Behavioral Despair Research Articles

A circuit from lateral hypothalamic to dorsal hippocampal dentate gyrus modulates behavioral despair in mice.

Behavioral despair is one of the clinical manifestations of major depressive disorder and an important cause of disability and death. However, the neural circuit mechanisms underlying behavioral despair are poorly understood. In a well-established chronic behavioral despair (CBD) mouse model, using a combination of viral tracing, in vivo fiber photometry, chemogenetic and optogenetic manipulations, in vitro electrophysiology, pharmacological profiling techniques, and behavioral tests, we investigated the neural circuit mechanisms in regulating behavioral despair. Here, we found that CBD enhanced CaMKIIα neuronal excitability in the dorsal dentate gyrus (dDG) and dDGCaMKIIα neurons involved in regulating behavioral despair in CBD mice. Besides, dDGCaMKIIα neurons received 5-HT inputs from median raphe nucleus (MRN) and were mediated by 5-HT1A receptors, whereas MRN5-HT neurons received CaMKIIα inputs from lateral hypothalamic (LH) and were mediated by AMPA receptors to regulate behavioral despair. Furthermore, fluvoxamine exerted its role in resisting behavioral despair through the LH-MRN-dDG circuit. These findings suggest that a previously unidentified circuit of LHCaMKIIα-MRN5-HT-dDGCaMKIIα mediates behavioral despair induced by CBD. Furthermore, these support the important role of AMPA receptors in MRN and 5-HT1A receptors in dDG that might be the potential targets for treatment of behavioral despair, and explain the neural circuit mechanism of fluvoxamine-resistant behavioral despair.

Dorsal raphe dopaminergic neurons target CaMKII+ neurons in dorsal bed nucleus of the stria terminalis for mediating depression-related behaviors

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 DRNDA → dBNSTCaMKII+ 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.

Ginsenoside Rg1 Enriches Gut Microbial Indole-3-acetic acid to Alleviate Depression-like Behavior in Mice via Oxytocin Signaling

Background and purposeAlthough a large collection of data has shown that ginsenosides, the major active ingredients from Ginseng, have neuroprotective and anti-depressant effect, the mechanism of action is incompletely understood. This study aims to elucidate the antidepressant mechanism of ginsenoside Rg1 (Rg1), a poorly absorbed ginsenoside, from the perspective of gut microbe to brain signaling. MethodsA mouse model of depression was induced by unpredictable mild stress (UMS). Behavioral and neurochemical tests were conducted to evaluate the effect and mechanism of Rg1 on depressive behavior. Non-target and target metabolomics were performed to identify the signaling metabolites underlying the antidepressant efficacy of Rg1. Gut microbial structure was analyzed by 16S rRNA sequencing and the potential functional strains associated with Rg1 action were investigated by in vitro bacterial culture. Chemical intervention was used to explore the mechanism of Rg1 and signaling metabolite. ResultsRg1 improved UMS-induced despair, anxiety-like and social avoidance behaviors in mice, which were accompanied by increased hypothalamic oxytocin secretion and restored neural proliferation in the hippocampus. Metabolomic analysis of gut-brain axis revealed that Rg1 increased the concentration of serum and brain indole-3-acetic acid (IAA), a bacterial metabolite that was partially attributed to the enrichment of Lactobacillus murinus in the gut microbiome. Oral supplementation of IAA mimicked the anti-depressant action of Rg1, while oxytocin receptor antagonist abrogated the anti-depressant effects of both Rg1 and IAA. ConclusionOur work provides a new gut-to-brain signaling mechanism for the antidepressant effects of Rg1. In particular, Rg1 enriches the abundance of Lactobacillus murinus, which in turn increases the level of brain IAA and potentiates hypothalamic oxytocin signal. These findings suggest a promising pathway for producing antidepressant effects through gut-brain crosstalk.

CDNF Exerts Anxiolytic, Antidepressant-like, and Procognitive Effects and Modulates Serotonin Turnover and Neuroplasticity-Related Genes.

Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor because it does not bind to a known specific receptor on the plasma membrane and functions primarily as an unfolded protein response (UPR) regulator in the endoplasmic reticulum. Data on the effects of CDNF on nonmotor behavior and monoamine metabolism are limited. Here, we performed the intracerebroventricular injection of a recombinant CDNF protein at doses of 3, 10, and 30 μg in C57BL/6 mice. No adverse effects of the CDNF injection on feed and water consumption or locomotor activity were observed for 3 days afterwards. Decreases in body weight and sleep duration were transient. CDNF-treated animals demonstrated improved performance on the operant learning task and a substantial decrease in anxiety and behavioral despair. CDNF in all the doses enhanced serotonin (5-HT) turnover in the murine frontal cortex, hippocampus, and midbrain. This alteration was accompanied by changes in the mRNA levels of the 5-HT1A and 5-HT7 receptors and in monoamine oxidase A mRNA and protein levels. We found that CDNF dramatically increased c-Fos mRNA levels in all investigated brain areas but elevated the phosphorylated-c-Fos level only in the midbrain. Similarly, enhanced CREB phosphorylation was found in the midbrain in experimental animals. Additionally, the upregulation of a spliced transcript of XBP1 (UPR regulator) was detected in the midbrain and frontal cortex. Thus, we can hypothesize that exogenous CDNF modulates the UPR pathway and overall neuronal activation and enhances 5-HT turnover, thereby affecting learning and emotion-related behavior.

SAL0114: a novel deuterated dextromethorphan-bupropion combination with improved antidepressant efficacy and safety profile.

Esketamine, the first Food and Drug Administration-approved fast-acting antidepressant, has limited use because of its addictive properties. Although the combination of dextromethorphan and bupropion partially addresses the limitations of esketamine, concerns remain regarding neurologic side effects related to dextromethorphan metabolites, and seizure risks associated with high-dose bupropion. SAL0114, a novel formulation combining deuterated dextromethorphan (in which hydrogen atoms are replaced with deuterium) with bupropion, seeks to enhance dextromethorphan stability through deuteration of its metabolic sites. This approach is expected to increase antidepressant efficacy, reduce metabolite-induced safety issues, and allow for lower bupropion dosages. Radioligand competition binding assays were used to evaluate the impact of deuterium substitution on the in vitro activity of dextromethorphan and its metabolite, dextrorphan. In vitro hepatic microsomal stability and in vivo mouse pharmacokinetic assays were performed to assess the effects of deuteration on dextromethorphan stability. Two mouse models of behavioral despair were used to determine the antidepressant and synergistic effects of deuterated dextromethorphan and bupropion. Additionally, a reserpine-induced hypothermia rat model and an ammonia-induced cough mouse model were used to assess the in vivo effects from a pathological perspective. Deuterated dextromethorphan maintained the same in vitro activity as dextromethorphan while exhibiting twice the metabolic stability both in vitro and in vivo. Combination with bupropion further improved its in vivo stability, increasing the exposure by 2.4 times. The combination demonstrated efficacy and synergistic effects in all tested animal models, showing superior efficacy compared with the dextromethorphan-bupropion combination. Deuteration improved dextromethorphan metabolic stability without altering its in vitro activity. Bupropion enhanced this stability and synergistically boosted the antidepressant effect by increasing deuterated dextromethorphan exposure in vivo. This enhanced metabolic stability suggests a reduction in dextromethorphan metabolites associated with clinical neurological side effects. Consequently, SAL0114 is hypothesized to offer improved efficacy and safety compared with the non-deuterated combination, potentially allowing for lower bupropion dosages. Further clinical studies are required to confirm these preclinical findings.

Evaluation of behavioral responses to restraint stress in the house mouse (Mus musculus musculus) of wild origin

Stress is a fundamental concept for many areas of animal research. In laboratory rodents, exposure to various stressors results in immediate and postponed behavioral changes that can be measured with standard tests. Less is known about how wild rodents that have not undergone domestication respond to stressors in laboratory settings. This study was aimed at evaluating behavioral responses to restraint stress in male and female wild-derived house mice (Mus musculus musculus). One week after the end of three daily restraint sessions, alterations in mouse behavior were assessed in two tests. In the open field test, stressed mice (n = 23) entered the unprotected central zone less frequently (P < 0.05) and showed increased duration of self-grooming (P < 0.05) compared to controls (n = 23), indicating elevated anxiety. In the forced swim test, most mice (44 out of 46) displayed episodes of behavioral despair, but the influence of stress was insignificant. To characterize baseline performance of wild-derived mice, their behavior was compared to that of a laboratory strain. As compared to C57BL/6 males (n = 10), M. m. musculus males (n = 14) showed significantly greater exploratory activity in the open field and longer latency of the first immobility episode in the forced swim test (P < 0.001). Overall, these findings confirm ecological validity of the widely used animal model of restraint stress and may serve as a basis for future studies.

Coenzyme Q10 and vitamin E alleviate heat stress-induced mood disturbances in male mice: Modulation of inflammatory pathways and the HPA axis

Heat stress, as an environmental stressor, can lead to temperature dysregulation and neuroinflammation, causing depression and anxiety by disrupting brain physiology and functional connectivity. This study looked at how co-enzyme Q10 (Q10) and vitamin E (Vit E), alone and together, affected heat stress-caused anxiety and depression symptoms and inflammation in male mice. Five groups were utilized in the study: control, heat stress (NS), Q10, Vit E, and the combination group (Q10+Vit E). The mice were subjected for 15 min/day to a temperature of 43°C for 14 consecutive days, followed by daily treatments for two weeks with either normal saline, Q10 (500 mg/kg), Vit E (250 mg/kg), or their combination. The forced swimming test (FST) and tail suspension test (TST) were employed to evaluate despair behavior, whereas the elevated plus maze (EPM) and open field test (OFT) were used to assess anxious behaviors. Subsequently, the animals were sacrificed, and serum corticosterone levels, protein expression of inflammasome-related proteins, and hsp70 gene expression were evaluated in the prefrontal cortex (PFC). The study revealed that treatment with Vit E and Q10, alone or together, provided anxiolytic and antidepressant effects in the heat-stress-subjected animals. Also, giving Vit E and Q10 alone or together greatly lowered serum corticosterone levels. In the PFC, they also lowered the levels of hsp70 mRNA and NF-κB, caspase 1, NLRP3, and IL-1β proteins. It is speculated that treatment with Q10 and Vit E can attenuate heat stress-associated anxious and depressive responses by inhibiting the inflammatory pathways and modulating the hypothalamus-pituitary-adrenal axis.

Nervonic acid improves depression like behaviors and demyelination of medial prefrontal cortex in chronic restraint stress mice

Major depressive disorder (MDD) is a psychiatric disorder characterized by depressed mood, behavioral despair and anhedonia. Demyelination in specific brain regions underlies the pathology of MDD, raising the alleviating demyelination as a potential strategy for MDD therapy. Nervonic acid (NA) has the potential to improve brain demyelination, offering benefits for various neurological disorders. However, its effects on depression remain undetermined. Mice were subjected to 14 days of chronic restraint stress (CRS) to induce depression-like behaviors, and were injected with NA (70 mg/kg) daily. The administration of NA significantly improved depressive-like behaviors in CRS mice. CRS led to significant demyelination in the medial prefrontal cortex (mPFC), which were reversed by NA treatment. In addition, NA ameliorated the upregulation of inflammatory cytokines and downregulation of brain-derived neurotrophic factor, improved the alternations in axonal spines observed in the mPFC of CRS mice. Our results highlighted the potential of NA as an antidepressant, with its benefits likely attributed to its effects in alleviating demyelination in the mPFC.

Fluoxetine attenuates the anxiolytic effects of the probiotic VSL#3 in a stress-vulnerable genetic line of aves in the chick social-separation stress test, a dual screening assay

Anxiety disorders represent one of the most common and debilitating illnesses worldwide. However, the development of novel therapeutics for anxiety disorders has lagged compared to other mental illnesses. A growing body of research suggests the gut microbiota plays a role in the etiopathology of anxiety disorders and may, therefore, serve as a novel target for their treatment through the use of probiotics. The use of dietary supplements like probiotics is increasing and their interaction with pharmacotherapies is not well understood. Utilizing the chick social-separation stress test, the primary aim of this study was to evaluate the commercially-available multi-strain probiotic found in VSL#3 for potential anxiolytic-like and/or antidepressant-like effects in the stress-vulnerable Black Australorp genetic line. A secondary aim was to evaluate the interaction between probiotics and the SSRI fluoxetine. Animals were treated with either saline, probiotics, fluoxetine, or probiotics + fluoxetine for 8 days prior to exposure to a 90-min isolation stressor that produces both a panic-like (i.e., anxiety-like) state followed by a state of behavioral despair (i.e., depression-like). The 8-day probiotic regimen produced anxiolytic-like effects but did not attenuate behavioral despair. Fluoxetine failed to significantly alter behavior in either of the two phases. Moreover, the combination of fluoxetine with probiotics attenuated the anxiolytic-like effects of probiotics. The fluoxetine + probiotics combination had no effect on behavioral despair. The results of the current study align with other preclinical studies and some clinical trials suggesting probiotics may offer beneficial effects on anxiety. Investigations examining the anxiolytic-like mechanism of probiotics are needed before any conclusions can be made. Additionally, as the use of probiotics becomes more popular, research on the interactions between probiotic-microbiota and psychotropic medications is necessary.

GluN2B on Adult-Born Granule Cells Modulates (R,S)-Ketamine's Rapid-Acting Effects in Mice.

Standard antidepressant treatments often take weeks to reach efficacy and are ineffective for many patients. (R,S)-ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be a rapid-acting antidepressant and to decrease depressive symptoms within hours of administration. While previous studies have shown the importance of the GluN2B subunit of the NMDA receptor on interneurons in the medial prefrontal cortex, no study to our knowledge has investigated the influence of GluN2B-expressing adult-born granule cells. Here, we examined whether (R,S)-ketamine's efficacy depends on adult-born hippocampal neurons using a genetic strategy to selectively ablate the GluN2B subunit of the NMDA receptor from Nestin+ cells in male and female mice, tested across an array of standard behavioral assays. We report that in male mice, GluN2B expression on 6-week-old adult-born neurons is necessary for (R,S)-ketamine's effects on behavioral despair in the forced swim test and on hyponeophagia in the novelty suppressed feeding paradigm, as well on fear behavior following contextual fear conditioning. In female mice, GluN2B expression is necessary for effects on hyponeophagia in novelty suppressed feeding. These effects were not replicated when ablating GluN2B from 2-week-old adult-born neurons. We also find that ablating neurogenesis increases fear expression in contextual fear conditioning, which is buffered by (R,S)-ketamine administration. In line with previous studies, these results suggest that 6-week-old adult-born hippocampal neurons expressing GluN2B partially modulate (R,S)-ketamine's rapid-acting effects. Future work targeting these 6-week-old adult-born neurons may prove beneficial for increasing the efficacy of (R,S)-ketamine.

Adenosine A2A signaling in mood disorders: How far have we come?

Over the years, evidence has continued to support the role of the adenosinergic system in shaping emotional behavior and its impact on the development of mood disorders. In the 1980s, pioneering studies revealed that tricyclic antidepressants could modulate the levels of adenosine and adenosine metabolism. Moreover, evidence from animal models support a regulation of adenosine receptors in brain regions involved in emotional responses, and the role of pharmacological manipulation of adenosine receptors on behavioral despair, anxiety, locomotion, rewards processing and cognition. Clinical research has focused on the effects of caffeine, a non-selective adenosine receptor antagonist, and in genetic polymorphisms in adenosine receptors on emotional regulation in psychiatric patients. Recently, the approval of Istradefylline as an adjunctive treatment for Parkinson's disease holds great promise to expand our understanding of adenosine A2A receptors (A2AR) blockade in humans. Furthermore, recent advancements in transgenic lines and optogenetic techniques have highlighted the role of adenosine receptors in specific cell types and brain circuits that control emotional behavior. In this review, our focus will be on A2AR, given their strong association to stress-related conditions, mood disorders, and the potential of A2AR antagonists in clinical research. We will discuss the progress achieved in understanding its role in emotional regulation, emphasizing functions across distinct cell types and potential applications as a pharmacological target for mood disorders in the upcoming years.

LT-102, an AMPA receptor potentiator, alleviates depression-like behavior and synaptic plasticity impairments in prefrontal cortex induced by sleep deprivation

BackgroundSleep loss is closely related to the onset and development of depression, and the mechanisms involved may include impaired synaptic plasticity. Considering the important role of glutamate α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) in synaptic plasticity as well as depression, we introduce LT-102, a novel AMPARs potentiator, to evaluate the potential of LT-102 in treating sleep deprivation-induced depression-like behaviors. MethodsWe conducted a comprehensive behavioral assessment to evaluate the effects of LT-102 on depression-like symptoms in male C57BL/6J mice. This assessment included the open field test to measure general locomotor activity and anxiety-like behavior, the forced swimming test and tail suspension test to assess despair behaviors indicative of depressive states, and the sucrose preference test to quantify anhedonia, a core symptom of depression. Furthermore, to explore the impact of LT-102 on synaptic plasticity, we utilized a combination of Western blot analysis to detect protein expression levels, Golgi-Cox staining to visualize neuronal morphology, and immunofluorescence to examine the localization of synaptic proteins. Additionally, we utilized primary cortical neurons to delineate the signaling pathway modulated by LT-102. ResultsTreatment with LT-102 significantly reduced depression-like behaviors associated with sleep deprivation. Quantitative Western blot (WB) analysis revealed a significant increase in GluA1 phosphorylation in the prefrontal cortex (PFC), triggering the Ca2+/calmodulin-dependent protein kinase II/cAMP response element-binding protein/brain-derived neurotrophic factor (CaMKII/CREB/BDNF) and forkhead box protein P2/postsynaptic density protein 95 (FoxP2/PSD95) signaling pathways. Immunofluorescence imaging confirmed that LT-102 treatment increased spine density and co-labeling of PSD95 and vesicular glutamate transporter 1 (VGLUT1) in the PFC, reversing the reductions typically observed following sleep deprivation. Golgi staining further validated these results, showing a substantial increase in neuronal dendritic spine density in sleep-deprived mice treated with LT-102. Mechanistically, application of LT-102 to primary cortical neurons, resulted in elevated levels of phosphorylated AKT (p-AKT) and phosphorylated glycogen synthase kinase-3 beta (p-GSK3β), key downstream molecules in the BDNF signaling pathway, which in turn upregulated FoxP2 and PSD95 expression. LimitationsIn our study, we chose to exclusively use male mice to eliminate potential influences of the estrous cycle on behavior and physiology. As there is no widely accepted positive drug control for sleep deprivation studies, we did not include one in our research. ConclusionOur results suggest that LT-102 is a promising therapeutic agent for counteracting depression-like behaviors and synaptic plasticity deficits induced by sleep deprivation, primarily through the activation of CaMKII/CREB/BDNF and AKT/GSK3β/FoxP2/PSD95 signaling pathways.

Preventing social defeat stress-induced behavioural and neurochemical alterations by repeated treatment with a mix of Centella asiatica, Echinacea purpurea and Zingiber officinale standardized extracts.

Background: Prolonged exposure to stress is a risk factor for the onset of several disorders. Modern life is burdened by a pervasive prevalence of stress, which represents a major societal challenge requiring new therapeutic strategies. In this context, botanical drug-based therapies can have a paramount importance. Methods: Here we studied the preventive effects of a repeated treatment (p.o. daily, 3weeks) with a combination of Centella asiatica (200mg/kg), Echinacea purpurea (20mg/kg) and Zingiber officinale (150mg/kg) standardized extracts, on the chronic social defeat stress (CSDS) deleterious outcomes. After 10days of CSDS exposure, male mice' performances were evaluated in paradigms relevant for social (social interaction test), emotional (tail suspension test), cognitive (novel object recognition) domains as well as for pain perception (cold plate and von Frey tests) and motor skills (rotarod). Mice were then sacrificed, the spinal cords, hippocampi and frontal cortices dissected and processed for RT-PCR analysis. Results: Extracts mix treatment prevented stress-induced social aversion, memory impairment, mechanical and thermal allodynia and reduced behavioural despair independently of stress exposure. The treatment stimulated hippocampal and cortical BDNF and TrkB mRNA levels and counteracted stress-induced alterations in pro- (TNF-α, IL-1β and IL-6) and anti-inflammatory (IL4, IL10) cytokines expression in the same areas. It also modulated expression of pain related genes (GFAP and Slc1a3) in the spinal cord. Conclusion: The treatment with the extracts mix obtained from C. asiatica, E. purpurea and Z. officinale may represent a promising strategy to promote resilience and prevent the deleterious effects induced by extended exposure to psychosocial stress.

An escape-enhancing circuit involving subthalamic CRH neurons mediates stress-induced anhedonia in mice

Chronic predator stress (CPS) is an important and ecologically relevant tool for inducing anhedonia in animals, but the neural circuits underlying the associated neurobiological changes remain to be identified. Using cell-type-specific manipulations, we found that corticotropin-releasing hormone (CRH) neurons in the medial subthalamic nucleus (mSTN) enhance struggle behaviors in inescapable situations and lead to anhedonia, predominately through projections to the external globus pallidus (GPe). Recordings of in vivo neuronal activity revealed that CPS distorted mSTN-CRH neuronal responsivity to negative and positive stimuli, which may underlie CPS-induced behavioral despair and anhedonia. Furthermore, we discovered presynaptic inputs from the bed nucleus of the stria terminalis (BNST) to mSTN-CRH neurons projecting to the GPe that were enhanced following CPS, and these inputs may mediate such behaviors. This study identifies a neurocircuitry that co-regulates escape response and anhedonia in response to predator stress. This new understanding of the neural basis of defensive behavior in response to predator stress will likely benefit our understanding of neuropsychiatric diseases.

Prophylactic effects of Tibetan goat kefir on depression-like behaviors in chronic unpredictable stress model through the gut-brain axis.

Depression is a common psychological disorder, and traditional therapeutic drugs often result in side effects such as emesis, dry mouth, headache, dysentery and constipation. Probiotics and goat milk have garnered widespread attention for their ability to modulate immune function and regulate the endocrine system, and for their anti-inflammatory effects. In this work, the effects of Tibetan goat kefir on the behavior, immune status, neuroendocrine response and gut microbiological composition of chronic unpredictable mild stress (CUMS) mouse models were evaluated. The results indicated that Tibetan kefir goat milk significantly alleviated behavioral despair in mice. Furthermore, the results demonstrated that Tibetan kefir goat milk mitigated the inflammatory response in the mice and moderated the hyperactivity of the hypothalamic-pituitary-adrenal axis and the expression of brain-derived neurotrophic factor. Meanwhile, chronic stress-induced gut microbial abnormalities were restored. In addition, the correlation between gut microbiota and nervous system was evaluated. These results explained the potential mechanism of Tibetan kefir in the antidepressant effect on the CUMS model and enriched diets for depressed patients. © 2024 Society of Chemical Industry.

The influence of exercise intensity on comorbid anxious behavior in psychiatric conditions

Many experts have extensively studied the potential of exercise as a treatment option for psychiatric conditions, including depression and autism spectrum disorder (ASD). Despite their core symptoms, these conditions exhibits comparable component traits, an anxiety. In this study, we explored the effect of exercise on behavioral abnormalities in psychiatric conditions, focusing on its intensity and emotional resilience. Shank3B knockout (KOSED) mice displaying self-injurious repetitive behavior and C57BL/6J mice, susceptible to stress as ASD and depression model, respectively, were subjected to moderate-intensity exercise (ME) for 2 weeks. ME mitigated the core symptoms (excessive grooming traits and behavioral despair) but did not exert a significant anxiolytic effect. Notably, exercise intensity has emerged as a critical determinant of its efficacy, as evidenced by a lower ventilation threshold and anxiolytic effect mediated by low-intensity exercise. The findings substantiate the notion that exercise is promising as a disease-modifying treatment, but intensity matters for emotional resilience.Graphical

Subchronic administration of scopolamine reverses UCMS-induced behavior in mice via eEF2 protein dephosphorylation

BackgroundThe 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.MethodsRapid 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.ResultsScopolamine 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).ConclusionSubchronic 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.

Cajaninstilbene acid ameliorates depression-like behaviors in mice by suppressing TLR4/NF-κB mediated neuroinflammation and promoting autophagy

Depression is a life-threatening neurodegenerative disease lacking a complete cure. Cajaninstilbene acid (CSA), a potent stilbene compound, has demonstrated neuroprotective effects, however, studies on its antidepressant mechanisms are still scarce. This study examined the effects of CSA on lipopolysaccharide (LPS)-induced and chronic unpredictable mild stress (CUMS)-induced depression in mice, investigating its mechanisms related to inflammation and autophagy. Mice were treated with CSA (7.5, 15, and 30 mg/kg) daily for 3 weeks before intraperitoneal LPS injection (0.8 mg/kg). Another cohort underwent the same doses of CSA (7.5–30 mg/kg) daily for 6 weeks in accompany with CUMS stimulation. Behavioral assessments were conducted, and cortical samples were collected for molecular analysis. Findings indicate that CSA ameliorated depressive behaviors induced by both LPS and CUMS. Notably, CSA (15 mg/kg) reversed despair behavior in mice more persistently than amitriptyline, indicating that optimal doses of CSA may effectively decelerate the procession of mood despair and yield a good compliance. CSA countered CUMS-induced activation of TLR4/NF-κB pathway and the reduction in autophagy levels. Furthermore, CSA attenuated the CUMS-induced decline in neuroplasticity. Collectively, these findings suggest that CSA mitigates depression-like behaviors in mice by inhibiting TLR4/NF-κB-mediated neuroinflammation and enhancing autophagy. This research provides further insights into CSA’s mechanisms of action in ameliorating depressive behaviors, offering a scientific foundation for developing CSA-based antidepressants.

Identification of antidepressant constituents from Xiangfu-chuanxiong herbal medicine pair via spectrum-effect relationship analyses, molecular docking and corticosterone-induced PC12 cells

Herbal medicine pair, composed of two single herbs, is a relatively fixed minimum prescription unit in the traditional Chinese medicine's formula and has special significance in clinic. The combination of Xiangfu (the rhizoma of Cyperus rotundus L, XF) and Chuanxiong (the rhizoma of Ligusticum chuanxiong Hort, CX) has been recoded as an herbal medicine pair XF-CX in the Yuan Dynasty (1347 CE) of China and widely used in traditional Chinese medicine formula, including Chaihu Shugan San, which has been clinically used for treatment of depression. However, the optimal ratio of the XF-CX herbal medicine pair and its antidepressant constituents are still unclear. Herein, the antidepressive-like effects of XF-CX herbal medicine pairs with different ratios of XF and CX (2:1, 1:1, 1:2) were evaluated using behavioral despair animal models in mice, and then its potential antidepressant constituents were recognized by spectrum-effect relationship analyses. Finally, the potential antidepressant constituents of the XF-CX herbal medicine pair were validated by molecular docking with glucocorticoid receptor and corticosterone (CORT)-induced PC12 cell injury model. The results indicated that different ratios of XF-CX pairs had antidepressive-like effects, and the XF-CX (2:1) exhibited a more significant effect. Thirty-two potential antidepressant constituents in the XF-CX herbal medicine pair were screened out from the spectrum-effect relationship combined molecular docking analyses. Among them, senkyunolide A, cyperotundone, Z-ligustilide, and levistilide A were validated to have protective effects against CORT-induced injury in PC12 cells. Our findings not only obtained the optimal ratio of XF-CX in the herbal medicine pair for the treatment of depression but also its potential antidepressant constituents, which will benefit in elucidating the mechanism of action and promoting the application of the herbal medicine pair in the clinic.

Targeting Phactr4 to rescue chronic stress-induced depression-like behavior in rats via regulating neuroinflammation and neuroplasticity

Depression is a neuropsychiatric disorder characterized by persistent pleasure loss and behavioral despair. However, the potential mechanisms and therapeutic targets for depression treatment remain unclear. Therefore, identifying the underlying pathogenesis of depression would promote the development of novel treatment and provide effective targets for antidepressant drugs. In this study, proteomics analysis showed that the expression level of phosphatase and actin regulator 4 (Phactr4) was significantly increased in the CA1 hippocampus of depressed rats. The upregulated Phactr4 might induce dysfunction of the synaptic structure via suppressing the p-LIMK/p-Cofilin signaling pathway, and promote neuroinflammation via activating the NF-κB/NLRP3 pathway, which ultimately contributes to the pathogenesis of depression. In contrast, the downregulation of Phactr4 in hippocampal CA1 of depressed rats alleviated depression-like behaviors, along with reducing neuroinflammation and improving synaptic plasticity. In conclusion, these findings provide evidence that Phactr4 plays an important role in regulating neuroinflammatory response and impairment of synaptic plasticity, effects seem to involve in the pathogenesis of depression, and Phactr4 may serve as a potential target for antidepressant treatment.