Forced Swim Test Research Articles

One-Week Maternal Separation Caused Sex-Specific Changes in Behavior and Hippocampal Metabolomics of Offspring Rats

To investigate the effects of one-week maternal separation (MS) on anxiety- and depression-like behaviors in adolescent and adulthood as well as adult hippocampal metabolomics simultaneously in offspring female and male rats. In the MS group, newborn SD rats were separated from their mothers for 3 h per day from postnatal days (PND) 2 to 8. The open field test (OFT), elevated plus mazes (EPM), novelty suppressed feeding test (NSFT), and forced swimming test (FST) were conducted during adolescence and adulthood. Serum corticosterone, mRNA expression of hippocampal inflammatory cytokines, and hippocampal untargeted metabolomics of offspring adult rats were examined using an assay kit, qRT-PCR, and UPLC-Q-TOF/MS. Both MS female and male rats showed similar behaviors in OFT, EPM, NSFT, and SPT, except for the latency to feeding during adolescence and the open arm entries during adulthood, showed statistical significance only in MS female rats. Serum corticosterone and hippocampal pro-inflammatory cytokines IFN-γ were significantly elevated in both female and male rats, and IL-1β and TNF-α were significantly increased only in female rats. In hippocampal metabolism, the identification of differential metabolites displayed 53 and 37 in female rats and male rats, respectively (with 35 common metabolites), which were involved in 33 and 30 metabolic pathways with 28 common pathways. One-week MS induced sex-specific anxiety- and depression-like behaviors in female and male offspring rats during adolescence and adulthood, as well as sex-differentiated characteristics in the hippocampus inflammatory cytokines and metabolomics of adult MS rats. From the experimental data, the effects of MS on the female offspring rats were more severe than those of the male offspring rats.

PM2.5 Exposure Triggers Hypothalamic Oxidative and ER Stress Leading to Depressive-like Behaviors in Rats

Epidemiological studies have linked fine dust pollution to depression, yet the underlying mechanisms remain unclear. Oxidative stress and endoplasmic reticulum (ER) stress are known contributors to depression, but their induction by particulate matter (PM), particularly PM2.5, in animal models has been limited. This study aimed to establish a rat model of PM2.5-induced depression-like behaviors and elucidate the underlying molecular mechanisms. Adult male Sprague–Dawley rats received daily intranasal PM2.5 for four weeks. Behavioral assessments, including the open field test (OFT), forced swim test (FST), and light-dark box (LDB) test, were conducted weekly. PM2.5-exposed rats displayed depressive-like behaviors, particularly in the FST, reflecting decreased motivation and learned helplessness. Molecular analyses indicated a specific increase in ER stress markers (CHOP, eIF2α, GRP78, and P16) and NOX4 in the hypothalamus, while other brain regions (striatum, cortex, and hippocampus) were not as pronounced. Additionally, PM2.5 exposure reduced tyrosine hydroxylase (TH) levels in the hypothalamus, suggesting impaired dopamine synthesis. These findings indicate that PM2.5 induces depressive-like behaviors via hypothalamic ER stress and oxidative stress pathways, leading to dopaminergic dysfunction. Targeting oxidative and ER stress within the hypothalamus may offer new therapeutic strategies for treating depression associated with environmental pollutants.

Evaluation of Anti-depressant activity of Hibiscus rosa sinensis leaves in mice

Objective: The present is to evaluate antidepressant activity of ethanolic extract of Hibiscus rosa sinensis leaves using experimental animals. Method: The current study employed male Swiss albino mice weighing between 20 and 35 g and aged between 6 and 8 weeks. Hibiscus rosa sinensis extract were administered p.o to mice daily in two different doses (200 & 400 mg/kg/p.o) for 14 days regularly. After administration of the extract, the animal will be observed continuously for the first 2 hours and at 24 hrs to detect changes in behavioral responses and also for tremors, convulsion, salivation, diarrhea, lethargy, sleep, and coma and also will be monitored up to 14 days for the toxic symptoms and mortality. On 15th days, the animal subjected to Tail Suspension test (TST) and forced swim test (FST) and plasma corticosterone level. Result: The mice of Hibiscus rosa sinensis extract (200 & 400 mg/kg/p.o) treated group showed no significantly (p<0.05) difference in locomotors activity as compared to control group. Treatment with FXT (10 mg/kg p.o.)also showed no significant change as compared to control group. The above observation suggests that Hibiscus rosa sinensis leaves has antidepressant activity. Conclusion: The Ethanolic extract of Hibiscus rosa sinensis 400 mg/kg showed the most remarkable activity. This plant can be further subjected to isolation of the therapeutic Antidepressant compound and carry out further pharmacological evaluation. Keywords: Depression, herbal medications. Hibiscus rosa sinensis, antidepressant plants

HDC downregulation induced by chronic stress promotes ovarian cancer progression via the IL-6/STAT3/S100A9 pathway

ObjectiveThis study aimed to investigate the underlying mechanism of chronic stress promoting ovarian cancer growth comorbid with depression and evaluate the potential role of histamine (HIS) in treating this comorbidity.MethodsChronic unpredictable mild stress (CUMS) was used to establish a comorbid mouse model of ovarian cancer and depression. The behavioral phenotypes were assessed using the sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), and open field test (OFT). Ovarian cancer growth was monitored by tracking the tumor volume and weight. Histidine decarboxylase (HDC) expression in the tumor tissue was analyzed using Western blot and qRT-PCR techniques. The serum levels of inflammatory factors (IL-6 and IL-17A), stress hormones (norepinephrine, NE and cortisol, and COR), histamine, and 5-hydroxytryptamine (5-HT) were detected by enzyme-linked immunosorbent assay (ELISA). In vitro experiments were conducted to explore the direct impacts of stress hormones on A2780 and ES-2 ovarian cancer cell lines, as well as the modulation of these effects by histamine. HDC knockdown and overexpression approaches were used to study its regulatory role in the IL-6/STAT3/S100A9 signaling pathway.ResultsChronic stress not only induced depressive behaviors but also accelerated ovarian cancer growth in mice by downregulating HDC expression in tumors, whereas exogenous HIS treatment alleviated depressive symptoms, suppressed cancer growth, and countered the decreased levels of HIS and increased levels of IL-6, IL-17A, NE, COR, and 5-HT induced by CUMS. Furthermore, HIS positively modulated the immune response by increasing the populations of CD3+T and CD8+ T cells and reducing IL-17A secretion. In vitro experiments revealed that stress hormones downregulated HDC expression, consequently promoting cancer cell proliferation, migration, and invasion via the IL-6/STAT3/S100A9 pathway. Knockdown of HDC activated this pathway, whereas HDC overexpression inhibited its activation.ConclusionChronic stress leads to the downregulation of HDC expression, thereby facilitating the progression of ovarian cancer through the IL-6/STAT3/S100A9 pathway. HIS might serve as a potential molecule for treating the comorbidities of ovarian cancer and depression.

Delta opioid receptor agonists activate PI3K-mTORC1 signaling in parvalbumin-positive interneurons in mouse infralimbic prefrontal cortex to exert acute antidepressant-lie effects.

The delta opioid receptor (DOP) is a promising target for novel antidepressants due to its potential for rapid action with minimal adverse effects; however, the functional mechanism underlying acute antidepressant actions remains elusive. We report that subcutaneous injection of the selective DOP agonist KNT-127 reduced immobility in the forced swimming test, and that this antidepressant-like response was reversed by intracerebroventricular injection of the selective mechanistic (or mammalian) target of rapamycin (mTOR) inhibitor rapamycin or the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002. KNT-127 also alleviated social avoidance and reduced sucrose consumption (anhedonia) among chronic vicarious social defeat stress model mice, which were similarly reversed by PI3K and mTOR inhibitors. In addition, KNT-127 increased phosphorylation levels of the mTOR signaling-related proteins Akt and p70S6 kinase in medial prefrontal cortex as revealed by immunoblotting. In the forced swimming test, a microinfusion of KNT-127 and another DOP agonist SNC80 in the infralimbic prefrontal cortex (IL-PFC) attenuated the immobility, which were blocked by rapamycin and LY294002. Perfusion of KNT-127 onto IL-PFC slices increased miniature excitatory postsynaptic current frequency and reduced miniature inhibitory postsynaptic current frequency in pyramidal neurons as measured by whole-cell patch-clamping, and both responses were reversed by rapamycin. Imaging of brain slices from transgenic mice with DOP-promoter-driven green fluorescent protein revealed that most DOPs were expressed in parvalbumin-positive interneurons in the IL-PFC. These findings suggest that DOP agonists exert antidepressant-like actions by suppressing GABA release from parvalbumin-positive interneurons via the PI3K-Akt-mTORC1-p70S6 kinase pathway, thereby enhancing IL-PFC pyramidal neuron excitation.

Endocannabinoid involvement in beneficial effects of caloric restriction in a rodent model of comorbid depression and epilepsy

Clinically, patients with depression are at a heightened risk for developing epilepsy, and vice versa, suggesting shared mechanisms for this bidirectional comorbidity. Unfortunately, comorbid depression and epilepsy is associated with worsened quality of life and treatment refractoriness, highlighting the need for novel treatment targets and nonpharmacologic supplements to existing therapies. The present study used the Swim-Low Active rat, a well-validated model of depression and epilepsy comorbidity that was selectively bred based on forced swim test behavior, to assess the safety and efficacy of caloric restriction in treating this comorbidity. The study also investigated the role of endocannabinoids in the effects of caloric restriction on the behavioral endpoints and to determine whether there were any sex differences in these effects.Male rats restricted to approximately 80 % of their daily food intake for an acute 24-h period showed elevated struggling behavior in the Porsolt (Forced) Swim Test and increased latency to pilocarpine-induced seizure; this same caloric restriction yielded a significant increase in hippocampal anandamide levels compared to ad lib rats. These effects were not seen in female rats, although female rats did show anticonvulsant effects of chronic caloric restriction. Administration of 1 mg/kg SR141716 alongside an acute caloric restriction in male rats blocked the antidepressant-like effects of caloric restriction but did not affect seizure responses. Combined, these results suggest caloric restriction may be both safe and modestly effective in benefitting depression- and epilepsy-related behaviors in male SwLo rats, and that the endocannabinoid system may be a promising target for treating this comorbidity.

Evaluation of a user-friendly CSDS cage apparatus for studying depressive-like behaviors in rodents.

Previously, a chronic social defeat stress (CSDS) model has been widely-adopted for assessing depressive-like behaviors in animals. However, there is still room for improvement in the CSDS model to safeguard study accuracy and the welfare of lab rodents. Our study team developed a novel, standardized apparatus to induce CSDS in rodents and assessed the model's practical adaptability. An innovative CSDS cage apparatus and water bottle was designed. To evaluate the effectiveness of the newly developed tools, a variety of animal models, including the tail suspension test (TST), sucrose preference test, forced swimming test (FST), novelty-suppressed feeding test, female urine sniffing test, and open field test (OFT), were adopted to assess depressive-like behaviors in mice. Fluoxetine treatment was also administered to observe the reversal effect, as part of the validation. The CSDS cage apparatus resulted in the manifestation of depressive-like behaviors in the model mice. Significant reductions in sucrose preference and urine sniffing time were observed, while the OFT revealed decreased central zone total distance, residence time, and frequency of entry. Moreover, increased immobility was found in the FST and TST. Fluoxetine treatment was found to successfully reverse the modeling effect. The CSDS cage apparatus was validated for enhanced usability and addressed the previous challenges of water bottle leakage and lab rodent welfare issues. The consistent results from multiple behavioral tests also supported real-world application of the apparatus, offering researchers a promising alternative to conventional rodent cages.

Exploring the contribution of the dopaminergic and noradrenergic systems in the antidepressant-like action of 1-(2-(4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl)phenyl)ethanone in mice.

1-(2-(4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl)phenyl)ethanone (ETAP) is a novel hybrid compound containing 1,2,3-triazole and acetophenone. It exhibits antidepressant-like effects in male mice, linked to modulation of serotonergic receptors and monoamine oxidase A (MAO-A) inhibition. This study aimed to evaluate the involvement of the dopaminergic and noradrenergic systems, as well as MAO-B activity inhibition, in the antidepressant-like effect of ETAP in male mice, and to evaluate the antidepressant-like effect of ETAP in female mice. Male mice were treated with different dopaminergic and noradrenergic receptors antagonists 15min before administering ETAP (1mg/kg, intragastrically, i.g.). The tail suspension test (TST) was performed 30minutes later. Different male mice were treated with ETAP (1mg/kg, i.g.), and 30minutes later, were euthanized to assess MAO-B activity in the prefrontal cortex and hippocampus. To evaluate the antidepressant-like of ETAP in female mice, ETAP (1mg/kg, i.g.) was administered, followed by the TST and the forced swimming test (FST) 30minutes later. The dopaminergic antagonists haloperidol (0.05mg/kg, intraperitoneally, i.p.), SCH23390 (0.01mg/kg, subcutaneously, s.c.), and sulpiride (50mg/kg, i.p.), as well the noradrenergic antagonists prazosin (1mg/kg, i.p.), yohimbine (1mg/kg, i.p.), and propranolol (2mg/kg, i.p.), prevented the antidepressant-like effect of ETAP in the TST. MAO-B activity was unaffected by ETAP in both the prefrontal cortex and hippocampus. ETAP (1mg/kg, i.g.) induced a significant antidepressant-like effect in female mice in the TST and FST. These findings provide valuable insights into the antidepressant-like effect of ETAP, highlighting its potential for developing more effective depression treatments.

Electroacupuncture combined with NSCs-Exo alters the response of hippocampal neurons in a chronic unpredictable mild stress paradigm in ovx rats

Electroacupuncture (EA) is a form of Traditional Chinese Medicine (TCM) that combines acupuncture with microcurrents mimicking the body's bioelectricity to prevent and treat diseases. Previous studies have demonstrated its antidepressant-like effects in chronic unpredictable mild stress (CUMS)-induced ovariectomy (OVX) rats. Neural stem cell-derived exosomes (NSCs-Exo) are heterogeneous and targeted, effectively promoting nerve regeneration and repairing neuronal damage, while potentially conveying the effects of EA. However, the precise mechanism remains unclear. In this study, perimenopausal depressive disorder (PDD) rat model were established using a two-step protocol CUMS + OVX. Treatment with EA combined with NSCs-Exo (EA-Exo) significantly improved depression-like behaviors in PDD rats, as indicated by increased sucrose intake in the Sucrose Preference Test (SPT), reduced immobility in the Forced Swimming Test (FST), and prolonged activity in the Out-of-Field Test (OFT). EA-Exo treatment improved depression-like behaviors by increasing serum levels of 5-hydroxytryptamine (5-HT) and decreasing immobility in the FST. It also alleviated OVX-CUMS-induced disturbances in energy metabolism, inflammation, and oxidative stress responses by enhancing serum levels of 5-HT, dopamine (DA), ATP, superoxide dismutase (SOD), and interleukin-10 (IL-10), while reducing cyclic AMP (cAMP), interleukin-6 (IL-6), reactive oxygen species (ROS), and malondialdehyde (MDA). Furthermore, EA-Exo treatment reversed structural and functional impairments in hippocampal synapses and mitochondria. This was evidenced by reductions in hippocampal synaptic plasticity proteins PSD95, SYN, and GAP43, as well as decreased expression of energy metabolism pathway proteins AMPK, NRF1, PGC1α, and TFAM. These findings suggest that EA-Exo ameliorates depressive behavior in OVX-CUMS rats by modulating synaptic plasticity and activating the AMPK/NRF1/PGC1α/TFAM signaling pathway.

Investigating the optimistic in-vitro and in-vivo therapeutic effects of wild grape: Vitis jacqumantii R. Parker

Vitis jacquemontii R. Parker is a wild grape traditionally used by indigenous people as a substitute for cultivated grapes. However, its therapeutic effects have not been extensively studied. In this study, we investigated the antioxidant, anticholinesterase, analgesic, and antidepressant properties of V. jacquemontii. The antioxidant potential of this wild fruit plant was evaluated using two widely recognized assays: 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2-asino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). In-vitro anticholinesterase effects were determined by assessing butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) inhibition. The analgesic activity was assessed through writhing and tail immersion test models, while the antidepressant effect was evaluated using forced swimming and tail suspension test models. Results revealed the exceptional potential of V. jacquemontii as a valuable natural resource. The fruit extract (VJF-Crd) demonstrated remarkable free radical scavenging abilities, with an impressive IC50 value of 34.96 μg/mL for DPPH and 56.48 μg/mL for ABTS. The leaf extract (VJL-Crd) also exhibited considerable antioxidant properties, with IC50 values of 73.68 μg/mL for DPPH and 86.72 μg/mL for ABTS. Furthermore, VJF-Crd and VJL-Crd extracts displayed potent inhibitory activity against cholinesterase enzymes, with VJF-Crd demonstrating strong inhibition and VJL-Crd showing moderate inhibition. In terms of analgesia, these extracts exhibited dose-dependent responses in various pain models, with significant protection against acetic acid-induced writhing and tail immersion, showcasing their potential as natural pain relievers. Moreover, both VJF-Crd and VJL-Crd extracts displayed a notable decrease in immobility in the forced swimming and tail suspension test models, indicating their potential as natural antidepressants. These findings underscore the untapped potential of V. jacquemontii as a source of valuable chemical constituents. The isolation and identification of phyto-constituents from this plant hold promise for new bioactive compounds, particularly in pain management. This study sheds light on the multifaceted medicinal attributes of V. jacquemontii and opens new avenues for developing natural remedies for different ailments, especially pain management.

SEP-363856 attenuates CUMS-induced depression-like behaviours and reverses hippocampal neuronal injuries

Objectives This study employed a chronic unpredictable mild stress (CUMS) model to examine the antidepressant properties of SEP-363856. Methods The sucrose preference test (SPT) was employed to evaluate anhedonia, the open field test (OFT) to measure locomotor activity and exploratory behaviour, the elevated plus-maze (EPM) to assess anxiety-like behaviour, and the tail suspension test (TST) and forced swimming test (FST) to determine despair behaviour. qRT-PCR was implemented to evaluate gene expression levels in the hippocampus. Western blot, and ELISA were implemented to evaluate hippocampal protein expression, and Nissl staining was implemented to identify hippocampal neuronal injury. Results The 10 mg/kg dosage of SEP-363856 and fluoxetine significantly improved depressive-like behaviours as assessed by the SPT, OFT, EPM, TST, and FST. This was associated with improved hippocampal neuronal damage, enhanced mRNA expression of brain-derived neurotrophic factor, synaptophysin, and postsynaptic density 95. SEP-363856 increased the levels of insulin-like growth factor-1 (IGF-1), IGF-1 receptor β, phospho-phosphatidylinositide 3-kinase, and phospho-protein kinase B in the brain. Conclusions The antidepressant-like effects of SEP-363856 are linked to increased hippocampal neurotrophic factors, decreased hippocampus neuronal lesions, and activation of the IGF-1Rβ/PI3K/AKT signalling pathway. The latter may serve as a novel drug target for the treatment of depression.

Doxophylline, a Non-Selective Phosphodiesterase Inhibitor, Protects Against Chronic Fatigue-Induced Neurobehavioral, Biochemical, and Mitochondrial Alterations.

Chronic fatigue stress (CFS) is a multisystem disorder which exhibits multiple signs of neurological complications like brain fog, cognitive deficits and oxidative stress with no specific treatment. Doxophylline, a non-selective phosphodiesterase inhibitor (PDEI), has anti-inflammatory properties with enhanced blood-brain barrier penetration and tissue specificity. We have evaluated the neuroprotective potential of doxophylline in a murine model of forced swim test (FST) induced CFS and in H2O2 (hydrogen peroxide) induced oxidative stress in PC12 cells. An FST model to induce a state of CFS in mice was induced by forcing them to swim daily for 6min for 15 days. The drug was administered daily 30min prior to FST. The immobility period was compared for day 1 and day 15. Animals were sacrificed on day 16 for biochemical, mitochondrial, and histopathological estimations in the brain. Cytotoxicity assay, reactive oxygen species (ROS) and nuclear morphology determination were carried out in PC12 cells. A significant increase in immobility has been observed on the 15th day in CFS-induced mice compared to doxophylline treated group. Neurobehavioral studies revealed hypo locomotion, anxiety, motor incoordination, and memory deficit. Biochemical analysis showed a significant change in oxidative stress markers (superoxide dismutase (SOD), reduced glutathione (GSH), catalase, lipid peroxidation (LPO) and nitrite levels) and acetylcholinesterase enzyme activity (AChE) in brain homogenates. Doxophylline pre-treatment protects against these impairments. In PC12 cell lines, doxophylline exhibits alleviation against H2O2-induced oxidative stress, intracellular ROS generation, and changes in nuclear morphology. Doxophylline could be promising and possess therapeutic potential in CFS treatment. Further research is needed to test if doxophylline can be repurposed for neurological disorders.

PDGFR-α Mediated the Neuroinflammation and Autophagy via the JAK2/STAT3 Signaling Pathway Contributing to Depression-Like Behaviors in Myofascial Pain Syndrome Rats.

Depression often occurs in patients with additional co-morbidities, particularly in cases of chronic pain. Currently, there is a lack of research on the molecular mechanisms of depression under chronic pain conditions and suitable animal models. Due to the contradiction exhibited by platelet-derived growth factor receptor (PDGF/PDGFR) in neuroprotection, further investigation is required. In the present study, we investigated the roles of PDGFR-α in the hippocampus based on rat models of chronic pain (myofascial pain syndrome, MPS) that exhibited depressive phenotypes. The depression-like phenotypes were assessed by the sucrose preference test, forced swimming test, tail suspension test, and the levels of BDNF and 5HT1AR. Electron microscopic analysis and altered expression of autophagy-related proteins revealed reduced autophagy levels in the hippocampus of MPS rats. Phosphorylation PDGFR-α was significantly upregulated in the MPS rat model of depression, as well as the levels of inflammatory factors and p-JAK2/p-STAT3. Treatment with inhibitors of PDGFR-α or JAK2/STAT3 alleviated depressive behaviors, Nissl bodies staining, increased the protein levels of BDNF and 5HT1AR, and decreased the levels of inflammatory factors in MPS rats. Additionally, it restored autophagy levels. These results indicate that PDGFR-α induces neuroinflammation, altered autophagy, and depressive behavior, potentially mediated by the JAK2/STAT3 signaling pathway in MPS rats. PDGFR-α may thus represent a promising therapeutic target for the treatment of this type of depression.

5-HT1B receptor activation produces rapid antidepressant-like effects in rodents

Ketamine is noted for its rapid onset antidepressant response and effectiveness in patients with treatment resistant depression. While most research has focused on glutamatergic mechanisms, recent studies show that antidepressant-like effects in rodents are dependent upon the serotonergic (5-HT) system and suggest a potential contribution of the 5-HT1B receptor. In this study we utilized CP-94253 to examine whether 5-HT1B receptor agonism produces rapid and sustained antidepressant-like effects, focusing on rodent models and treatment approaches commonly used to demonstrate the differentiated response to ketamine. We first confirmed that CP-94253 is a potent 5-HT1B agonist in vitro and that CP-94253 occupies brain 5-HT1B receptors at the doses tested. CP-94253 reduced immobility in the mouse forced swim test (FST) and exhibited a prominent antidepressant signature in the mouse-behavior phenotyping platform SmartCube®. When examined 24 h after acute treatment, CP-94253 reduced FST immobility in both naïve rats and in rats receiving chronic interferon alpha treatment. Ex vivo hippocampal long-term potentiation was also enhanced in naïve rats receiving acute CP-94253 treatment, 24 h prior to the recordings. In mice exposed to chronic social defeat stress, antidepressant-like effects in the tail suspension and sucrose preference tests were seen 1 h and 24 h after acute treatment, respectively. Finally, whole brain c-fos imaging in mice showed that CP-94253 modulates neuronal activity in discrete brain regions including the lateral habenula circuit implicated in depression and the ketamine treatment response. Collectively these results support the further investigation of 5-HT1B agonism as a novel treatment approach for major depressive disorder.

St. John's Wort Extract Ze 117 and Escitalopram Alter Plasma and Hippocampal Lipidome in a Rat Model of Chronic-Stress-Induced Depression.

Chronic stress is a key factor in the development of depression. It leads to hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, which in turn increases the formation of glucocorticoids (GCs). Chronically elevated GC levels disrupt neuroplasticity and affect brain lipid metabolism, which may, ultimately, contribute to the development of depression. This study aimed to investigate the effects of the antidepressants St. John's Wort extract and escitalopram on lipid metabolism in vivo. Therefore, repeated corticosterone injections were used to induce depression-like behavior in rats. Male Sprague-Dawley rats were stressed with corticosterone injections (40 mg/kg, s.c.) over 22 consecutive days and were concomitantly treated with varying doses of the St. John's wort extract Ze 117 (30, 90 or 180 mg/kg, p.o.) or escitalopram (10 mg/kg, p.o.) and behavioral changes were evaluated using a modified forced swim test. The results indicate that repeated corticosterone injections significantly decreased the latency to first immobility. Furthermore, co-treatment of corticosterone with Ze 117 increased latency to first immobility significantly compared to rats treated with corticosterone alone. To further investigate the biochemical effects of corticosterone-induced stress, as well as the possible counter-regulation by antidepressants, the lipidomes of the plasma and hippocampus samples were analyzed by shotgun mass spectrometry. Corticosterone-induced stress significantly altered key lipid metabolites in the plasma but not in the hippocampal samples. In the hippocampus, however, specific glycerophospholipids such as lysophosphatidylethanolamines (LPEs) increased with escitalopram treatment and with Ze 117, both showing significant correlations with behavioral parameters. In summary, our study shows significant behavioral- and lipidome-altering processes with Ze 117 and escitalopram in rat plasma and hippocampal samples, thereby providing new targets and biomarker ideas for clinical diagnosis and antidepressant intervention.

Semen Cuscutae flavonoids activated the cAMP-PKA-CREB-BDNF pathway and exerted an antidepressant effect in mice.

Semen Cuscutae flavonoids (SCFs) constitute a class of metabolites of Semen Cuscutae, a botanical drug that was recently found to have an anti-depression effect. This study aimed to evaluate the anti-depression effects of SCFs in chronic unpredictable mild stress (CUMS)-induced mice and to interrogate the underlying mechanisms. The CUMS mice were used for assessing the effects of SCFs treatments on depression. Mice were randomly divided into five groups. Four groups were subjected to the CUMS induction and concomitantly administered orally with either the vehicle or with a high-, medium-, and low-dose of SCFs, once per day for 4weeks. One group was kept untreated as a control. The mice were then assessed for their statuses of a number of depression-related parameters, including body weight, food intake, sucrose preference test (SPT), open field test (OFT), tail suspension test (TST), and forced swim test (FST). In addition, a day after the completion of these tests, biopsies from the hippocampus were harvested and used to perform metabolomics by HPLC-MS/MS and to assess the levels of cAMP by ELISA and the levels of PKA, CREB, p-CREB, and BDNF by Western blot analyses. SCFs resulted in significant increases in both body weight and food intake and in the amelioration of the depressive-like behaviors in CUMS mice. A high-dose SCFs treatment led to significant alterations in 72 metabolites, of which 26 were identified as potential biomarkers for the SCFs treatment. These metabolites are associated with lipid, amino acid, and nucleotide metabolism. Among 26 metabolites, cAMP was positively correlated with body weight, SPT, OFT-total distance, and OFT-central residence time, while negatively correlated with immobility time in TST and FST, linking a change in cAMP with the SCFs treatment and the significant improvement in depressive symptoms in CUMS mice. Further analyses revealed that the levels of cAMP, PKA, CREB, p-CREB, and BDNF were reduced in the hippocampus of CUMS mice but were all increased following the SCFs treatments. SCFs could ameliorate hippocampal metabolic disturbances and depressive behaviors and cause the activation of the cAMP-PKA-CREB-BDNF signaling pathway in the hippocampus of CUMS mice.

Myelin Transcription Factor 1 (MyT1) overexpression mitigates social isolation-induced behavioral deficits: Insights into cortical synaptotagmin 1 regulation and antidepressant-like effects

Social isolation (SI) stress is increasingly recognized as a concern, associated with detrimental effects on mood and emotional well-being. Myelin Transcription Factor 1 (MyT1) is known for its pivotal role in nervous system development and mood regulation. This study delves into the potential of MyT1 to mitigate SI-induced behavioral abnormalities in mice. Utilizing a chronic SI model involving neonatal and post-weaning SI, male and female mice were subjected to lentiviral overexpression of MyT1 specifically in the medial prefrontal cortex (mPFC). A battery of behavioral assessments, including novelty-suppressed feeding, sucrose preference, sucrose splash, tape grooming, tail suspension, and forced swim tests, revealed notable antidepressant-like effects in both sexes upon MyT1 overexpression. Enhanced MyT1 expression corresponded with increased feeding initiation, sucrose preference, and self-grooming, alongside decreased immobility time. Importantly, the upregulation of MyT1 was accompanied by a significant reduction in cortical synaptotagmin 1 (Syt1) level. These findings underscore the involvement of MyT1 in mitigating SI-induced depression-like behavior. Moreover, the observed alterations in behavior are closely associated with changes in cortical Syt1 expression, suggesting its potential role as a target for unraveling the molecular mechanisms underlying mood disorders induced by SI. This study sheds light on the intricate interplay between MyT1 and cortical function in modulating responses to SI, paving the way for potential therapeutic interventions targeting these pathways.

The antidepressant-like effects of kisspeptin-10 are reversed by kisspeptin antagonist peptide 234 in male rats.

Kisspeptins are reported to be the most potent activators of the hypothalamus-pituitary-gonadal (HPG) axis known to date. Kisspeptin potently elicits gonadotropin-releasing hormone (GnRH) release and luteinizing hormone (LH) secretion, even in the pre-pubertal period. Beyond the hypothalamus, kisspeptin is also expressed in limbic and paralimbic brain regions, which are areas of the neurobiological network primarily implicated in emotional behaviors alongside sexual functions. Therefore, an increasing body of studies has implicated kisspeptin as having many influences on emotional behaviors. The study was set out to explore if the kisspeptin/GPR54 signaling system is required for the anti-depressant-like effect of kisspeptin-10 (KP-10), besides the regulation of the HPG axis. To test this concept, peptide 234 (P234), a kisspeptin antagonist, was given to the male rats, and its modulatory effect on the anti-depressant-like effects of kisspeptin was investigated by using a forced swimming test (FST). The study has also sought to know whether kisspeptin can exert its effects through adrenergic and serotonergic receptors. To investigate this, the agents yohimbine (Yoh), an alpha-2 adrenergic receptor antagonist, and cyproheptadine (Cry), a non-selective 5-HT2 serotonergic receptor antagonist, were administered in the experiments. Our results indicate that, in rats, the anti-depressant-like effects of KP-10 in a modified rat FST are mediated by GPR54 receptors, since the kisspeptin antagonist peptide 234 reversed kisspeptin-induced anti-depressant-like effects. Our data also demonstrate that the anti-depressant-like effects of kisspeptin, at least in part, are mediated by an interaction of the alpha-2 adrenergic and 5-HT2 serotonergic receptors.

The impact of social isolation on depression-like behavior in carioca high- and low-conditioned freezing rats.

This study investigated the impact of social isolation in Carioca High-Conditioned Freezing (CHF) rats, an animal model of generalized anxiety disorder (GAD). Animals selected for high (CHF), low trait anxiety (Carioca Low-Conditioned Freezing, CLF), and control rats from randomly bred populations (CTL) were housed in groups or kept isolated in their cages for 14 consecutive days. On the fifteenth day, all animals underwent the Forced Swimming Test (FST), where the latency to immobility was assessed as a depressive-like measure. Under standard grouping conditions, CHF rats showed a shorter latency to immobility in the FST compared to CTL and CLF animals, indicating depressive-like characteristics and possible GAD comorbidity. Social isolation decreased the latency to immobility in CLF and CTL animals, while it paradoxically increased this measure in CHF animals. Therefore, social isolation exerted a depressive-like action in CTL and CLF rats, but had a protective or "antidepressant-like" effect in CHF animals. Since, CHF rats are housed with other animals with high trait anxiety, such protective action induced by social isolation might have been due to the mitigation of what has been referred to as "social stress contagion". These results are discussed regarding the association between depressive-like behaviors and reduced social engagement.

Noradrenergic Projections from the Locus Coeruleus to the Medial Prefrontal Cortex Enhances Stress Coping Behavior in Mice Following Long-Term Intermittent Fasting.

Intermittent fasting has been shown to alleviate stress, anxiety, and depressive symptoms. Although noradrenaline, also known as norepinephrine (NE), is implicated in stress regulation, the dynamics of NE release and the associated neural pathways during stress coping behaviors in fasting mice remain poorly understood. In this study, we employed the forced swimming test (FST) to evaluate the effects of intermittent fasting on stress coping behavior in mice. Our results demonstrate that mice subjected to long-term intermittent fasting exhibited significantly more active coping behaviors in the FST compared to control mice. In contrast, acute fasting did not produce similar effects. Using the fluorescent GRAB-NE sensor to measure NE release with sub-second temporal resolution during the FST, we found that intermittent fasting modulates the locus coeruleus-medial prefrontal cortex (LC-mPFC) pathway, which underlies these behavioral adaptations. Moreover, chemogenetic activation of LC-mPFC projections strongly promoted active coping in the FST. These findings suggest that enhanced LC-mPFC activity mediates the increased active coping behavior observed in fasting mice. This study provides new insights into the neural mechanisms through which intermittent fasting may ameliorate depressive-like behaviors, offering potential therapeutic targets for stress-related disorders.