Major depressive disorder (MDD) is a prevalent psychiatric illness and a significant contributor to the global burden of disease. However, the molecular mechanisms underlying depression are complex and have yet to be fully elucidated. Previous studies demonstrated that collapsin response mediator protein 2 (CRMP2) involved in the onset of depression, but its role is unclear yet. To explore the mechanism of CRMP2 in depression and whether it ameliorates depressive-like behaviours by modulating synaptic functions, we manipulate the expression of CRMP2 by adeno-associated virus (AAV) injected into the hippocampal CA1 region and then induced depressive-like behaviour by subjecting the mice to chronic unpredictable mild stress (CUMS). Sucrose preference test (SPT), open field test (OFT), elevated plus maze test (EPM), forced swimming test (FST), and tail suspension test (TST) are utilized to detect behavioral changes. Golgi-Cox staining and electron microscopy were applied to examine alterations in the structure and morphology of neural synapses. Synaptophysin (SYP), synaptophysin 1 (SYN1), growth-associated protein 43 (GAP43), glutamate receptor 2 (GLUR2) and postsynaptic density protein 95 (PSD95) is tested for synaptic function. The proteins interacting with CRMP2 were comprehensively investigated utilizing Immunoprecipitation-Mass Spectrometry (IP-MS) analysis and the direct binding between CRMP2 and PSD95 was validated. In our study, we observed CRMP2 in the hippocampal CA1 region was downregulated following CUMS. Knockdown of CRMP2 resulted in impaired synaptic structure and decreased expression of synapse-associated proteins, accompanied by increased depressive-like behaviour, like anhedonia and hopelessness. Conversely, overexpression of CRMP2 significantly ameliorated behavioural deficits associated with depression and restore the compromised synaptic structure and function. Our findings suggest that CRMP2 exerts a crucial function in modulating depressive-like behaviours by influencing the synaptic structure and function, and it can directly interact with PSD95.

Changpu San (CPS) is a traditional Chinese medicine (TCM) formula historically used to treat symptoms resembling depression. However, its antidepressant effects and underlying mechanisms remain unclear.

This study aims to evaluate CPS's antidepressant effects and elucidate its mechanisms by combining network pharmacology with untargeted metabolomics.

A chronic unpredictable mild stress (CUMS) mouse model was used to assess CPS's antidepressant effects via behavioral tests and body weight monitoring. By integrating network pharmacology and untargeted metabolomics, both based on UPLC-Q-Exactive-Orbitrap-MS for CPS chemical profiling and serum metabolite analysis, a key pathway was identified. This pathway was validated through UPLC-QQQ-MS/MS and ELISA by measuring relevant biomarkers, while its association with colonic microbiota was further investigated using 16S rDNA sequencing.

CPS alleviated depression-like behaviors in CUMS mice. A total of 140 compounds were identified in CPS, revealing 140 core targets related to depression. Metabolomics analysis identified 42 serum metabolites significantly altered in CUMS mice, with tryptophan metabolism emerging as a shared pathway across both approaches. Experimental validation showed CPS partially reversed tryptophan metabolism dysregulation, significantly increasing tryptophan levels and reducing kynurenine levels in the brain. Moreover, CPS modulated the colonic microbiota, with key genera such as Prevotella and Bacillus showing correlations with tryptophan metabolism and inflammation.

CPS shows promise as an effective antidepressant, potentially through modulating tryptophan metabolism and reshaping colonic microbiota. This study provides valuable insights into its mechanisms and offers a methodological reference for researching other TCM formulas.

Nitrous oxide (N2O) induces rapid and durable antidepressant effects. The cellular and circuit mechanisms mediating this process are not known. Here we find that a single dose of inhaled N2O induces rapid and specific activation of layer V (L5) pyramidal neurons in the cingulate cortex of rodents exposed to chronic stress conditions. N2O-induced L5 activation rescues a stress-associated hypoactivity state, persists following exposure, and is necessary for its antidepressant-like activity. Although NMDA-receptor antagonism is believed to be a primary mechanism of action for N2O, L5 neurons activate even when NMDA-receptor function is attenuated through both pharmacological and genetic approaches. By examining different molecular and circuit targets, we identify N2O-induced inhibition of calcium-sensitive potassium (SK2) channels as a key molecular interaction responsible for driving specific L5 activity along with ensuing antidepressant-like effects. These results suggest that N2O-induced L5 activation is crucial for its fast antidepressant action and this effect involves novel and specific molecular actions in distinct cortical cell types.

Gut microbiome is implicated in the onset and progression of major depressive disorder (MDD), but the dynamic alterations of depressive symptoms, gut microbiome, and fecal metabolome across different stages of stress exposure remain unclear. Here, we modified the chronic social defeat stress (CSDS) model to evaluate mice subjected to social defeat stress for 1, 4, 7, and 10 days. Behavioral tests, 16S rRNA, metagenomics, and fecal metabolomics were conducted to investigate the impact of stress exposure on behaviors, gut microbiota and fecal metabolites. We observed that depressive-like behaviors, such as anhedonia and social avoidance, worsened significantly as stress exposure increased. The microbial composition, function, and fecal metabolites exhibited distinct separations across the different social defeat stress groups. Mediation analysis identified key bacteria, such as Lachnospiraceae_UCG-001 and Bacteroidetes, and fecal metabolites like valeric acid and N-acetylaspartate. In our clinical depression cohort, we confirmed that fecal valeric acid levels, were significantly lower in depressive-like mice and MDD patients, correlating closely with stress exposure and anhedonia in mice. Further analysis of serum and brain metabolites in mice revealed sustained changes of N-acetylaspartate abundance in fecal, serum, and cortical samples following increasing stress exposure. Together, this study elucidated the characteristics of depressive-like behaviors, gut microbiome, and fecal metabolome across various social defeat stress exposure, and identified key bacteria and fecal metabolites potentially involved in modulating social defeat stress response and depressive-like behaviors, providing new insights into the pathogenesis and intervention of depression.

Chronic stress in daily life is a well-known trigger for various health issues. Despite advancements in obesity research, the mechanisms governing lipid metabolism in adipose tissue during cachexia remain poorly understood.

A chronic restraint stress (CRS) model was used to induce significant physiological and psychological stress in mice. Mice were subjected to 6 h of restraint daily in 50 mL plastic tubes for seven consecutive days. A fasting control group was included for comparison. Post-stress assessments included behavioural tests, glucose and insulin tolerance tests and indirect calorimetry. Blood and adipose tissue samples were collected for mRNA and protein analyses.

CRS induced significant psychological and physiological changes in mice, including depression-like behaviours, weight loss and reduced insulin sensitivity. Notably, CRS caused extensive adipose tissue remodelling. White adipose tissue (WAT) underwent significant 'browning' accompanied by an increase in the expression of thermogenic proteins. This counteracted the stress-induced 'whitening' of brown adipose tissue (BAT), which exhibited impaired thermogenesis and functionality, thereby maintaining energy balance systematically. The glucocorticoid receptor (GR) plays a crucial role in lipid metabolism regulation during these changes. GR expression levels were inversely correlated in BAT and WAT, but aligned with the expression patterns of thermogenic proteins across adipose tissues. These findings suggest that under chronic metabolic stress, GR mediates tissue-specific responses in adipose tissues, driving functional and phenotypic transitions in BAT and WAT to maintain energy homeostasis.

This study provides novel insights into the contrasting thermogenic phenotypes of BAT and WAT under emaciation and highlights the critical role of GRs in adipose tissue remodelling during CRS and its potential as a therapeutic target. Addressing GR-mediated changes in adipose tissues may help alleviate BAT dysfunction in cachexia and promote WAT browning, enhancing metabolic stress resistance.

Inhibiting the protein-protein interaction (PPI) between Keap1 and Nrf2 is theoretically an effective and safe strategy for activation of Nrf2 pathway to treat major depressive disorder (MDD). In this study, through bioinformatic analysis of the brain tissues and peripheral blood of MDD patients and depressive mice, we confirmed the involvement of oxidative stress, inflammation, and the Keap1-Nrf2 pathway in depression. Subsequently, we developed a series of phosphodiester amino acidic diaminonaphthalene compounds as Keap1-Nrf2 PPI inhibitors for the first time. Screening using the LPS-stimulated SH-SY5Y and BV2 cell models identified compound 4-95 showing the best anti-oxidative stress and anti-inflammatory efficacy. The ability of 4-95 to penetrate the blood-brain-barrier was significantly enhanced. In a chronic unpredictable mild stress mouse model, treatment with 4-95 effectively ameliorated anxiety and depression behavior and restored serum neurotransmitter levels by promoting the Nrf2 nuclear translocation. Consequently, oxidative stress was reduced, and the expression of synaptic plasticity biomarkers, such as postsynaptic density protein 95 (PSD95) and synapsin 1 (SYN1) were significantly increased, suggesting the recovery of neuronal function. Collectively, our findings demonstrate that the Keap1-Nrf2 PPI inhibitor holds great promise as a preclinical candidate for the treatment of depression.

BDNF (Brain-derived neurotrophic factor)/TrkB (tropomyosin receptor kinase B) signaling has great therapeutic potential for depression, but the underlying mechanism remains unclear. This study aims to investigate the molecular mechanism underlying the BDNF/TrkB signaling-mediated antidepressant effects. Chronic Cort drinking for 4 weeks and a single injection of LPS for 24 h were used to induce depression-like behaviors; this study used 7,8-dihydroxyflavone (7,8-DHF, 10 mg/kg, i.p.), a selective TrkB receptor agonist, to activate the BDNF/TrkB signaling and examined its rapid-acting antidepressant-like effects; levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in BV2 microglial cells and synapse-related factors (BDNF, GluA1, Synapsin-1, and PSD95) in HT22 cells were examined by ELISA. Our behavioral results suggested that 7,8-DHF (10 mg/kg, i.p.) exerted rapid-acting antidepressant-like effects in Cort/LPS-treated mice; our immunofluorescence staining results suggested that Cort/LPS reduced the number of NeuN + HT22 cells and increased the number of Iba1 + BV2 microglial cells, which were completely reversed by 7,8-DHF pre-treatment. Our ELISA results suggested that 7,8-DHF significantly normalized the release of synapse-related factors (BDNF, GluA1, and PSD95) in HT22 cells and suppressed the production of inflammatory cytokines (IL-1β, IL-6, and TNF-α) in BV2 microglial cells. Taken together, this study suggested that pharmacologically activating the BDNF/TrkB signaling pathway exerted rapid-acting antidepressant-like effects through improving synaptic plasticity and inhibiting neuroinflammation, which provided new insights for developing next-generation rapid-acting antidepressants.

A novel rearranged C20-diterpenoid alkaloid, carmiseconapline A (1), featuring a unique 10,20:11,12-di-seco-napelline skeleton with a fused 5/6/5/6/7 pentacyclic ring system, was isolated from Aconitum carmichaelii Debeaux. Compound 1 exhibited remarkable antidepressive activity, being twice as potent as fluoxetine (10 mg/kg) at 0.06 mg/kg in mice. Further mechanism studies showed that 1 effectively activated adenosine 5'-monophosphate-activated protein kinase (AMPK), protected HT22 cells from mitochondrial dysfunction, and inhibited apoptosis. These findings suggested 1 as a potential AMPK activator for antidepressant development.

Pain is a multifactorial debilitating condition associated with some psychiatric comorbidities such as generalized anxiety and depression. Concerning pharmacological treatment, which is often inefficient or associated with intense side effects, the physical and social context may be fundamental for patient's health improvement. In this sense, we sought to assess the impact of an enriched environment (EE) on neuropathic pain (NP) and depression comorbid. For this purpose, mice exposed to EE or non-enriched conditions for three weeks were submitted to either a chronic constriction injury (CCI) of the ischiadicus nervus or a sham procedure. After three weeks of EE or non-enriched exposition, allodynia (recorded by von Frey and acetone tests), hyperalgesia (recorded by hot plate test), despair behavioral response (recorded by tail suspension test), and apathy (recorded by sucrose spray test) were evaluated. Mice submitted to CCI procedure showed increased rates of hyperalgesia and allodynia, as well as depression-like behaviors compared to the sham procedure-submitted mice. Exposure to EE significantly increased pain thresholds and significantly diminished depression-related behaviors. These findings suggest that the sensory, physical, and social context can be an extra tool for controlling not only sensory-discriminative pain but also emotional pain-related psychiatric comorbidities, such as depression.

Astragalin (AST) is a flavonoid glycoside commonly found in edible plants and medicinal herbs with a variety of therapeutic effects. This study aimed to investigate whether AST protects the integrity of the blood-brain barrier (BBB) and inhibits neuroinflammation, thereby alleviating depressive-like behaviors. LPS-stimulated cultured cells and LPS-induced BBB disruption and depressive-like behavior mice models were employed. We founded that AST inhibited LPS-induced inflammatory responses in microglial BV2 cells and protected SH-SY5Y cells from inflammatory injury. In mice, AST effectively ameliorated LPS-induced depressive-like behaviors, which was attributed to its ability to maintain BBB integrity and inhibit inflammatory damage caused by LPS invasion. Furthermore, AST suppressed LPS-induced activation of glial cells, protecting neuronal dendritic spines, synapses, and mitochondria from inflammatory damage. It also reduced the elevation of pro-inflammatory factors such as TNF-α, IL-1β, and IL-6, and normalized the aberrant activation of inflammatory signaling pathways, including RIPK1/RIPK3/MLKL and mTOR/NF-κB. In conclusion, AST protects BBB integrity and brain tissue from inflammatory damage, offering new insights for drug development and clinical interventions in systemic inflammatory responses, such as sepsis-induced encephalitis.

Background/Objectives: Chronic stress disrupts neurochemical balance, triggers inflammation, and compromises neuronal integrity, contributing to the development of stress-related disorders. This study aimed to evaluate the preventative effects of Tremella fuciformis Berk (TF) enzymatic extracts on chronic restraint stress (CRS)-induced behavioral, neurochemical, and inflammatory dysfunctions in mice. Methods: Male C57BL/6N mice were administered TF at doses of 50 mg/kg and 100 mg/kg daily via oral gavage for 21 days during CRS exposure. Behavioral assessments, including anxiety and depression-like behavior tests, were conducted. Neurochemical and inflammatory markers were analyzed using PCR and ELISA, while histological examinations of hippocampal regions were performed to assess neuronal integrity. In vitro assays evaluated neuronal cell viability, protection against corticosterone (CORT)-induced cytotoxicity, and inhibition of monoamine oxidase (MAO) activity. Results: TF supplementation alleviated CRS-induced weight loss, normalized serum CORT levels, increased locomotor activity, reduced immobility time, and decreased anxiety-like behaviors. TF upregulated brain-derived neurotrophic factor (BDNF) mRNA, downregulated pro-inflammatory markers (CXCL2, iNOS, IFNG), and mitigated neuronal apoptosis in the hippocampus. In vitro, TF improved neuronal cell viability, protected against CORT-induced cytotoxicity, and significantly inhibited MAO activity, particularly MAO-A. Conclusions: These findings demonstrate the neuroprotective and anti-stress effects of Tremella fuciformis Berk enzymatic extracts, supporting its potential as a natural therapeutic intervention for stress-related disorders.

Imbalance in inhibitory and excitatory neurotransmitters have been reported in tinnitus. Acamprosate modulates the excitatory and inhibitory neurotransmission in the nucleus accumbens (NAc). This study aims to assess the effect of Acamprosate on tinnitus, anxiety, depression, and molecular changes in nucleus accumbens (NAc), in Sodium-Salisylate (S-salicylate) model of tinnitus.

Forty-four adult male wistar rats were used in this study. The study included Control, Saline, and S-salicylate groups during the first week, which then subdivided into five groups as Control, Saline, S-salicylate, Acamprosate, and S-salicylate+Acamprosate. Gap-in Noise (GIN) and pre-pulse inhibition (PPI) were used to assessment of tinnitus at baseline, day7 and day14. Anxiety and depression were evaluated on day 14, by elevated plus maze (EPM), open field (OF), and tail suspension (TST) tests. The protein expression of GABAAR-δ, NR1 and NR2B in NAc were also measured using western blot technique.

After seven days GIN reduced in S-salicylate compare to Control and Saline groups (P < 0.5), while PPI unchanged. After 14 days, GIN reduced in S-salicylate and S-salicylate+Acamprosate groups compare to Control; Saline; and Acamprosate groups (P < 0.5). Additionally, GIN was higher in S-salicylate+Acamprosate compare to S-salicylate group (P < 0.5). PPI was not changed after 14 days. Open arm time in EPM test was decreased in S-salicylate and S-salicylate+Acamprosate groups compare to Control; Saline; and Acamprosate groups (P < 0.5). Central Zone time in OF test was reduced in S-salicylate group compare to Control, Saline, Acamprosate, and S-salicylate+Acamprosate groups (P < 0.5). Immobility Time in TST was increased in S-salicylate group compare to Control, Saline, Acamprosate, and S-salicylate+Acamprosate groups (P < 0.5). GABAAR-δ was decreased in S-salicylate groups compare to Control, Saline, Acamprosate; and S-salicylate+Acamprosate groups (P < 0.5). NR1 and NR2B in NAc were increased in S-salicylate group compare to Control, Saline, Acamprosate, and S-salicylate+Acamprosate groups (P < 0.5).

S-salicylate can induce tinnitus-like behaviors in rat. Furthermore, S-salicylate induced depression/anxiety like behaviors, and changed the expression of GABAR and NMDAR subunits in NAc. Acamprosate partially reversed these changes. In conclusion, NAc may be involved in the pathophysiologic mechanisms of tinnitus.

Golden Syrian hamsters are an often-overlooked model in behavioral testing. While previously utilized for research examining circadian rhythms and mammalian reproduction, they are less common than murine models in both infectious disease and behavioral studies. However, coronavirus disease-19 (COVID-19) quickly pushed hamster modeling to the forefront due to its myriad of advantages over mice in recapitulating human pathology and transmission. At least 10 % of COVID-19 survivors suffer from post-acute sequelae of COVID-19 (PASC), a collection of some 200 sequelae with neurologic sequelae (neuro-PASC) presenting with potentially debilitating symptomology. This presents a clear need for a small animal model that recapitulates human disease with the ability to assess any potential long term neurological changes. We adapted and optimized a panel of behavioral tests from previously accepted murine models utilizing the golden Syrian hamster model for use within biocontainment facilities. Our panel includes grip strength, Porsolt forced swim, and novel object recognition testing to measure muscle fatigue or weakness, depression, and memory loss or cognitive impairment, respectively. Apart from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), this panel of tests is applicable to other pathogens that cause neurologic sequelae, such as Nipah or eastern equine encephalitis viruses, or any other model systems that require the use of hamsters. In this manuscript, we detail the methods for each of these three behavioral tests, how to interpret and analyze the resulting data, and emphasize additional factors for consideration. We also provide baseline data for both male and female golden Syrian hamsters.

Sigma-1 receptors (S1Rs) are widely expressed throughout the central nervous system and modulate neuron intracellular calcium levels, leading to changes in neurotransmitter release and neuronal activity. They also interact with various proteins and signaling pathways, playing a key role in regulating synaptic plasticity in brain areas such as the hippocampus, thereby influencing learning and memory processes. This opens a research avenue to explore S1R modulation as a potential therapeutic target in diseases involving hippocampal synaptic alterations and compromised cognitive processes, such as Alzheimer's disease (AD). Here, we hypothesize that pharmacological activation of S1R could counteract synaptic plasticity deficits and hippocampal-dependent cognitive alterations in an early-stage amyloidosis model of Alzheimer's disease, induced by intracerebroventricular (icv) administration of Aβ1-42 oligomers (oAβ1-42). For that purpose, we investigate ex vivo CA3-CA1 synaptic plasticity, while in vivo, we performed open field habituation and social recognition tasks to assess contextual and social memory, respectively. Our data show that pharmacological activation of S1Rs with the selective agonist PRE-084 counteract oAβ1-42 deleterious effects on CA3-CA1 long-term synaptic plasticity (LTP), and hippocampal-dependent contextual and social memory, without alterations of spontaneous behaviors. Together, these results provide further evidence for the role of S1Rs in ameliorating hippocampal synaptic and contextual memory dysfunctions and introduce novel insight into their involvement in early amyloid-induced social memory deficits, highlighting their potential for developing comprehensive treatments for early AD. Also, the absence of adverse behavioral outcomes associated with PRE-084 treatment suggests a favorable safety profile in preclinical models, supporting its potential as a therapeutic option.

Recent studies have implicated autophagy in both weight regulation and depression. This study aimed to investigate the relationship between stress-induced weight loss and autophagy-related gene expression in a mouse model of depression.

Male C57BL/6 mice were subjected to a chronic immobilization stress (CIS) protocol for 14 days to induce depressive-like behavior. Body weight was measured before and after the CIS, and depressive-like behavior was assessed using the tail suspension test (TST). The expression levels of autophagy-related genes (Atg5, Atg7, Atg12, Becn1, Mmp9, Fkbp5, and Map1lc3b) in the hippocampus and midbrain were evaluated using reverse transcription-quantitative PCR (RT-qPCR). Serum cortisol levels were also measured.

The CIS resulted in significant weight loss and increased immobility time in the TST, indicating depressive-like behavior. Serum cortisol levels were not different between CIS-depression model and control mice. In the hippocampus, the expression levels of Fkbp5, Mmp9, and Map1lc3b were significantly higher in CIS-depression model mice than in control mice. In the midbrain, the expression levels of Fkbp5 and Mmp9 were significantly higher in CIS-depression model mice than in control mice. Increased autophagy-related gene expressions in CIS-depression model mice were consistent with the previous studies in the postmortem brains of patients with depression. A significant negative correlation was also found between Fkbp5 mRNA expression in the hippocampus and the weight change ratio before and after the CIS.

The findings suggest that enhanced autophagy may be related to the pathology of depression and that Fkbp5, an autophagy regulator, mediates stress-induced weight loss.

Jieyu I Formula (JY-I) is an improved version of the classic formula "Sini San" documented in the books Shanghan Lun, which is known for regulating the liver and treating depression. However, the disturbance of neuronal signal transmission in the neural circuit of the brain is closely related to the occurrence of depression, yet its neural mechanism is still unclear.

This study aimed to observe the antidepressant effect of JY-I on depressed mice induced by lipopolysaccharide and its underlying central nervous system mechanisms, focusing on the prefrontal cortex (PFC) to lateral habenular nucleus (LHb) neural circuit in the depressed mice model.

JY-I comprised herbs include Bupleurum chinense, Fructus Aurantii, Paeonia lactiflora, Lotus Seed Heart, Schisandra chinensis, and Hypericum perforatum, which are prepared in a ratio of 2:2:2:2:1:1. The mouse model of depression was induced by lipopolysaccharide. The antidepressant efficacy of JY-I was observed by behavioral tests. Observation of the PFC/LHb neuron activity in mice using in-vivo electrophysiological combined with optogenetic technology. Subsequently, the activity of the LHb neuron was observed using immunofluorescence staining analysis and Western blot. Inject Rabies virus into the LHb brain region and observe the projection of the PFC from upstream brain regions received by the LHb. Using chemogenetic techniques to activate/inhibit the PFC-LHb neural circuit and investigate the effect of JY-I on depression-like behaviors.

Depression-like behaviors in mice can be induced by intraperitoneal administration of lipopolysaccharide, the behavior changes were reversed with the administration of the JY-I. The combination of optogenetics and electrophysiological recording result indicates that JY-I activates glutamate (Glu) neurons in the PFC, thus maintaining an optimal excitatory/inhibitory (E/I) balance and ameliorating depression-like behaviors. Notably, the PFC, a crucial brain area for emotion regulation, exerts its antidepressant effect on downstream LHb region through the activation of Glu neurons.

JY-I can significantly improve lipopolysaccharide-induced depression-like behaviors. JY-I exerts antidepressant effects by activating the PFC Glu neurons projecting to the LHb, revealing a promising therapeutic target for depression.

Optogenetics and chemogenetics are emerging neuromodulation techniques that have attracted significant attention in recent years. These techniques enable the precise control of specific neuronal types and neural circuits, allowing researchers to investigate the cellular mechanisms underlying depression. The advancement in these techniques has significantly contributed to the understanding of the neural circuits involved in depression; when combined with other emerging technologies, they provide novel therapeutic targets and diagnostic tools for the clinical treatment of depression. Additionally, these techniques have provided theoretical support for the development of novel antidepressants. This review primarily focuses on the application of optogenetics and chemogenetics in several brain regions closely associated with depressive-like behaviors in rodent models, such as the ventral tegmental area, nucleus accumbens, prefrontal cortex, hippocampus, dorsal raphe nucleus, and lateral habenula and discusses the potential and challenges of optogenetics and chemogenetics in future research. Furthermore, this review discusses the potential and challenges these techniques pose for future research and describes the current state of research on sonogenetics and odourgenetics developed based on optogenetics and chemogenetics. Specifically, this study aimed to provide reliable insights and directions for future research on the role of optogenetics and chemogenetics in the neural circuits of depressive rodent models.

Throughout millennia, medicinal plants have been crucial in preserving human well-being and enhancing the whole human experience. Mimosa pudica, sometimes referred to as the "sensitive plant," possesses considerable promise in the discovery of innovative herbal remedies. The objective of our research is to examine the various pharmacological uses of this mysterious plant by undertaking a thorough investigation of its methanolic extract. We employed sophisticated laboratory techniques to carefully extract and examine the chemical constituents of M. pudica. This examination uncovered a wide range of advantageous phytochemicals, such as alkaloids, flavonoids, tannins, and saponins. In order to evaluate the neuro-pharmacological effects of the extract, we conducted a comprehensive set of neurobehavioral tests on Swiss Albino mice. These tests included the open field test, light-dark box test, elevated plus maze test, tail suspension test, forced swim test, Y-maze test, hole cross test, and social interaction test. The extract, given at doses of 200 mg/kg and 400 mg/kg body weight, showed notable effects on neurobehavioral parameters, similar to the conventional medications Diazepam and Escitalopram (1 mg/kg body weight). In addition, we conducted in-silico activities on hMAO A and hMAO B receptors by performing molecular docking studies on 11 compounds that were identified using GC-MS analysis. The results of our investigation revealed the chemical properties of M. pudica and emphasized its potential as a substance that can reduce anxiety and depression. It also has effects on memory and learning, which could lead to significant gains in pharmaceutical development and medical progress.

The study investigated the anxiolytic, antidepressant, sedative/hypnotic and in silico molecular docking properties of the synthetic ephedrine-based derivative of thiourea, 3-benzothioyl-1-(3-hydroxy-3-phenyl-3-propyl)-1-methylthiourea. Safety profile of the compound at various doses was determined in an acute toxicity test. Results showed significant anti-anxiety effects of the compound in all mice studies. In the elevated plus maze (EPM), the time spent and entries into open arms were significantly increased upon treatment with the test compound. In the light-dark (LD) box test the drug increased the time spent in the light compartment. In hole board (HB) assay, exploration of hole and rearing significantly increased. For anxiolytic activity, 20 mg/kg was determined to represent the optimal dose, while at a higher dose (i.e., 40 mg/kg), it caused significant sedation and increased sleep duration in thiopental-induced sleep test. Escape latency in the tail suspension test (TST) and in the forced swim test (FST) increased and immobility was significantly reduced upon 3-benzothioyl-1-(3-hydroxy-3-phenyl-3-propyl)-1-methylthiourea administration. The molecular docking analysis was performed against the various protein target involved in the pathogenesis of anxiety. The molecular docking, molecular dynamic (MD) simulation and free energy calculation showed high binding affinity and stability of ligand with the 7VOD and 2C65 protein. Taken together, it is concluded from both the in vivo assays and molecular modeling studies that 3-benzothioyl-1-(3-hydroxy-3-phenyl-3-propyl)-1-methylthiourea possesses significant anxiolytic and antidepressant activity in concomitant with a high safety profile.

The sex difference in depression has long been an unsolved issue. Women are twice as likely to suffer from depression as men. However, there were significant differences in the composition of gut microbiota between women and men. There is a lack of studies linking sex differences in depression to microbiota, and the specific mechanisms of this process have not been explained in detail. The main purpose of this study was to explore the gender differences in the intestinal tract of male and female depressed mice. In this study, chronic restraint stress (CRS) mouse models were used to simulate chronic stress, and behavioral tests were conducted, including the open field test (OFT), tail suspension test (TST) and forced swimming test (FST). Microbial diversity analysis and metabolomics were performed on collected mouse feces. The results showed that female mice were highly active and prone to anxious behavior before stress, and the levels of f-Rikenellaceae, f-Ruminococcaceae and 16α-hydroxyestrone were significantly different from those in male mice. After 21 days (Days) of stress, female mice showed depression-like behavior, and the levels of f-Erysipelotrichaceae, 5α-pregnane-3,20-dione, and 2-hydroxyestradiol were significantly different from those in male mice. After 14 days of stress withdrawal, the depression-like behavior continued to worsen in female mice, and the levels of 5α-pregnane-3,20-dione, estrone glucuronide and f-Erysipelotrichaceae were significantly different from those in male mice. In summary, female mice have stronger stress sensitivity and weaker resilience than male mice, which may be related to differences in bacterial diversity and estrogen metabolism disorders.

Geniposide (GP) and shanzhiside methyl ester (SM) are the two important bioactive compounds in the classical traditional Chinese herbal medicine Yueju Pill, which is currently used as an over-the-counter (OTC) medicine in China. Yueju has been demonstrated with antidepressant-like effects with the prescriptional dose. As GP and SM both have antidepressant potential, the synergism of them could be crucial to the function of Yueju.

The neuropeptide pituitary adenylyl cyclase-activating polypeptide (PACAP) has been implicated in the onset of antidepressant-like response. Here we investigated the synergism of the chronic treatment with GP and SM, at proportional doses to Yueju, on antidepressant-like effects, and underlying mechanism of PACAP-related signaling in a neuroinflammation-based depression model.

Depression-related behaviors were tested in the lipopolysaccharide (LPS)-induced depression model. The molecular signaling of neuroinflammation and neuroplasticity was investigated using Western blot analysis, immunofluorescence and pharmacological inhibition of mTOR signaling.

Chronic treatment of GP and SM (GS) at the dose which is proportional to the prescriptional dose of Yueju synergistically elicited antidepressant-like effects. Chronic treatment of the GS or the conventional antidepressant fluoxetine (FLX) showed antidepressant-like effects in LPS-injected mice. In vitro analysis indicated the synergism of GS on PACAP expression. In the hippocampus of LPS-injected mice, both GS and FLX enhanced PACAP expression, downregulated the inflammatory signaling of Iba-1/NF-кB/IL-1β and NLRP3, and upregulated the neuroplasticity signaling of mTOR-BDNF/PSD95. Additionally, both treatments reduced microglia activation indicated by Iba-1 immunofluorescent staining. Rapamycin, an mTOR inhibitor, blunted the antidepressant-like effects and the upregulation of BDNF expression induced by chronic GS.

The antidepressant-like effects elicited by chronic fluoxetine or by synergistic doses of GS were involved in the upregulation of hippocampal PACAP levels, in association with ameliorated neuroinflammation and neuroplasticity signaling in LPS-injected mice. GS synergism may play a key part in the antidepressant-like effects of the prescriptional dose of Yueju.

Obesity increases the risk of depression. Evidence shows that peripheral inflammation, glycemic dysregulation, and hyperactivity within the hypothalamic-pituitary-adrenal axis are implicated in both obesity and depression. In this study we investigated the impact of visceral adipose tissue (VAT), a crucial characteristic of obesity, on stress susceptibility in obese mice. Age-matched mice were fed with chow diet (CD) or high-fat diet (HFD), respectively, for 12 weeks. CD mice were deprived of VAT and received transplantation of VAT from HFD mice (TransHFD) or CD mice (TransCD). Extracellular vesicles (EVs) were prepared from VAT of CD or HFD mice, and intravenously injected (100 μg, 4 times in 2 weeks) in naïve mice or injected into hippocampus (5 μg, 4 times in 2 weeks) through implanted bilateral cannula. Depression-like behaviors were assessed 14 days after transplantation. We showed that HFD mice exhibited significantly higher body weight gain and impaired insulin and glucose tolerance, accompanied by increased stress susceptibility. Transplantation of VAT or VAT-derived EVs from HFD mice caused synaptic damage and promoted stress susceptibility in recipient mice. Through inhibiting miRNA biogenesis in the VAT and miRNA sequencing analysis, we demonstrated that miR-140-5p was significantly upregulated in both VAT-EVs and hippocampus of HFD mice. Overexpression of hippocampal miR-140-5p in naïve mice not only facilitated acute stress-induced depression-like behaviors, but also decreased hippocampal CREB-BDNF signaling cascade and synaptic plasticity. Conversely, knockdown of miR-140-5p in the VAT, VAT-EVs or hippocampus of HFD mice protected against acute stress, reducing stress susceptibility that were mediated via CREB-BDNF pathway. In summary, VAT-EVs or the cargo miRNAs in obese mice promote synaptic damage and stress susceptibility, providing potential therapeutic targets for metabolism-related affective disorders.

Transient exposure to ketamine can trigger lasting changes in behavior and mood. We found that brief ketamine exposure causes long-term suppression of futility-induced passivity in larval zebrafish, reversing the "giving-up" response that normally occurs when swimming fails to cause forward movement. Whole-brain imaging revealed that ketamine hyperactivates the norepinephrine-astroglia circuit responsible for passivity. After ketamine washout, this circuit exhibits hyposensitivity to futility, leading to long-term increased perseverance. Pharmacological, chemogenetic, and optogenetic manipulations show that norepinephrine and astrocytes are necessary and sufficient for ketamine's long-term perseverance-enhancing aftereffects. In vivo calcium imaging revealed that astrocytes in adult mouse cortex are similarly activated during futility in the tail suspension test and that acute ketamine exposure also induces astrocyte hyperactivation. The cross-species conservation of ketamine's modulation of noradrenergic-astroglial circuits and evidence that plasticity in this pathway can alter the behavioral response to futility hold promise for identifying new strategies to treat affective disorders.

Engineered extracellular vesicles play an increasingly important role in the treatment of spinal cord injury. In order to prepare more effective engineered extracellular vesicles, we biologically modified M2 microglia. Angiopep-2 (Ang2) is an oligopeptide that can target the blood-brain barrier. Through single-cell sequencing and immunofluorescence experiments, we confirmed that the expression of LRP-1, the targeted receptor of Ang2, was elevated after spinal cord injury. Subsequently, we integrated the Ang2 peptide segment into M2 microglia to obtain Ang2-EVs, which could successfully target the site of spinal cord injury. However, in order to improve the function of Ang2-EVs, we pretreated M2 microglia with melatonin, which has anti-inflammatory effects, to obtain M-Ang2-EVs. The results of single-nucleus sequencing of the mouse spinal cord verified that neurons and OPCs gradually transformed into subtypes related to nerve repair functions after treatment with M-Ang2-EVs. This is consistent with the sequencing and enrichment analysis of miRNAs contained in M-Ang2-EVs. We further verified through experiments that M-Ang2-EVs can promote microglia/macrophages to phagocytose sphingomyelin, promote axon remyelination and axon elongation, and maintain the integrity of the blood-spinal barrier. Since Ang2 can also target the blood-brain barrier, we found that M-Ang2-EVs can also reduce brain inflammation that results from spinal cord injury. Our study applied the Angiopep-2 peptide to spinal cord injury to enhance the targeting of injured cells, and successfully construct engineered extracellular vesicles that can target the spinal cord injury site and the brain.

During adolescence, acute stress can modify neuronal excitability in various brain regions, leading to negative behavioral outcomes. However, the impact of chronic stress during adolescence on neuronal responses to acute stimuli remains unclear. To address this, we subjected adolescent mice to 12 days of chronic unpredictable stress (CUS). Anxiety and depressive behaviors were evaluated, along with changes in c-Fos expression, which is one of the most widely used markers of neuronal activation. By comparing c-Fos immunoreactivity between the CUS and control groups both before and after the tail suspension test (TST), we found that adolescent CUS induced depressive behaviors in male mice, but not in female mice. Adolescent CUS primarily affected the excitability of neurons in the infralimbic cortex (IL), the dorsomedial and dorsolateral area of the bed nucleus of the stria terminalis (BNST), and the ventral hippocampus CA3. TST exerted a significant main effect on the density of c-Fos+ neurons in the prelimbic cortex (PL), infralimbic cortex (IL), cingulate areas 1 and 2 (Cg1, Cg2), the lateral septum (LS), BNST, and lateral habenular (LHb). Furthermore, the excitability of neurons in the paraventricular thalamic nucleus (PVT) was impacted by sex. These data suggest that adolescent CUS elicits region- and sex-specific modifications in TST-induced c-Fos expression, establishing a theoretical basis for understanding the pathophysiological alterations in mood disorders following adolescent stress.

Schizophrenia is an esteemed neuropsychiatric condition delineated by the manifestation which role of the N-methyl-D-aspartate receptor (NMDAR) is important. Lutein administration exhibits protective effects via NMDA receptors. Thus, the main goal of this research was to investigate how lutein can possibly act as an antioxidant and provide protection for the brain against schizophrenia-like behaviours in mice. In total, 24 male mice were divided into four experimental groups: control, ketamine (20 mg/kg, i.p), lutein (10 mg/kg, i.p) and a mix of ketamine (20 mg/kg, i.p) and lutein (10 mg/kg, i.p). Lutein was given to the mice for 30 days, while ketamine was given from Days 16 to 30 to create a model of schizophrenia in the animals. After giving drugs, schizophrenia-like behaviours were evaluated with novel object recognition test (NORT), tail suspension test (TST), forced swimming test (FST) and open field tests. Furthermore, the amounts of brain malondialdehyde (MDA), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) were assessed. The findings showed a noteworthy decrease in the crossings during the open field test and increase in immobility duration in the TST and FST as a result of ketamine administration (p < 0.05). Prior administration of lutein showed a decrease in the detrimental effects of ketamine on the open field assay, along with a reduction in immobility duration in the TST and FST experiments (p < 0.05). Administration of ketamine caused a notable reduction in the discrimination index, while pretreatment with lutein was associated with a rise in the discrimination index (p < 0.05). Furthermore, the administration of ketamine significantly increased the levels of MDA in both cortical and subcortical regions, which were then reduced by lutein pretreatment (p < 0.05). Moreover, ketamine use led to a significant decrease in tissue SOD, GPx and CAT levels in both cortical and subcortical brain regions in mice (p < 0.05). Nonetheless, lutein pretreatment significantly enhanced SOD, GPx and CAT levels in cortical and subcortical regions (p < 0.05). These results indicate that lutein may have protective effects on the brain to improve behavioural problems.

Neuroinflammation is an undoubted hallmark of neurodegenerative processes characterized by memory impairment, loss of coordination and muscle strength in diseases such as Alzheimer's disease, Parkinson's disease and multiple sclerosis as well as depressive disorders. Cyclosporine A (CSA) has already been identified as a promising neuroprotective peptide, due to its well-known anti-inflammatory properties. Herein, CSA was encapsulated into α-tocopherol polyethylene glycol 1000 succinate (TPGS) micelles and intranasally administered to a lipopolysaccharide (LPS) induced mouse model of neuroinflammation. After the treatment, mice were subjected to behavioral tests to assess cognitive and motor skills, while the biodistribution of CSA in plasma and olfactory bulb was studied by a new HPLC method validated for precision and accuracy. The results highlighted that in comparison to the classic oral CSA suspension, the intranasal (IN) administration showed significatively better safety and efficiency profiles. Notably, IN administration of CSA micelles showed relevant antidepressive effects and a certain ability to revert LPS-induced motor impairment. This work pointed out that the innovative and noninvasive IN administration of TPGS micelles could represent a safe and effective alternative to the classic oral route to deliver CSA at the Central Nervous System level, where its beneficial activity against neuroinflammation can be exploited.

The interferon (IFN)-induced STAT1 signaling pathway is a canonical immune pathway that has also been implicated in regulating neuronal activity. The pathway is enriched in brains of individuals with autism spectrum disorder (ASD) and schizophrenia (SZ). Over-activation of the STAT1 pathway causes pathological transcriptional responses, however it is unclear how these responses might translate into behavioral phenotypes. We hypothesized that prolonged STAT1 signaling in neurons would be sufficient to cause behavioral deficits associated with neurodevelopmental disorders. In this study, we developed a novel mouse model with the clinical STAT1 gain-of-function mutation, T385M, in neurons. These mice were hyperactive and displayed neural hypoactivity with less neuron counts in the caudate putamen. Driving the STAT1 gain-of-function mutation exclusively in dopaminergic neurons, which project to the caudate putamen of the dorsal striatum, mimicked some hyperactive behaviors without a reduction of neurons. Moreover, we demonstrated that this phenotype is neuron specific, as mice with prolonged STAT1 signaling in all excitatory or inhibitory neurons or in microglia were not hyperactive. Overall, these findings suggest that STAT1 signaling in neurons is a crucial player in regulating striatal neuron activity and aspects of motor behavior.

Depressive disorder is a chronic, recurring, and potentially life-endangering neuropsychiatric disease. According to a report by the World Health Organization, the global population suffering from depression is experiencing a significant annual increase. Despite its prevalence and considerable impact on people, little is known about its pathogenesis. One major reason is the scarcity of reliable animal models due to the absence of consensus on the pathology and etiology of depression. Furthermore, the neural circuit mechanism of depression induced by various factors is particularly complex. Considering the variability in depressive behavior patterns and neurobiological mechanisms among different animal models of depression, a comparison between the neural circuits of depression induced by various factors is essential for its treatment. In this review, we mainly summarize the most widely used behavioral animal models and neural circuits under different triggers of depression, aiming to provide a theoretical basis for depression prevention.

Previous studies have shown that neurons in the Bed Nucleus of the Stria Terminalis (BNST) respond to stress and play a key role in mental health. However, the cellular bases of BNST in adolescent depression remain elusive.

Male C57BL/6 mice were randomly assigned to the control (Ctrl) or chronic unpredictable stress (CUS) groups. The CUS mice, aged 28 days, were subjected to diverse stressors at various times of the day for 12 days. Depression-like behaviors were assessed through the sucrose preference test (SPT) and tail suspension test (TST). Immunostaining was used to investigate the neural activity and subtypes in the brain. A chemogenetic tool was conducted to examine the role of specific neural activity in CUS-induced depression-like behaviors.

CUS led to a significant decrease in preference for sucrose solution in the SPT and increased immobility time in the TST. C-Fos immunostaining showed hyperactivity of the GABAergic neurons within the dorsal BNST (dBNSTGABA). Chemogenetic activation of dBNSTGABA neurons increased depression-like behaviors. Conversely, chemogenetic inhibition of dBNSTGABA neurons led to a decrease in CUS-induced depression.

These results suggest that adolescent CUS induces hyperactivity of dBNSTGABA neurons, subsequently giving rise to depression-like behaviors and that reducing dBNSTGABA neuronal activity might constitute a novel and efficacious therapeutic approach for adolescent depression.

Cordycepin, the main active component of Cordyceps militaris, exhibits various pharmacological activities, including anti-tumor and antioxidant effects. However, its antidepressant effect and the underlying mechanisms remain unclear.

This study aimed to explore the antidepressant effect of cordycepin and elucidate the potential molecular mechanisms.

Chronic unpredictable mild stress (CUMS) rat model was established to assess antidepressant effect of cordycepin. Gas chromatography-mass spectrometry (GC-MS) metabolomics with integrated network pharmacology were used to find differential metabolites in serum, brain, and cerebrospinal fluid of rats and identify potential target by cordycepin. Western blot and Real-time PCR were applied to validate the signaling pathway.

Cordycepin alleviated CUMS-induced depression-like behaviors by weight gain, sucrose preference increment, immobility time reduction, total travelling distance extension and serum corticosterone levels reduction. Metabolomics showed that cordycepin reversed CUMS-induced metabolic disturbances through alanine and TCA cycle metabolism pathways. Network pharmacology identified GSK3β as a potential target. Cordycepin increased protein levels of p-GSK3β, β-catenin and nuclear β-catenin, and enhanced transcription of downstream genes PKM, LDHA, Cyclin D1 and C-myc in brains of CUMS-induced rats.

This study indicated that cordycepin exerted antidepressant effect by modulating GSK3β/β-catenin pathway, suggesting its potential as a candidate agent for depression.

Stretching exercises such as yoga are recommended for cancer survivors to manage symptoms and promote wellbeing in clinical settings. Although other types of exercise (e.g. running) can reduce the growth of tumors in animal models, the role of stretching on tumor growth remains unclear, and the lack of a preclinical self-stretching model has impeded mechanistic studies on health benefits of stretching. We sought to develop a voluntary stretching animal model to address this research gap and apply it to breast cancer research.

Using food, water, and enrichment in the home cage as motivators for stretching, a two-week 24/7 behavior monitoring was conducted in a video-based customizable home-cage behavior tracking system, Noldus PhenoTyper, to promote self-stretching in FVB mice. Subsequently, this model was utilized in a comparative study of voluntary stretching and voluntary running on tumor growth and plasma protein profiles in the MET-1 orthotopic mammary tumor FVB mouse model.

The new voluntary stretching model effectively elicited mouse self-stretching in the custom cage setting in the long-term observation and significantly inhibited tumor growth as effectively as voluntary wheel running. Moreover, plasma proteomic analysis demonstrated that voluntary stretch versus voluntary running distinctly impacted systemic protein profiles, possibly linking to different cellular and molecular mechanisms underlying anti-cancer effects and, potentially, exercise-induced benefits in other health conditions.

Our work provides the first preclinical voluntary stretching model, which may be well suited to breast cancer research and a valuable research tool to facilitate investigations of stretching health benefits across various research fields.

Memory and emotion are especially vulnerable to psychiatric disorders such as post-traumatic stress disorder (PTSD), which is linked to disruptions in serotonin (5-HT) metabolism. Over 90% of the 5-HT precursor tryptophan (Trp) is metabolized via the Trp-kynurenine (KYN) metabolic pathway, which generates a variety of bioactive molecules. Dysregulation of KYN metabolism, particularly low levels of kynurenic acid (KYNA), appears to be linked to neuropsychiatric disorders. The majority of KYNA is produced by the aadat (kat2) gene-encoded mitochondrial kynurenine aminotransferase (KAT) isotype 2. Little is known about the consequences of deleting the KYN enzyme gene.

In CRISPR/Cas9-induced aadat knockout (kat2-/-) mice, we examined the effects on emotion, memory, motor function, Trp and its metabolite levels, enzyme activities in the plasma and urine of 8-week-old males compared to wild-type mice.

Transgenic mice showed more depressive-like behaviors in the forced swim test, but not in the tail suspension, anxiety, or memory tests. They also had fewer center field and corner entries, shorter walking distances, and fewer jumping counts in the open field test. Plasma metabolite levels are generally consistent with those of urine: antioxidant KYNs, 5-hydroxyindoleacetic acid, and indole-3-acetic acid levels were lower; enzyme activities in KATs, kynureninase, and monoamine oxidase/aldehyde dehydrogenase were lower, but kynurenine 3-monooxygenase was higher; and oxidative stress and excitotoxicity indices were higher. Transgenic mice displayed depression-like behavior in a learned helplessness model, emotional indifference, and motor deficits, coupled with a decrease in KYNA, a shift of Trp metabolism toward the KYN-3-hydroxykynurenine pathway, and a partial decrease in the gut microbial Trp-indole pathway metabolite.

This is the first evidence that deleting the aadat gene induces depression-like behaviors uniquely linked to experiences of despair, which appear to be associated with excitatory neurotoxic and oxidative stresses. This may lead to the development of a double-hit preclinical model in despair-based depression, a better understanding of these complex conditions, and more effective therapeutic strategies by elucidating the relationship between Trp metabolism and PTSD pathogenesis.

Schizophrenia (SZ) is a deleterious brain disorder characterised by its heterogeneity and complex symptomatology consisting of positive, negative and cognitive deficits. Current antipsychotic drugs ameliorate the positive symptomatology, but are inefficient in treating the negative symptomatology and cognitive deficits. The neurodevelopmental glutamate hypothesis of SZ has opened new avenues in the development of drugs targeting the glutamatergic system. One of these new therapies involves the positive allosteric modulators (PAMs) of metabotropic glutamate receptors, mainly types 2/3 (mGluR2/3). mGluR2/3 PAMs are selective for the receptor, present high tolerability and can modulate the activity of the receptor for long periods. There is not much research in clinical trials regarding mGluR2/3 PAMs. However, several lines of evidence from animal models have indicated the efficiency of mGluR2/3 PAMs. In this review, focusing on in vivo animal studies, we will specifically discuss the utilization of SZ animal models and the various methods employed to assess animal behaviour before summarising the evidence obtained to date in the field of mGluR2/3 PAMs. By doing so, we aim to deepen our understanding of the underlying mechanisms and the potential efficiency of mGluR2/3 PAMs in treating SZ. Overall, mGluR2/3 PAMs have demonstrated efficiency in attenuating SZ-like behavioural and molecular deficits in animal models and could be useful for the early management of the disorder or to treat specific subsets of patients.

Microglia are progressively activated by inflammation and exhibit phagocytic dysfunction in the pathogenesis of neurodegenerative diseases. Lipid-droplet-accumulating microglia were identified in the aging mouse and human brain; however, little is known about the formation and role of lipid droplets in microglial neuroinflammation of Alzheimer's disease (AD). Here, we report a striking buildup of lipid droplets accumulation in microglia in the 3xTg mouse brain. Moreover, we observed significant upregulation of PKM2 and sterol regulatory element binding protein 1 (SREBP1) levels, which were predominantly localized in microglia of 3xTg mice. PKM2 dimerization was necessary for SREBP1 activation and lipogenesis of lipid droplet-accumulating microglia. RNA sequencing analysis of microglia isolated from 3xTg mice exhibited transcriptomic changes in lipid metabolism, innate inflammation, and phagocytosis dysfunction; these changes were improved with capsaicin-mediated pharmacological activation of TRPV1 via inhibition of PKM2 dimerization and reduction of SREBP1 activation. Lipid droplet-accumulating microglia exhibited increased mitochondrial injury accompanied by impaired mitophagy, which was abrogated upon of TRPV1 activation. Capsaicin also rescued neuronal loss, tau pathology, and memory impairment in 3xTg mice. Our study suggests that TRPV1-PKM2-SREBP1 axis regulation of microglia lipid metabolism could be a therapeutic approach to alleviate the consequences of AD.

Kratom (Mitragyna speciosa, Korth.) is a tropical tree that is indigenous to Southeast Asia. When ingested, kratom leaves or decoctions from the leaves have been reported to produce complex stimulant and opioid-like effects. For generations native populations in Southeast Asia have used kratom products to stave off fatigue, improve mood, alleviate pain and manage symptoms of opioid withdrawal. Over the past 15-20 years, kratom use has spread to Western nations including the United States, where many individuals are using kratom products for the self-management of pain, opioid use disorder, anxiety and depression. The increased use of kratom has triggered a surge in research into the biochemistry, pharmacology and behavioral effects of kratom and its active constituents, especially mitragynine and 7-hydroxymitragynine. In this review, we highlight some of the recent animal studies showing that kratom and its constituent compounds have potential beneficial effects in animal models of pain, anxiety, depression and opioid dependence. We also highlight studies showing that kratom can modulate the functioning of opioid, noradrenergic, serotonergic and dopaminergic systems. The highlighted studies strongly suggest that kratom and its constituents may form the basis for the development of novel therapeutic agents.