Astrocytic ALKBH5 in stress response contributes to depressive-like behaviors in mice.

Epigenetic mechanisms bridge genetic and environmental factors that contribute to the pathogenesis of major depression disorder (MDD). However, the cellular specificity and sensitivity of environmental stress on brain epitranscriptomics and its impact on depression remain unclear. Here, we found that ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), was increased in MDD patients' blood and depression models. ALKBH5 in astrocytes was more sensitive to stress than that in neurons and endothelial cells. Selective deletion of ALKBH5 in astrocytes, but not in neurons and endothelial cells, produced antidepressant-like behaviors. Astrocytic ALKBH5 in the mPFC regulated depression-related behaviors bidirectionally. Meanwhile, ALKBH5 modulated glutamate transporter-1 (GLT-1) m6A modification and increased the expression of GLT-1 in astrocytes. ALKBH5 astrocyte-specific knockout preserved stress-induced disruption of glutamatergic synaptic transmission, neuronal atrophy and defective Ca2+ activity. Moreover, enhanced m6A modification with S-adenosylmethionine (SAMe) produced antidepressant-like effects. Our findings indicate that astrocytic epitranscriptomics contribute to depressive-like behaviors and that astrocytic ALKBH5 may be a therapeutic target for depression.

Role of the prefrontal cortical protease TACE/ADAM17 in neurobehavioral responses to chronic stress during adolescence.

INTRODUCTION: Chronic adolescent stress profoundly affects prefrontal cortical networks regulating top-down behavior control. However, the neurobiological pathways contributing to stress-induced alterations in the brain and behavior remain largely unknown. Chronic stress influences brain growth factors and immune responses, which may, in turn, disrupt the maturation and function of prefrontal cortical networks. The tumor necrosis factor alpha-converting enzyme/a disintegrin and metalloproteinase 17 (TACE/ADAM17) is a sheddase with essential functions in brain maturation, behavior, and inflammatory responses. This study aimed to determine the impact of stress on the prefrontal cortex and whether TACE/ADAM17 plays a role in these responses. METHODS: We used a Lewis rat model that incorporates critical elements of chronic psychosocial stress, such as uncontrollability, unpredictability, lack of social support, and re-experiencing of trauma. RESULTS: Chronic stress during adolescence reduced the acoustic startle reflex and social interactions while increasing extracellular free water content and TACE/ADAM17 mRNA levels in the medial prefrontal cortex. Chronic stress altered various ethological behavioral domains in the observation home cages (decreased ingestive behaviors and increased walking, grooming, and rearing behaviors). A group of rats was injected intracerebrally either with a novel Accell™ SMARTpool TACE/ADAM17 siRNA or a corresponding siRNA vehicle (control). The RNAscope Multiplex Fluorescent v2 Assay was used to visualize mRNA expression. Automated puncta quantification and analyses demonstrated that TACE/ADAM17 siRNA administration reduced TACE/ADAM17 mRNA levels in the medial prefrontal cortex (59% reduction relative to control). We found that the rats that received prefrontal cortical TACE/ADAM17 siRNA administration exhibited altered eating patterns (e.g., increased food intake and time in the feeding zone during the light cycle). CONCLUSION: This study supports that the prefrontal cortex is sensitive to adolescent chronic stress and suggests that TACE/ADAM17 may be involved in the brain responses to stress.

Emotional Stress Induces Adaptive Response in Rat Lymphocytes to Subsequent Ionizing Radiation Exposure.

We studied the molecular mechanisms of cross-adaptation to ionizing radiation (1 Gy) of lymphocytes isolated from rats subjected to emotional stress. The effects of chronic (CES; various types of stress exposure) and acute (AES; forced swimming) emotional stress in rats on indicators of oxidative stress, cell death, and levels of NRF2 and NOX4 proteins involved in the development of the adaptive response were analyzed in isolated lymphocytes. It was found that stress induced an adaptive response in rat lymphocytes and triggered processes similar to the adaptive response induced by low doses of ionizing radiation: an increase in the level of oxidized DNA and cell death, as well as an increase in the content of NOX4 and NRF2 proteins. In animals subjected to emotional stress, suppressed DNA oxidation in response to irradiation, reduced levels of protective factor NRF2, as well as lymphocyte death were observed.

Correlations of Expression Levels of Lung Cancer Marker Gene Eno2 and Genes of Carcinogenesis and Apoptosis in the Hypothalamus of Mice with Depression-Like Behavior.

We experimentally demonstrated that chronic social stress during the development of a depression-like state enhances lung metastasis and modifies the expression of many carcinogenesis- and apoptosis-related genes in the hypothalamus of mice, including genes involved in lung cancer pathogenesis in humans. Analysis of the expression of genes encoding the major clinical markers of lung cancer in the hypothalamus of mice with depression-like behavior revealed increased expression of the Eno2 gene encoding neuron-specific enolase, a blood marker of lung cancer progression in humans. It was shown that the expression of this gene in the hypothalamus correlated with the expression of many carcinogenesis- and apoptosis-related genes. The discovered phenomenon may have a fundamental significance and requires further studies.

Cathepsin K deficiency prevented stress-related thrombosis in a mouse FeCl3 model.

BACKGROUND: Exposure to chronic psychological stress (CPS) is a risk factor for thrombotic cardiocerebrovascular diseases (CCVDs). The expression and activity of the cysteine cathepsin K (CTSK) are upregulated in stressed cardiovascular tissues, and we investigated whether CTSK is involved in chronic stress-related thrombosis, focusing on stress serum-induced endothelial apoptosis. METHODS AND RESULTS: Eight-week-old wild-type male mice (CTSK+/+) randomly divided to non-stress and 3-week restraint stress groups received a left carotid artery iron chloride3 (FeCl3)-induced thrombosis injury for biological and morphological evaluations at specific timepoints. On day 21 post-stress/injury, the stress had enhanced the arterial thrombi weights and lengths, in addition to harmful alterations of plasma ADAMTS13, von Willebrand factor, and plasminogen activation inhibitor-1, plus injured-artery endothelial loss and CTSK protein/mRNA expression. The stressed CTSK+/+ mice had increased levels of injured arterial cleaved Notch1, Hes1, cleaved caspase8, matrix metalloproteinase-9/-2, angiotensin type 1 receptor, galactin3, p16IN4A, p22phox, gp91phox, intracellular adhesion molecule-1, TNF-α, MCP-1, and TLR-4 proteins and/or genes. Pharmacological and genetic inhibitions of CTSK ameliorated the stress-induced thrombus formation and the observed molecular and morphological changes. In cultured HUVECs, CTSK overexpression and silencing respectively increased and mitigated stressed-serum- and H2O2-induced apoptosis associated with apoptosis-related protein changes. Recombinant human CTSK degraded γ-secretase substrate in a dose-dependent manor and activated Notch1 and Hes1 expression upregulation. CONCLUSIONS: CTSK appeared to contribute to stress-related thrombosis in mice subjected to FeCl3 stress, possibly via the modulation of vascular inflammation, oxidative production and apoptosis, suggesting that CTSK could be an effective therapeutic target for CPS-related thrombotic events in patients with CCVDs.

Neurophysiological analysis of disadvantageous social inequity: Exploring emotional behavior changes and c-Fos expression in a male rat model.

Humans and other animals exhibit aversive behavioral and emotional responses to unequal reward distributions compared with their conspecifics. Despite the significance of this phenomenon, experimental animal models designed to investigate social inequity aversion and delve into the underlying neurophysiological mechanisms are limited. In this study, we developed a rat model to determine the effects of socially equal or unequal reward and stress on emotional changes in male rats. During the training session, the rats were trained to escape when a sound cue was presented, and they were assigned to one of the following groups: all escaping rats [advantageous equity (AE)], freely moving rats alongside a restrained rat [advantageous inequity (AI)], all restrained rats [disadvantageous equity (DE)], and a rat restrained in the presence of freely moving companions [disadvantageous inequity (DI)]. During the test session, rats in the advantageous group (AE and AI) escaped after the cue sound (expected reward acquisition), whereas rats in the disadvantageous group (DE and DI) could not escape despite the cue being presented (expected reward deprivation). Emotional alteration induced by exposure to restraint stress under various social interaction circumstances was examined using an open field test. Notably, the DI group displayed reduced exploration of the center zone during the open field tests compared with the other groups, indicating heightened anxiety-like behaviors in response to reward inequity. Immunohistochemical analysis revealed increased c-Fos expression in the medial prefrontal and orbitofrontal cortices, coupled with reduced c-Fos expression in the striatum and nucleus accumbens under DI conditions, in contrast to the other experimental conditions. These findings provide compelling evidence that rats are particularly sensitive to reward inequity, shedding light on the neurophysiological basis for distinct cognitive processes that manifest when individuals are exposed to social equity and inequity situations.

Medicinal cannabis oil improves anxiety-like and depressive-like behaviors in CCS mice via the BDNF/TRPC6 signaling pathway.

BACKGROUND: Post-traumatic stress disorder (PTSD) refers to a chronic impairing psychiatric disorder occurring after exposure to the severe traumatic event. Studies have demonstrated that medicinal cannabis oil plays an important role in neuroprotection, but the mechanism by which it exerts anti-PTSD effects remains unclear. METHODS: The chronic complex stress (CCS) simulating the conditions of long voyage stress for 4 weeks was used to establish the PTSD mice model. After that, behavioral tests were used to evaluate PTSD-like behaviors in mice. Mouse brain tissue index was detected and hematoxylin-eosin staining was used to assess pathological changes in the hippocampus. The indicators of cell apoptosis and the BDNF/TRPC6 signaling activation in the mice hippocampus were detected by western blotting or real-time quantitative reverse transcription PCR experiments. RESULTS: We established the PTSD mice model induced by CCS, which exhibited significant PTSD-like phenotypes, including increased anxiety-like and depression-like behaviors. Medicinal cannabis oil treatment significantly ameliorated PTSD-like behaviors and improved brain histomorphological abnormalities in CCS mice. Mechanistically, medicinal cannabis oil reduced CCS-induced cell apoptosis and enhanced the activation of BDNF/TRPC6 signaling pathway. CONCLUSIONS: We constructed a PTSD model with CCS and medicinal cannabis oil that significantly improved anxiety-like and depressive-like behaviors in CCS mice, which may play an anti-PTSD role by stimulating the BDNF/TRPC6 signaling pathway.

Single administration of a psychedelic [(R)-DOI] influences coping strategies to an escapable social stress.

Psychedelic compounds have potentially rapid, long-lasting anxiolytic, antidepressive and anti-inflammatory effects. We investigated whether the psychedelic compound (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI], a selective 5-HT2A receptor partial agonist, decreases stress-related behavior in male mice exposed to repeated social aggression. Additionally, we explored the likelihood that these behavioral changes are related to anti-inflammatory properties of [(R)-DOI]. Animals were subjected to the Stress Alternatives Model (SAM), an escapable social stress paradigm in which animals develop reactive coping strategies - remaining in the SAM arena (Stay) with a social aggressor, or dynamically initiated stress coping strategies that involve utilizing the escape holes (Escape) to avoid aggression. Mice expressing these behavioral phenotypes display behaviors like those in other social aggression models that separate animals into stress-vulnerable (as for Stay) or stress-resilient (as for Escape) groups, which have been shown to have distinct inflammatory responses to social stress. These results show that Stay animals have heightened cytokine gene expression, and both Stay and Escape mice exhibit plasma and neural concentrations of the inflammatory cytokine tumor necrosis factor-α (TNFα) compared to unstressed control mice. Additionally, these results suggest that a single administration of (R)-DOI to Stay animals in low doses, can increase stress coping strategies such as increasing attention to the escape route, promoting escape behavior, and reducing freezing during socially aggressive interaction in the SAM. Lower single doses of (R)-DOI, in addition to shifting behavior to suggest anxiolytic effects, also concomitantly reduce plasma and limbic brain levels of the inflammatory cytokine TNFα.

Association between social dominance hierarchy and PACAP expression in the extended amygdala, corticosterone, and behavior in C57BL/6 male mice.

The natural alignment of animals into social dominance hierarchies produces adaptive, and potentially maladaptive, changes in the brain that influence health and behavior. Aggressive and submissive behaviors assumed by animals through dominance interactions engage stress-dependent neural and hormonal systems that have been shown to correspond with social rank. Here, we examined the association between social dominance hierarchy status established within cages of group-housed mice and the expression of the stress peptide PACAP in the bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA). We also examined the relationship between social dominance rank and blood corticosterone (CORT) levels, body weight, motor coordination (rotorod) and acoustic startle. Male C57BL/6 mice were ranked as either Dominant, Submissive, or Intermediate based on counts of aggressive/submissive encounters assessed at 12 weeks-old following a change in homecage conditions. PACAP expression was significantly higher in the BNST, but not the CeA, of Submissive mice compared to the other groups. CORT levels were lowest in Submissive mice and appeared to reflect a blunted response following events where dominance status is recapitulated. Together, these data reveal changes in specific neural/neuroendocrine systems that are predominant in animals of lowest social dominance rank, and implicate PACAP in brain adaptations that occur through the development of social dominance hierarchies.

Inflammation and Connexin 43 profiles in the prefrontal cortex are relevant to stress susceptibility and resilience in mice.

Depression is a major chronic mental illness worldwide, characterized by anhedonia and pessimism. Exposed to the same stressful stimuli, some people behave normally, while others exhibit negative behaviors and psychology. The exact molecular mechanisms linking stress-induced depressive susceptibility and resilience remain unclear. Connexin 43 (Cx43) forms gap junction channels between the astrocytes, acting as a crucial role in the pathogenesis of depression. Cx43 dysfunction could lead to depressive behaviors, and depression down-regulates the expression of Cx43 in the prefrontal cortex (PFC). Besides, accumulating evidence indicates that inflammation is one of the most common pathological features of the central nervous system dysfunction. However, the roles of Cx43 and peripheral inflammation in stress-susceptible and stress-resilient individuals have rarely been investigated. Thus, animals were classified into the chronic unpredictable stress (CUS)-susceptible group and the CUS-resilient group based on the performance of behavioral tests following the CUS protocol in this study. The protein expression of Cx43 in the PFC, the Cx43 functional changes in the PFC, and the expression levels including interleukin (IL)-1ß, tumor necrosis factor-α, IL-6, IL-2, IL-10, and IL-18 in the peripheral serum were detected. Here, we found that stress exposure triggered a significant reduction in Cx43 protein expression in the CUS-susceptible mice but not in the CUS-resilient mice accompanied by various Cx43 phosphorylation expression and the changes of inflammatory signals. Stress resilience is associated with Cx43 in the PFC and fluctuation in inflammatory signaling, showing that therapeutic targeting of these pathways might promote stress resilience.

NK3R signalling in the posterodorsal medial amygdala is involved in stress-induced suppression of pulsatile LH secretion in female mice.

Psychosocial stress negatively impacts reproductive function by inhibiting pulsatile luteinizing hormone (LH) secretion. The posterodorsal medial amygdala (MePD) is responsible in part for processing stress and modulating the reproductive axis. Activation of the neurokinin 3 receptor (NK3R) suppresses the gonadotropin-releasing hormone (GnRH) pulse generator, under hypoestrogenic conditions, and NK3R activity in the amygdala has been documented to play a role in stress and anxiety. We investigate whether NK3R activation in the MePD is involved in mediating the inhibitory effect of psychosocial stress on LH pulsatility in ovariectomised female mice. First, we administered senktide, an NK3R agonist, into the MePD and monitored the effect on pulsatile LH secretion. We then delivered SB222200, a selective NK3R antagonist, intra-MePD in the presence of predator odour, 2,4,5-trimethylthiazole (TMT) and examined the effect on LH pulses. Senktide administration into the MePD dose-dependently suppresses pulsatile LH secretion. Moreover, NK3R signalling in the MePD mediates TMT-induced suppression of the GnRH pulse generator, which we verified using a mathematical model. The model verifies our experimental findings: (i) predator odour exposure inhibits LH pulses, (ii) activation of NK3R in the MePD inhibits LH pulses and (iii) NK3R antagonism in the MePD blocks stressor-induced inhibition of LH pulse frequency in the absence of ovarian steroids. These results demonstrate for the first time that NK3R neurons in the MePD mediate psychosocial stress-induced suppression of the GnRH pulse generator.

Glioma induces atypical depression-like behaviors in mice through the 5-HT and glutamatergic synapse pathways.

Glioma patients often undertake psychiatric disorders such as depression and anxiety. There are several clinical epidemiological studies on glioma-associated depression, but basic research and corresponding animal experiments are still lacking. Here, we observed that glioma-bearing mice exhibited atypical depression-like behaviors in orthotopic glioma mouse models. The concentrations of monoamine neurotransmitters were detected by enzyme-linked immunosorbent assay (ELISA), revealing a decrease in 5-hydroxytryptamine (5-HT) levels in para-glioma tissues. The related gene expression levels also altered, detected by quantitative RT-PCR. Then, we developed a glioma-depression comorbidity mouse model. Through sucrose preference test (SPT), forced swimming test (FST), tail suspension test (TST) and other tests, we found that the occurrence of glioma could lead to changes in depression-like behaviors in a chronic unpredictable mild stress (CUMS) mouse model. The results of RNA sequencing (RNA-seq) indicated that the altered expression of glutamatergic synapse related genes in the paratumor tissues might be one of the main molecular features of the comorbidity model. Our findings suggested that the presence of glioma caused and altered depression-like behaviors, which was potentially related to the 5-HT and glutamatergic synapse pathways.

Monomeric pilose antler peptide improves depression-like behavior in mice by inhibiting FGFR3 protein expression.

ETHNOPHARMACOLOGICAL RELEVANCE: It has been found that pilose antler peptide has an antidepressant effect on depression. However, the exact molecular mechanism of its antidepressant effect is still unclear. AIM OF THE STUDY: The study sought to determine the impact of monomeric pilose antler peptide (PAP; sequence LVLVEAELRE) on depression as well as investigate potential molecular mechanisms. MATERIALS AND METHODS: Chronic unexpected mild stress (CUMS) was used to establish the model, and the effect of PAP on CUMS mice was detected by the behavioral test. The influence of PAP on neuronal cells and dendritic spine density was observed by immunofluorescence and Golgi staining. FGFR3 and the CaMKII-associated pathway were identified using quantitative real-time polymerase chain reaction, and Western blot analysis was utilized to measure their proteins and gene expression levels. Molecular docking and microscale thermophoresis were applied to detect the binding of PAP and FGFR3. Finally, the effect of FGFR3's overexpression on PAP treatment of depression was detected. RESULTS: PAP alleviated the changes in depressive behavior induced by CUMS, promoted the growth of nerve cells, and the density of dendritic spines was increased to its original state. PAP therapy successfully downregulated the expression of FGFR3 and ERK1/2 while upregulating the expression of CREB, BDNF, and CaMKII. CONCLUSION: Based on the current research, PAP has a therapeutic effect on depression brought on by CUMS by inhibiting FGFR3 expression and enhancing synaptic plasticity.

Down-regulation of MKP-1 in hippocampus protects against stress-induced depression-like behaviors and neuroinflammation.

Chronic stress is the primary environmental risk factor for major depressive disorder (MDD), and there is compelling evidence that neuroinflammation is the major pathomechanism linking chronic stress to MDD. Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a negative regulator of MAPK signaling pathways involved in cellular stress responses, survival, and neuroinflammation. We examined the possible contributions of MKP-1 to stress-induced MDD by comparing depression-like behaviors (anhedonia, motor retardation, behavioral despair), neuroinflammatory marker expression, and MAPK signaling pathways among rats exposed to chronic unpredictable mild stress (CUMS), overexpressing MKP-1 in the hippocampus, and CUMS-exposed rats underexpressing MKP-1 in the hippocampus. Rats exposed to CUMS exhibited MKP-1 overexpression, greater numbers of activated microglia, and enhanced expressions of neuroinflammatory markers (interleukin [IL]-6, [IL]-1ß, tumor necrosis factor [TNF]-ɑ, and decreased phosphorylation levels of ERK and p38 in the hippocampus as well as anhedonia in the sucrose preference test, motor retardation in the open field, and greater immobility (despair) in the forced swimming tests. These signs of neuroinflammation and depression-like behaviors and phosphorylation levels of ERK and p38 were also observed in rats overexpressing MKP-1 without CUMS exposure, while CUMS-induced neuroinflammation, microglial activation, phosphorylation levels of ERK and p38, and depression-like behaviors were significantly reversed by MKP-1 knockdown. Moreover, MKP-1 knockdown promoted the activation of the MAPK isoform ERK, implying that the antidepressant-like effects of MKP-1 knockdown may be mediated by the ERK pathway disinhibition. These findings suggested that hippocampal MKP-1 is an essential regulator of stress-induced neuroinflammation and a promising target for antidepressant development.

Antidepressant effects of Parishin C in chronic social defeat stress-induced depressive mice.

ETHNOPHARMACOLOGY RELEVANCE: Parishin C (Par), a prominent bioactive compound in Gastrodia elata Blume with little toxicity and shown neuroprotective effects. However, its impact on depression remains largely unexplored. AIM OF THE STUDY: This study aims to investigate the antidepressant effects of Par using a chronic social defeat stress (CSDS) mouse model and elucidate its molecular mechanisms. MATERIALS AND METHODS: The CSDS-induced depression mouse model was used to evaluate the therapeutic efficacy of Par. The social interaction test (SIT) and sucrose preference test (SPT), tail suspension test (TST) and forced swim test (FST) were conducted to assess the effects of Par on depressive-like behaviours. The levels of corticosterone, neurotransmitters (5-HT, DA and NE) and inflammatory cytokines (IL-1ß, TNF-α, and IL-6) were evaluated by enzyme-linked immunosorbent assay (ELISA). Activation of a microglia was assessed by immunofluorescence labeling Iba-1. The protein expressions of NLRP3, ASC, caspase-1, and IL-6 verified by Western blot. RESULT: Oral administration of Par (4 and 8 mg/kg) and fluoxetine (10 mg/kg, administration significantly ameliorate depression-like behaviors induced by CSDS, as shown by the increase social interaction in SIT, increase sucrose preference in SPT and the decrease immobility in TST and FST. Par administration decreased serum corticosterone level and increased the 5-HT, DA and NE concentration in the hippocampus and prefrontal cortex. Furthermore, Par treatment suppressed microglial activation (Iba1) as well as reduced levels of IL-1ß, TNF-α, and IL-6) with decreased protein expressions of NLRP3, ASC, caspase-1, and IL-6. CONCLUSIONS: our study provides the first evidence that Par exerts antidepressant-like effects in mice with CSDS-induced depression. This effect appears to be mediated by the normalization of neurotransmitter and corticosterone levels, inhibition of NLRP3 inflammasome activation. This newfound antidepressant property of Par offers a novel perspective on its pharmacological effects, providing valuable insights into its potential therapeutic and preventive applications in depression treatment.

Chronic Variable Stress and Cafeteria Diet Combination Exacerbate Microglia and c-fos Activation but Not Experimental Anxiety or Depression in a Menopause Model.

The menopause transition is a vulnerable period for developing both psychiatric and metabolic disorders, and both can be enhanced by stressful events worsening their effects. The present study aimed to evaluate whether a cafeteria diet (CAF) combined with chronic variable stress (CVS) exacerbates anxious- or depressive-like behavior and neuronal activation, cell proliferation and survival, and microglia activation in middle-aged ovariectomized (OVX) rats. In addition, body weight, lipid profile, insulin resistance, and corticosterone as an index of metabolic changes or hypothalamus-pituitary-adrenal (HPA) axis activation, and the serum pro-inflammatory cytokines IL-6, IL-ß, and TNFα were measured. A CAF diet increased body weight, lipid profile, and insulin resistance. CVS increased corticosterone and reduced HDL. A CAF produced anxiety-like behaviors, whereas CVS induced depressive-like behaviors. CVS increased serum TNFα independently of diet. A CAF and CVS separately enhanced the percentage of Iba-positive cells in the hippocampus; the combination of factors further increased Iba-positive cells in the ventral hippocampus. A CAF and CVS increased the c-fos-positive cells in the hippocampus; the combination of factors increased the number of positive cells expressing c-fos in the ventral hippocampus even more. The combination of a CAF and CVS generates a slight neuroinflammation process and neuronal activation in a hippocampal region-specific manner and differentially affects the behavior.

Depression promotes breast cancer progression by regulating amino acid neurotransmitter metabolism and gut microbial disturbance.

INTRODUCTION: Breast cancer (BC) is the most prevalent type of cancer and has the highest mortality among women worldwide. BC patients have a high risk of depression, which has been recognized as an independent factor in the progression of BC. However, the potential mechanism has not been clearly demonstrated. METHODS: To explore the correlation and mechanism between depression and BC progression, we induced depression and tumor in BC mouse models. Depression was induced via chronic unpredictable mild stress (CUMS) and chronic restraint stress (CRS). Amino acid (AA) neurotransmitter-targeted metabonomics and gut microbiota 16S rDNA gene sequencing were employed in the mouse model after evaluation with behavioral tests and pathological analysis. RESULTS: The tumors in cancer-depression (CD) mice grew faster than those in cancer (CA) mice, and lung metastasis was observed in CD mice. Metabonomics revealed that the neurotransmitters and plasma AAs in CD mice were dysregulated, namely the tyrosine and tryptophan pathways and monoamine neurotransmitters in the brain. Gut microbiota analysis displayed an increased ratio of Firmicutes/Bacteroides. In detail, the abundance of f_Lachnospiraceae and s_Lachnospiraceae increased, whereas the abundance of o_Bacteroidales and s_Bacteroides_caecimuris decreased. Moreover, the gut microbiota was more closely associated with AA neurotransmitters than with plasma AA. CONCLUSION: Depression promoted the progression of BC by modulating the abundance of s_Lachnospiraceae and s_Bacteroides_caecimuris, which affected the metabolism of monoamine neurotransmitters in the brain and AA in the blood.

The Prenatal Hypoxic Pathology Associated with Maternal Stress Predisposes to Dysregulated Expression of the chrna7 Gene and the Subsequent Development of Nicotine Addiction in Adult Offspring.

INTRODUCTION: Previous studies have shown that fetal hypoxia predisposes individuals to develop addictive disorders in adulthood. However, the specific impact of maternal stress, mediated through glucocorticoids and often coexisting with fetal hypoxia, is not yet fully comprehended. METHODS: To delineate the potential effects of these pathological factors, we designed models of prenatal severe hypoxia (PSH) in conjunction with maternal stress and prenatal intrauterine ischemia (PII). We assessed the suitability of these models for our research objectives by measuring HIF1α levels and evaluating the glucocorticoid neuroendocrine system. To ascertain nicotine dependence, we employed the conditioned place aversion test and the startle response test. To identify the key factor implicated in nicotine addiction associated with PSH, we employed techniques such as Western blot, immunohistochemistry, and correlational analysis between chrna7 and nr3c1 genes across different brain structures. RESULTS: In adult rats exposed to PSH and PII, we observed increased levels of HIF1α in the hippocampus (HPC). However, the PSH group alone exhibited reduced glucocorticoid receptor levels and disturbed circadian glucocorticoid rhythms. Additionally, they displayed signs of nicotine addiction in the conditioned place aversion and startle response tests. We also observed elevated levels of phosphorylated DARPP-32 protein in the nucleus accumbens (NAc) indicated compromised glutamatergic efferent signaling. Furthermore, there was reduced expression of α7 nAChR, which modulates glutamate release, in the medial prefrontal cortex (PFC) and HPC. Correlation analysis revealed strong associations between chrna7 and nr3c1 expression in both brain structures. CONCLUSION: Perturbations in the glucocorticoid neuroendocrine system and glucocorticoid-dependent gene expression of chrna7 associated with maternal stress response to hypoxia in prenatal period favor the development of nicotine addiction in adulthood.

Depressed, stressed, and inflamed: C-reactive protein linked with depression symptoms in midlife women with both childhood and current life stress.

To determine whether the relationship between inflammatory factors and clinically significant depression symptoms is moderated by high exposure to adverse childhood experiences and current life stressors in a longitudinal community cohort of midlife women. Methods: Participants from the Penn Ovarian Ageing Study community cohort (age at baseline: M = 45.3 [SD = 3.8]) were included in analyses if they had a blood sample measuring basal inflammatory markers during at least one visit where depression symptom severity and current stressful life events were also assessed (N = 142, average number of visits per participant = 1.75 [SD = 0.92]). Approximately annually over the course of 16 years, participants self-reported depression symptom severity using the Centre for Epidemiologic Studies Depression (CESD) Scale, provided menstrual diaries to determine menopause stage, and contributed blood samples. Residual blood samples were assayed for interleukin (IL)-6, IL 1-beta (IL-1ß), tumour necrosis factor alpha (TNF-α), and high sensitivity C-reactive protein (hsCRP). Early life stress was quantified using the Adverse Childhood Experiences questionnaire (low [0-1 experience(s)] versus high [≥ 2 experiences]). Current stressful life events were assessed using a structured interview (low [0-1 events] vs. high [≥ 2 events]). Generalised estimating equation models were used to model associations with the outcome of interest-clinically significant depression symptoms (CESD ≥16)-and risk factors: inflammatory marker levels (log transformed), adverse childhood experiences group, and current life stressors group. Covariates included menopause stage, age at study baseline, body mass index, race, and smoking status. We found a significant three-way interaction between log hsCRP levels, adverse childhood experiences group, and current life stressors group on likelihood of experiencing clinically significant depression symptoms (OR: 4.33; 95% CI: 1.22, 15.46; p = 0.024) after adjusting for covariates. Solely for women with high adverse childhood experiences and with high current life stressors, higher hsCRP was associated with higher odds of having clinically significant depression symptoms (OR: 1.46; 95% CI 1.07, 1.98; p = 0.016). This three-way interaction was not significant for IL-6, IL-1ß, or TNF-α. For women in midlife with exposure to high adverse childhood experiences and multiple current life stressors, elevated levels of CRP were uniquely associated with clinically significant depression symptoms. Early life adversity and current life stressors represent identifiable individual risk factors whose negative impact may be curtailed with inventions to target inflammation in midlife women.

PGAM5 knockout causes depressive-like behaviors in mice via ATP deficiency in the prefrontal cortex.

INTRODUCTION: Major depressive disorder (MDD) affects about 17% population in the world. Although abnormal energy metabolism plays an important role in the pathophysiology of MDD, however, how deficiency of adenosine triphosphate (ATP) products affects emotional circuit and what regulates ATP synthesis are still need to be elaborated. AIMS: Our study aimed to investigate how deficiency of PGAM5-mediated depressive behavior. RESULTS: We firstly discovered that PGAM5 knockout (PGAM5-/- ) mice generated depressive-like behaviors. The phenotype was reinforced by the observation that chronic unexpected mild stress (CUMS)-induced depressive mice exhibited lowered expression of PGAM5 in prefrontal cortex (PFC), hippocampus (HIP), and striatum. Next, we found, with the using of functional magnetic resonance imaging (fMRI), that the functional connectivity between PFC reward system and the PFC volume were reduced in PGAM5-/- mice. PGAM5 ablation resulted in the loss of dendritic spines and lowered density of PSD95 in PFC, but not in HIP. Finally, we found that PGAM5 ablation led to lowered ATP concentration in PFC, but not in HIP. Coimmunoprecipitation study showed that PGAM5 directly interacted with the ATP F1 F0 synthase without influencing the interaction between ATP F1 F0 synthase and Bcl-xl. We then conducted ATP administration to PGAM5-/- mice and found that ATP could rescue the behavioral and neuronal phenotypes of PGAM5-/- mice. CONCLUSIONS: Our findings provide convincing evidence that PGAM5 ablation generates depressive-like behaviors via restricting neuronal ATP production so as to impair the number of neuronal spines in PFC.