Anti-angiogenesis and anti-immunosuppression gene therapy through targeting COUP-TFII in an in situ glioblastoma mouse model.

Glioblastoma (GBM) is the most common and aggressive primary brain cancer; angiogenesis and immunosuppression exacerbate GBM progression. COUP-TFII demonstrates pro-angiogenesis activity; however, its role in glioma progression remains unclear. This study revealed that COUP-TFII promotes angiogenesis in gliomas by inducing transdifferentiation of glioma cells into endothelial-like cells. Mechanistic investigation suggested that COUP-TFII as a transcription factor exerts its function via binding to the promoter of TXNIP. Interestingly, COUP-TFII knockdown attenuated tumorigenesis and tumor progression in an immunocompetent mouse model but promoted tumor progression in an immuno-deficient mouse model. As an explanation, repression of COUP-TFII induces cellular senescence and activates immune surveillance in glioma cells in vitro and in vivo. In addition, we used heparin-polyethyleneimine (HPEI) nanoparticles to deliver COUP-TFII shRNA, which regulated tumor angiogenesis and immunosuppression in an in situ GBM mouse model. This study provides a novel strategy and potential therapeutic targets to treat GBM.

Effect of glutathione-assisted continuous renal replacement therapy in sepsis patients with acute renal injury.

This study explored the effect of glutathione assisted continuous renal replacement therapy (CRRT) on peripheral blood receptors in sepsis patients with acute kidney injury. A total of 196 sepsis patients with acute kidney injury were recruited to perform a retrospective cohort study, 98 patients treated with glutathione combined with CRRT were included as the combination group, and then 98 patients treated with CRRT alone were included as the control group during the same period. The outcome was changes in the levels of blood urea nitrogen (BUN), serum creatinine (Scr), peripheral blood receptors, acute physiology and chronic health evaluation (APACHE) II, and sequential organ failure assessment (SOFA) before and after treatment. After treatment, the levels of BUN and Scr in both groups of patients were significantly lower than those before treatment, and the levels in the combination group were lower than those in the control group. After treatment, toll-like receptor (TLR) 4 and TLR2 levels in both groups of patients were lower than those before treatment, and the levels in the combination group were lower than those in the control group. After treatment, the APACHE II and SOFA scores of the two groups were lower than those before treatment, and the scores in the combination group were lower than those in the control group. Glutathione-assisted CRRT can improve the renal function of patients and reduce the immune inflammatory response of sepsis patients with acute kidney injury, which can be widely promoted in the clinic.

How do lateral septum projections to the ventral CA1 influence sociability?

JOURNAL/nrgr/04.03/01300535-202408000-00033/figure1/v/2023-12-16T180322Z/r/image-tiff Social dysfunction is a risk factor for several neuropsychiatric illnesses. Previous studies have shown that the lateral septum (LS)-related pathway plays a critical role in mediating social behaviors. However, the role of the connections between the LS and its downstream brain regions in social behaviors remains unclear. In this study, we conducted a three-chamber test using electrophysiological and chemogenetic approaches in mice to determine how LS projections to ventral CA1 (vCA1) influence sociability. Our results showed that gamma-aminobutyric acid (GABA)-ergic neurons were activated following social experience, and that social behaviors were enhanced by chemogenetic modulation of these neurons. Moreover, LS GABAergic neurons extended their functional neural connections via vCA1 glutamatergic pyramidal neurons, and regulating LSGABA→vCA1Glu neural projections affected social behaviors, which were impeded by suppressing LS-projecting vCA1 neuronal activity or inhibiting GABAA receptors in vCA1. These findings support the hypothesis that LS inputs to the vCA1 can control social preferences and social novelty behaviors. These findings provide new insights regarding the neural circuits that regulate sociability.

LncRNA MIR31HG fosters stemness malignant features of non-small cell lung cancer via H3K4me1- and H3K27Ace-mediated GLI2 expression.

Non-coding RNAs are responsible for oncogenesis and the development of stemness features, including multidrug resistance and metastasis, in various cancers. Expression of lncRNA MIR31HG in lung cancer tissues and peripheral sera of lung cancer patients were remarkably higher than that of healthy individuals and indicated a poor prognosis. Functional analysis showed that MIR31HG fosters stemness-associated malignant features of non-small cell lung cancer cells. Further mechanistic investigation revealed that MIR31HG modulated GLI2 expression via WDR5/MLL3/P300 complex-mediated H3K4me and H3K27Ace modification. In vivo MIR31HG repression with an antisense oligonucleotide attenuated tumor growth and distal organ metastasis, whereas MIR31HG promotion remarkably encouraged cellular invasion in lung and liver tissues. Our data suggested that MIR31HG is a potential diagnostic indicator and druggable therapeutic target to facilitate multiple strategic treatments for lung cancer patients.

Role and mechanism of PVN-sympathetic-adipose circuit in depression and insulin resistance induced by chronic stress.

Chronic stress induces depression and insulin resistance, between which there is a bidirectional relationship. However, the mechanisms underlying this comorbidity remain unclear. White adipose tissue (WAT), innervated by sympathetic nerves, serves as a central node in the interorgan crosstalk through adipokines. Abnormal secretion of adipokines is involved in mood disorders and metabolic morbidities. We describe here a brain-sympathetic nerve-adipose circuit originating in the hypothalamic paraventricular nucleus (PVN) with a role in depression and insulin resistance induced by chronic stress. PVN neurons are labelled after inoculation of pseudorabies virus (PRV) into WAT and are activated under restraint stress. Chemogenetic manipulations suggest a role for the PVN in depression and insulin resistance. Chronic stress increases the sympathetic innervation of WAT and downregulates several antidepressant and insulin-sensitizing adipokines, including leptin, adiponectin, Angptl4 and Sfrp5. Chronic activation of the PVN has similar effects. ß-adrenergic receptors translate sympathetic tone into an adipose response, inducing downregulation of those adipokines and depressive-like behaviours and insulin resistance. We finally show that AP-1 has a role in the regulation of adipokine expression under chronic stress.

Computed tomography-determined skeletal muscle density predicts 3-year mortality in initial-dialysis patients in China.

BACKGROUND: Skeletal muscle mass and quality assessed by computed tomography (CT) images of the third lumbar vertebra (L3) level have been established as risk factors for poor clinical outcomes in several illnesses, but the relevance for dialysis patients is unclear. A few studies have suggested a correlation between CT-determined skeletal muscle mass and quality at the first lumbar vertebra (L1) level and adverse outcomes. Generally, chest CT does not reach beyond L1. We aimed to determine whether opportunistic CT scan (chest CT)-determined skeletal muscle mass and quality at L1 are associated with mortality in initial-dialysis patients. METHODS: This 3-year multicentric retrospective study included initial-dialysis patients from four centres between 2014 and 2017 in China. Unenhanced CT images of the L1 and L3 levels were obtained to assess skeletal muscle mass [by skeletal muscle index, (SMI), cm2 /m2 ] and quality [by skeletal muscle density (SMD), HU]. Skeletal muscle measures at L1 were compared with those at L3. The sex-specific optimal cutoff values of L1 SMI and L1 SMD were determined in relation to all-cause mortality. The outcomes were all-cause death and cardiac death. Cox regression models were applied to investigate the risk factors for death. RESULTS: A total of 485 patients were enrolled, of whom 257 had both L1 and L3 images. Pearson's correlation coefficient between L1 and L3 SMI was 0.84 (P < 0.001), and that between L1 and L3 SMD was 0.90 (P < 0.001). No significant association between L1 SMI and mortality was observed (P > 0.05). Low L1 SMD (n = 280, 57.73%) was diagnosed based on the optimal cutoff value (<39.56 HU for males and <33.06 HU for females). Multivariate regression analysis revealed that the low L1 SMD group had higher risks of all-cause death (hazard ratio 1.80; 95% confidence interval 1.05-3.11, P = 0.034) and cardiac death (hazard ratio 3.74; 95% confidence interval 1.43-9.79, P = 0.007). CONCLUSIONS: In initial-dialysis patients, there is high agreement between the L1 and L3 measures for SMI and SMD. Low SMD measured at L1, but not low SMI, is an independent predictor of both all-cause death and cardiac death.

Medial prefrontal cortical PPM1F alters depression-related behaviors by modifying p300 activity via the AMPK signaling pathway.

AIMS: Protein phosphatase Mg2+/Mn2+-dependent 1F (PPM1F) is a serine/threonine phosphatase, and its dysfunction in depression in the hippocampal dentate gyrus has been previously identified. Nevertheless, its role in depression of another critical emotion-controlling brain region, the medial prefrontal cortex (mPFC), remains unclear. We explored the functional relevance of PPM1F in the pathogenesis of depression. METHODS: The gene expression levels and colocalization of PPM1F in the mPFC of depressed mice were measured by real-time PCR, western blot and immunohistochemistry. An adeno-associated virus strategy was applied to determine the impact of knockdown or overexpression of PPM1F in the excitatory neurons on depression-related behaviors under basal and stress conditions in both male and female mice. The neuronal excitability, expression of p300 and AMPK phosphorylation levels in the mPFC after knockdown of PPM1F were measured by electrophysiological recordings, real-time PCR and western blot. The depression-related behavior induced by PPM1F knockdown after AMPKα2 knockout or the antidepressant activity of PPM1F overexpression after inhibiting acetylation activity of p300 was evaluated. RESULTS: Our results indicate that the expression levels of PPM1F were largely decreased in the mPFC of mice exposed to chronic unpredictable stress (CUS). Behavioral alterations relevant to depression emerged with short hairpin RNA (shRNA)-mediated genetic knockdown of PPM1F in the mPFC, while overexpression of PPM1F produced antidepressant activity and ameliorated behavioral responses to stress in CUS-exposed mice. Molecularly, PPM1F knockdown decreased the excitability of pyramidal neurons in the mPFC, and restoring this low excitability decreased the depression-related behaviors induced by PPM1F knockdown. PPM1F knockdown reduced the expression of CREB-binding protein (CBP)/E1A-associated protein (p300), a histone acetyltransferase (HAT), and induced hyperphosphorylation of AMPK, resulting in microglial activation and upregulation of proinflammatory cytokines. Conditional knockout of AMPK revealed an antidepressant phenotype, which can also block depression-related behaviors induced by PPM1F knockdown. Furthermore, inhibiting the acetylase activity of p300 abolished the beneficial effects of PPM1F elevation on CUS-induced depressive behaviors. CONCLUSION: Our findings demonstrate that PPM1F in the mPFC modulates depression-related behavioral responses by regulating the function of p300 via the AMPK signaling pathway.

N6-methyladenine-mediated aberrant activation of the lncRNA SOX2OT-GLI1 loop promotes non-small-cell lung cancer stemness.

Despite the advent of precision medicine and immunotherapy, mortality due to lung cancer remains high. The sonic hedgehog (SHH) cascade and its key terminal factor, glioma-associated oncogene homolog 1 (GLI1), play a pivotal role in the stemness and drug resistance of lung cancer. Here, we investigated the molecular mechanism of non-canonical aberrant GLI1 upregulation. The SHH cascade was upregulated in stem spheres and chemo-resistant lung cancer cells and was accountable for drug resistance against multiple chemotherapy regimens. GLI1 and the long non-coding RNA SOX2OT were positively regulated, and the GLI1-SOX2OT loop mediated the proliferation of parental and stem-like lung cancer cells. Further mechanistic investigation revealed that SOX2OT facilitated METTL3/14/IGF2BP2-mediated m6A modification and stabilization of the GLI1 mRNA. Additionally, SOX2OT upregulated METTL3/14/IGF2BP2 by sponging miR-186-5p. Functional analysis corroborated that GLI1 acted as a downstream target of METTL3/14/IGF2BP2, and GLI1 silencing could block the oncogenicity of lung cancer stem-like cells. Pharmacological inhibition of the loop remarkably inhibited the oncogenesis of lung cancer cells in vivo. Compared with paired adjacent normal tissues, lung cancer specimens exhibited consistently upregulated GLI1/SOX2OT/METTL3/14/IGF2BP2. The m6A-modified GLI1-SOX2OT loop may serve as a potential therapeutic target and prognostic predictor for lung cancer therapy and diagnosis in the clinic.

Role of Hippocampal miR-132-3p in Modifying the Function of Protein Phosphatase Mg2+/Mn2+-dependent 1 F in Depression.

Depression is a common, severe, and debilitating psychiatric disorder of unclear etiology. Our previous study has shown that protein phosphatase Mg2+/Mn2+-dependent 1F (PPM1F) in the hippocampal dentate gyrus (DG) displays significant regulatory effects in depression-related behaviors. miR-132-3p plays a potential role in the etiology of depression. This study explored the effect of miR-132-3p on the onset of depression and the possible underlying mechanism for modulating PPM1F expression during the pathology of depression. We found that miR-132-3p levels in the hippocampus of depressed mice subjected to chronic unpredictable stress (CUS) were dramatically reduced, which were correlated with depression-related behaviors. Knockdown of miR-132-3p in hippocampal DG resulted in depression-related phenotypes and increased susceptibility to stress. miR-132-3p overexpression in hippocampal DG alleviated CUS-induced depression-related performance. We then screened out the potential target genes of miR-132-3p, and we found that the expression profiles of sterol regulatory element-binding transcription factor 1 (Srebf1) and forkhead box protein O3a (FOXO3a) were positively correlated with PPM1F under the condition of miR-132-3p knockdown. Finally, as anticipated, we revealed that the activities of Ca2+/calmodulin-dependent protein kinase II (CAMKII) and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) were reduced, which underlies the target signaling pathway of PPM1F. In conclusion, our study suggests that miR-132-3p was designed to regulate depression-related behaviors by indirectly regulating PPM1F and targeting Srebf1 and FOXO3a, which have been linked to the pathogenesis and treatment of depression.

The colonic interleukin-19 aggravates the dextran sodium sulfate/stress-induced comorbidities due to colitis and anxiety.

Comorbidities due to inflammatory bowel disease (IBD) and anxiety are commonly acknowledged; however, their underlying basis is unclear. In the current study, we first conducted a clinical retrospective analysis to identify the enhancive incidence rate of IBD before or after the epidemic of Corona Virus Disease 2019 (COVID-19), with higher Generalized Anxiety Disorder-7 (GAD-7), as well as poorer Gastrointestinal Quality of Life Index (GIQLI). Then, the dextran sodium sulfate (DSS) and chronic unpredictable stress (CUS)-induced IBD and anxiety comorbid models were established with the correlational relations between symptoms of IBD and anxiety-related behaviors. We found dysfunctional up-regulation of a new inflammatory factor interleukin (IL)-19 in the colon of DSS/CUS treated mice. Overexpression of IL-19 in colon induced anxious phenotypes, and accelerated the anxious condition and symptoms of colitis in the DSS/CUS model by promoting the expression of inducible nitric oxide synthase (iNOS), IL-1ß, and IL-6 pro-inflammatory factors, and activating signal transducer and activator of transcription 3 (STAT3) signaling pathway in the colon. Furthermore, overexpression of IL-19 in the colon also reduced the expression levels of brain-derived neurotrophic factor (BDNF), extracellular signal-regulated kinase (ERK), and cAMP-response element binding protein (CREB) signaling pathways activity in the hippocampus. These results suggest that IL-19 was a pivotal player in DSS/CUS-induced comorbidities of colitis and anxiety with different signaling pathways for the colon and hippocampus, which provides a candidate gene to explore the pathophysiology of comorbidities due to colitis and anxiety.

The altered sensitivity of acute stress induced anxiety-related behaviors by modulating insular cortex-paraventricular thalamus-bed nucleus of the stria terminalis neural circuit.

The dysregulation of neuronal networks contributes to the etiology of psychiatric diseases, including anxiety. However, the neural circuits underlying anxiety symptoms remain unidentified. We observed acute restraint stress activating excitatory neurons in the paraventricular thalamus (PVT). Activation of PVT neurons caused anxious behaviors, whereas suppression of PVT neuronal activity induced an anxiolytic effect, achieved by using a chemogenetic method. Moreover, we found that the PVT neurons showed plentiful neuronal projections to the bed nucleus of the stria terminalis (BNST). Activation of PVT-BNST neural projections increased the susceptibility of stress-induced anxiety-related behaviors, and inhibition of this neural circuit produced anxiolysis. The insular cortex (IC) is an important upstream region projecting to PVT. Activation of IC-PVT neuronal projections enhanced susceptibility to stress induced anxious behaviors. Inhibiting this neural circuit suppressed anxious behaviors. Moreover, anterograde monosynaptic tracing results showed that the IC exerts strong neuronal projections to PVT, forming synaptic connections with its neurons, and these neurons throw extensive neuronal fibers to form synapse with BNST neurons. Finally, our results showed that ablation of neurons in PVT receiving monosynaptic input from IC attenuated the anxiety-related phenotypes induced by activating IC neurons. Lesions of the neurons in BNST synaptic origination from PVT blocked the anxiety-related phenotypes induced by activating PVT neurons. Our findings indicate that the PVT is a crucial anxiety-regulating nucleus, and the IC-PVT-BNST neural projection is an essential pathway affecting anxiety morbidity and treatment.

Large-Scale Preparation of Silver Nanowire-Based Flexible Transparent Film Heaters by Slot-Die Coating.

Highly flexible silver nanowire-based transparent conductive films (AgNWs TCFs) were large-scale fabricated by slot-die coating AgNWs inks on a flexible polyethylene terephthalate (PET) substrate, and further fabricated into a transparent film heater. Appropriate flow rate, coating speed, and AgNWs concentration allow the construction of the 15 cm × 15 cm AgNW TCFs with a sheet resistance (Rs) of less than 20 Ω/sq, a transmittance (T) at 550 nm higher than 95%, and a haze less than 3.5%. The resultant AgNW TCFs heater possesses high uniformity and superior mechanical stability and can reach a Joule heating temperature of 104 °C with a voltage of 12 V. The slot-die coating method has great potential for large-scale production of AgNW based film heaters promisingly used in window defrost and deicer systems.

Inhibition of glioblastoma progression by Urolithin A in vitro and in vivo by regulating Sirt1-FOXO1 axis via ERK/AKT signaling pathways.

Glioblastoma (GBM) is the most universal and devastating primary intracranial neoplasm in the central nervous system. Urolithin A (UA) possesses many pharmacological and biological activities, but its function in GBM is not clear. CCK-8 and colony formation test were used to measure the anti-proliferative potency of UA against GBM cells. Flow cytometry was applied to evaluate cell cycle arrest and apoptosis of U251 and U118 MG cells upon UA incubation. Quantitative real-time PCR and western blotting were conducted to test the regulatory effect of UA on the expression of Sirt1 and FOXO1. Immunodeficient mice were implanted with GBM cells for in vivo validation of the anti-cancer effect of UA. We found UA repressed the proliferation, migration and invasion of glioblastoma cells, while also inhibiting the induction of colony formation ability and epithelial to mesenchymal transition (EMT) in a time- or dose-dependent manner. The does-dependent relationship of UA inducing the cell cycle arrest and apoptosis of glioblastoma cells was identified. Furthermore, UA could enhance the expression levels of Sirt1 and FOXO1 and the knockdown of Sirt1 blocked the inhibitory effects of UA on the proliferation and migration of glioblastoma cells and correspondingly modified the expression level of FOXO1. Overexpression of Sirt1 restored the despaired inhibitory effect of UA induced by Sirt1 knockout on the proliferation and migration of glioblastoma cells. In animal experiments, UA decreased the tumor size and weight of glioblastoma in xenograft nude mice and promoted the expression of Sirt1 and FOXO1 in transplanted tumors. Our findings presented in this study indicate that UA exerts a repressive effect on glioblastoma cells in vivo and in vitro by regulating the Sirt1-FOXO1 axis via the ERK and AKT pathways, indicating that UA is a new novel therapeutic candidate for the treatment of glioblastoma.

Cryptotanshinone ameliorates CUS-induced depressive-like behaviors in mice.

OBJECTIVES: Cryptotanshinone (CPT), a natural quinoid diterpene, isolated from Salvia miltiorrhiza, has shown various pharmacological properties. However, its effect on chronic unpredictable stress (CUS)-induced depression phenotypes and the underlying mechanism remain unclear. Therefore, the aim of this study was to investigate whether CPT could exert an antidepressant effect. METHODS: We investigated the effects of CPT in a CUS-induced depression model and explored whether these effects were related to the anti-inflammatory and neurogenesis promoting properties by investigating the expression levels of various signaling molecules at the mRNA and protein levels. RESULTS: Administration of CPT improved depression-like behaviors in CUS-induced mice. CPT administration increased the levels of doublecortin-positive cells and reversed the decrease in the expression levels of brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling transduction, as well as the downstream functional proteins, phosphorylated extracellular regulated protein kinases (p-ERK), and cyclic adenosine monophosphate (cAMP)-response element-binding protein levels (p-CREB) in hippocampus. CPT treatment also inhibited the activation of microglia and suppressed M1 microglial polarization, while promoting M2 microglial polarization by monitoring the expression levels of arginase 1 (Arg-1) and inducible nitric oxide synthase (iNOS), and further inhibited the expression of proinflammatory cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α), and increased the expression of the anti-inflammatory cytokine IL-10 by regulating nuclear factor-κB (NF-κB) activation. CONCLUSIONS: CPT relieves the depressive-like state in CUS-induced mice by enhancing neurogenesis and inhibiting inflammation through the BDNF/TrkB and NF-κB pathways and could therefore serve as a promising candidate for the treatment of depression.

The paraventricular thalamus input to central amygdala controls depression-related behaviors.

The dysregulation of neuronal networks may contribute to the etiology of major depressive disorder (MDD). However, the neural connections underlying the symptoms of MDD have yet to be elucidated. Here, we observed that glutamatergic neurons in the paraventricular thalamus (PVT) were activated by chronic unpredictable stress (CUS) with higher expression numbers of ΔFosB-labeled neurons and protein expression levels, activation of PVT neurons caused depressive-like phenotypes, whereas suppression of PVT neuronal activity induced an antidepressant effect in male, but not female mice, which were achieved by using a chemogenetic approach. Moreover, we found that PVT glutamatergic neurons showed strong neuronal projections to the central amygdala (CeA), activation of the CeA-projecting neurons in PVT or the neuronal terminals of PVT-CeA projection neurons induced depression-related behaviors or showed enhanced stress-induced susceptibility. These results suggest that PVT is a key depression-controlling nucleus, and PVT-CeA projection regulates depression-related behaviors in a sex-dependent manner, which could be served as an essential pathway for morbidity and treatment of depression.

PPM1F in Dentate Gyrus Modulates Anxiety-Related Behaviors by Regulating BDNF Expression via AKT/JNK/p-H3S10 Pathway.

Anxiety is a serious psychiatric disorder, with a higher incidence rate in women than in men. Protein phosphatase Mg2+/Mn2+-dependent 1F (PPM1F), a serine/threonine phosphatase, has been shown to have multiple biological and cellular functions. However, the effects of PPM1F and its neuronal substrates on anxiety remain largely unclear. In this study, we showed that chronic restraint stress (CRS) induced anxiety-related behaviors only in female mice, while acute restraint stress (ARS) produced anxiety-related behaviors in both male and female mice in light-dark and elevated plus maze tests and induced upregulation of PPM1F and downregulation of brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Adeno-associated virus-mediated overexpression of PPM1F or conditional knockout of BDNF in dentate gyrus (DG) led to a more pronounced anxiety-related behavior in female than in male mice as indicated by the behavioral evaluations. Meanwhile, overexpression of PPM1F in the DG decreased total Bdnf exon-specific messenger RNA expression in the hippocampus with the decreased binding activity of phosphorylated H3S10 to its individual promoters in female mice. Furthermore, we identified that overexpression of PPM1F decreased the phosphorylation levels of AKT and JNK in the hippocampus of female mice. These results may suggest that PPM1F regulates anxiety-related behaviors by modulating BDNF expression and H3S10 phosphorylation-mediated epigenetic modification, which may be served as potentially pathological genes associated with anxiety or other mental diseases.

Regulation of depression-related behaviors by GABAergic neurons in the lateral septum through periaqueductal gray neuronal projections.

Major depressive disorder (MDD) is a serious and widespread mental illness worldwide. The abnormality of neuronal networks may contribute to the etiology of MDD. However, the neural connections underlying the main symptoms of MDD need further elucidation. Here, we found that GABAergic neurons in the lateral septum (LS) were activated by chronic unpredictable stress (CUS), with increased numbers of ΔFosB-labeled neurons. LS neuronal activity was modulated using a chemogenetic approach. Activation of LS neurons caused a depressive phenotype, as shown by increased immobility in the forced swim test, and induced increased susceptibility to subthreshold chronic stress, as indicated by decreased female urine sniffing time and preference for sucrose in depression-related behavior detection, whereas suppression of LS neuronal activity induced an antidepressant effect under basal and stressed conditions. Moreover, we found that the LS showed strong neuronal projections to the dorsal periaqueductal gray (dPAG); activation of dPAG-projecting GABAergic neurons in the LS produced the same depressive behaviors and stress susceptibility as induced by the activation of the majority of LS GABAergic neurons. Finally, we found that activation of neuronal fibers in the dPAG derived from the LS showed depression-related behaviors, as suggested by the decreased female urine sniffing time and sucrose preference in female urine sniffing and sucrose preference tests respectively. Our findings indicate that LS is a key depression-controlling nucleus, and that the LS-PAG projection is an essential effector circuit for morbidity and treatment in depression.

Leptin regulates exon-specific transcription of the Bdnf gene via epigenetic modifications mediated by an AKT/p300 HAT cascade.

Leptin is an adipocyte-derived hormone with pleiotropic functions affecting appetite and mood. While leptin's role in the regulation of appetite has been extensively studied in hypothalamic neurons, its function in the hippocampus, where it regulates mood-related behaviors, is poorly understood. Here, we show that the leptin receptor (LepRb) colocalizes with brain-derived neurotrophic factor (BDNF), a key player in the pathophysiology of major depression and the action of antidepressants, in the dentate gyrus of the hippocampus. Leptin treatment increases, whereas deficiency of leptin or leptin receptors decreases, total Bdnf mRNA levels, with distinct expression profiles of specific exons, in the hippocampus. Epigenetic analyses reveal that histone modifications, but not DNA methylation, underlie exon-specific transcription of the Bdnf gene induced by leptin. This is mediated by stimulation of AKT signaling, which in turn activates histone acetyltransferase p300 (p300 HAT), leading to changes in histone H3 acetylation and methylation at specific Bdnf promoters. Furthermore, deletion of Bdnf in the dentate gyrus, or specifically in LepRb-expressing neurons, abolishes the antidepressant-like effects of leptin. These findings indicate that leptin, acting via an AKT-p300 HAT epigenetic cascade, induces exon-specific Bdnf expression, which in turn is indispensable for leptin-induced antidepressant-like effects.

The BDNF-FoxO1 Axis in the medial prefrontal cortex modulates depressive-like behaviors induced by chronic unpredictable stress in postpartum female mice.

Postpartum depression (PPD) is a serious psychiatric disorder, affecting not only the childbearing women but also the health of their offsprings. The brain-derived neurotrophic factor (Bdnf) gene is an important target gene for the study of depression and antidepressant therapy. FoxO1, belonging to the FoxO subfamily is involved in the development of major depressive disorders. However, the role of BDNF and its functional brain regions involved in PPD remains unknown. Here, we report that chronic unpredictable stress (CUS) can produce depression-associated behaviors in postpartum female mice. CUS can decrease total Bdnf mRNA and exon specific mRNAs in the medial prefrontal cortex (mPFC), accompanied by reduced protein levels, that were correlated with depression-related behaviors. Moreover, postpartum, not virgin female mice showed increased susceptibility to subthreshold stress-induced depression-related behaviors. Selective deletion of BDNF in the mPFC induced anhedonia as indicated by reduced sucrose preference and increased latency to food in the novelty suppressed food test in postpartum, but not in virgin female mice. Furthermore, we found that FoxO1 is also decreased in CUS-treated postpartum female mice with a significant correlation with depression-related behaviors. BDNF-specific knockout in the mPFC decreased FoxO1 expression in female mice. Our results indicate that the BDNF-FoxO1 axis in mPFC can regulate depression-related behaviors and stress vulnerability in postpartum female mice.

Brain-derived neurotrophic factor in 5-HT neurons regulates susceptibility to depression-related behaviors induced by subchronic unpredictable stress.

Chronic stress is a major risk factor for the development of depression. Brain-derived neurotrophic factor (BDNF) plays an important role in neural functions and exhibits antidepressant effects. However, studies on depression-related behavioral response to BDNF have mainly focused on the limbic system, whereas other regions of the brain still require further exploration. Here, we report that exposure to chronic unpredictable stress (CUS) can induce depression-associated behaviors in mice. CUS could decrease total Bdnf mRNA and protein levels in the dorsal raphe nucleus (DRN), which correlated with depression-related behaviors. A corresponding reduction in exon-specific Bdnf mRNA was observed in the DRN of CUS mice. Bdnf was highly expressed in 5- Hydroxytryptamine (5-HT) neurons from the DRN. Selective deletion of Bdnf in 5-HT neurons alone could not induce anhedonia and behavioral despair in male or female mice, as indicated by the unchanged female urine sniffing time and preference for sucrose/saccharin. However, it could increase the latency to food in female mice, but not in male mice as shown by novelty-suppressed food test. Nevertheless, enhanced stress-induced susceptibility is observed in these male mice as suggested by the decrease in female urine sniffing time, and for female mice by the reduced sucrose preference and increased immobility in forced swim test. Furtherly, total Bdnf mRNA levels in DRN were correlated with depression-related behaviors of female, but not male 5-HT neurons specific Bdnf knockout mice. Our results indicate that BDNF might act on 5-HT neurons to regulate depression-related behaviors and stress vulnerability in a sex-dependent manner.