Depressive-like Phenotype Research Articles

Bibliometric analysis of research hotspots and trends on the relationship between the gut microbiota and depression from 2020 to 2024

IntroductionIn recent years, an increasing body of research has illustrated a strong correlation between gut microbiota and depression. However, there has yet to be a comprehensive discussion or summary of the latest advancements and trends in this field.MethodsWe retrieved research articles focused on gut microbiota and depression through the WOS database from 2020 to 2024, using visual text analysis tools such as CiteSpace and VOSviewer.ResultsThe literature on the relationship between gut microbiota and depression surged from 396 papers in 2020 to 711 by 2024. During this period, the journal with the highest publication rate was Nutrients. China led the countries in contributions, while University College Cork topped the institutions. Kenji Hashimoto emerged as the most prolific author. The most cited paper was authored by Cryan JF et al., published in 2019 in Physiol Rev. The keywords “gut microbiota,” “depression,” and “anxiety” appeared most frequently, while recent years saw explosive increases in terms such as “growth performance,” “receptors,” “depression-like phenotypes,” “stress response,” “gastrointestinal symptoms,” “reliability,” and “neurogenesis.”DiscussionOur article displayed the overview of the relationship between the gut microbiome and depression from 2020 to 2024 using bibliometric methods, providing perspectives and research hotspots for studies exploring the correlation between the gut microbiome and depression.

Dietary Intervention with Omega-3 Fatty Acids Mitigates Maternal High-Fat Diet-Induced Behavioral and Myelin-Related Alterations in Adult Offspring.

Maternal high-fat diet (HFD) during pregnancy and lactation induces depression- like phenotype and provokes myelin-related changes in rat offspring in the prefrontal cortex (PFCTX), which persist even to adulthood. Due to the plasticity of the developing brain, it was decided to analyze whether depressionlike phenotype and myelin-related changes in the early lifetime induced by maternal HFD (60% energy from fat) could be reversed by the omega-3 fatty acid-enriched diet (Ω3D) given from the postweaning period until adulthood (63rd day of life) in offspring. We analyzed the effect of post-weaning Ω3D on the depressive-like phenotype (assessed by the forced swimming test) and myelin-related changes (measured using RT-qPCR, ELISA, and immunofluorescence staining) in the PFCTX of adult offspring. Ω3D reversed increased immobility time in adult offspring induced by maternal HFD, without affecting the animals' locomotor activity. Molecularly, Ω3D normalized the reduced expression levels of myelin-oligodendrocyte glycoprotein (MOG), as well as myelin and lymphocyte protein (MAL) in males and MOG in females in the PFCTX, changes initially induced by maternal HFD. Additionally, Ω3D normalized the quantity of oligodendrocyte precursor cells and mature oligodendrocytes in the prelimbic, infralimbic, and cingulate cortex in males, which were reduced following maternal HFD exposure. In females, the Ω3D effect was less pronounced, with normalization of oligodendrocyte precursors occurring only in the infralimbic cortex. These findings suggest that Ω3D may play a significant role in correcting behavioral and neurobiological changes caused by adverse prenatal conditions.

Probiotics by Modulating Gut-Brain Axis Together With Brivaracetam Mitigate Seizure Progression, Behavioral Incongruities, and Prevented Neurodegeneration in Pentylenetetrazole-Kindled Mice.

The microbiota-gut-brain axis (MGBA) is a central nexus that integrates higher cognitive and emotional centers of the central nervous system (CNS) within the intricate functioning of the intestine. Accumulating evidence suggests that dysbiosis in the taxonomic diversity of gut flora plays a salient role in the progression of epilepsy and comorbid secondary complications. In the current study, we investigated the impact of long-term oral bacteriotherapy (probiotics; 10 mL/kg; 109 colony-forming unit/ml) as an adjunctive treatment intervention with brivaracetam (BRV; 10 mg/kg) over 21 days on pentylenetetrazole (PTZ) induced augmented epileptic response and associated electrographical and behavioral perturbations in mice. Moreover, we also unveiled antioxidant capacity and histopathologic changes in treated versus non-treated animals. Results revealed combination increases seizure threshold and prevented high ictal spiking. Additionally, it alleviated PTZ-induced neuropsychiatric disturbances such as anxiety and depressive-like phenotype along with cognitive deficits. Furthermore, dual therapy prompted physiological oxidant/antioxidant balance as evidenced by increased activity of antioxidant enzymes (SOD and catalase) and reduced levels of oxidative stressor (MDA). This therapeutic intervention with commensal species suppressed network-driven neuroinflammation and preserved normal cytoarchitecture with intact morphology in the pyramidal layers of cornu ammonis (CA1 and CA3). Our study provides supporting evidence for the use of probiotics as adjunctive therapy with anti-seizure medications to modulate epileptogenic processes and related multimorbidities, particularly in individuals with drug-resistant seizures.

Extracellular signal-regulated protein kinase-2 signaling in the nucleus accumbens facilitates stress-susceptibility and cocaine reinstatement.

BackgroundSecond messenger signaling within the mesolimbic reward circuit plays a key role in the negative effects of stress and the underlying mechanisms that promote drug abuse. Since the nucleus accumbens (NAc) integrates reward valence, we investigated how extracellular signal-regulated protein kinase-2 (ERK2) signaling affects the development of stress-related comorbidities, including negative affect and drug sensitivity. MethodsWe assessed how chronic unpredictable stress (CUS) influenced the phosphorylation of ERK2-signaling proteins within the NAc of male Sprague Dawley rats. Using a herpes-simplex virus, we either upregulated or downregulated NAc ERK2 activation and evaluated behavioral responses to stress-eliciting stimuli (elevated plus maze, open field, forced-swim test) and cocaine-seeking behavior (conditioned place preference, self-administration). We also examined ERK2-mediated modifications in spine morphology of medium spiny neurons (MSNs) within the NAc. ResultsCUS increased the phosphorylation of ERK2-signaling proteins within the NAc. Viral-mediated activation of NAc ERK2 enhanced susceptibility to both depression- and anxiety-related stimuli and increased cocaine-seeking behavior (conditioned place preference and reinstatement). These behavioral changes were associated with an increase in stubby and mushroom spines of NAc MSNs. Conversely, downregulation of ERK2 activation attenuated affect-related behavioral responses in the forced swim test and blunted cocaine’s rewarding effects, without influencing NAc spine morphology. ConclusionsNAc ERK2 contributes to stress-induced behavioral deficits, including anxiety- and depression-like phenotypes, while promoting cocaine-seeking behavior. These findings suggest that ERK2 signaling in the NAc plays a role in the comorbidity of these related syndromes.

Conceptualization and standardization of a non-invasive closed head injury model using directed shockwave to mice

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, with closed head injury (CHI) being one of the most common forms of TBI. Preclinical modeling of TBI is challenging due to confounding factors like craniectomy and poorly controlled injury severity. This study proposes a non-invasive CHI model using directed shockwaves. The mice heads were exposed to the shockwave and accommodated together following the implantation of RFID tags for automated neurocognitive assessment. Following a 13-day paradigm, mice underwent a digital gait analysis and subsequent classical behavioral test paradigms for affective, cognitive, and locomotor functions. Qualitative and quantitative histopathological assessment was carried out for shockwave pulses-dependent changes in terms of lesion volume, neuronal death, dendritic complexity, and spine density. Studies showed shockwave pulses-dependent differences in survivability, righting reflex, neural damage, and death. Shockwave-exposed mice showed significantly impaired learning and cognitive flexibility. Interestingly, exposed mice showed locomotor hyperactivity and risk-taking behavior (lack of anxiety) along with depression-like phenotypes. Our result suggests that the shockwave-based CHI models result in the clinically relevant phenotype and are precisely controlled for reproducibility.

SARM1 Deficiency Induced Depressive-like Behavior via AMPKα/p-eEF2 axis to Synapse Dysfunction

Sterile Alpha and TIR Motif Containing 1 (SARM1) are proteins implicated in various neurological processes; however, their role in depression remains unexplored. This study investigated the contribution of SARM1 to depressive-like behaviors in a chronic stress-induced depression model and SARM1 knockout (KO) mice. Depressive-like behaviors were assessed using a battery of behavioral tests, including the Open Field Test (OFT), the Forced Swim Test (FST), the Sucrose Preference Test (SPT), and the Tail Suspension Test (TST). Mitochondrial energy metabolism alteration, cytokine level changes, and other related molecular signalling protein expression were evaluated using ELISA and western blotting techniques to investigate the underlying mechanisms. Behavioral assessments (OFT, FST, SPT, TST) revealed depressive-like phenotypes in SARM1 KO mice, accompanied by altered mitochondrial energy metabolism (NAD+, ATP) in the cortex. Intriguingly, SARM1 depletion led to peripheral inflammation, as evidenced by elevated cytokine levels in plasma but not in brain regions (cortex). In addition, we found dysregulated energy metabolism, AMPK signaling, and synaptic plasticity in the cortex of SARM1 KO mice. Notably, AICAR (Acadesine), an AMPK activator, ameliorated depressive-like behaviors and synaptic dysfunction, while Compound C, an AMPK inhibitor, reversed these effects. Additionally, NH125, an eEF2 kinase inhibitor, improved depressive-like behaviors in SARM1 KO mice. These findings demonstrate that SARM1 is critical in regulating depressive-like behaviours through the AMPKα/p-eEF2 signalling pathway. Targeting AMPK signaling and synaptic function may offer novel therapeutic avenues for depression.

Gut microbiota dysbiosis-mediated ceramides elevation contributes to corticosterone-induced depression by impairing mitochondrial function

The role of gut microbiota (GM) dysbiosis in the pathogenesis of depression has received widespread attention, but the mechanism remains elusive. Corticosterone (CORT)-treated mice showed depression-like behaviors, reduced hippocampal neurogenesis, and altered composition of the GM. Fecal microbial transplantation from CORT-treated mice transferred depression-like phenotypes and their dominant GM to the recipients. Fecal metabolic profiling exposed remarkable increase of gut ceramides in CORT-treated and recipient mice. Oral gavage with Bifidobacterium pseudolongum and Lactobacillus reuteri could induce elevations of gut ceramides in mice. Ceramides-treated mice showed depressive-like phenotypes, significant downregulation of oxidative phosphorylation-associated genes, and hippocampal mitochondrial dysfunction. Our study demonstrated a link between chronic exposure to CORT and its impact on GM composition, which induces ceramides accumulation, ultimately leading to hippocampal mitochondrial dysfunction. This cascade of events plays a critical role in reducing adult hippocampal neurogenesis and is strongly associated with the development of depression-like behaviors.

QRFP and GPR103 in the paraventricular nucleus play a role in chronic stress-induced depressive-like symptomatology by enhancing the hypothalamic-pituitary-adrenal axis

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis during chronic stress is essential for depression neurobiology. As the latest member of the RFamide peptide family in mammals, pyroglutamylated RFamide peptide (QRFP) is closely implicated in neuroendocrine maintenance by activating G-protein-coupled receptor 103 (GPR103). We hypothesized that QRFP and GPR103 might contribute to chronic stress-induced depression by promoting corticotropin-releasing hormone (CRH) release from neurons in the paraventricular nucleus (PVN), and various methods were employed in this study, with male C57BL/6J mice adopted as the experimental subjects. Chronic stress induced not only depression-like behaviors but also significant enhancement in QRFP and GPR103 in the PVN. Genetic overexpression of QRFP/GPR103 and stereotactic infusion of QRFP-26/QRFP-43 peptide in the PVN all mimicked chronic stress that induced various depression-like phenotypes in naïve mice, and this was mediated by promoting CRH biosynthesis and HPA activity. In contrast, genetic knockdown of QRFP/GPR103 in the PVN produced notable antidepressant-like effects in mice exposed to chronic stress. Furthermore, genetic knockout of QRFP also protected against chronic stress in mice. In addition, both the C-terminal biological region of QRFP and the downstream PKA/PKC-CREB signaling coupled to GPR103 stimulation underlie the role of QRFP and GPR103 in depression. Collectively, QRFP and GPR103 in PVN neurons could be viable targets for novel antidepressants.

Follicle-stimulating hormone induces depression-like phenotype by affecting synaptic function.

Depression is one of the most common affective disorders in people's life. Women are susceptibility to depression during puberty, peripartum and menopause transition, when they are suffering from sex hormone fluctuation. A lot of studies have demonstrated the neuroprotective effect of estrogen on depression in women, however, the effect of FSH on depression is unclear. In this study, we investigated the role of FSH on depression in mice. Our study demonstrated that FSH induced depression-like behaviors in mice in a dose-dependent manner. This induction was associated with elevated levels of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α in both serum and hippocampal tissues. Additionally, FSH treatment resulted in impaired synaptic plasticity and a reduction in the expression of key synaptic proteins. It is noteworthy that the depression-like behaviors, inflammatory cytokines expression and synaptic plasticity impairment induced by FSH could be alleviated by knocking down the expression of FSH receptor (FSHR) in the hippocampus of the mice. Therefore, our findings reveal that FSH may play an important role in the pathogenesis of depression and targeting FSH may be a potential therapeutic strategy for depression during hormone fluctuation in women.

Understanding the Antidepressant Mechanisms of Acupuncture: Targeting Hippocampal Neuroinflammation, Oxidative Stress, Neuroplasticity, and Apoptosis in CUMS Rats.

Depression is recognized globally as one of the most intractable diseases, and its complexity and diversity make treatment extremely challenging. Acupuncture has demonstrated beneficial effects in various psychiatric disorders. However, the underlying mechanisms of acupuncture's antidepressant action, particularly in depression, remain elusive. Therefore, this study aimed to investigate the effects of acupuncture on chronic unpredictability stress (CUMS)-induced depressive symptoms in rats and to further elucidate its underlying molecular mechanisms. All rats were exposed to CUMS of two stressors every day for 28 days, except for the control group. One hour before CUMS, rats were given a treatment with acupuncture, electroacupuncture, sham-acupuncture, or fluoxetine (2.1 mg/kg). Behavioral tests and biological detection methods were conducted in sequence to evaluate depression-like phenotype in rats. The findings of this study demonstrate that acupuncture therapy effectively ameliorated depression-like behavior induced by CUMS in rats. Additionally, acupuncture exerted a restorative effect on the alterations induced by CUMS in the levels of malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), cyclic AMP response element-binding protein (CREB), postsynaptic density95 (PSD95), gamma-aminobutyric acid (GABA), and acetylcholine (ACh). Additionally, our findings indicate that acupuncture also modulates the ERK and Caspase-3 apoptotic pathways in the hippocampus of CUMS rats. This study suggests that acupuncture may play a potential preventive role by regulating hippocampal neuroinflammatory response, levels of oxidative stress, apoptotic processes, and enhancing synaptic plasticity.

Quercetin ameliorates depressive-like phenotypes and memory deficits in hypoxia-induced murine model of stress

BackgroundHypoxia is believed to induce a form of stress that contributes to the exacerbation of certain disease conditions such as heart diseases. Most of these conditions revolve around the central nervous system (CNS) since the brain consumes a significant percentage of oxygen. PurposeThis study aims to determine the specific effect of hypoxia on mood and cognitive behaviours using behavioural assessment and histological methods in mice. Additionally, this study investigated the counter effect of quercetin (QCN) on the hypoxia-induced changes. MethodsA total of thirty (30) mice were equally divided into five (5) groups. Group 1 and 2 received 5 % DMSO while only the latter was subjected to the hypoxia protocol. Groups 3–5 received graded doses of quercetin (10, 20 and 40 mg/kg), respectively. Approximately 24 h after a consecutive seven-day treatment, the mice were tested for depressive-like symptoms as well as dysfunctional memory function using recognized pharmacological tests. Afterwards, histology of specific brain regions was conducted. Finally, the data were analysed by one-way ANOVA and statistical significance was set at p<0.05. ResultsIn comparison with the normal control, mice of the model control group scored significantly (p<0.05) higher in the tests that assess depression and significantly (p<0.05) lower in the tests that assessed memory function, both indicators of adverse effects of hypoxia. Also, the contributing brain regions were also negatively affected by hypoxia. However, a significant attenuation of these effects was observed in the groups that received quercetin. ConclusionIn conclusion, quercetin is a nutritional flavonoid that possesses the ability to improve behaviour and cognition in individuals regularly exposed to hypoxia or suffering from conditions that affect oxygen delivery within the body.

The Car1 Knockout Mice Exhibit Antidepressant-like Behaviors Accompanied with Gut Microbiota Disturbance.

Major depressive disorder (MDD) is a severe mental disorder with largely unknown mechanisms. Carbonic anhydrases convert CO2 to carbonates and protons, playing roles in various brain functions. Carbonic anhydrase 1 (Car1) is particularly abundant and may be linked to microbiota at interstitial sites. We developed Car1-deficient mice to explore the relationship between depression-like behaviors and gut microbiota. Behavioral tests confirmed depression-like behavior in Car1-/- mice. Fecal samples from Car1-/- and WT mice were collected, and 16S rRNA gene sequencing identified distinct microbiota components between the groups. Car1-/- mice exhibited significantly increased immobility in the tail suspension test (TST) compared to WT mice. The gut microbiota composition differed at the phylum level in p_Bacteroidetes, p_Verrucomicrobia, p_Firmicutes, and p_Tenericutes. At the family level, Car1-/- mice had significantly different abundances in eight microbiota groups compared to WT mice. Car1 deficiency is associated with depressive-like behavior and gut microbiota dysbiosis, potentially linked to depressive-like phenotypes.

Ketamine reverses chronic corticosterone-induced behavioral deficits and hippocampal synaptic dysfunction by regulating eIF4E/BDNF signaling

Major depressive disorder (MDD) is a debilitating illness with a high global burden. While Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, offers rapid-acting antidepressant effects, its mechanism remains incompletely understood. Recent research suggests that dysregulation of mRNA translation via the Eukaryotic initiation factor 4E (eIF4E) pathway might contribute to depression pathophysiology. This study investigates whether Ketamine modulates eIF4E signaling in the hippocampus during its antidepressant action. Herein, adult male mice were exposed to Corticosterone, a well-established model for anxiety and depression, followed by behavioral testing and biochemical analysis. Corticosterone induced depression-like symptoms and disrupted synaptic function, including reduced TrkB/BDNF and eIF4E/MNK1/p-eIF2α/ubiquitin signaling. Ketamine treatment reversed these deficits. Notably, the eIF4E/MNK1 signaling inhibitor, eFT508, blocked Ketamine's antidepressant effect, leading to a return of depression-like phenotype and impaired synaptic signaling. Importantly, these effects were reversed by 7,8-DHF, a BDNF/TrkB signaling agonist. Mice treated with Corticosterone, Ketamine, and eFT508 and subsequently exposed to 7,8-DHF displayed normalized depression-like behaviors and restored synaptic signaling, including increased eIF4E phosphorylation and MNK1 expression. Besides, 7,8-DHF treatment enhanced p-eIF2α levels compared to the eFT508-treated group. These findings suggest that Ketamine exerts its antidepressant action through the regulation of the eIF4E/BDNF signaling pathway in the hippocampus. This study provides novel insights into the molecular mechanisms underlying Ketamine's therapeutic effects and highlights the potential of targeting this pathway for future MDD treatment strategies.

Antidepressive synergism between crocin and D-AP5 in acute restraint-stressed mice.

Emerging evidence suggests that crocin rescues stress-induced depressive symptoms in mice via stimulation of hippocampal neurogenesis. Glutamate modulators mainly involving N-methyl- d -aspartate (NMDA) receptors (NMDARs) have highlighted a role in neural development, synaptic plasticity, and depression. The research presented here was designed to appraise the interaction between NMDAR agents and crocin on depressive-related behaviors in the NMRI male mice exposed to acute restraint stress (ARS) for a period of 4 h. The mice were submitted to the splash test, forced swimming test, and tail suspension test to evaluate depressive-like behavior. The ARS decreased the grooming duration in the splash test and increased immobility time in the forced swimming test and tail suspension test, suggesting a depressive-like phenotype. NMDA (0.25 and 0.5 μg/mouse, intracerebroventricular) did not alter depression-related profiles in both non-acute restraint stress (NARS) and ARS mice, while the same doses of NMDAR antagonist D-AP5 potentiated the antidepressive-like activities in the ARS mice compared with the NARS mice. Moreover, a low dose of NMDA did not change depression-related parameters in the crocin-treated NARS or ARS mice, while D-AP5 enhanced the crocin response in the NARS and ARS mice. Isobologram analysis noted a synergism between crocin and D-AP5 on antidepressive-like behavior in the NARS and ARS mice. Collectively, the combination of crocin and D-AP5 was shown to mitigate depression symptoms and can be potentially used for the treatment of depression disorders.

Neurokinin-1 receptors in the nucleus accumbens shell influence sensitivity to social defeat stress and stress-induced alcohol consumption in male mice

Chronic social defeat stress (SDS) is a widely employed preclinical model of depression involving repeated exposure to physical defeats using a resident-intruder model in male mice. Exposure to SDS induces depressive-like phenotypes including anhedonia, social withdrawal, and increased drug and alcohol consumption. Previously, we found that expression of the neurokinin-1 receptor (NK1R) is increased in the nucleus accumbens (NAC) of mice that are sensitive to this stressor and increase their alcohol intake. The NK1R is the endogenous receptor for the neuropeptide substance P (SP) and plays a prominent role in stress, anxiety, and addiction. In the present study, we assessed changes in NK1R protein levels in the NAC shell and implemented viral vector strategies to demonstrate a functional role of the NK1R in sensitivity to SDS. Specifically, we found that NK1R protein levels were increased in the NAC shell following SDS exposure. Next, we found that NK1R overexpression in the NAC shell increased the sensitivity to SDS and stress-induced alcohol consumption. Together, these experiments provide evidence for a role of the NK1R in the NAC shell in the sensitivity to SDS and the subsequent escalation in alcohol intake.

Is anxiety and depression transmissible? Depressed mother rats transmit anxiety- and depression-like phenotypes to cohabited rat pups through gut microbiota assimilation

ObjectiveThis study is to investigate the role of gut microbiota transmission in the development of anxiety/depression in offspring exposed to maternal depression. MethodOffspring rats were cohabitated with their depressed mother or father rats (which exposed to chronic unpredictable mild stress (CUMS)) for 2, 4, and 6 months, the anxiety- and depression-like behaviors, and interaction/caring activities between mother/father and their pups were detected. The gut microbiota composition and its relationship with behaviors were analyzed. Fecal microbiota transplantation (FMT) was performed to establish the gut microbiota of depressed/normal mother rats in the offspring rats to further confirm the role of “depressive gut microbiota” transmission in mediating the anxiety/depression in the pups. ResultsAnxiety and depression phenotypes can be transmitted from depressed mother rats to their cohabited offspring. Frequent interactions and gut microbiota assimilation were observed between rat mothers and their pups. Remodeling of the gut microbiota in pups by FMT could induce or attenuate anxiety- and depression-like phenotypes depending on the origin of the fecal microbiota. By comparison, the pups cohabiting with depressed father rats exhibited milder anxiety and depression. ConclusionsThese data together support that depressed mothers can transmit anxiety/depression to their pups through gut microbiota assimilation, which is related to frequent interactions. Our study reinforces the significance of mental health of mothers in preventing the occurrence of childhood anxiety and depression, and pointing out the possibility of remodeling intestinal microbiota as an effective therapeutic approach for treating anxiety/depression in children.

Prefrontal cortex molecular clock modulates development of depression-like phenotype and rapid antidepressant response in mice

Depression is associated with dysregulated circadian rhythms, but the role of intrinsic clocks in mood-controlling brain regions remains poorly understood. We found increased circadian negative loop and decreased positive clock regulators expression in the medial prefrontal cortex (mPFC) of a mouse model of depression, and a subsequent clock countermodulation by the rapid antidepressant ketamine. Selective Bmal1KO in CaMK2a excitatory neurons revealed that the functional mPFC clock is an essential factor for the development of a depression-like phenotype and ketamine effects. Per2 silencing in mPFC produced antidepressant-like effects, while REV-ERB agonism enhanced the depression-like phenotype and suppressed ketamine action. Pharmacological potentiation of clock positive modulator ROR elicited antidepressant-like effects, upregulating plasticity protein Homer1a, synaptic AMPA receptors expression and plasticity-related slow wave activity specifically in the mPFC. Our data demonstrate a critical role for mPFC molecular clock in regulating depression-like behavior and the therapeutic potential of clock pharmacological manipulations influencing glutamatergic-dependent plasticity.

Low Dose Lipopolysaccharide-Induced Depressive-Like Phenotype is Mediated by Proinflammatory Cytokines in Mice and Role of Ketamine

Low Dose Lipopolysaccharide-Induced Depressive-Like Phenotype is Mediated by Proinflammatory Cytokines in Mice and Role of Ketamine

Effect of RANKL on Lower Depressive Symptoms In Hemodialysis Patients.

Depression and osteoporosis are common diseases in dialysis patients. In addition, patients with osteoporosis are more susceptible to depression. Contrary to previous anti-osteoporosis agents, denosumab and romosozumab could be used in dialysis patients and have similar action mechanisms for blocking RANKL. RANKL causes bone resorption after binding RANKL, but binding with OPG leads to suppress of bone resorption. In recent mice study, inhibition of RANKL with denosumab improved depressive-like phenotype. Besides, it was found that OPG was associated with depression. Therefore, this study aimed to investigate the association of depressive symptoms with RANKL and OPG in hemodialysis patients. We conducted a cross-sectional study with a total of 172 hemodialysis patients. The participants were measured for plasma RANKL, OPG, MMP-2, and MMP-9 levels. Logistic regression analysis was performed to evaluate the effect of RANKL and OPG on the presence of depressive symptoms. The depressive symptoms were observed in 90 (52.3%) subjects. RANKL tertile 3 had negative association with BDI score (β - 4.527, 95% CI - 8.310 to - 0.743) in univariate analysis, and this association persisted even after multivariate adjustments (β - 5.603, 95% CI - 9.715 to -1.491) in linear regression. In logistic regression between RANKL tertiles and depressive symptoms, RANKL tertile 3 had significantly lower unadjusted OR (0.40, 95% CI 0.19-0.86), and multivariate-adjusted OR (0.31, 95% CI 0.12-0.82) for depressive symptoms. OPG was not significantly associated with depressive symptoms. Higher plasma RANKL concentrations were significantly associated with lower depressive symptoms in HD patients.Trial registration WHO registry, No. KCT0003281, date: January 12, 2017.

Reversing anxiety by targeting a stress-responsive signaling pathway

Current treatments of anxiety and depressive disorders are plagued by considerable side effects and limited efficacies, underscoring the need for additional molecular targets that can be leveraged to improve medications. Here, we have identified a molecular cascade triggered by chronic stress that exacerbates anxiety- and depressive-like behaviors. Specifically, chronic stress enhances Src kinase activity and tyrosine phosphorylation of calmodulin, which diminishes MyosinVa (MyoVa) interaction with Neuroligin2 (NL2), resulting in decreased inhibitory transmission and heightened anxiety-like behaviors. Importantly, pharmacological inhibition of Src reinstates inhibitory synaptic deficits and effectively reverses heightened anxiety-like behaviors in chronically stressed mice, a process requiring the MyoVa-NL2 interaction. These data demonstrate the reversibility of anxiety- and depressive-like phenotypes at both molecular and behavioral levels and uncover a therapeutic target for anxiety and depressive disorders.