Chronic unpredictable stress induces autophagic death of adult hippocampal neural stem cells.

Chronic psychological stress is a critical factor for neurological complications like anxiety disorders, dementia, and depression. Our previous results show that chronic restraint stress causes cognitive deficits and mood dysregulation by inducing autophagic death of adult hippocampal neural stem cells (NSCs). However, it is unknown whether other models of psychological stress also induce autophagic death of adult hippocampal NSCs. Here, we show that chronic unpredictable stress (CUS) for 10 days impaired memory function and increased anxiety in mice. Immunohistochemical staining with SOX2 and KI67 revealed a significant reduction in the number of NSCs in the hippocampus following exposure to CUS. However, these deficits were prevented by NSC-specific, inducible conditional deletion of Atg7. These findings suggest that autophagic death of adult hippocampal NSCs is a critical pathogenic mechanism underlying stress-induced brain disorders.

Localizing Syntactic Composition with Left-Corner Recurrent Neural Network Grammars.

In computational neurolinguistics, it has been demonstrated that hierarchical models such as recurrent neural network grammars (RNNGs), which jointly generate word sequences and their syntactic structures via the syntactic composition, better explained human brain activity than sequential models such as long short-term memory networks (LSTMs). However, the vanilla RNNG has employed the top-down parsing strategy, which has been pointed out in the psycholinguistics literature as suboptimal especially for head-final/left-branching languages, and alternatively the left-corner parsing strategy has been proposed as the psychologically plausible parsing strategy. In this article, building on this line of inquiry, we investigate not only whether hierarchical models like RNNGs better explain human brain activity than sequential models like LSTMs, but also which parsing strategy is more neurobiologically plausible, by developing a novel fMRI corpus where participants read newspaper articles in a head-final/left-branching language, namely Japanese, through the naturalistic fMRI experiment. The results revealed that left-corner RNNGs outperformed both LSTMs and top-down RNNGs in the left inferior frontal and temporal-parietal regions, suggesting that there are certain brain regions that localize the syntactic composition with the left-corner parsing strategy.

Optogenetic control of mRNA condensation reveals an intimate link between condensate material properties and functions.

Biomolecular condensates, often assembled through phase transition mechanisms, play key roles in organizing diverse cellular activities. The material properties of condensates, ranging from liquid droplets to solid-like glasses or gels, are key features impacting the way resident components associate with one another. However, it remains unclear whether and how different material properties would influence specific cellular functions of condensates. Here, we combine optogenetic control of phase separation with single-molecule mRNA imaging to study relations between phase behaviors and functional performance of condensates. Using light-activated condensation, we show that sequestering target mRNAs into condensates causes translation inhibition. Orthogonal mRNA imaging reveals highly transient nature of interactions between individual mRNAs and condensates. Tuning condensate composition and material property towards more solid-like states leads to stronger translational repression, concomitant with a decrease in molecular mobility. We further demonstrate that ß-actin mRNA sequestration in neurons suppresses spine enlargement during chemically induced long-term potentiation. Our work highlights how the material properties of condensates can modulate functions, a mechanism that may play a role in fine-tuning the output of condensate-driven cellular activities.

Predicting conversational satisfaction of face-to-face conversation through interpersonal similarity in resting-state functional connectivity.

When conversing with an unacquainted person, if it goes well, we can obtain much satisfaction (referred to as conversational satisfaction). Can we predict how satisfied dyads will be with face-to-face conversation? To this end, we employed interpersonal similarity in whole-brain resting-state functional connectivity (RSFC), measured using functional magnetic resonance imaging before dyadic conversation. We investigated whether conversational satisfaction could be predicted from interpersonal similarity in RSFC using multivariate pattern analysis. Consequently, prediction was successful, suggesting that interpersonal similarity in RSFC is an effective neural biomarker predicting how much face-to-face conversation goes well. Furthermore, regression coefficients from predictive models suggest that both interpersonal similarity and dissimilarity contribute to good interpersonal relationships in terms of brain activity. The present study provides the potential of an interpersonal similarity approach using RSFC for understanding the foundations of human relationships and new neuroscientific insight into whether success in human interactions is predetermined.

What Controls the Sulfur Isotope Fractionation during Dissimilatory Sulfate Reduction?

Sulfate often behaves conservatively in the oxygenated environments but serves as an electron acceptor for microbial respiration in a wide range of natural and engineered systems where oxygen is depleted. As a ubiquitous anaerobic dissimilatory pathway, therefore, microbial reduction of sulfate to sulfide has been of continuing interest in the field of microbiology, ecology, biochemistry, and geochemistry. Stable isotopes of sulfur are an effective tool for tracking this catabolic process as microorganisms discriminate strongly against heavy isotopes when cleaving the sulfur-oxygen bond. Along with its high preservation potential in environmental archives, a wide variation in the sulfur isotope effects can provide insights into the physiology of sulfate reducing microorganisms across temporal and spatial barriers. A vast array of parameters, including phylogeny, temperature, respiration rate, and availability of sulfate, electron donor, and other essential nutrients, has been explored as a possible determinant of the magnitude of isotope fractionation, and there is now a broad consensus that the relative availability of sulfate and electron donors primarily controls the magnitude of fractionation. As the ratio shifts toward sulfate, the sulfur isotope fractionation increases. The results of conceptual models, centered on the reversibility of each enzymatic step in the dissimilatory sulfate reduction pathway, are in qualitative agreement with the observations, although the underlying intracellular mechanisms that translate the external stimuli into the isotopic phenotype remain largely unexplored experimentally. This minireview offers a snapshot of our current understanding of the sulfur isotope effects during dissimilatory sulfate reduction as well as their potential quantitative applications. It emphasizes the importance of sulfate respiration as a model system for the isotopic investigation of other respiratory pathways that utilize oxyanions as terminal electron acceptors.

Emodin coupled with high LET neutron beam-a novel approach to treat on glioblastoma.

The primary motivation of this investigative study is trying to find an alternative treatment that can be used to slow down or treat glioblastoma due to the witnessed toxic side effects of the current drugs coupled with limited effectiveness in overall treatment. Consequently, a Chinese plant extract emodin proves to play a critical role in this investigative study since results from the Western blot and the other accompanying assays for anti-cancer effects indicate that it cannot work a lot to suppress cell migration and possible invasion, but rather emodin can be combined with radiation to give desired outcomes. Our result shows that the kind of radiation which acts well with emodin is neutron radiation rather than gamma radiation. Emodin significantly enhanced the radiosensitivity of LN18 and LN428 cells to γ-rays through MTT assay and cell counting. Accordingly, exposure to neutron radiation in the presence of emodin induced apoptotic cell death and autophagic cell death to a significantly higher extent, and suppressed cell migration and invasiveness more robustly. These effects are presumably due to the ability of emodin to amplify the effective dose from neutron radiation more efficiently. Thus, the study below is one such trial towards new interventional discovery and development in relation to glioblastoma treatment.

Aripiprazole sensitizes head and neck cancer cells to ionizing radiation by enhancing the production of reactive oxygen species.

Drug repositioning is an alternative process for drug development in cancer. Specifically, it is a strategy for the discovery of new antitumor drugs by screening previously approved clinical drugs. On the basis of this strategy, aripiprazole, an antipsychotic drug, was found to have anticancer activity. In this study, we investigated the radiosensitizing effects of aripiprazole on head and neck cancer cells at sublethal doses of ionizing radiation (IR) in vitro and in vivo. Treatment with aripiprazole suppressed the growth of head and neck cancer cells in a concentration-dependent manner, as evidenced by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Intriguingly, aripiprazole significantly enhanced the sensitivity of these cells to the IC50 dose of IR. The combination of aripiprazole with IR synergistically increased annexin and propidium iodide double-positive and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cell populations, and induced cleaved poly(ADP-ribose) polymerase and caspase-3 expression, indicating the induction of apoptosis in these cells. Aripiprazole and IR-induced apoptosis were accompanied by an increase in reactive oxygen species and was almost completely suppressed by the addition of the antioxidant, N-acetylcysteine. Finally, aripiprazole greatly sensitized xenograft tumors to IR at doses that did not affect tumor growth. Taken together, these results suggest that aripiprazole could be considered a potent radiosensitizer for head and neck cancer.

Interaction of curcumin with glioblastoma cells via high and low linear energy transfer radiation therapy inducing radiosensitization effects.

Glioblastoma is a deadly cancer tumor in the brain and has a survival rate of about 15 months. Despite the high mortality rate, temozolomide has proven to increase the survival rate of patients when combined with radiotherapy. However, its effects may be limited because some patients develop therapeutic resistance. Curcumin has proven to be a cancer treatment due to its broad anticancer spectrum, high efficiency and low toxic level. Additionally, curcumin significantly enhanced radiation efficacy under high and low Linear Energy Transfer (LET) radiation conditions in vitro. In combination with radiation, curcumin increased the cell population in the sub-G1 phase and the reactive oxygen species (ROS) level, ultimately increasing GBM cellular apoptosis. The radiosensitizing effects of curcumin are much higher in neutron (high LET)-irradiated cell lines than in γ (low LET)-irradiated cell lines. Curcumin plus neutron combination significantly inhibited cell invasion compared with that of single treatment or curcumin combined γ-ray treatment. Curcumin enhances the radiosensitivity of Glioblastoma (GBM), suggesting it may have clinical utility in combination cancer treatment with neutron high-LET radiation.

Cortico-striatal-thalamic loop as a neural correlate of neuroticism in the mind-body interface.

OBJECTIVE: Although brain structural studies have demonstrated the neural correlates of neuroticism, the outcomes are not easily identified because of the various possible brain regions involved, low statistical power (low number of subjects), and brain structural measures available, such as mean diffusivity (MD), which are more suitable than standard regional measures of grey and white-matter volume (rGMV, rWMV) and fractional anisotropy (FA). We hypothesized that neuroticism neural correlates could be detected by MD and differentially identified using other measures. We aimed to visualize the neural correlates of neuroticism. METHODS: A voxel-by-voxel regression analysis was performed using the MD, rGMV, rWMV, or FA value as the dependent variable and with neuroticism scores based on the NEO-FFI and its confounding factors as independent variables in 1207 (693 men and 514 women; age, 20.7 ± 1.8, 18-27 years), non-clinical students in a cross-sectional study. RESULTS: MD in the cortico- (orbitofrontal cortex, anterior cingulate cortex, and posterior insula) striatal- (caudate and putamen) thalamic loop regions, including the right posterior limb of the internal capsule, were positively associated with neuroticism using the threshold-free cluster enhancement method with a family-wise error-corrected threshold of P < 0.0125 (0.05/4, Bonferroni correction for four types of MRI data [MD, rGMV, rWMV, and FA]) at the whole-brain level. CONCLUSIONS: An increased MD has generally been associated with reduced neural tissues and possibly area function. Accordingly, this finding helps elucidate the mechanism of somatization in neuroticism because the regions related to neuroticism are considered neural correlates of somatoform disorders.

Neural Evidence of Language Membership Control in Bilingual Word Recognition: An fMRI Study of Cognate Processing in Chinese-Japanese Bilinguals.

This study aims to examine the neural mechanisms of resolving response competition during bilingual word recognition in the context of language intermixing. During fMRI scanning, Chinese-Japanese unbalanced bilinguals were required to perform a second-language (L2) lexical decision task composed of cognates, interlingual homographs, matched control words from both Chinese (first language) and Japanese (L2), and pseudowords. Cognate word processing showed longer reaction times and greater activation in the supplementary motor area (SMA) than L2 control word processing. In light of the orthographic and semantic overlap of cognates, these results reflect the cognitive processing involved in resolving response conflicts enhanced by the language membership of non-target language during bilingual word recognition. A significant effect of L2 proficiency was also observed only in the SMA, which is associated with the task decision system. This finding supports the bottom-up process in the BIA+ model and the Multilink model. The task/decision system receives the information from the word identification system, making appropriate responses during bilingual word recognition.

GSK3B induces autophagy by phosphorylating ULK1.

Unc-51-like autophagy activating kinase 1 (ULK1), a mammalian homolog of the yeast kinase Atg1, has an essential role in autophagy induction. In nutrient and growth factor signaling, ULK1 activity is regulated by various posttranslational modifications, including phosphorylation, acetylation, and ubiquitination. We previously identified glycogen synthase kinase 3 beta (GSK3B) as an upstream regulator of insulin withdrawal-induced autophagy in adult hippocampal neural stem cells. Here, we report that following insulin withdrawal, GSK3B directly interacted with and activated ULK1 via phosphorylation of S405 and S415 within the GABARAP-interacting region. Phosphorylation of these residues facilitated the interaction of ULK1 with MAP1LC3B and GABARAPL1, while phosphorylation-defective mutants of ULK1 failed to do so and could not induce autophagy flux. Furthermore, high phosphorylation levels of ULK1 at S405 and S415 were observed in human pancreatic cancer cell lines, all of which are known to exhibit high levels of autophagy. Our results reveal the importance of GSK3B-mediated phosphorylation for ULK1 regulation and autophagy induction and potentially for tumorigenesis.

Neural mechanisms of language learning from social contexts.

Humans learn languages in real-life situations by integrating multiple signals, including linguistic forms, their meanings, and the actions and intentions of speakers. However, little is known about the neural bases underlying the social learning of a second language (L2) in adults. In this study, 36 adults were asked to learn two sets of L2 spoken words through translation versus simulated social interactive videos (social learning). Brain activation during word learning was measured using fMRI. Greater activation was observed in the bilateral superior temporal sulcus, posterior middle temporal gyri, and right inferior parietal lobule during social learning as compared with translation learning. Furthermore, higher activity in the right temporal parietal junction, right hippocampus, and motor areas was observed during the initial stage of social learning, with the more successful performance being at the time of overnight testing. We argue that social learning may strengthen the link from new L2 forms to rich L2 semantic representations wherein memory properties are embodied, multimodal, and richly contextualized.

Effects of training of shadowing and reading aloud of second language on working memory and neural systems.

Shadowing and reading aloud both involve multiple complex cognitive processes, and both are considered effective methods for second-language learning. The working memory system, particularly the phonological loop, has been suggested to be involved in shadowing and reading aloud. The purpose of this study was to investigate the effects of a 4-week intensive adaptive training including shadowing and reading aloud of second language on working-memory capacity, regional gray matter volume (rGMV), and functional activation related to the n-back working-memory task in young adults. The results showed that compared with the training groups without speaking (listening to compressed speech and active control involving the second language), the training groups with speaking (shadowing and reading aloud) showed a tendency for greater test-retest increases in digit-span scores, and significantly greater test-retest decreases in N-back task reaction time (increase in working memory performance). Imaging analyses revealed compared with the active control group, shadowing group exhibited decreases in rGMV and brain activity during the working memory task (2-back task), in the left cerebellum and reading group exhibited decreases in them in the right anterior insula. These regions are parts of the phonological loop, suggesting the presence of training-induced neural plasticity in these neurocognitive mechanisms.

Brain activity predicts future learning success in intensive second language listening training.

This study explores neural mechanisms underlying how prior knowledge gained from pre-listening transcript reading helps comprehend fast-rate speech in a second language (L2) and applies to L2 learning. Top-down predictive processing by prior knowledge may play an important role in L2 speech comprehension and improving listening skill. By manipulating the pre-listening transcript effect (pre-listening transcript reading [TR] vs. no transcript reading [NTR]) and type of languages (first language (L1) vs. L2), we measured brain activity in L2 learners, who performed fast-rate listening comprehension tasks during functional magnetic resonance imaging. Thereafter, we examined whether TR_L2-specific brain activity can predict individual learning success after an intensive listening training. The left angular and superior temporal gyri were key areas responsible for integrating prior knowledge to sensory input. Activity in these areas correlated significantly with gain scores on subsequent training, indicating that brain activity related to prior knowledge-sensory input integration predicts future learning success.

Prefrontal Inter-brain Synchronization Reflects Convergence and Divergence of Flow Dynamics in Collaborative Learning: A Pilot Study.

Flow is a highly motivated and affectively positive state in which a person is deeply engaged in an activity and feeling enjoyment from it. In collaborative activities, it would be optimal if all participants were in a state of flow. However, flow states fluctuate amongst individuals due to differences in the dynamics of motivation and cognition. To explore the possibility that inter-brain synchronization can provide a quantitative measure of the convergence and divergence of collective motivational dynamics, we conducted a pilot study to investigate the relationship between inter-brain synchronization and the interpersonal similarity of flow state dynamics during the collaborative learning process. In two English as a Foreign Language (EFL) classes, students were divided into groups of three-four and seated at desks facing each other while conducting a 60-min group work. In both classes, two groups with four members were randomly selected, and their medial prefrontal neural activities were measured simultaneously using wireless functional near-infrared spectroscopy (fNIRS) devices. Later the participants observed their own activities on recorded videos and retrospectively rated their subjective degree of flow state on a seven-point scale for each 2-min period. For the pairs of students whose neural activities were measured, the similarity of their flow experience dynamics was evaluated by the temporal correlation between their flow ratings. Prefrontal inter-brain synchronization of the same student pairs during group work was evaluated using wavelet transform coherence. Statistical analyses revealed that: (1) flow dynamics were significantly more similar for the student pairs within the same group compared to the pairs of students assigned across different groups; (2) prefrontal inter-brain synchronization in the relatively short time scale (9.3-13.9 s) was significantly higher for the within-group pairs than for the cross-group pairs; and (3) the prefrontal inter-brain synchronization at the same short time scale was significantly and positively correlated with the similarity of flow dynamics, even after controlling for the effects of within- vs. cross-group pair types from the two variables. These suggest that inter-brain synchronization can indeed provide a quantitative measure for converging and diverging collective motivational dynamics during collaborative learning, with higher inter-brain synchronization corresponding to a more convergent flow experience.

Differential roles of amygdala and posterior superior temporal sulcus in social scene understanding.

Neuropsychology and neuroimaging studies provide distinct views on the key neural underpinnings of social scene understanding (SSU): the amygdala and multimodal neocortical areas such as the posterior superior temporal sulcus (pSTS), respectively. This apparent incongruity may stem from the difference in the assumed cognitive processes of the situation-response association and the integrative or creative processing of social information. To examine the neural correlates of different SSU types using functional magnetic resonance imaging (fMRI), we devised a clothing recommendation task in three types of client's standpoint. Situation-response association was induced by a situation-congruent standpoint (ecological SSU), whereas the integrative and creative processing of social information was elicited by a lack and situation incongruence of the standpoint (perceptual and elaborative SSUs, respectively). Activation characteristic of the ecological SSU was identified in the right amygdala, while that of the perceptual SSU and elaborative SSU demand was identified in the right pSTS and left middle temporal gyrus (MTG), respectively. Thus, the current results provide evidence for the conceptual and neural distinction of the three types of SSU, with basic ecological SSU being supported by a limbic structure while sophisticated integrative or creative SSUs being developed in humans by multimodal association cortices.

The social brain of language: grounding second language learning in social interaction.

For centuries, adults may have relied on pedagogies that promote rote memory for the learning of foreign languages through word associations and grammar rules. This contrasts sharply with child language learning which unfolds in socially interactive contexts. In this paper, we advocate an approach to study the social brain of language by grounding second language learning in social interaction. Evidence has accumulated from research in child language, education, and cognitive science pointing to the efficacy and significance of social learning. Work from several recent L2 studies also suggests positive brain changes along with enhanced behavioral outcomes as a result of social learning. Here we provide a blueprint for the brain network underlying social L2 learning, enabling the integration of neurocognitive bases with social cognition of second language while combining theories of language and memory with practical implications for the learning and teaching of a new language in adulthood.

Autophagy as a decisive process for cell death.

Autophagy is an intracellular catabolic pathway in which cellular constituents are engulfed by autophagosomes and degraded upon autophagosome fusion with lysosomes. Autophagy serves as a major cytoprotective process by maintaining cellular homeostasis and recycling cytoplasmic contents. However, emerging evidence suggests that autophagy is a primary mechanism of cell death (autophagic cell death, ACD) and implicates ACD in several aspects of mammalian physiology, including tumor suppression and psychological disorders. However, little is known about the physiological roles and molecular mechanisms of ACD. In this review, we document examples of ACD and discuss recent progress in our understanding of its molecular mechanisms.

Autophagic death of neural stem cells mediates chronic stress-induced decline of adult hippocampal neurogenesis and cognitive deficits.

Macroautophagy/autophagy is generally regarded as a cytoprotective mechanism, and it remains a matter of controversy whether autophagy can cause cell death in mammals. Here, we show that chronic restraint stress suppresses adult hippocampal neurogenesis in mice by inducing autophagic cell death (ACD) of hippocampal neural stem cells (NSCs). We generated NSC-specific, inducible Atg7 conditional knockout mice and found that they had an intact number of NSCs and neurogenesis level under chronic restraint stress and were resilient to stress- or corticosterone-induced cognitive and mood deficits. Corticosterone treatment of adult hippocampal NSC cultures induced ACD via SGK3 (serum/glucocorticoid regulated kinase 3) without signs of apoptosis. Our results demonstrate that ACD is biologically important in a mammalian system in vivo and would be an attractive target for therapeutic intervention for psychological stress-induced disorders.Abbreviations: AAV: adeno-associated virus; ACD: autophagic cell death; ACTB: actin, beta; Atg: autophagy-related; ASCL1/MASH1: achaete-scute family bHLH transcription factor 1; BafA1: bafilomycin A1; BrdU: Bromodeoxyuridine/5-bromo-2'-deoxyuridine; CASP3: caspase 3; cKO: conditional knockout; CLEM: correlative light and electron microscopy; CORT: corticosterone; CRS: chronic restraint stress; DAB: 3,3'-diaminobenzidine; DCX: doublecortin; DG: dentate gyrus; GC: glucocorticoid; GFAP: glial fibrillary acidic protein; HCN: hippocampal neural stem; i.p.: intraperitoneal; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MKI67/Ki67: antigen identified by monoclonal antibody Ki 67; MWM: Morris water maze; Nec-1: necrostatin-1; NES: nestin; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NSC: neural stem cell; PCD: programmed cell death; PFA: paraformaldehyde; PX: Phox homology; PtdIns3P: phosphatidylinositol-3-phosphate; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; SGK: serum/glucocorticoid-regulated kinases; SGZ: subgranular zone; SOX2: SRY (sex determining region Y)-box 2; SQSTM1: sequestosome 1; STS: staurosporine; TAM: tamoxifen; Ulk1: unc-51 like kinase 1; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VIM: vimentin; WT: wild type; ZFYVE1: zinc finger, FYVE domain containing 1; Z-VAD/Z-VAD-FMK: pan-caspase inhibitor.

Prior physical synchrony enhances rapport and inter-brain synchronization during subsequent educational communication.

Physical synchrony has been suggested to have positive effects on not only concurrent but also subsequent communication, but the underlying neural processes are unclear. Using functional near-infrared spectroscopy (fNIRS) hyperscanning, we tested the effects of preceding physical synchrony on subsequent dyadic teaching-learning communication. Thirty-two pairs of participants performed two experimental sessions. In each session, they underwent a rhythmic arm movement block with synchronous or asynchronous conditions, and then taught/learned unknown words to/from each other according to a given scenario. Neural activities in their medial and left lateral prefrontal cortex (PFC) were measured and inter-brain synchronization (IBS) during the teaching-learning blocks was evaluated. Participants rated their subjective rapport during the teaching-learning blocks, and took a word memory test. The analyses revealed that (1) prior physical synchrony enhanced teacher-learner rapport; (2) prior physical synchrony also enhanced IBS in the lateral PFC; and (3) IBS changes correlated positively with rapport changes. Physical synchrony did however not affect word memory performance. These results suggest that IBS can be useful to measure the effects of social-bonding facilitation activities for educational communication.