in MDD. METHODS: In this study, we collected resting-state functional magnetic resonance imaging data from 46 unmedicated patients with MDD at baseline and after 12 weeks of escitalopram treatment. We also collected data from 58 healthy controls (HCs) at the same time point with the same interval. Using spectral dynamic causal modeling and parametric empirical Bayes, we examined group differences, time effect and their interaction on the casual interactions among the regions of interest in the three networks. RESULTS: Compared with HCs, patients with MDD showed increased positive (excitatory) connections within the DMN, decreased positive connections within the SN and DAN, decreased absolute value of negative (inhibitory) connectivity from the SN and DAN to the DMN, and decreased positive connections between the DAN and the SN. Furthermore, we found that six connections related to the DAN showed decreased group differences in effective connectivity between MDD and HCs during follow-up compared to the baseline. CONCLUSIONS: Our findings suggest that escitalopram therapy can partly improve the disrupted effective connectivity among high-order brain functional networks in MDD. These findings deepened our understanding of the neural basis of antidepressants' effect on brain function in patients with MDD.

The CaSR/TRPV4 coupling mediates pro-inflammatory macrophage function.

AIM: Although calcium-sensing receptor (CaSR) and transient receptor potential vanilloid 4 (TRPV4) channels are functionally expressed on macrophages, it is unclear if they work coordinately to mediate macrophage function. The present study investigates whether CaSR couples to TRPV4 channels and mediates macrophage polarization via Ca2+ signaling. METHODS: The role of CaSR/TRPV4/Ca2+ signaling was assessed in lipopolysaccharide (LPS)-treated peritoneal macrophages (PMs) from wild-type (WT) and TRPV4 knockout (TRPV4 KO) mice. The expression and function of CaSR and TRPV4 in PMs were analyzed by immunofluorescence and digital Ca2+ imaging. The correlation factors of M1 polarization, CCR7, IL-1ß, and TNFα were detected using q-PCR, western blot, and ELISA. RESULTS: We found that PMs expressed CaSR and TRPV4, and CaSR activation-induced marked Ca2+ signaling predominately through extracellular Ca2+ entry, which was inhibited by selective pharmacological blockers of CaSR and TRPV4 channels. The CaSR activation-induced Ca2+ signaling was significantly attenuated in PMs from TRPV4 KO mice compared to those from WT mice. Moreover, the CaSR activation-induced Ca2+ entry via TRPV4 channels was inhibited by blocking phospholipases A2 (PLA2)/cytochromeP450 (CYP450) and phospholipase C (PLC)/Protein kinase C (PKC) pathways. Finally, CaSR activation promoted the expression and release of M1-associated cytokines IL-1ß and TNFɑ, which were attenuated in PMs from TRPV4 KO mice. CONCLUSION: We reveal a novel coupling of the CaSR and TRPV4 channels via PLA2/CYP450 and PLC/PKC pathways, promoting a Ca2+ -dependent M1 macrophage polarization. Modulation of this coupling and downstream pathways may become a potential strategy for the prevention/treatment of immune-related disease.

Cl- induces endothelium-dependent mesenteric arteriolar vasorelaxation through the NKCC1/TRPV4/NCX axis.

AIMS: Although absorbed NaCl increases intestinal blood flow to facilitate absorption and transportation, it is unclear if it can directly mediate mesenteric arterial relaxation. We aimed to investigate and test our hypothesis that Cl- induces mesenteric arterial vasorelaxation via endothelium-dependent hyperpolarization (EDH). MAIN METHODS: We used wire myograph to study NaCl-induced vasorelaxation of mesenteric arteries isolated from mice. Cl-, Ca2+ and K+ imaging was performed in human vascular endothelial cells pre-treated with pharmacological agents. KEY FINDINGS: The Cl- concentration-dependently induced vasorelaxation of mesenteric arteries likely through EDH. The Cl--induced vasorelaxation was attenuated in TRPV4 KO mice and inhibited by selective blockers of Na+-K+-2Cl- cotransporter 1 (NKCC1) (bumetanide, 10 µM), transient receptor potential vanilloid 4 (TRPV4) (RN-1734, 40 µM), and small conductance Ca2+-activated K+ channels (SKCa) (apamin, 3 µM)/ intermediate conductance Ca2+-activated K+ channels (IKCa) (TRAM-34, 10 µM) and myoendothelial gap junction (18α-glycyrrhetinic acid, 10 µM), but enhanced by a selective activator of IKCa/SKCa (SKA-31, 0.3 µM). Cl- decreased intracellular K+ concentrations in endothelial cells, which was reversed by apamin (200 nM) plus TRAM-34 (500 nM). Extracellular Cl- raised intracellular Cl- concentrations in endothelial cells, which was attenuated by bumetanide (10 µM). Finally, Cl- induced a transient Ca2+ signaling via TRPV4 in endothelial cells, which became sustained when the Ca2+ exit mode of Na+-Ca2+ exchanger (NCX) was blocked. SIGNIFICANCE: Cl- induces a pure EDH-mediated vasorelaxation of mesenteric arteries through activation of endothelial NKCC1/TRPV4/NCX axis. We have provided a novel insight into the role of Cl--induced vasorelaxation via EDH mechanism.

Neuroanatomical and functional substrates of the hypomanic personality trait and its prediction on aggression.

Hypomanic personality manifests a close link with several psychiatric disorders and its abnormality is a risk indicator for developing bipolar disorders. We systematically investigated the potential neuroanatomical and functional substrates underlying hypomanic personality trait (HPT) and its sub-dimensions (i.e., Social Vitality, Mood Volatility, and Excitement) combined with structural and functional imaging data as well as their corresponding brain networks in a large non-clinical sample across two studies (n = 464). Behaviorally, HPT, specifically Mood Volatility and Excitement, was positively associated with aggressive behaviors in both studies. Structurally, sex-specific morphological characteristics were further observed in the motor and top-down control networks especially for Mood Volatility, although HPT was generally positively associated with grey matter volumes (GMVs) in the prefrontal, temporal, visual, and limbic systems. Functionally, brain activations related to immediate or delayed losses were found to predict individual variability in HPT, specifically Social Vitality and Excitement, on the motor and prefrontal-parietal cortices. Topologically, connectome-based prediction model analysis further revealed the predictive role of individual-level morphological and resting-state functional connectivity on HPT and its sub-dimensions, although it did not reveal any links with general brain topological properties. GMVs in the temporal, limbic (e.g., amygdala), and visual cortices mediated the effects of HPT on behavioral aggression. These findings suggest that the imbalance between motor and control circuits may be critical for HPT and provide novel insights into the neuroanatomical, functional, and topological mechanisms underlying the specific temperament and its impacts on aggression.

Effects of forward and backward span trainings on working memory: Evidence from a randomized controlled trial.

Both forward and backward working memory span tasks have been used in cognitive training, but no study has been conducted to test whether the two types of trainings are equally effective. Based on data from a randomized controlled trial, this study (N = 60 healthy college students) tested the effects of backward span training, forward span training, and no intervention. Event-related potential (ERP) signals were recorded at the pre-, mid-, and post-tests while the subjects were performing a distractor version of the change detection task, which included three conditions (2 targets and 0 distractor [2T0D]; 4 targets and 0 distractor [4T0D]; and 2 targets and 2 distractors [2T2D]). Behavioral data were collected from two additional tasks: a multi-object version of the change detection task, and a suppress task. Compared to no intervention, both forward and backward span trainings led to significantly greater improvement in working memory maintenance, based on indices from both behavioral (Kmax) and ERP data (CDA_2T0D and CDA_4T0D). Backward span training also improved interference control based on the ERP data (CDA_filtering efficiency) to a greater extent than did forward span training and no intervention, but the three groups did not differ in terms of behavioral indices of interference control. These results have potential implications for optimizing the current cognitive training on working memory.