A Prelimbic Cortex-Thalamus Circuit Bidirectionally Regulates Innate and Stress-Induced Anxiety-Like Behavior.

Anxiety-related disorders respond to cognitive behavioral therapies, which involved the medial prefrontal cortex (mPFC). Previous studies have suggested that subregions of the mPFC have different and even opposite roles in regulating innate anxiety. However, the specific causal targets of their descending projections in modulating innate anxiety and stress-induced anxiety have yet to be fully elucidated. Here, we found that among the various downstream pathways of the prelimbic cortex (PL), a subregion of the mPFC, PL-mediodorsal thalamic nucleus (MD) projection, and PL-ventral tegmental area (VTA) projection exhibited antagonistic effects on anxiety-like behavior, while the PL-MD projection but not PL-VTA projection was necessary for the animal to guide anxiety-related behavior. In addition, MD-projecting PL neurons bidirectionally regulated remote but not recent fear memory retrieval. Notably, restraint stress induced high-anxiety state accompanied by strengthening the excitatory inputs onto MD-projecting PL neurons, and inhibiting PL-MD pathway rescued the stress-induced anxiety. Our findings reveal that the activity of PL-MD pathway may be an essential factor to maintain certain level of anxiety, and stress increased the excitability of this pathway, leading to inappropriate emotional expression, and suggests that targeting specific PL circuits may aid the development of therapies for the treatment of stress-related disorders.

PV network plasticity mediated by neuregulin1-ErbB4 signalling controls fear extinction.

Neuroplasticity in the medial prefrontal cortex (mPFC) is essential for fear extinction, the process of which forms the basis of the general therapeutic process used to treat human fear disorders. However, the underlying molecules and local circuit elements controlling neuronal activity and concomitant induction of plasticity remain unclear. Here we show that sustained plasticity of the parvalbumin (PV) neuronal network in the infralimbic (IL) mPFC is required for fear extinction in adult male mice and identify the involvement of neuregulin 1-ErbB4 signalling in PV network plasticity-mediated fear extinction. Moreover, regulation of fear extinction by basal medial amygdala (BMA)-projecting IL neurons is dependent on PV network configuration. Together, these results uncover the local molecular circuit mechanisms underlying mPFC-mediated top-down control of fear extinction, suggesting alterative therapeutic approaches to treat fear disorders.

CeRNA network identified hsa-miR-17-5p, hsa-miR-106a-5p and hsa-miR-2355-5p as potential diagnostic biomarkers for tuberculosis.

This study aims to analyze the regulatory non-coding RNAs in the pathological process of tuberculosis (TB), and identify novel diagnostic biomarkers. A longitudinal study was conducted in 5 newly diagnosed pulmonary tuberculosis patients, peripheral blood samples were collected before and after anti-TB treatment for 6 months, separately. After whole transcriptome sequencing, the differentially expressed RNAs (DE RNAs) were filtrated with |log2 (fold change) | > log2(1.5) and P value < .05 as screening criteria. Then functional annotation was actualized by gene ontology enrichment analysis, and enrichment pathway analysis was conducted by Kyoto Encyclopedia of Genes and Genomes database. And finally, the competitive endogenous RNA (ceRNA) regulatory network was established according to the interaction of ceRNA pairs and miRNA-mRNA pairs. Five young women were recruited and completed this study. Based on the differential expression analysis, a total of 1469 mRNAs, 996 long non-coding RNAs, 468 circular RNAs, and 86 miRNAs were filtrated as DE RNAs. Functional annotation demonstrated that those DE-mRNAs were strongly involved in the cellular process (n = 624), metabolic process (n = 513), single-organism process (n = 505), cell (n = 651), cell part (n = 650), organelle (n = 569), and binding (n = 629). Enrichment pathway analysis revealed that the differentially expressed genes were mainly enriched in HTLV-l infection, T cell receptor signaling pathway, glycosaminoglycan biosynthesis-heparan sulfate/heparin, and Hippo signaling pathway. CeRNA networks revealed that hsa-miR-17-5p, hsa-miR-106a-5p and hsa-miR-2355-5p might be regarded as potential diagnostic biomarkers for TB. Immunomodulation-related genes are differentially expressed in TB patients, and hsa-miR-106a-5p, hsa-miR-17-5p, hsa-miR-2355-5p might serve as potential diagnostic biomarkers.

Study on the geometry characteristics of soil primary mineral particles under cryogenic action.

Repeated freeze-thaw causes the fragmentation and aggregation of soil particles, which affect particle shape (aspect ratio, roundness, etc.), and this process is a cryogenic weathering process. Changes in soil particle morphology record information about freeze-thaw processes and have the unique characteristics of freeze-thaw traces. To prove this conjecture, four soil specimens were selected in the experiment, and each specimen was studied after 0, 5, 10, 50 and 100 freeze-thaw cycles. The test results show that: Freeze-thaw will change the aspect ratio of particles, and the aspect ratio of particles is mainly distributed between 1 and 4. The particles with aspect ratio of 1.26 are stable and not easy to fragment, and the particles with aspect ratio more than 4 are easy to fragment. The freeze-thaw effect leads to changes in particle roundness, with different manners of change for the four specimens, but all undergo repeated freeze-thaw fragmenting and rounding process. Repeated freezing and thawing can not only lead to fragmentation particle edges and increased particle roundness, but also to fragmentation large-size particles and reduced particle roundness. Compared with the roundness before freeze-thaw and after 100 cycles of freeze-thaw, the coarse sand grains increased the most in roundness, indicating that the large grain size grains showed the most rounding. This study helps to understand the geometric characteristics of soil primary mineral particles under the action of cryogenic environments, and also helps to discern whether the particles have experienced the action of cryogenic environments, which is important for the study of cryogenic soil in cold environments.

Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease.

Aberrant localization of proteins to mitochondria disturbs mitochondrial function and contributes to the pathogenesis of Huntington's disease (HD). However, the crucial factors and the molecular mechanisms remain elusive. Here, we found that heat shock transcription factor 1 (HSF1) accumulates in the mitochondria of HD cell models, a YAC128 mouse model, and human striatal organoids derived from HD induced pluripotent stem cells (iPSCs). Overexpression of mitochondria-targeting HSF1 (mtHSF1) in the striatum causes neurodegeneration and HD-like behavior in mice. Mechanistically, mtHSF1 facilitates mitochondrial fission by activating dynamin-related protein 1 (Drp1) phosphorylation at S616. Moreover, mtHSF1 suppresses single-stranded DNA-binding protein 1 (SSBP1) oligomer formation, which results in mitochondrial DNA (mtDNA) deletion. The suppression of HSF1 mitochondrial localization by DH1, a unique peptide inhibitor, abolishes HSF1-induced mitochondrial abnormalities and ameliorates deficits in an HD animal model and human striatal organoids. Altogether, our findings describe an unsuspected role of HSF1 in contributing to mitochondrial dysfunction, which may provide a promising therapeutic target for HD.

Phloretin inhibited the pathogenicity and virulence factors against Candida albicans.

Oral candidiasis is one of the most common types of fungal infection caused by Candida albicans (C. albicans). The present study aims to investigate the antifungal effects of phloretin (a dihydrochalcone flavonoid) against the C. albicans pathogenicity. In this work, we treated C. albicans SC5314 with 37.28, 74.55, or 149.10 µg/mL (equivalent to 0.5×, 1× or 2× MIC) phloretin in vitro. Besides, we established a mice model of oral candidiasis by a sublingual infection of C. albicans suspension (1 × 107 colony-forming unit/mL), and mice were treated with phloretin (3.73 or 7.46 mg/mL, which were equivalent to 50× or 100× MIC) twice a day starting on day one post-infection. The results showed that the MIC of phloretin against C. albicans was 74.55 µg/mL. Phloretin exerted antifungal activity by inhibiting the biofilm formation and suppressing the yeast-to-hyphae transition upon the downregulation of hypha-associated genes including enhanced adherence to polystyrene 1, the extent of cell elongation gene 1, hyphal wall protein 1 gene, and agglutinin-like sequence gene 3. Next, phloretin repressed the secretion of proteases and phospholipases via reducing the expression of protease-encoding genes secreted aspartyl proteases (SAP)1 and SAP2, as well as phospholipase B1. Subsequently, the in vivo antifungal activity of phloretin was testified by the reverse of the enhanced lesion severity, inflammatory infiltration, and the increased colony-forming unit counts caused by C. albicans of tongue tissues in oral candidiasis mice. In conclusion, phloretin suppressed the pathogenicity and virulence factors against C. albicans both in vivo and in vitro.

Distinct projections from the infralimbic cortex exert opposing effects in modulating anxiety and fear.

Anxiety-related disorders can be treated by cognitive therapies and transcranial magnetic stimulation, which involve the medial prefrontal cortex (mPFC). Subregions of the mPFC have been implicated in mediating different and even opposite roles in anxiety-related behaviors. However, precise causal targets of these top-down connections among diverse possibilities have not been established. Here, we show that the lateral septum (LS) and the central nucleus of the amygdala (CeA) represent 2 direct targets of the infralimbic cortex (IL), a subregion of the mPFC that modulates anxiety and fear. Two projections were unexpectedly found to exert opposite effects on the anxious state and learned freezing: the IL-LS projection promoted anxiety-related behaviors and fear-related freezing, whereas the IL-CeA projection exerted anxiolytic and fear-releasing effects for the same features. Furthermore, selective inhibition of corresponding circuit elements showed opposing behavioral effects compared with excitation. Notably, the IL-CeA projection implemented top-down control of the stress-induced high-anxiety state. These results suggest that distinct IL outputs exert opposite effects in modulating anxiety and fear and that modulating the excitability of these projections with distinct strategies may be beneficial for the treatment of anxiety disorders.

ErbB4 knockdown in serotonergic neurons in the dorsal raphe induces anxiety-like behaviors.

There is a close relationship between serotonergic (5-HT) activity and anxiety. ErbB4, a receptor tyrosine kinase, is expressed in 5-HT neurons. However, whether ErbB4 regulates 5-HT neuronal function and anxiety-related behaviors is unclear. Here, using transgenic and viral approaches, we show that mice with ErbB4 deficiency in 5-HT neurons exhibit heightened anxiety-like behavior and impaired fear extinction, possibly due to an increased excitability of 5-HT neurons in the dorsal raphe nucleus (DRN). Notably, the chemogenetic inhibition of 5-HT neurons in the DRN of ErbB4 mutant mice rescues anxiety-like behaviors. Altogether, our results unravel a previously unknown role of ErbB4 signaling in the regulation of DRN 5-HT neuronal function and anxiety-like behaviors, providing novel insights into the treatment of anxiety disorders.

Erbin in Amygdala Parvalbumin-Positive Neurons Modulates Anxiety-like Behaviors.

BACKGROUND: Anxiety disorders are the most common psychiatric diseases, affecting 28% of people worldwide within their lifetime. The excitation-inhibition imbalance in the amygdala is thought to be an underlying pathological mechanism; however, the cellular and molecular control of amygdala excitation-inhibition balance is largely unknown. METHODS: By using mice expressing chemogenetic activator or inhibitor channel in amygdala parvalbumin (PV) neurons, Erbin mutant mice, and mice with Erbin specifically knocked down in amygdala PV neurons, we systematically investigated the role of amygdala PV neurons and Erbin expressed therein in the pathogenesis of anxiety disorders using the combined approaches of immunohistochemistry, electrophysiology, and behavior. RESULTS: In naïve mice, chemogenetic inhibition of PV neurons produced anxiogenic effects, suggesting an essential role in the regulation of anxiety. In stressed mice with anxiety, excitatory postsynaptic responses on amygdala PV neurons were selectively diminished, accompanied by a decreased expression of Erbin specifically in amygdala PV neurons. Remarkably, both Erbin mutant mice and amygdala PV-specific Erbin knockdown mice exhibited impaired excitatory postsynaptic responses on amygdala PV neurons and increased anxiety-like behaviors. Furthermore, chemogenetic activation of amygdala PV neurons normalized anxiety behaviors in amygdala PV-specific Erbin knockdown mice and stressed mice. CONCLUSIONS: Together, these results demonstrate that Erbin in PV neurons is critical for maintaining the excitation-inhibition balance in the amygdala and reveal a novel pathophysiological mechanism for anxiety disorders.

Satb2 Ablation Impairs Hippocampus-Based Long-Term Spatial Memory and Short-Term Working Memory and Immediate Early Genes (IEGs)-Mediated Hippocampal Synaptic Plasticity.

Special AT-rich sequence-binding protein 2 (Satb2) is a protein binding to the matrix attachment regions of DNA and important for gene regulation. Patients with SATB2 mutation usually suffer moderate to severe mental retardation. However, the mechanisms for the defects of intellectual activities in patients with SATB2 mutation are largely unclear. Here we established the heterozygous Satb2 mutant mice and Satb2 conditional knockout mice to mimic the patients with SATB2 mutation and figured out the role of Satb2 in mental activities. We found that the spatial memory and working memory were significantly damaged in the heterozygous Satb2 mutant mice, early postnatal Satb2-deficient mice (CaMKIIα-Cre+Satb2fl/fl mice), and adult Satb2 ablation mice (Satb2fl/fl mice injected with CaMKIIα-Cre virus). Functionally, late phase long-term potentiation (L-LTP) in these Satb2 mutant mice was greatly impaired. Morphologically, in CA1 neurons of CaMKIIα-Cre+Satb2fl/fl mice, we found decreased spine density of the basal dendrites and less branches of apical dendrites that extended into lacunar molecular layer. Mechanistically, expression levels of immediate early genes (IEGs) including Fos, FosB, and Egr1 were significantly decreased after Satb2 deletion. And, Satb2 could regulate expression of FosB by binding to the promoter of FosB directly. In general, our study uncovers that Satb2 plays an important role in spatial memory and working memory by regulating IEGs-mediated hippocampal synaptic plasticity.