Chaihu Shugan San exerts antidepressant effects in female mice by suppressing hippocampal IL-6 and activating the cAMP-CaMKII-BDNF pathway.

Behavioral and emotional abnormalities in mice with orthotopic colitis-associated colorectal cancer.

Antidepressant effects of combined eucommia-gastrodia extract via modulation of the HIF-1α-EPO/cAMP-CREB-BDNF pathway: An integrated network pharmacology and in vivo study.

Antidepressant effects of supercritical CO2 extract of Citri Reticulatae Pericarpium through mediating gut microbiota dysbiosis, tryptophan and bile acid metabolisms.

The efficacy of cannabinoid-based medication as analgesic and neuroprotective in multiple sclerosis (MS) has been described, but little is known on other cannabis active compounds, such as terpenes. To investigate the therapeutic potential and molecular mechanism of non-psychotropic Cannabis sativa L. essential oil (EO) in an animal model of MS. Chemical composition of EO was analyzed using GC-MS and GC-FID. Mouse model of experimental autoimmune encephalomyelitis (EAE) was employed to evaluate EO efficacy on pain (hot and cold plate test, von Frey test), motor disability (clinical score, rotarod), emotional alterations (sucrose splash test, tail suspension test, open field, light-dark box test) (n = 11). Tissues and LPS-stimulated BV2 cells were analyzed by Western blot, immunofluorescence, Luxol Fast Blue (LFB), hematoxylin and eosin (H&E) staining, UHPLCHRMS analysis. β-caryophyllene, α-humulene, and caryophyllene oxide were the most abundant EO constituents. Intranasal administration of EO attenuated thermal and mechanical hypersensitivity, promoted motor function recovery, and induced antidepressant- and anxiolytic-like effects in EAE mice. EO increased LFB staining and MBP content while reducing H&E staining. In spinal cord and hippocampal tissues, EO reduced proinflammatory microglia (CD11b/IBA-1 ratio), restored the IL-17/IL-10 balance, and promoted a shift of microglia toward an anti-inflammatory phenotype by increasing CD206 and FoxP3 expression. Mechanistically, EO markedly upregulated CB2 receptor expression in both EAE mice and LPS-stimulated BV2 cells. The protective effect of EO was abolished by a CB2 antagonist (AM630) but not by CB1 blockade (AM251). Intranasal EO alleviates EAE symptoms and comorbidities through a CB2-mediated attenuation of neuroinflammation and demyelination.

Sleep quality and social isolation are two of the numerous environmental, social and health-related factors that contribute to major depressive disorder (MDD). In human studies, a strong association has been found between sleep quality and perceived loneliness, with each potentially exacerbating the other. In mouse studies, sleep deprivation is performed on either group-housed or individually housed mice, depending on the protocol, but the effect of social isolation is often not assessed. Here, we aimed to investigate the potential synergistic effects of sleep disturbances and social isolation in adolescent (Postnatal day 36) and young adult (9 weeks old) female mice. The mice were subjected to sleep disturbances for 7 days, consisting of 4 h of sleep restriction during the light phase, while group- or single-housed for 7 days. Both the individual and combined effects of sleep disturbance and social isolation were assessed. Our findings reveal significantly longer immobility in the tail suspension test in young adult mice after 7 days of sleep disturbance + social isolation compared to those in the sleep disturbance + socially housed group. The same effect was not seen with adolescent mice. This interaction between sleep disturbance and social isolation in the young adult group suggests a synergistic effect. In conclusion, single housing of mice can change the behavioural outcome of a sleep disturbance protocol. Further, adolescent mice appeared more resilient to the adverse behavioural effects of sleep disturbance in combination with social isolation than young adult mice.

High-throughput screening for the discovery of antidepressants targeting adenosine A2A receptors.

High-fat diet exposure from prenatal life to early adulthood induces sex-specific neuropsychiatric vulnerability in mice.

Major depressive disorder (MDD) remains a global concern, with current treatments often showing delayed or limited efficacy. This research describes the development of novel estradiol-indole hybrids designed to inhibit the serotonin transporter (SERT) and activate the estrogen receptor β (ERβ). Among 18 synthesized compounds, I11 exhibited potent SERT inhibition (IC50 = 16.92 ± 1.71 nM), strong ERβ agonism (EC50 = 3.66 ± 0.55 nM, approximately 6-fold selectivity over ERα), and favorable oral absorption and brain penetration. Notably, I11 reduced immobility in forced swim and tail suspension tests in chronic unpredictable mild stress (CUMS) mice and improved social interaction while reducing inactivity in chronic social defeat stress (CSDS) models. Consistent with coordinated involvement of ERβ signaling and SERT regulation, I11 increased hippocampal serotonin levels and altered ERβ/SERT expression and downstream markers such as phosphorylated cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF). These results position I11 as a promising dual-target antidepressant candidate with superior efficacy.

Threatening situations require animals to rapidly select appropriate defensive strategies, either disengaging behavior to avoid harm or engaging actions that allow escape or avoidance. The lateral habenula (LHb) is a key hub in aversive processing, and its projection to the rostromedial tegmental nucleus (RMTg) suppresses dopaminergic activity and promotes behavioral disengagement. However, although LHb neurons also project directly to the ventral tegmental area (VTA) and encode aversive signals, how this pathway contributes to learning and behavior remains poorly understood. In this study, we tested the hypothesis that VTA-projecting LHb neurons encode aversive signals that facilitate associative learning and promote escape behavior. Using a retrograde viral strategy, we targeted VTA-projecting LHb neurons and monitored calcium activity during active avoidance training in male and female mice. These neurons were activated by aversive stimuli and predictive cues as mice acquired avoidance responses and showed increased activity at movement onset during the tail suspension test (TST). Silencing LHb→VTA transmission impaired avoidance learning, prolonged escape latency, and reduced persistence and vigor of active responses in the TST, without affecting baseline locomotion. Anatomical and ex vivo electrophysiology revealed that LHb terminals innervate both dopaminergic (TH⁺) and non-dopaminergic (TH⁻) VTA neurons, exhibiting session-specific synaptic adaptations during avoidance learning. Together, these findings identify the LHb→VTA pathway as a source of aversive predicting signals required for the acquisition of avoidance behavior and the persistence of active responses in aversive contexts, supporting the idea that distinct LHb outputs may differentially regulate behavioral disengagement and active defensive responses.Significance Statement Threats demand fast decisions: freeze or act. We show that a direct pathway from the lateral habenula (LHb) to the ventral tegmental area (VTA) is essential for learning to avoid danger and for engaging active defensive responses. LHb→VTA neurons respond to aversive events, cues that predict them, and movement onset, linking prediction to action. Constitutive silencing of this pathway impairs avoidance learning and reduces adaptive escape behavior in threatening contexts. Anatomically, LHb inputs contact both dopamine and non-dopamine VTA neurons, and their synaptic responses change with learning, indicating plasticity in this circuit. These results identify a key pathway coupling threat prediction to action, informing models of stress-sensitive behavior.

The active ingredient Monotropein in Morinda officinalis alleviates neuroinflammation via inhibiting cGAS/STING signaling pathway.

Diabetes is one of the main cause and major risk factor for the developmentof neurodegenerative and neuropsychiatric disorders, including depression, with rising prevalence and increasing co-morbidities worldwide. However, the relationship between diabetes and depression in animal models has not been thoroughly investigated. The present study aimed to investigate the antidepressant potential of empagliflozin (EMPA) in diabetic mice subjected to a chronic unpredictable mild stress (CUMS) model, focusing on its interaction with the corticotropin-releasing factor 1 receptor (CRF1). Initially, diabetes was induced in animals by injection of streptozotocin (STZ) at low dose (35mg/kg, i.p.), followed by CUMS to provoke depression-like state (1-20days). EMPA at doses of 5 and 10mg/kg was administered orally as the test compound, while metformin (MET; 200mg/kg) and clomipramine (CLMP, 10mg/kg) alone and in combination (MET + CLMP) were used as standard treatments. All treatments were given once daily for 14 consecutive days (21-35days). Behavioral assessments were carried out from days 36 to 41, using several paradigms like splash tests, sucrose preference test, open field test, tail suspension test, and forced swim test, respectively. EMPA, particularly at 10mg/kg, significantly improved behavioral outcomes, indicated by increased distance traveled, higher open-arm entries, reduced immobility time, and shorter grooming latency. Biochemically, EMPA restored antioxidant levels (glutathione and catalase), reduced lipid peroxidation in the brain, and decreased blood corticosterone (CORT) levels. In silico molecular docking and MD-simulation analysis revealed strong binding affinity and interactions between EMPA and CRF1. This proposes that the potential of EMPA to regulate CUMS-induced aggravated depression in diabetic animals may be mediated through CRF1 modulation. These results suggested that EMPA has potential as a therapeutic agent for depression, especially in diabetic conditions linked to oxidative stress, likely through the CRF1-receptor.

IntroductionMaternal infection (MI) can result in significant neurodevelopmental abnormalities and long-term neurological sequelae in offspring. This study was designed to investigate MI-induced alterations in synaptic protein expression, axonal morphology, dendritic, and spine morphology, and behaviour in a neonatal rat model of bacterial meningitis.MethodsOn gestational day 10, pregnant rats were randomly assigned to the following groups: (1) control (Ctrl), (2) MI (pregnant rats were infected with Cronobacter sakazakii by rectovaginal colonization), (3) MI +matrix metalloproteinase inhibitor (MI+MMPI) (C. sakazakii infected pregnant rats received a MMP-9 inhibitor). Male offspring from experimental groups were examined in the novel odor recognition (NOR) test on postnatal day (PND) 15 and the tail suspension test (TST) on PND-60.ResultsOffspring from the MI group were impaired in NOR and exhibited depressive behaviour during TST, whereas MI+MMPI group responses were comparable to the Ctrl group. In addition, MI upregulated the expression of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), MMP-9, and nuclear factor erythroid 2-related factor 2 (Nrf2) in their offspring. In turn, MI downregulating Na+/K+-ATPase activity, postsynaptic density protein (PSD)-95, and multiple ankyrin repeat domain protein (SHANK3) altered the conversion of mature brain-derived neurotrophic factor precursor to mature (mBDNF). Further, MI induced bending and shortening of pyramidal neuronal axon length, reduced dendritic branching complexity, and alerted dendritic and spine morphology. Treatment with MMPI minimized these MI-induced effects.ConclusionMI can cause microstructural rearrangements in the developing brain and behavioural deficits. Our experimental model mimics the neurological sequelae of neonatal meningitis and could be useful for developing therapeutic strategies.

Antidepressant-like activity of JZ-1201 in male rodents: a novel selective 5-HT/NE reuptake inhibitor and 5-HT1A receptor partial agonist.

Depression is a complicated mental disorder that has a high rate of occurrence all over the world and still ranks as the main reason for the occurrence of both disability and death. Although a lot has been discovered, the neurobiological mechanisms underlying depression are still not fully comprehended, and the current pharmacotherapies, most of the time, are not enough to bring about the desired results, thus leading to a large number of patients with treatment-resistant symptoms. Animal models, especially those in rodents, are crucial in the entire process of discovering the mechanisms of depression and evaluating new therapeutic strategies. This paper introduces a critical perspective on the different models and behavioral paradigms that are frequently utilized to simulate depressive-like phenotypes such as anhedonia, hopelessness, apathy, cognitive dysfunction, anxiety, and social withdrawal, among others. A major focus is placed on the dimensions of model validity-construct, face, and predictive validity-as well as reliability, which collectively determine the translational potential of animal studies. Importantly, this article focuses on the Species, Strain, and Sex framework as a guiding principle for model selection, emphasizing its value in improving reproducibility and generalizability across studies. Key paradigms such as Chronic Mild Stress (CMS), Learned Helplessness (LH), Chronic Social Defeat Stress (CSDS), and pharmacological models are evaluated in terms of their strengths, limitations, and relevance to human depressive disorders. In addition, behavioral assays, including Forced Swim Test (FST), Tail Suspension Test (TST), Open Field Test (OFT), Sucrose Preference Test (SPT), and social interaction paradigms, are discussed for their utility in assessing depressive-like behaviors and antidepressant efficacy. Finally, the review highlights the need for refinement and innovation in preclinical depression research. A better integration of neurobiological insights with carefully chosen animal models will enhance translational validity, aid the discovery of novel therapeutic targets, and improve clinical outcomes for depressive disorders.

N-(3-((3-(trifluoromethyl)phenyl)selanyl)prop-2-yn-1-yl) benzamide ameliorates lipopolysaccharide-induced depression-like behavior in mice targeting inflammatory, apoptotic, and oxidative pathways.

Depression is a significant global health issue characterized by complex underlying mechanisms. This study aimed to investigate the role of cholinergic neuron-specific heat shock protein 60 (HSP60) in modulating lipopolysaccharide (LPS)-induced neuroinflammation and depressive-like behaviours in mice. Cholinergic neuron-specific HSP60 knockout mice were generated by crossing Hsp60-flox mice with Chat-cre mice. Genotyping confirmed the successful creation of the knockout. The effects of LPS on weight loss, behavioural changes, cytokine levels, neuroinflammation markers and signalling pathway proteins were assessed. Behavioural assessments included the tail suspension test and sucrose preference test. HSP60 knockout mice exhibited mitigated weight loss in response to LPS. Behavioural tests indicated that HSP60 deficiency alleviated LPS-mediated depressive-like behaviours without affecting locomotor activity. In the hippocampus, LPS treatment significantly altered cytokine levels, increasing pro-inflammatory cytokines at the same time as decreasing anti-inflammatory cytokines. HSP60 knockout mice partially reversed these effects, showing increased anti-inflammatory and decreased pro-inflammatory cytokines. LPS-induced upregulation of neuroinflammation markers such as glial fibrillary acidic protein, NLRP3 (i.e. NOD-, LRR- and pyrin domain-containing protein 3) and p-IKKα/β [i.e. the phosphorylated forms of the catalytic subunits of the IκB kinase (IKK) complex, specificallyIKKα(CHUK) andIKKβ] was significantly reduced in HSP60 knockout mice. Additionally, LPS-induced elevation of phosphorylated eukaryotic translation initiation factor 2α levels in the hippocampus was attenuated by HSP60 deficiency, without affecting other signalling pathway proteins. These findings suggest that HSP60 in cholinergic neurons plays a critical role in regulating LPS-induced neuroinflammation and depressive-like behaviours. Targeting HSP60 in cholinergic neurons may provide a therapeutic approach for mitigating neuroinflammation and associated depressive symptoms. KEY POINTS: Specific knockout of HSP60 in cholinergic neurons could protect against LPS-induced physiological and behavioral impairments, including mitigated weight loss, improved depressive-like behaviors, and unaffected locomotor activity. Cholinergic neuron-specific HSP60 deletion could attenuate neuroinflammation by reversing LPS-induced cytokine imbalance, suppressing key inflammatory markers (GFAP, NLRP3, cGAS, p-IKKα/β), and crucially, by preserving hippocampal acetylcholine levels, a key neurotransmitter with established anti-inflammatory properties. HSP60 deficiency selectively reduces the LPS-induced phosphorylation of the eukaryotic translation initiation factor 2α (p-eIF2α) in the hippocampus, indicating a targeted modulation of the cellular stress and protein synthesis regulation pathway, without altering other major signaling molecules.

Anxiety and depression are two debilitating conditions that are often preceded by a triggering event. The experimental formula which contains an equal portion of Maerua angolensis DC. leaves and Borago officinalis L. leaves, is used by the Hausa community of Kano state for both depression and anxiety. This study aims to scientifically assess the antidepressant and anxiolytic effects of the mixture and establish its safety profile in laboratory animals. The LD50 of the extract was estimated to be approximately 2154 mg/kg in mice. The extract showed neither significant reduction in immobility time in forced swim and tail suspension test, nor impact on line crossing following an open field task. The extract at 600 and 300 mg/kg significantly increased the number of entries and permanence time into open arms in elevated plus maze test and increased both the number of head-dip and upward stairs climbed following hole board and staircase tasks respectively. Following 28-days administration, the extract significantly increased the level of alkaline phosphatase. The findings suggest that the formula has shown some level of anxiolytic activity with no significant effect in animal models of depression. The herbal mixture was also found to be relatively safe in animal model.

Pharmacological and neurobehavioral evaluation of the bifunctional opioid peptide Gluten exorphin B5.

Butyrate, a short-chain fatty acid derived from the gut microbiota, has been linked to depression through correlational studies; however, whether it might act as a sufficient downstream mediator of the antidepressant effects of a probiotic remains poorly understood. To explore this, a chronic unpredictable mild stress (CUMS) rat model was established to evaluate the potential antidepressant effects of Weizmannia coagulans BC99. Behavioral assessments included the sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST), and open field test (OFT). In addition, 16S rRNA sequencing, serum metabolomics, and short-chain fatty acid (SCFA) profiling were performed. Levels of inflammatory cytokines (IL-1β, IL-6, IL-4, and LPS) and brain-derived neurotrophic factor (BDNF) were measured in serum, hippocampus, and colon by ELISA. An independent sodium butyrate supplementation experiment was conducted to test functional sufficiency, and hippocampal BDNF/TrkB/CREB signaling was assessed by Western blotting. Treatment with BC99 was associated with alleviation of CUMS-induced depressive-like behaviors, increased butyrate levels, reduced neuroinflammation (IL-1β, IL-6, LPS, and IL-4), and restored hippocampal BDNF levels. BC99 also enriched butyrate-producing bacterial taxa (e.g., Lactobacillus, Bifidobacterium, Faecalibaculum) and normalized tryptophan and sphingolipid metabolism. Notably, sodium butyrate alone recapitulated several of the behavioral and anti-inflammatory effects observed with BC99 and, as shown by Western blot, partially restored hippocampal BDNF/TrkB/CREB signaling, which was impaired in CUMS rats. Together, these findings suggest that butyrate may be associated with the antidepressant effects of W. coagulans BC99, potentially acting through suppression of neuroinflammation and activation of the BDNF pathway. Our results support further investigation of butyrate-enhancing strategies as a nutritional approach for depression.