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Ulcerative colitis is a chronic pathology characterized by relapsing-remitting phases of intestinal inflammation. Additionally, some patients develop neuropsychiatric disorders, such as depression and anxiety, or cognitive deficits. We aimed to investigate whether the development of chronic colitis elicits memory, locomotion, and mood impairments. It further examined whether these impairments are influenced by the relapsing-remitting phases of the colitis or by sex. Here, we used a chronic colitis model in male and female rats, induced with sodium dextran sulfate, mirroring the phases of human ulcerative colitis. Our results revealed that the severity of colitis was slightly higher in males than females. Chronic colitis triggered motor and short-term memory deficits and induced anxiety- and depression-like behaviors that remained throughout the development of the disease. There are also sex differences under control or inflammatory conditions. Therefore, in both situations, females compared to males displayed: (i) slightly lower locomotion, (ii) increased anxiety-like behaviors, (iii) similar depression-like behaviors, and (iv) similar short-term memory deficit. Additionally, under control conditions, the mRNA levels of IL-1β, IL-6, and TNF-α were higher in the female hippocampus. In both sexes, when chronic colitis was established, the neuroinflammation was evidenced by increased mRNA levels of these three cytokines in the hippocampus and in the motor and prefrontal cortices. Interestingly, this neuroinflammation was slightly greater in males. In summary, we show that the development of chronic colitis caused persistent behavioral abnormalities, highlighting sex differences, and that could be a consequence, at least in part, of the increase in IL-1β, IL-6, and TNF-α in the brain., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Ethnopharmacological Relevance: Rehmannia glutinosa Libosch. (RGL) is a famous ethnic medicine contained in antidepressant Chinese medicine formulas and is traditionally clinically used for depression. We have recently confirmed that RGL enhanced synaptic plasticity in a mouse model of Chinese medical syndrome and that catalpol may be the representatively pharmacological component responsible for its improvement in synaptic plasticity and treatment of depression. Impaired synaptic plasticity is closely linked to major depression. Tyrosine kinase receptor B (TrkB) signaling has recently been discovered as a key pathway for synaptic plasticity improvement and antidepressant discovery. However, to date, it is unknown whether the target of catalpol to improve synaptic plasticity involves TrkB and whether its antidepressant mechanism involves synaptic plasticity mediated by TrkB signaling., Aim of Study: This study aims to elucidate the potential antidepressant target and mechanisms of catalpol, the main active compound of RGL, through TrkB signaling-mediated synaptic plasticity., Materials and Methods: We have recently predicted through molecular networking strategy (including network pharmacology, molecular docking, and molecular dynamics simulation) that catalpol may exert its antidepressant effects by regulating TrkB signaling and thus modulating essential synaptic plasticity proteins. Then, this study used classic behavioral tests, targeted diagnostic reagents, Nissl and Golgi staining, immunohistochemical analysis, immunofluorescence analysis, Western blot, enzyme-linked immunosorbent assay, and Real-time PCR to confirm the potential target and signaling of catalpol to improve synaptic plasticity for the treatment of depression., Results: The data showed that catalpol could improve synaptic plasticity and depressive behaviors, and its action pathway was predicted to involve TrkB signaling. Subsequently, the blockade of TrkB abolished the improvement of synaptic plasticity by catalpol and its antidepressant properties, which validated that TrkB signaling was the key pathway for catalpol to improve synaptic plasticity and exert antidepressant properties. Inhibition of COX-2 was likely to be a necessary facilitator for the antidepressant efficacy of catalpol via the TrkB target and TrkB-mediated synaptic plasticity., Conclusion: TrkB signaling-mediated synaptic plasticity plays a key role in the antidepressant properties of catalpol. This study provides critical information for the development of new and targeted antidepressant therapies or treatment strategies by catalpol. However, considering the existence of sex differences in depression (female depression is 2-3 times than that of males) and not exploring the antidepressant sex specificity of catalpol is a limitation, we will investigate the sex specificity of the antidepressant effects and molecular mechanisms of catalpol on sex-specific animals in the future to provide a preclinical basis for more accurate and targeted medication of catalpol., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Depression is high in prevalence rate, recurrence rate and disability rate. Acupuncture is effective on depression. The paper reviewed the regulatory effect of acupuncture on five prominent signaling pathways, i.e. mitogen activated protein kinase (MAPK), Wnt/β-catenin, Notch, adenyl ate cyclase/cyclic adenosine phosphate/protein kinase (AC/cAMP/PKA) and NO/cyclic guanosine monophosphate (cGMP)； and elaborated the structure of each signaling pathway, the association with depression onset, and the relevant research progress of acupuncture in treatment of depression. In view of the regulation of signal pathways, acupuncture can up-regulate AC/cAMP/PKA and extracellular signal-regulated kinase (ERK), promote the expression of neurotrophic factors or Bcl-2, prevent from and repair neuronal damage, advance neurogenesis and improve synaptic plasticity； it can modulate the Wnt/β-catenin and Notch signal pathways to protect neurons and increase cell proliferation； and down-regulate JNK and up-regulate NO/cGMP signal pathways to inhibit stress that leads to abnormal apoptosis of neurosis and attenuate neurotoxicity and neuronal damage so that anti-depression of acupuncture is obtained. This review provides a new approach to the mechanism research of acupuncture in treatment of depression through regulating the relevant single pathways.

Objectives: To observe the effect of manual acupuncture stimulation on changes of behavior and hippocampal signaling pathways of AMP-activated kinase (AMPK)/UNC-51-like kinase 1 (ULK1) in rats with chronic unpredictable mild stress (CUMS)-induced depression, so as to explore its molecular mechanism underlying improvement of depression., Methods: Thirty-two male SD rats were randomly divided into normal control, model, acupuncture and medication (fluoxetine) groups, with 8 rats in each group. The depression model was established by using CUMS (fasting, water depredation, restraint, swimming in cold water, crowding, stroboscope stimulation, and tail clipping, each of which was used once a week) for 6 weeks. Manual acupuncture stimulation was applied to "Baihui"(GV20) and "Yintang"(EX-HN3) for 10 min, once daily, 6 times a week for 6 weeks before every-day modeling. Rats of the medication group received gavage of fluoxetine (10 mg/kg) once a day for 6 weeks before every-day modeling. The percentage of sucrose preference, and the percentages of open arm times and open arm time in the elevated plus maze experiments were detected. The expression levels of AMPK, phosphorylated (p)-AMPK, ULK1, p-ULK1, mammalian target of rapamycin (mTOR) and p-mTOR proteins in the hippocampus tissue were detected by Western blot, and the expression of autophagy effecting protein (Beclin-1) and the selective autophagy receptors (p62) mRNA in the hippocampal tissue was detected using real-time fluorescence quantitative PCR, respectively., Results: Compared with the normal group, the percentage of sucrose preference, percentage of times of entering the open arm and percentage of open arm time, the expression levels of p-AMPK /AMPK ratio, p-ULK1 /ULK1 ratio of proteins, and Beclin-1 mRNA were significantly decreased ( P <0.01, P <0.05), and the expression levels of p-mTOR /mTOR ratio and p62 mRNA were significantly increased ( P <0.01, P <0.05) in the model group. In comparison with the model group, the percentage of sucrose preference, percentage of open arm times and open arm time, the expression levels of p-AMPK /AMPK ratio, p-ULK1/ULK1 ratio of proteins, and Beclin-1 mRNA were significantly increased in both acupuncture and medication groups ( P <0.01, P <0.05), while the expression levels of p-mTOR /mTOR ratio of proteins, and p62 mRNA were markedly decreased only in the medication group ( P <0.05)., Conclusions: Acupuncture treatment can alleviate depression-like behavior in CUMS rats, which may be related to its functions in up-regulating AMPK/ULK1 signaling pathway to induce cellular autophagy in the hippocampus.

In recent years, the incidence of food allergies in children has been increasing annually, significantly affecting the quality of life for patients and their families. It has long been suspected that childhood allergies might potentially lead to behavioral and psychological issues in adulthood, but the specific connection remains unclear. In this study, we established a model of young mice allergic to milk α S1 -casein, conducted behavioral tests, and employed transcriptomics, immunohistochemistry, Golgi staining, and fecal microbiota transplantation to explore the link between early life allergies and adult psychological problems. The results showed that early life milk protein allergy significantly increased intestinal epithelial permeability in mice, leading to the translocation of gut microbiota metabolites. This process subsequently activated astrocyte lysosomes via SLC15a3, making astrocytes more susceptible. This susceptibility caused mice with early life milk protein allergy to have more activated astrocytes and excessive dendritic spine phagocytosis (normal group: 5.4 ± 1.26 spines/10 μm, allergy group: 3.2 ± 0.92 spines/10 μm) under acute stress in adulthood, leading to anxiety and depressive behaviors.

Compromised mitochondrial electron transport chain (ETC) activities are associated with depression in humans and rodents. However, the effects of the enhancement of mitochondrial ETC activities on depression remain elusive. We recently reported that an extremely low-frequency electromagnetic field (ELF-EMF) of as low as 10 μT induced hormetic activation of mitochondrial ETC complexes in human/mouse cultured cells and mouse livers. Chronic social defeat stress (CSDS) for 10 consecutive days caused behavioral defects mimicking depression in mice, and using an ELF-EMF for two to six weeks ameliorated them. CSDS variably decreased the mitochondrial ETC proteins in the prefrontal cortex (PFC) in 10 days, which were increased by an ELF-EMF in six weeks. CSDS had no effect on the mitochondrial oxygen consumption rate in the PFC in 10 days, but using an ELF-EMF for six weeks enhanced it. CSDS inactivated SOD2 by enhancing its acetylation and increased lipid peroxidation in the PFC. In contrast, the ELF-EMF activated the Sirt3-FoxO3a-SOD2 pathway and suppressed lipid peroxidation. Furthermore, CSDS increased markers for mitophagy, which was suppressed by the ELF-EMF in six weeks. The ELF-EMF exerted beneficial hormetic effects on mitochondrial energy production, mitochondrial antioxidation, and mitochondrial dynamics in a mouse model of depression. We envisage that an ELF-EMF is a promising therapeutic option for depression.

Depression is characterized by both neuroinflammation and neurodegeneration. Exosomes (Exo) have been shown to function as inhibitors of inflammation and promoters of neurogenesis. Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid, can combat depression by increasing levels of docosapentaenoic acid (DPA). This study explored the effects of DPA on the therapeutic potential of Exo derived from human umbilical cord mesenchymal stem cells (hUCMSCs) in glia-induced neuroinflammation associated with depression. Exposure to chronic unpredictable mild stress (CUMS) over six weeks induced depression- and anxiety-like behaviors, while decreasing the levels of serotonin and dopamine. Molecularly, CUMS increased the concentrations of the microglial M1 markers Iba1, iNOS, and IL-1β, while reducing the M2 markers Arg1, CD206, and IL-10 in the prefrontal cortex and hippocampus. However, Exo therapy reversed these effects. Moreover, DPA treatment of Exo demonstrated superior efficacy in alleviating depressive behaviors, neurotransmitter deficiencies, and M1 microglial activation. In vitro, Exo suppressed LPS-stimulated BV2 cell viability and M1 microglial activation, while mitigating the SH-SY5Y cell apoptosis triggered by treatment with the conditioned medium from LPS-activated BV2 cells. Furthermore, administration of DPA enhanced this effect. Mechanically, DPA enhanced Exo function by upregulating miR125b-5p expression, thereby targeting the MyD88/TRAF6/NF-κB signaling pathway. In summary, Exo exhibited antidepressant effects by suppressing M1 microglial neuroinflammation, while DPA treatment provided a more potent therapeutic effect on depression-like changes through the upregulation of miR125b-5p targeting the MyD88/TRAF6/NF-κB pathway., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Major depression is a severe neuropsychiatric disorder that poses a significant challenge to health. However, development of an effective therapy for the disease has long been difficult. Here, we investigate the efficacy of a novel combinatorial treatment employing sub-effective doses of Ro25-6981, an antagonist targeting GluN2B-containing NMDA receptors, in conjunction with ZL006, an inhibitor of the PSD95/nNOS, on mouse models of depression. We employed social isolation, chronic restraint stress, or a combination of both to establish a depressed mouse model. Treatment with the drug combination reduced depressive-like behaviors without affecting locomotor activity in mice subjected to social isolation or chronic restraint stress. Furthermore, the combination therapy ameliorated depressive-like behaviors induced by combined stress of chronic restraint followed by social isolation. Mechanistic studies revealed that the combined treatment downregulated the hippocampal nitric oxide level. However, the therapeutic benefits of this combination were negated by the activation of NMDA receptors with a low dose of NMDA or by increasing nitric oxide levels with l-arginine. Moreover, the combinatorial treatment had negligible effects on object memory and contextual fear memory. Our data establish a combined therapy paradigm, providing a potential strategy targeting major depression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Although depression is linked to an increased risk of dementia, the association between late-onset depression (LOD) and amyloid burden remains unclear. This study aimed to determine amyloid deposition in patients with LOD compared to healthy controls (HC) using amyloid-beta (Aβ) positron emission tomography (PET) images and neuropsychological assessments., Methods: Forty patients first diagnosed with major depressive disorder after the age of 60 (LOD) and twenty-one healthy volunteers (HC) were enrolled. Depression and anxiety were evaluated using the 17-item Hamilton Depression Scale, Hamilton Anxiety Rating Scale, and Clinical Global Impression Scale. Cognitive function was assessed using the Korean versions of the Mini-Mental Status Examination, Montreal Cognitive Assessment, and Seoul Neuropsychological Screening Battery at baseline and 3-month follow-up. 18 F-florbetapir PET images were co-registered with T1-weighted magnetic resonance images., Results: There was no significant difference in Aβ deposition between LOD and HC groups. No significant correlation between Aβ burden and depressive symptom severity was found in LOD patients. Higher somatic anxiety was correlated with lower Aβ burden in multiple brain regions, including the left inferior frontal lobe (p = 0.009), right anterior cingulate (p = 0.003), and right superior frontal lobe (p = 0.009). Despite cognitive recovery in areas such as attention (Digit Span Forward, p = 0.026), memory (Auditory Verbal Learning Test Recall Total, p = 0.010; Rey Complex Figure Test Delayed Recall, p = 0.039), and frontal executive function (Contrasting Program, p = 0.033) after three months of antidepressant treatment, cognitive improvement showed no association with amyloid deposition., Conclusions: These findings suggest distinct mechanisms may underlie amyloid deposition in neurodegenerative changes associated with depression. While amyloid burden in specific brain regions negatively correlated with somatic anxiety, it showed no significant correlation with the severity of depression or overall cognitive function., (© 2024. The Author(s).)

Depression, a prevalent mental illness, is intricately linked with the neurotransmitters in the brain, while serotonin as a crucial regulator of mood, energy levels, and memory, has been implicated in depression. So, the release of serotonin by serotonergic neurons plays a significant role in the development of depression. Notably, the foremost marker of oxidative stress, hydrogen peroxide (H 2 O 2 ), can interfere with the functioning of serotonergic neurons and potentially contribute to depression. Investigating the impact of H 2 O 2 on serotonergic neurons could offer valuable insights into the mechanisms underlying depression. However, there have been no effective tools for selectively imaging H 2 O 2 in these neurons so far. To address this gap, we created a small molecular fluorescent probe, PF-H2O2, designed specifically for imaging H 2 O 2 in serotonergic neurons under oxidative stress. PF-H2O2 exerts excellent serotonergic neuron-targetability and notable selectivity for H 2 O 2 . Furthermore, we discovered increased H 2 O 2 in serotonergic neurons of mice with depressive symptoms. Altogether, this endeavour unveils a pioneering tool for exploring pathophysiology linked to serotonergic neuronal dysfunction.

Depression is a global health concern affecting nearly 280 million individuals. It not only imposes a significant burden on economies and healthcare systems but also manifests complex physiological connections and consequences. Agmatine, a putative neuromodulator derived primarily from beneficial gut microbes specially Lactobacillus, has emerged as a potential therapeutic agent for mental health. The microbiota-gut-brain axis is involved in the development of depression through the peripheral nervous system, endocrine system, and immune system and may be a key factor in the effect of agmatine. Therefore, this study aimed to investigate the potential mechanism of agmatine in antibiotic-induced dysbiosis and depression-like behavior in rats, focusing on its modulation of the gut-brain axis. Depression-like behavior associated with dysbiosis was induced through a seven-day regimen of the broad-spectrum antibiotic, comprising ampicillin and metronidazole and validated through microbial, biochemical, and behavioral alterations. On day 8, antibiotic-treated rats exhibited loose fecal consistency, altered fecal microbiota, and depression-like behavior in forced swim test. Pro-inflammatory cytokines were elevated, while agmatine and monoamine levels decreased in the hippocampus and prefrontal cortex. Antibiotic administration disrupted tight junction proteins in the ileum, affecting gut architecture. Oral administration of agmatine alone or combined with probiotics significantly reversed antibiotic-induced dysbiosis, restoring gut microbiota and mitigating depression-like behaviors. This intervention also restored neuro-inflammatory markers, increased agmatine and monoamine levels, and preserved gut integrity. The study highlights the regulatory role of endogenous agmatine in the gut-brain axis in broad-spectrum antibiotic induced dysbiosis and associated depression-like behavior., Competing Interests: Declaration of competing interest Authors declare that there are no conflicts of any interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Depression and anxiety are prominent symptoms of withdrawal syndrome, often caused by the abuse of addictive drugs like morphine. N-palmitoylethanolamide (PEA), a biologically active lipid, is utilized as an anti-inflammatory and analgesic medication. Recent studies have highlighted PEA's role in mitigating cognitive decline and easing depression resulting from chronic pain. However, it remains unknown whether PEA can influence negative emotions triggered by morphine withdrawal. This study seeks to explore the impact of PEA on such emotions and investigate the underlying mechanisms. Mice subjected to morphine treatment underwent a 10-day withdrawal period, followed by assessments of the effect of PEA on anxiety- and depression-like behaviors using various tests. Enzyme-linked immunosorbent assay was conducted to measure levels of monoamine neurotransmitters in specific brain regions. The findings indicate that PEA mitigated anxiety and depression symptoms and reduced 5-hydroxytryptamine, noradrenaline, and dopamine levels in the hippocampus and prefrontal cortex. In summary, PEA demonstrates a significant positive effect on negative emotions associated with morphine withdrawal, accompanied with the reduction in levels of monoamine neurotransmitters in key brain regions. These insights could be valuable for managing negative emotions arising from morphine withdrawal., (Copyright © 2024. Published by Elsevier B.V.)

Carnosine, anserine, and homocarnosine are histidine-containing dipeptides (HCDs) abundant in the skeletal muscle and nervous system in mammals. To date, studies have extensively demonstrated effects of carnosine and anserine, the predominant muscular HCDs, on muscular functions and exercise performance. However, homocarnosine, the predominant brain HCD, is underexplored. Moreover, roles of homocarnosine and its related HCDs in the brain and behaviors remain poorly understood. Here, we investigated potential roles of endogenous brain homocarnosine and its related HCDs in behaviors by using carnosine synthase-1-deficient (Carns1 -/- ) mice. We found that old Carns1 -/- mice (female 12 months old) exhibited hyperactivity- and depression-like behaviors with higher plasma corticosterone levels on light-dark transition and forced swimming tests, but had no defects in spontaneous locomotor activity, repetitive behavior, olfactory functions, and learning and memory abilities, as compared with their age-matched wild-type (WT) mice. We confirmed that homocarnosine and its related HCDs were deficient across brain areas of Carns1 -/- mice. Homocarnosine deficiency exhibited small effects on its constituent γ-aminobutyric acid (GABA) in the brain, in which GABA levels in hypothalamus and olfactory bulb were higher in Carns1 -/- mice than in WT mice. In WT mice, homocarnosine and GABA were highly present in hypothalamus, thalamus, and olfactory bulb, and their brain levels did not decrease in old mice when compared with younger mice (3 months old). Our present findings provide new insights into roles of homocarnosine and its related HCDs in behaviors and neurological disorders., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Thanutchaporn Kumrungsee reports financial support was provided by the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT, Tokyo), Japan. Thanutchaporn Kumrungsee reports financial support was provided by Danone Institute of Japan Foundation, Japan. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Three-needle electroacupuncture (TNEA) has shown promise as a non-pharmacological treatment for post-stroke depression (PSD). However, the underlying mechanisms of its therapeutic effects remain unclear. In this study, we investigated the potential molecular and synaptic mechanisms by which TNEA ameliorates depressive-like behaviors in a mouse model of PSD. Male C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO) to induce PSD and subsequently treated with TNEA for three weeks at specific acupoints (GV24 and bilateral GB13). Through a combination of behavioral tests, neuronal activation assessment, synaptic function examination, transcriptomic analysis, and various molecular techniques, we found that TNEA treatment significantly improved anxiety and depressive-like behaviors in PSD mice. These improvements were accompanied by enhanced neuronal activation in the medial prefrontal cortex (mPFC) and primary somatosensory cortex (PSC), as well as the promotion of excitatory synapse formation and transmission function in the mPFC. Transcriptomic analysis revealed that TNEA upregulated the expression of Netrin-G Ligand-3 (NGL-3), a postsynaptic cell adhesion molecule, in the mPFC. Further investigation showed that the extracellular domain of NGL-3 binds to the presynaptic protein L1cam, promoting the formation of Vesicular Glutamate Transporter 1 (vGluT1) puncta on neuronal dendrites. Notably, cortical neuron-specific knockout of NGL-3 abolished the antidepressant-like effects of TNEA in PSD mice, confirming the crucial role of the NGL-3/L1cam pathway in mediating the therapeutic effects of TNEA. These findings provide novel insights into the molecular and synaptic mechanisms underlying the therapeutic effects of acupuncture in the treatment of PSD and highlight the potential of targeting the NGL-3/L1cam pathway for the development of alternative interventions for PSD and other depressive disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Depression, a leading cause of disability worldwide, is characterized by dysfunction of immature neurons, resulting in dysregulated calcium homeostasis and impaired structural plasticity. Jujuboside A (JuA), a biologically active compound derived from Semen Ziziphi Spinosae , has demonstrated anti-anxiety and anti-insomnia properties. Recent studies suggest that JuA may be a promising antidepressant, but its underlying mechanisms remain unclear., Methods: Sprague-Dawley rats were subjected to chronic unpredictable mild stress (CUMS) to induce a depression model. JuA (12.5 mg/kg, 25 mg/kg, 50 mg/kg) was administered orally for 4 weeks. Emotional and cognitive function were assessed. Monoamine neurotransmitter levels were measured using enzyme-linked immunosorbent assay (ELISA). The number of immature neurons and calcium homeostasis were evaluated by immunofluorescence. Western blotting and immunofluorescence were employed to detect the expression of Sonic hedgehog (Shh) signaling proteins. Additionally, lentiviral vector expressing Shh shRNA (LV-Shh-RNAi) were infused intracerebrally to investigate the role of Shh in JuA's antidepressant effects., Results: JuA significantly ameliorated depressive-like behavior and cognitive dysfunction in CUMS rats, increased monoamine neurotransmitter levels in serum and hippocampal tissue, reduced the number of BrdU/DCX (bromodeoxyuridine/doublecortin)-positive immature neurons, and attenuated calcium ion (Ca 2+ ) concentration and Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) levels in immature neurons. JuA also markedly elevated synaptic density and prominence complexity, upregulated Shh, Gli family zinc finger 1 and 2 (Gli1/2), synaptophysin (Syn) and postsynaptic density protein-95 (PSD-95) expression in the ventral dentate gyrus (vDG). However, knockdown of Shh in the vDG counteracted JuA's therapeutic effects., Conclusion: These findings collectively suggest that JuA improves depressive-like behavior in CUMS rats by modulating calcium homeostasis and synaptic structural plasticity in immature neurons through the Shh signaling pathway., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Zhong et al.)

Abnormal neuronal morphological features, such as dendrite branching, axonal branching, and spine density, are thought to contribute to the symptoms of depression and anxiety. However, the role and molecular mechanisms of aberrant neuronal morphology in the regulation of mood disorders remain poorly characterized. Here, we show that neuritin, an activity-dependent protein, regulates the axonal morphology of serotonin neurons. Male neuritin knock-out (KO) mice harbored impaired axonal branches of serotonin neurons in the medial prefrontal cortex and basolateral region of the amygdala (BLA), and male neuritin KO mice exhibited depressive and anxiety-like behaviors. We also observed that the expression of neuritin was decreased by unpredictable chronic stress in the male mouse brain and that decreased expression of neuritin was associated with reduced axonal branching of serotonin neurons in the brain and with depressive and anxiety behaviors in mice. Furthermore, the stress-mediated impairments in axonal branching and depressive behaviors were reversed by the overexpression of neuritin in the BLA. The ability of neuritin to increase axonal branching in serotonin neurons involves fibroblast growth factor (FGF) signaling, and neuritin contributes to FGF-2-mediated axonal branching regulation in vitro. Finally, the oral administration of an FGF inhibitor reduced the axonal branching of serotonin neurons in the brain and caused depressive and anxiety behaviors in male mice. Our results support the involvement of neuritin in models of stress-induced depression and suggest that neuronal morphological plasticity may play a role in controlling animal behavior., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Mental health is affected by tryptophane (TRP) metabolism regulation. Diet-influenced gut microbiome regulates TRP metabolism. Thus, the present study aimed to explore the relationship between type of dietary protein intake, gut microbiota, TRP metabolites homeostasis, and mental well-being in healthy women. 91 healthy females aged 18-50 were recruited based on the study protocol. Validate and reliable questionnaires assessed dietary intake and mental health. Biochemical tests and gut microbiota composition were analyzed following the manufacturer's instructions for each enzyme-linked immune sorbent assay (ELISA) kit and Real-time quantitative polymerase chain reaction (qPCR) methods respectively. Regression methods were used to estimate the considered associations. The results show that in the fully adjusted model, plant protein consumption was partially inversely associated with depression risk (OR = 0.27; 95% CI: 0.06, 1.09; P = 0.06). Higher dietary animal protein intake was marginally associated with psychological distress (OR = 2.59; 95% CI: 0.91, 7.34; P = 0.07). KYN to serotonin ratio was inversely associated with animal protein consumption (ß = 1.10; 95% CI: -0.13, 2.33; P = 0.07). Firmicutes/Bacteriodetes ratio (β = -1.27 × 103, SE = 5.99 × 102, P = 0.03) was lower in the top tertile of plant protein. A partially negative correlation was found between dietary animal protein and Prevotella abundance (β = -9.20 × 1018, SE = 5.04 × 1018, P = 0.06). Overall, significant inverse associations were found between a diet high in plant protein with mental disorders, KYN levels, and Firmicutes to Bacteroidetes ratio while adhering to higher animal protein could predispose women to psychological stress., (© 2024. The Author(s).)

The intrinsic correlation between depression and serotonin (5-HT) is a highly debated topic, with significant implications for the diagnosis, treatment, and advancement of drugs targeting neurological disorders. To address this important question, it is of utmost priority to understand the action mechanism of serotonin in depression through fluorescence imaging studies. However, the development of efficient molecular probes for serotonin is hindered by the lack of responsive sites with high selectivity for serotonin at the present time. Herein, we developed the first highly selective serotonin responsive site, 3-mercaptopropionate, utilizing thiol-ene click cascade nucleophilic reactions. The novel responsive site was then employed to construct the powerful molecular probe SJ-5-HT for imaging the serotonin level changes in the depression cells and brain tissues. Importantly, the imaging studies reveal that the level of serotonin in patients with depression may not be the primary factor, while the ability of neurons in patients with depression to release serotonin appears to be more critical. Additionally, this serotonin release capability correlates strongly with the levels of mTOR (intracellular mammalian target of rapamycin). These discoveries could offer valuable insights into the molecular mechanisms underpinning depression and furnish mTOR as a novel direction for the advancement of antidepressant therapies., (© 2024 Wiley-VCH GmbH.)

The basolateral amygdala (BLA) is increasingly recognized as a key regulator of depression and anxiety-like behaviors. However, the specific contribution of individual BLA neurons to these behaviors remains poorly understood. Building on our previous study, which demonstrated increased activity in glutamatergic BLA neurons in response to aversive stimuli and that enhancing inhibition in the BLA can alleviate depressive-like behaviors, we investigated the role of individual BLA GABAergic neurons (BLA GABA ) in depressive and anxiety-like phenotypes. To address this question, we employed a comprehensive array of techniques, including c-fos staining, fiber photometry recording, optogenetic and chemogenetic manipulation, and behavior analysis. Our findings indicate that BLA GABA neurons show decreased activity during tail suspension and after chronic social defeat stress (CSDS) during social interaction. High-frequency activation of BLA GABA neurons attenuated depressive and anxiety-like behaviors, while low-frequency activation had no effect. Fiber photometry recordings revealed increased activity in BLA GABAergic neurons expressing somatostatin (SST), parvalbumin (PV), and cholecystokinin (CCK) during footshock aversive stimuli. Moreover, we found increased activity in PV and SST neurons and decreased activity in CCK-GABA neurons in the BLA during tail suspension stress. However, after CSDS, BLA PV neurons displayed decreased activity, while SST and CCK neurons showed no changes during the social interaction test. Behavioral analysis demonstrated that chemogenetic inhibition of PV and CCK-GABA neurons induced depressive and anxiety-like behaviors. whereas SST neuron inhibition had no effect. Conversely, chemogenetic activation of BLA PV neurons alleviated depressive behaviors, and activation of BLA CCK-GABA neurons alleviated at least partly both depressive and anxiety-like behaviors. This study provides compelling evidence that BLA PV neurons play a critical role in regulating depressive-like behaviors, and that BLA CCK-GABA neurons are involved, at least in part, in modulating both depressive-like and anxiety-like behaviors in mice., (© 2024. The Author(s).)

Depressive pseudodementia (DPD) is a debilitating cognitive dysfunction that accompanies major and/or frequent depressive attacks. DPD has gained significant research attention owing to its negative effects on the patients' quality of life and productivity. This study tested the procognitive potential of Flibanserin (FBN), the serotonin (5HT) receptor modulator, against propranolol (PRP), as β/5HT1A receptors blocker. Serving this purpose, female Wistar Albino rats were subjected to chronic unpredictable stress (CUS) and subsequently treated with FBN only (3 mg/kg/day, p.o), PRP only (10 mg/kg/day, p.o), or PRP followed by FBN, using the same doses. FBN ameliorated the behavioral/cognitive alterations and calmed the hypothalamic-pituitary-adrenal (HPA) axis storm by reducing the levels of stress-related hormones, viz, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), corticosterone (CORT) parallel to epinephrine (EPI) hyperstimulation. The maladaptive inflammatory response, comprising of interleukin (IL)-1β/6, and tumor necrosis factor (TNF)-α, was consequently blunted. This was contemporaneous to the partial restoration of the protein kinase-B (AKT)/glycogen synthase kinase (GSK)3β/signal transducer and activator of transcription (STAT)-3 survival trajectory and the reinstatement of the levels of brain derived neurotrophic factor (BDNF). Microscopically, FBN repaired the hippocampal architecture and lessened CD68/GFAP immunoreactivity. Pre-administration of PRP partially abolished FBN effect along the estimated parameters, except for 5HT2A receptor expression and epinephrine level, to prove 5HT1A receptor as a fulcrum initiator of the investigated pathway, while its sole administration worsened the underlying condition. Ultimately, these findings highlight the immense procognitive potential of FBN, offering a new paradigm for halting DPD advancement via synchronizing adrenergic/serotonergic circuitry., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Potassium channels stabilize the resting potential and neuronal excitability. Among them, erg (ether-à-go-go-related gene) K + channels represent a subfamily of voltage-gated channels, consisting of erg1, erg2, and erg3 subunits; however, their subunit-specific neuronal functions in vivo are barely understood. To find erg3- and erg1-mediated functions, we generated global Kcnh7 ( erg3 ) and conditional Kcnh2 ( erg1 ) knockout mice. We found that erg3 channels stabilize the resting potential and dampen spontaneous activity in cerebellar Purkinje cells (PCs) and hippocampal CA1 neurons, whereas erg1 channels have suprathreshold functions. Lack of erg3 subunits induced hyperexcitability with increased action potential firing in PCs, but not in CA1 neurons. Notably, erg3 depletion caused depressive-like behavior with reduced locomotor activity, strongly decreased digging behavior, and shorter latencies to fall off a rotating wheel, while learning and memory remained unchanged. Our data show that erg K + channels containing erg3 subunits mediate a neuronal subthreshold K + current that plays important roles in the regulation of locomotor behavior in vivo.

Chronic stress leads to social avoidance and anhedonia in susceptible individuals, a phenomenon that has been observed in both human and animal models. Nevertheless, the underlying molecular mechanisms underpinning stress susceptibility and resilience remain largely unclear. There is growing evidence that epigenetic histone deacetylase (HDAC) mediated histone acetylation is involved in the modulation of depressive-related behaviors. We hypothesized that histone deacetylase 5 (HDAC5), which is associated with stress-related behaviors and antidepressant response, may play a vital role in the susceptibility to chronic stress. In the current study, we detected the levels of HDAC5 and acetylation of histone 4 (H4) in the hippocampus subsequent to chronic social defeat stress (CSDS) in C57BL/6J mice. We found that CSDS induces a notable increase in HDAC5 expression, concomitant with a reduction in the acetylation of histone H4 at lysine 12 (H4K12) in the hippocampus of susceptible mice. Meanwhile, intrahippocampal infusion of HDAC5 shRNA or HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) both reversed the depression susceptibility in susceptible mice that subjected to CSDS. Furthermore, HDAC5 overexpression was sufficient to induce depression susceptibility following microdefeat stress, accompanied by a significant reduction in H4K12 level within the hippocampus of mice. Additionally, the Morris water maze (MWM) results indicated that neither CSDS nor HDAC5 exerted significant effects on spatial memory function in mice. Taken together, these investigations indicated that HDAC5-modulated histone acetylation is implicated in regulating the depression susceptibility, and may be serve as potential preventive targets for susceptible individuals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Dysregulation of brain homeostasis is associated with neuropsychiatric conditions such as major depressive disorder. However, underlying neural-circuit mechanisms remain not well-understood. We show in mice that chronic restraint stress (CRS) and social defeat stress (SDS) are both associated with disruption of excitation (E)-inhibition (I) balance, with increased E/I ratios, in medial preoptic area (MPOA) circuits, but through affecting different neuronal types. CRS results in elevated activity in glutamatergic neurons, and their suppression mitigates CRS-induced depressive-like behaviors. Paraventricular hypothalamic input to these neurons contributes to induction but not expression of depressive-like behaviors. Their projections to ventral tegmental area and periaqueductal gray/dorsal raphe suppress midbrain dopaminergic and serotonergic activity, respectively, and mediate expression of divergent depressive-like symptoms. By contrast, SDS results in reduced activity of GABAergic neurons, and their activation alleviates SDS-induced depressive-like behaviors. Thus, E/I imbalance with relatively increased excitation in MPOA circuits may be a general mechanism underlying depression caused by different etiological factors., (© 2024. The Author(s).)

Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidepressant drugs with novel mechanisms. Here, we found that norisoboldine (NOR) showed an antidepressant efficacy in the chronic social defeat stress (CSDS) depression model in the tail suspension, forced swimming, and sucrose consumption tests. We then utilized the drug-treated CSDS mice paradigm to segregate and gain differential protein groups of CSDS versus CON (CSDS CON ), imipramine (IMI)-treated versus CSDS (IMI CSDS ), and NOR-treated versus CSDS (NOR CSDS ) from the prefrontal cortex. These protein expression alterations were first analyzed by ANOVA with p < 0.05. The protein cluster 1 and cluster 3, in which the pattern of protein levels similar to the mood pattern, showed enrichment in functions and localizations related to mitochondrion, ribosome and synapses. Further GO analysis of the common proteins for NOR CSDS groups and NOR IMI groups supported the findings from ANOVA analysis. We employed Protein-Protein interaction (PPI) analysis to examine the proteins of NOR CSDS and NOR IMI, revealing an enrichment of the proteins associated with the mitochondrial ribosomal and synaptic functions. Further independent analysis using parallel reaction monitoring (PRM) revealed that Cox7c, Mrp142, Naa30, Ighm, Apoa4, Ssu72, Mrps30, Apoh, Acbd5, and Cdv3, exhibited regulation in the NOR-treated group to support the homeostasis of mitochondrial functions. Additionally, Dcx, Arid1b, Rnf112, and Fam3c, were also observed to undergo modulation in the NOR-treated groups to support the synaptic formation and functions. These findings suggest that the proteins involved in depression treatment exert effects in strengthen the mitochondrial and synaptic functions in the mice PFC. Western blot analysis supported the data that the levels of Mrpl42, Cox7c, Naa30, Rnf112, Dcx Apoa4, Apoh and Fam3c were altered in the CSDS mice, and rescued by NOR treatment, supporting the PRM data. NOR treatment also rescued the NLRP3 inflammasome activation in CSDS mice. In summary, the current proteomic research conducted on the prefrontal cortex has provided valuable insights into the specific and shared molecular mechanisms underlying pathophysiology and treatment to CSDS-induced depression, shedding light on the therapeutic effects of Norisoboldine., (© 2024. The Author(s).)

Dopamine (DA) neurons play a crucial role in the development and manifestation of depression, as well as in response to antidepressant treatments. While the function of the predominantly distributed DA neurons in the ventral tegmental area (VTA) is well established, the contribution of a small fraction of DA neurons in the dorsal raphe nucleus (DRN) during depression remains unclear. In this study, we found that chronic unpredictable stress (CUS) induces depression-related behaviors and decreases spontaneous firing rates, excitatory and inhibitory postsynaptic currents of DA neurons in the DRN associated with reduced excitatory synaptic transmission in male and female mice. The chemogenetic inhibition of DA neurons in the DRN produces depressive phenotypes. Conversely, their activation completely reversed the anhedonic and despair behaviors induced by CUS. Furthermore, we showed that a DRN dopaminergic projecting to the dorsal bed nucleus of the stria terminalis (dBNST) selectively controls depressive behaviors by influencing the neural activity and N-methyl-D-aspartate receptor (NMDAR) mediating EPSC of calcium/calmodulin-dependent protein kinase II + (CaMKII +) target neurons by regulating dopamine neurotransmitter and dopamine receptor 2 (DR2) in the dBNST. Overall, these findings highlight the essential role of the DRN DA  → dBNST CaMKII+ neural circuit in bi-directionally mediating stress-induced depression-related behaviors. Our findings indicate that DRN DA neurons are a key component of the neural circuitry involved in regulating depression-related behaviors, making them a potential therapeutic target for depression., (© 2024. The Author(s).)

Depression is a common and complex psychiatric illness with multiple clinical symptoms, even leading to the disability and suicide. Owing to the partial understanding of the pathogenesis of depressive-like disorders, available pharmacotherapeutic strategies are developed mainly based on the "monoamine hypothesis", resulting in a limited effectiveness and a number of adverse effects in the clinical practice. The concept of multiple pathogenic factors be helpful for clarifying the etiology of depression and developing the antidepressants. It is well documented that K + channels serve crucial roles in modulating the neuronal excitability and neurotransmitter release in the brain, and abnormality of these channels participated in the pathogenic process of diverse central nervous system (CNS) pathologies, such as seizure and Alzheimer's disease (AD). The clinical and preclinical evidence also delineates that the involvement of several types of K + channels in depressive-like behaviors appear to be evident, suggesting these channels being one of the multiple factors in the etiology of this debilitating disorder. Emerging data manifest that diverse antidepressants impact distinct K + channels, such as Kv, Kir and K 2P , meaning the functioning of these drug via a "multi-target" manner. On the other hand, the scenario of antidepressants impinging K + channels could render an alternative interpretation for the pharmacological effectiveness and numerous side effects in clinical trials. Furthermore, these channels serve to be considered as a "druggable target" to develop novel therapeutic compound to antagonize this psychiatry., (© 2024. The Author(s).)

Increasing research suggests a connection between gut microbiota and depressive disorders. Targeted changes to the intestinal flora may contribute to alleviating anxiety and depression. This study aimed to identify probiotics that could attenuate stress-induced abnormal behavior and explore potential mechanisms. The administration of LR.KY16 significantly reduced stress-induced abnormal behaviors and physiological dysfunction. The mechanism may be via regulating the structure of the intestinal microbiota in mice, increasing the abundance of Akkermansia muciniphila , prompting enterochromaffin cells to secrete 5-HTP in the gut, which enters the brain through the bloodstream and promotes the synthesis of 5-HT in the brain, and then activates brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) through the 5-HT1A receptor. In addition, LR.KY16 also increased the expression of claudin-7, occludin, and zonula occludens-1 (ZO-1) in the colon, inhibited microglial M1 polarization, and inhibited systemic inflammation.

This study was conducted to examine the effects of acupuncture on gut microbiota and expression of NLRP3 inflammasome in the colon in poststroke depression (PSD) model rats. Sprague-Dawley male rats were randomized into four groups: sham surgery group, poststroke depression group, acupuncture group, and probiotics group. Acupuncture therapy at Baihui (GV20), Shenting (GV24), bilateral Zusanli (ST36) acupoints in the acupuncture group and probiotic gavage therapy in the probiotics group were performed once per day for 2 weeks. Behaviors of depression were assessed by using weight measurements, sucrose preference test, open field test, and forced swimming test. Histopathological alterations in the colon were determined by hematoxylin-eosin staining, the expression of NLRP3/ASC/caspase-1 pathway-related proteins was analyzed by western blotting. Serum levels of IL-1β and IL-18 were derived from ELISA. The 16S rRNA gene sequencing was performed to examine and analyze the differences of gut microbiota of rats among all groups. Acupuncture was effective to increase weight and ameliorate depressive-like behaviors in PSD rats. Acupuncture increased the diversity of gut microbiota, upregulated the abundance of Bifidobacteriaceae and Lactobacillaceae, and decreased the relative abundance of Peptostreptococcaceae, Rikenellaceae, Eggerthellaceae, and Streptococcaceae at family level. Acupuncture effectively improved the pathological changes in the colon. Meanwhile, acupuncture reduced NLRP3, ASC, caspase-1 protein expressions in the colon, and serum levels of IL-18 and IL-1β. Acupuncture may reduce depressive-like behaviors of PSD by regulating the gut microbiota and suppressing hyperactivation of NLRP3 inflammasome in the colon. Microbiota-gut-brain axis may be an effective target pathway for acupuncture treatment of PSD., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The aim of this study was to investigate the impact and underlying molecular mechanisms of electroacupuncture on mice with poststroke depression (PSD). Mice were randomly allocated into sham, PSD, and electroacupuncture groups. Mice in the PSD and electroacupuncture groups underwent middle cerebral artery occlusion (MCAO) surgery following with sedentary behavior. Electroacupuncture targeting Zusanli (ST36) acupoint was performed 24 h after MCAO for 4 weeks in electroacupuncture group. The sucrose preference test, forced swimming test, open field test, tail suspension test, elevated plus maze, Catwalk analysis, RNA sequencing, Nissl staining, Golgi staining, TUNEL staining, Edu labeling, and doublecortin staining were performed. Lymphocyte subsets in peripheral blood and the levels of IL-1β, IL-6, TNF-α, and expression of Iba1/CD86, Iba1/NLRP3, TLR4/p38/NF-κB/NLRP3 pathways in the hippocampus were detected. Electroacupuncture effectively protected against the development of depression-like symptoms. The number of granulosa cells and doublecortin-positive cells in the dentate gyrus (DG) were significantly decreased in PSD group, which were significantly upregulated ( P  < 0.01) by electroacupuncture. Electroacupuncture also significantly reduced ( P  < 0.05) TUNEL-positive cells in the DG and CA1. RNA-seq revealed that electroacupuncture may exert antidepressant effect by regulating the inflammation mediated by TLR4/NF-κB/NLRP3 pathway in hippocampus. Electroacupuncture remarkably elevated ( P  < 0.01) the ratio of CD4+ to CD8+ T cells and percentage of CD3-CD49b+ cells in CD45+CD49b+ cells in the peripheral blood. Electroacupuncture significantly reduced ( P  < 0.05) the high levels of IL-1β, IL-6, TNF-α, iba1, TLR4, p-p38, p-NF-κB, and NLRP3 and sedentary behavior. Electroacupuncture was observed to mitigate depression symptoms and increase hippocampal neurogenesis in mice with PSD, possibly by inhibiting TLR4/p38/NF-κB/NLRP3 pathways and improving the microglia-mediated inflammatory microenvironment in the hippocampus., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Depression and anxiety are common mental health disorders affecting thoughts, behaviors, and emotions. This study aimed to investigate the effect of the angiotensin II type I receptor blocker (AT1RB), valsartan, on menopause-induced depression and anxiety-like behaviors, and to elucidate possible mechanisms of action by measuring levels of nod-like receptor protein 3 (NLRP3), interleukin-1beta (IL-1β), brain-derived neurotrophic factor (BDNF), and oxidative stress in brain tissue. Thirty-two Wistar albino female rats were randomly divided into four groups (n = 8 per group): Control, AT1RB, OVX, and AT1RB + OVX. Following the bilateral ovariectomy (OVX) protocol, physiological saline was used as valsartan solvent, in a maximum volume of 0.4 mL, and valsartan was administered via intragastric gavage at a dose of 40 mg/kg/day. Depression and anxiety-like behaviors were assessed using the forced swimming test and open field test. Levels of oxidative stress markers, NLRP3, IL-1β, BDNF, and CREB were analyzed in the hippocampus and prefrontal cortex tissues. Behavioral tests indicated that depression and anxiety-like behaviors significantly increased in OVX rats (p < 0.01), while AT1RB treatment significantly reduced these behaviors (p < 0.05). In the hippocampus of OVX rats, oxidative stress (p < 0.01), NLRP3 (p < 0.05), and IL-1β (p < 0.01) levels were elevated, whereas BDNF levels were significantly decreased (p < 0.01). AT1RB treatment significantly improved oxidative stress parameters (p < 0.05) and BDNF levels (p < 0.01) but did not significantly affect the increased levels of NLRP3 and IL-1β in OVX rats. In conclusion, AT1RB has a therapeutic effect on menopause-induced depression and anxiety-like behaviors, likely by reducing oxidative stress and increasing BDNF production in the hippocampus., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Neuroinflammation plays a vital role in neurodegenerative diseases and neuropsychiatric disorders, and microglia and astrocytes chiefly modulate inflammatory responses in the central nervous system (CNS). Toll-like receptors (TLRs), which are expressed in neurons, astrocytes, and microglia in the CNS, are critical for innate immune responses; microglial TLRs can regulate the activity of these cells, inducing protective or harmful effects on the surrounding cells, including neurons. Therefore, regulating TLRs in microglia may be a potential therapeutic strategy for neurological disorders. We examined the protective effects of GSP1-111, a novel synthetic peptide for inhibiting TLR signaling, on neuroinflammation and depression-like behavior. GSP1-111 decreased TLR2 expression and remarkably reduced the mRNA expression of inflammatory M1-phenotype markers, including tumor necrosis factor (TNF)α, interleukin (IL)-1β, and IL-6, while elevating that of the M2 phenotype markers, Arg-1 and IL-10. In vivo, GSP1-111 administration significantly decreased the depression-like behavior induced by lipopolysaccharide (LPS) in a forced swim test and significantly reduced the brain levels of M1-specific inflammatory cytokines (TNFα, IL-1β, and IL-6). GSP1-111 prevented the LPS-induced microglial activation and TLR2 expression in the brain. Accordingly, GSP1-111 prevented inflammatory responses and induced microglial switching of the inflammatory M1 phenotype to the protective M2 phenotype. Thus, GSP1-111 could prevent depression-like behavior by inhibiting TLR2. Taken together, our results suggest that the TLR2 pathway is a promising therapeutic target for depression, and GSP1-111 could be a novel therapeutic candidate for various neurological disorders.

Perinatal depression is a prevalent mental disorder among pregnant women, characterized by sleep disturbances, appetite changes, negative emotions, cognitive impairment, and suicidal or homicidal tendencies. These symptoms severely compromise personal well-being, disrupt family life, and burden society. Early detection and intervention are thus crucial. The tryptophan-kynurenine (TRP-KYN) pathway is central to the inflammatory hypothesis of depression and has gained significant attention in perinatal depression research. This pathway encompasses numerous metabolic enzymes and neuroactive metabolites that interact with other physiological systems, influencing neurotransmitter synthesis and neuronal development. Through these interactions, the TRP-KYN pathway exerts psychotropic effects. This article reviews the key metabolites and enzymes of the TRP-KYN pathway and examines its intersection with immune inflammation, hormones, and gut microbiota.

Background: Phosphodiesterases (PDEs) are enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate AMP (cAMP) and/or cyclic guanosine monophosphate (cGMP). PDE inhibitors can mitigate chronic pain and depression when these disorders occur individually; however, there is limited understanding of their role in concurrent chronic pain and depression. We aimed to evaluate the mechanisms of action of PDE using 2 mouse models of concurrent chronic pain and depression., Methods: C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) to induce chronic neuropathic pain or injected with complete Freund's adjuvant (CFA) to induce inflammatory pain, and both animals showed depression-like behavior. First, we determined the change in PDE expression in both animal models. Next, we determined the effect of PDE7 inhibitor BRL50481 or hippocampal PDE7A knockdown on PSNL- or CFA-induced chronic pain and depression-like behavior. We also investigated the role of cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling and neuroinflammation in the effect of PDE7A inhibition on PSNL- or CFA-induced chronic pain and depression-like behavior., Results: This induction of chronic pain and depression in the 2 animal models upregulated hippocampal PDE7A. Oral administration of PDE7 inhibitor, BRL50481, or hippocampal PDE7A knockdown significantly reduced mechanical hypersensitivity and depression-like behavior. Hippocampal PDE7 inhibition reversed PSNL- or CFA-induced downregulation of cAMP and BDNF and the phosphorylation of PKA, CREB, and p65. cAMP agonist forskolin reversed these changes and caused milder behavioral symptoms of pain and depression. BRL50481 reversed neuroinflammation in the hippocampus in PSNL mice., Conclusions: Hippocampal PDE7A mediated concurrent chronic pain and depression in both mouse models by inhibiting cAMP-PKA-CREB-BDNF signaling. Inhibiting PDE7A or activating cAMP-PKA-CREB-BDNF signaling are potential strategies to treat concurrent chronic pain and depression., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

Serotonin regulates multiple physiological and pathological processes in the brain, including mood and cognition. The serotonin receptors 5-HT1AR (also known as HTR1A) and 5-HT7R (also known as HTR7) have emerged as key players in stress-related disorders, particularly depression. These receptors can form heterodimers, which influence their functions. Here, we explored the developmental dynamics of 5-HT1AR and 5-HT7R expression and validated heterodimerization levels in the brain of control and stressed mice. In control animals, we found that there was an increase in 5-HT1AR expression over 5-HT7R in the prefrontal cortex (PFC) and hippocampus during development. Using a chronic unpredictable stress as a depression model, we found an increase in 5-HT7R expression exclusively in the PFC of resilient animals, whereas no changes in 5-HT1AR expression between control and anhedonic mice were obtained. Quantitative in situ analysis of heterodimerization revealed the PFC as the region exhibiting the highest abundance of 5-HT1AR-5-HT7R heterodimers. More importantly, upon chronic stress, the amount of heterodimers was significantly reduced only in PFC of anhedonic mice, whereas it was not affected in resilient animals. These results suggest an important role of brain-region-specific 5-HT1AR-5-HT7R heterodimerization for establishing depressive-like behaviour and for development of resiliency., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Depression is a complex disorder with substantial impacts on individual health and has major public health implications. Depression results from complex interactions between genetic and environmental factors. Epigenetic mechanisms, including DNA methylation, microRNAs (miRNAs), and histone modifications, can produce heritable phenotypic changes without a change in DNA sequence and recently were proven to mediate lasting increases in the risk of depression following exposure to adverse life events. Of these, miRNAs are gaining attention for their role in the pathogenesis of many stress-associated mental disorders, including depression. One such miRNA is microRNA-206 (miR-206), which is a critical candidate for increasing the susceptibility to stress. Although miR-206 is thought to be a typical muscle-specific miRNA, it is expressed throughout the brain, particularly in the hippocampus and prefrontal cortex. Until now, only a few studies have been conducted on rodents to understand the role of miR-206 in stress-related abnormalities in neurogenesis. However, the precise underlying molecular mechanism of miR-206-mediated depression-like behaviors remains largely unknown. Here, we reviewed recent advances in the field of biomedical and clinical research on the role of miR-206 in the pathogenesis of depression from studies using different tissues and various experimental designs and described how abnormalities in miR-206 expression in these tissues can affect neuronal functions. Moreover, we focused on studies investigating the brain-derived neurotrophic factor (BDNF) as a functional target of miR-206, where miR-206 has been implicated in the pathogenesis of depression by suppressing the expression of the BDNF. In summary, these studies confirm the existence of a tight correlation between the pathogenesis of depression and the miR-206/BDNF pathway., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

Perimenopausal depression is a subtype of depression and is prevalent among perimenopausal women, which has brought a heavy burden to family and society. The pathogenesis of perimenopausal depression is still unclear, which affects the prevention and treatment of perimenopausal depression to a certain extent. Quercetin is a flavonoid compound, and has estrogenic activity and pharmacological effects such as antioxidant, anti-inflammatory, and neuroprotective effects. This study investigated whether quercetin improved perimenopausal depression-like behaviors and potential mechanism. The results demonstrated that quercetin could alleviate the depression-like behaviors in perimenopausal depression rat model, inhibit astrocyte activation, improve ferroptosis-associated mitochondrial damage (such as mitochondrial pyknosis and mitochondrial cristae reduction) in hypothalamus, increase the expressions of histone 3 lysine 9 acetylation (acetyl-H3K9), ferroptosis-associated protein including glutathione peroxidase 4 (GPX4) and Xc- antiporter (SLC7A11), and reduce the expressions of endoplasmic reticulum stress-related proteins including inositol-requiring enzyme 1 (IRE1α), phosphorylated IRE1α (p-IRE1α), X-box binding protein 1 (XBP1) and glucose-regulated protein 78 (GRP78) in hypothalamus of perimenopausal depression rat model. Furtherly, in vitro study indicated that quercetin could restore histone acetylase (HAT)/histone deacetylase (HDAC) homeostasis through binding to estrogen receptors and increase the expression of acetyl-H3K9, inhibiting ferroptosis through IRE1α/XBP1 pathway in astrocytes of hypothalamus. Our findings demonstrated that acetyl-H3K9 is a crucial target in development of perimenopausal depression, and quercetin exhibited antidepressant effects through modulating acetyl-H3K9 mediated ferroptosis in perimenopausal depression. Quercetin might be the prevention and adjuvant treatment strategy of perimenopausal depression., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Stress is a major risk factor for the development of psychiatric disorders, including depression. However, its effects are not the same in all the subjects as only a portion of individuals exposed to stress will eventually develop negative mental outcomes, while others can be considered resilient. However, the biological processes underlying the development of a vulnerable or resilient phenotype are still poor understood. In order to cover this, we here used both transcriptomic and miRNomic based approaches in the ventral hippocampus of control (CON) and rats exposed to the chronic mild stress (CMS) paradigm, which were then divided into vulnerable (VULN) or resilient (RES) animals according to the sucrose consumption test. Transcriptomic analyses in VULN rats, compared to both the group of CON and RES animals, revealed the activation of inflammatory/immune-related pathways, specifically involved in antibodies and cytokine production, and the inhibition of pathways involved in protein synthesis. Conversely, transcriptomic data in RES animals suggested the activation of several pathways involved in neurotransmission. We then performed a mRNA-miRNA integration analysis by using miRComb R package, and we found that the most significant mRNA-miRNA pairs were involved in promoting the inflammatory status in VULN animals and, vice versa, by decreasing it in RES rats. Moreover, in VULN animals, the mRNA-miRNA combining analyses revealed the modulation of the olfactory sensory system, a key biological process that has been already found involved in the etiology of stress related disorders such as depression. Overall, our mRNA-miRNA integration-based approach identified distinct biological processes that are relevant for the development of a vulnerable or resilient phenotype in response to the negative effects of CMS exposure, which could allow the identification of novel targets for prevention or treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Individuals with depressive tendencies are considered to be at high risk for the onset of depressive disorders. Currently, most research focuses on the impairment of working memory in patients with depression, while there is less attention paid to the WM of individuals with depressive tendencies, and their neural mechanisms underlying it are poorly understood. Therefore, this study focuses on the characteristics and neural mechanisms of WM in individuals with depressive tendencies. This study uses functional near-infrared spectroscopy (fNIRS) to monitor the concentration of Oxy-Hb in the prefrontal cortex and employs the n-back paradigm, designing three levels of load: 0, 1, and 2, to examine the characteristics of WM and its neural mechanisms in individuals with depressive tendencies. Behavioral results show that the accuracy rates of individuals with depressive tendencies is significantly lower than that of healthy individuals, and under the 0-back condition, the reaction time of individuals with depressive tendencies is significantly higher than that of healthy control individuals. Near-infrared results indicate that the activation level in the frontal pole and the dorsal lateral prefrontal cortex of individuals with depressive tendencies is significantly lower than that of healthy control individuals. The β values of channels 2, 7, and 9 are significantly negatively correlated with the Beck Depression Inventory scores of the participants. The results suggest that the reduced activation of the frontal pole and dorsal lateral prefrontal cortex in individuals with depressive tendencies leads to poorer WM performance compared to healthy control individuals. This is a rare brain evidence of the characteristics of WM in individuals with depressive tendencies, which can provide a deeper understanding of the WM characteristics of individuals with depressive tendencies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The aging process causes anatomical and physiological changes that predispose to the development of late-life depression while reduces the efficacy of classical antidepressants. Novel fast-acting antidepressants such as ketamine might be good candidates to be explored in the context of aging, especially given the lack of previous research on its efficacy for this age period. Thus, the aim of the present study was to characterize ketamine's effects in older rats., Methods: The fast-acting (30 min) and repeated (7 days) antidepressant-like effects of ketamine (5 mg/kg, ip) were evaluated in 14-month-old single-housed rats through the forced-swim and novelty-suppressed feeding tests. In parallel, the modulation of neurotrophic-related proteins (i.e., mBDNF, mTOR, GSK3) was assessed in brain regions affected by the aging process, prefrontal cortex and hippocampus, as well as possible changes in hippocampal cell proliferation., Results: Acute ketamine induced a fast-acting antidepressant-like response in male aged rats, as observed by a reduced immobility in the forced-swim test, in parallel with a region-specific increase in mBDNF protein content in prefrontal cortex. However, repeated ketamine failed to induce antidepressant-like efficacy, but decreased mBDNF protein content in prefrontal cortex. The rate of hippocampal cell proliferation and/or other markers evaluated was not modulated by either paradigm of ketamine., Conclusions: These results complement prior data supporting a fast-acting antidepressant-like effect of ketamine in rats, to further extend its efficacy to older ages. Future studies are needed to further clarify the lack of response after the repeated treatment as well as its potential adverse effects in aging., (© 2024. The Author(s).)

Background and Purpose: Depression is closely linked with microglial activation and neuro-inflammation. Peroxisome proliferator-activated receptor-γ (PPAR-γ) plays an important role in M2 activation of microglia. Forkhead box (FOX) O3a has been implicated in the regulation of mood-relevant behaviour. However, little is known about the inflammatory mechanisms of in the microglia of the brain. Here, we have investigated the role of microglial FOXO3a/PPAR-γ in the development of depression., Experimental Approach: The effect of FOXO3a on microglia inflammation was analysed in vitro and in lipopolysaccharide (LPS)-induced depression-like behaviours in vivo. ChIP-seq and Dual-luciferase reporter assays were used to confirm the interaction between FOXO3a and PPAR-γ. Behavioural changes were measured, while inflammatory cytokines, microglial phenotype and morphological properties were determined by ELISA, qRT-PCR, western blotting and immunostaining., Key Results: Overexpression of FOXO3a significantly attenuated expression of PPAR-γ and enhanced the microglial polarization towards the M1 phenotype, while knockdown of FOXO3a had the opposite effect. FOXO3a binds to the promoters of PPAR-γ and decreases its transcription activity. Importantly, deacetylation and activation of FOXO3a regulate LPS-induced neuro-inflammation by inhibiting the expression of PPAR-γ in microglia cells, supporting the antidepressant potential of histone deacetylase inhibitors. Microglial FOXO3a deficiency in mice alleviated LPS-induced neuro-inflammation and depression-like behaviours but failed to reduce anxiety behaviour, whereas pharmacological inhibition of PPAR-γ by GW9662 restored LPS-induced microglial activation and depressive-like behaviours in microglial FOXO3a-deficient mice., Conclusion and Implications: FOXO3a/PPAR-γ axis plays an important role in microglial activation and depression, identifying a new therapeutic avenue for the treatment of major depression., (© 2024 British Pharmacological Society.)

Objective: Exposure to social-evaluative threat (SET) can elicit greater physiological responses, including cortisol, compared to non-SET stressors. An individual's level of depressive and anxious symptoms predicts variability in cortisol responses to stressors, and other research suggests that these individual differences may predict vulnerability to social evaluation. The current study integrates both lines of research, testing if there are different relationships between depressive and/or anxious symptoms and cortisol reactivity in the presence or absence of SET., Methods: Healthy undergraduate students ( N = 158, 65% female) were randomly assigned to deliver a speech in the presence (SET) or absence (non-SET) of two evaluators. Salivary cortisol was collected throughout, and self-reported depressive and anxious symptoms were assessed. We hypothesized that in the SET condition, higher levels of depressive and/or anxious symptoms would predict dysregulated cortisol responses compared to lower levels of symptoms and/or assignment to the non-SET group., Results: In spite of inconclusive p values (which might be attributed to low statistical power), individuals with high depressive or high anxious symptoms appeared to have exaggerated cortisol responses in the SET condition, as indicated by more concave trajectories., Conclusions: This study suggests that both depression and anxiety could be associated with increased cortisol reactivity to SET., (Copyright © 2024 by the American Psychosomatic Society.)

To contribute to research on female models of Alzheimer's disease (AD), our aim was to study the effect of intracerebroventricular (ICV) injection of streptozotocin (STZ) in female rats, and to evaluate a potential neuroprotective action of ovarian steroids against STZ. Female rats were either ovariectomized (OVX) or kept with ovaries (Sham) two weeks before ICV injections. Animals were injected with either vehicle (artificial cerebrospinal fluid, aCSF) or STZ (3 mg/kg) and separated into four experimental groups: Sham + aCSF, Sham + STZ, OVX + aCSF and OVX + STZ. Nineteen days post-injection, we assessed different behavioral aspects: burying, anxiety and exploration, object recognition memory, spatial memory, and depressive-like behavior. Immunohistochemistry and Immunoblot analyses were performed in the hippocampus to examine changes in AD-related proteins and neuronal and microglial populations. STZ affected burying and exploratory behavior depending on ovarian status, and impaired recognition but not spatial memory. STZ and ovariectomy increased depressive-like behavior. Interestingly, STZ did not alter the expression of β-amyloid peptide or Tau phosphorylated forms. STZ affected the neuronal population from the Dentate Gyrus, where immature neurons were more vulnerable to STZ in OVX rats. Regarding microglia, STZ increased reactive cells, and the OVX + STZ group showed an increase in the total cell number. In sum, STZ partially affected female rats, compared to what was previously reported for males. Although AD is more frequent in women, reports about the effect of ICV-STZ in female rats are scarce. Our work highlights the need to deepen into the effects of STZ in the female brain and study possible sex differences., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Positron emission tomography (PET) and magnetic resonance spectroscopy ( 1 H-MRS) are complementary techniques that can be applied to study how proteinopathy and neurometabolism relate to cognitive deficits in preclinical stages of Alzheimer's disease (AD)-mild cognitive impairment (MCI) and late-life depression (LLD). We acquired beta-amyloid (Aβ) PET and 7 T 1 H-MRS measures of GABA, glutamate, glutathione, N-acetylaspartate, N-acetylaspartylglutamate, myo-inositol, choline, and lactate in the anterior and posterior cingulate cortices (ACC, PCC) in 13 MCI and 9 LLD patients, and 13 controls. We used linear regression to examine associations between metabolites, Aβ, and cognitive scores, and whether metabolites and Aβ explained cognitive scores better than Aβ alone. In the ACC, higher Aβ was associated with lower GABA in controls but not MCI or LLD patients, but results depended upon MRS data quality control criteria. Greater variance in California Verbal Learning Test scores was better explained by a model that combined ACC glutamate and Aβ deposition than by models that only included one of these variables. These findings identify preliminary associations between Aβ, neurometabolites, and cognition., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Habitual caffeine consumption protects against depression but through unclear mechanisms. Although habitual caffeine use predicts cortisol release in response to other acute stressors (e.g., exercise), this is less examined with lab-based psychosocial stress in healthy adults. Furthermore, caffeine-induced cortisol increases may mask theory-predicted cortisol blunting to robust stress in people with elevated depression risk. In two samples, we tested whether acute (same-day) and habitual caffeine use would predict greater cortisol reactivity to lab-based stress, and whether caffeine would "mask" the effect of a depression risk factor, trait rumination, on blunted cortisol reactivity., Method: In sample 1, N = 128 emerging adults completed one of three Trier Social Stress Test conditions: nonevaluative control, ambiguously evaluative intermediate, or explicit negative evaluative. In sample 2, N = 148 emerging adults completed either a control or negative evaluative condition., Results: In both samples, multilevel growth curve modeling indicated that habitual caffeine use ( t = -1.99, p = .048; t = -2.73, p = .007, samples 1 and 2, respectively) but not acute caffeine use predicted heightened cortisol reactivity as a function of condition. In sample 1, the relationship between condition, rumination, and blunted cortisol was evident only in caffeine nonusers, which differed from users ( t = 2.82, p = .005), but in sample 2, the predicted blunting pattern was evident regardless of caffeine use., Conclusion: The results provide evidence that habitual caffeine use is associated with greater cortisol release under psychosocial lab-based stress and may mask the influence of psychosocial variables; future research should examine whether habitual caffeine-induced cortisol release has behaviorally activating effects that protect against depression., (Copyright © 2024 by the American Psychosomatic Society.)

Hair cortisol concentration (HCC) is a valuable biomarker for evaluating chronic stress in preschoolers. However, few studies have explored early life HCC and its associated factors. This prospective cohort study analysed the HCC in children aged 6-48 months and its associations with parental HCC as well as positive and negative parental mental health outcomes. We used data from the ongoing Longitudinal Examination Across Prenatal and Postpartum Health in Taiwan (LEAPP-HIT) project, conducted in Taipei between 2020 and 2024. Hair samples were collected from both parents and children in 177 families (91 samples obtained during pregnancy and 86 during the postpartum period). The parents also completed self-reported questionnaires. Multiple linear regression was conducted to analyse the data. We observed a significant positive correlation between parents' and preschoolers' HCC. Furthermore, maternal depression (adjusted beta coefficient [aβ] = 0.09, 95% confidence interval [CI] = 0.02, 0.16) and perceived stress (aβ = 0.15, 95% CI = 0.02, 0.26) were positively associated with preschoolers' HCC. By contrast, higher maternal eudaimonia was associated with lower HCC in preschoolers (aβ = -0.11, 95% CI = -0.20, -0.01). For parents, maternal depression, anxiety, and perceived stress were independently associated with an increased HCC during the postnatal period, whereas maternal eudaimonia was negatively associated with HCC. Our results indicate that both mothers and fathers affect children's responses to stress. Assessment of cortisol stress hormone concentrations through hair samples can be a key means of detecting preschoolers' stress levels and enabling early intervention., (© 2024 John Wiley & Sons Ltd.)

Background: The objective of the study was to ascertain the antidepressant potential of the co-administration of NMDA receptor ligands and selective adenosine A1 and A2A receptor antagonists., Methods: The forced swim test (FST) and spontaneous locomotor activity test were carried out in adult male naïve mice. Before the behavioral testing, animals received DPCPX (a selective adenosine A1 receptor antagonist, 1 mg/kg) or istradefylline (a selective adenosine A2A receptor antagonist, 0.5 mg/kg) in combination with L-701,324 (a potent NMDA receptor antagonist, 1 mg/kg), D-cycloserine (a partial agonist at the glycine recognition site of NMDA receptor, 2.5 mg/kg), CGP 37849 (a competitive NMDA receptor antagonist, 0.3 mg/kg) or MK-801 (a non-competitive NMDA receptor antagonist, 0.05 mg/kg). Additionally, serum BDNF level and the mRNA level of the Adora1, Comt, and Slc6a15 genes in the murine prefrontal cortex were determined., Results: The obtained results showed that DPCPX and istradefylline administered jointly with NMDA receptor ligands (except for DPCPX + D-cycloserine combination) produced an antidepressant effect in the FST in mice without enhancement in spontaneous motility of animals. An elevation in BDNF concentration was noted in the D-cycloserine-treated group. Adora1 expression increased with L-701,324, DPCPX + D-cycloserine, and DPCPX + CGP 37849, while D-cycloserine, CGP 37849, and MK-801 led to a decrease. Comt mRNA levels dropped with DPCPX + L-701,324, istradefylline + L-701,324/CGP 37849 but increased with D-cycloserine, MK-801, CGP 37849 and DPCPX + MK-801/ CGP 37849. Slc6a15 levels were reduced by D-cycloserine, DPCPX + L-701,324 but rose with DPCPX + CGP 37849/MK-801 and istradefylline + D-cycloserine/MK-801/CGP 37849., Conclusion: Our study suggests that selective antagonists of adenosine receptors may enhance the antidepressant efficacy of NMDA receptor ligands highlighting a potential synergistic interaction between the adenosinergic and glutamatergic systems. Wherein, A2A receptor antagonists are seen as more promising candidates in this context. Given the intricate nature of changes in BDNF levels and the expression of Adora1, Comt, and Slc6a15 seen after drug combinations exerting antidepressant properties, further research and integrative approaches are crucial understand better the mechanisms underlying their antidepressant action., (© 2024. The Author(s).)

Alzheimer's disease (AD) is a progressive and degenerative disorder accompanied by emotional disturbance, especially anxiety and depression. More and more evidence shows that the imbalance of mitochondrial Ca 2+ (mCa 2+ ) homeostasis has a close connection with the pathogenesis of anxiety and depression. The Mitochondrial Calcium Uniporter (MCU), a key channel of mCa 2+ uptake, induces the imbalance of mCa 2+ homeostasis and may be a therapeutic target for anxiety and depression of AD. In the present study, we revealed for the first time that MCU knockdown in hippocampal neurons alleviated anxious and depressive behaviors of APP/PS1/tau mice through elevated plus-maze (EPM), elevated zero maze (EZM), sucrose preference test (SPT) and tail suspension test (TST). Western blot analysis results demonstrated that MCU knockdown in hippocampal neurons increased levels of glutamate decarboxylase 67 (GAD67), vesicular GABA transporter (vGAT) and GABA A receptor α1 (GABRA1) and activated the PKA-CREB-BDNF signaling pathway. This study indicates that MCU inhibition has the potential to be developed as a novel therapy for anxiety and depression in AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: To study the role of the P2X4 receptor (P2X4R) in regulating hippocampal synaptic impairment in lipopolysaccharide (LPS)-induced depression., Methods: A rat model of depression was established by LPS injection. P2X4R expression was inhibited by 5-(3-bromophenyl)-1, 3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one (5-BDBD). Depressive symptoms were identified through behavioral tests. P2X4R and cytokine mRNA levels were measured by qRT-PCR, while synaptic protein levels were measured by Western blotting. Synaptic ultrastructure was assessed by transmission electron microscopy, and the colocalization of brain-derived neurotrophic factor (BDNF) with microglia, astrocytes, and neurons was determined by double immunofluorescence staining., Results: Injection of 5-BDBD alleviated LPS-induced depressive symptoms. LPS injection significantly increased the mRNA levels of P2X4R and proinflammatory cytokines in the hippocampus, especially in the CA1 region. The levels of synaptic proteins (BDNF, PSD95, and synapsin I) in the CA1 region were significantly lower than those in the other two regions of the hippocampus, and the synaptic ultrastructure in the hippocampal CA1 region was significantly altered. As expected, the Pearson's correlation R and the overlap coefficient R for the hippocampal colocalization of IBA-1 with BDNF were decreased, and 5-BDBD injection reversed these trends. Injection of 5-BDBD increased hippocampal BDNF mRNA expression., Conclusions: P2X4R may induce synaptic impairment in the hippocampal CA1 region by influencing microglial BDNF expression in the context of LPS-induced depression in rats., Competing Interests: Declaration of competing interest The authors of this study declare that they have nothing to disclose regarding funding or conflicts of interest with respect to this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The cholinergic system has been increasingly linked to the pathophysiology of mood disorders such as depression, with the potential involvement of nicotinic and/or muscarinic receptors. Conventional antidepressants usually require weeks of daily dosing to achieve a full antidepressant response. In contrast, clinical studies have shown that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, can induce potent and rapid antidepressant effects, requiring only a few days of treatment. This study aimed to examine the suitability of the unpredictable chronic mild stress (UCMS) model of depression to reproduce the above scopolamine antidepressant activity patterns., Methods: Rapid and sustained antidepressant-like effects were assessed by using the splash test, sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST) in animals undergoing the UCMS procedure and stress-naïve C57BL/6J mice. Western Blotting was used to measure tropomyosin receptor kinase B (TrkB), mammalian target of rapamycin (mTOR), eukaryotic elongation factor (eEF2) and postsynaptic density protein 95 (PSD95) levels., Results: Scopolamine induced antidepressant-like effects in a dose-dependent manner only after subchronic, but not single, administration in the UCMS model of depression in C57BL/6J mice without affecting locomotor activity. Specifically, scopolamine administered at a dose of 0.3 mg/kg for four consecutive days significantly reversed the UCMS-induced depressive-like behavior, such as apathy, anhedonia, and behavioral despair, while scopolamine, given at the same dose but only once, did not relieve the above symptoms. Scopolamine treatment was accompanied by eEF2 protein dephosphorylation and its subsequent reactivation in the prefrontal cortex (PFC)., Conclusion: Subchronic administration of scopolamine is needed to ameliorate UCMS-induced depressive-like behavior. The suggested mechanism of scopolamine action covers eEF2 protein activity in the PFC., (© 2024. The Author(s).)

Cognitive dysfunction is not only a common symptom of major depressive disorder, but also a more common residual symptom after antidepressant treatment and a risk factor for chronic and recurrent disease. The disruption of hypocretin regulation is known to be associated with depression, however, their exact correlation is remains to be elucidated. Hypocretin-1 levels are increased in the plasma and hypothalamus from chronic unpredictable mild stress (CUMS) model mice. Excessive hypocretin-1 conducted with hypocretin receptor 1 (HCRTR1) reduced lactate production and brain-derived neurotrophic factor (BDNF) expression by hypoxia-inducible factor-1α (HIF-1α), thus impairing adult hippocampal neuroplasticity, and cognitive impairment in CUMS model. Subsequently, it is found that HCRTR1 antagonists can reverse these changes. The direct effect of hypocretin-1 on hippocampal lactate production and cognitive behavior is further confirmed by intraventricular injection of hypocretin-1 and microPET-CT in rats. In addition, these mechanisms are further validated in astrocytes and neurons in vitro. Moreover, these phenotypes and changes in molecules of lactate transport pathway can be duplicated by specifically knockdown of HCRTR1 in hippocampal astrocytes. In summary, the results provide molecular and functional insights for involvement of hypocretin-1-HCRTR1 in altered cognitive function in depression., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)