Depression-related Behaviors Research Articles

Baihe Extracts Reduce the Activation and Apoptosis of Microglia in the Hippocampus of Mice with Depression-like Behaviors by Downregulating MYC.

The purpose of our investigation is to identify the potential effects and key molecular targets of Baihe extracts in depression treatment. Network meta-analysis was applied for the synthesis of efficacy outcomes of fluoxetine and three traditional Chinese medicine Baihe prescriptions in depression. Depression-related target genes were screened using "GeneCards" database and "Comparative Toxicogenomics Database (CTD)". The major active components and targets of Baihe were screened using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. The identified depression-related genes and the target genes of Baihe were intersected, an interaction network was constructed using the "String" database, and key target genes were determined based on their degree value. Functional enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) profiles was performed using the "ClusterProfiler" R package. A mouse model with depression-like behaviors was constructed to verify the putative roles of the in silico identified key genes. Microglia were isolated from the mouse hippocampus, and the effects of Baihe extract-containing serum on microglia activation and apoptosis by targeting the key genes were examined in vitro. The meta-analysis results revealed no obvious differences in depression treatment efficacy between fluoxetine and the three Baihe prescriptions, suggesting Baihe extracts as a safe and effective alternative treatment for depression. Using network pharmacology and bioinformatics analysis, Baihe extracts were found to modulate depression by regulating 15 key genes, with MYC as the key gene. Subsequent animal experiments demonstrated that Baihe extracts reduced depression-related behavior, microglial activation, and inflammatory mediator release in mice by inhibiting MYC. Serum containing Baihe extracts could inhibit the activation of microglia and the release of inflammatory mediators by downregulating MYC. In summary, Baihe extracts were found to diminish MYC expression to reduce microglial activation and inflammatory factor release, thereby exerting antidepressant effects.

Behavioral and Neuroanatomical Consequences of Cell-Type Specific Loss of Dopamine D2 Receptors in the Mouse Cerebral Cortex

Developmental dysregulation of dopamine D2 receptors (D2Rs) alters neuronal migration, differentiation, and behavior and contributes to the psychopathology of neurological and psychiatric disorders. The current study is aimed at identifying how cell-specific loss of D2Rs in the cerebral cortex may impact neurobehavioral and cellular development, in order to better understand the roles of this receptor in cortical circuit formation and brain disorders. We deleted D2R from developing cortical GABAergic interneurons (Nkx2.1-Cre) or from developing telencephalic glutamatergic neurons (Emx1-Cre). Conditional knockouts (cKO) from both lines, Drd2fl/fl, Nkx2.1-Cre+ (referred to as GABA-D2R-cKO mice) or Drd2fl/fl, Emx1-Cre+ (referred to as Glu-D2R-cKO mice), exhibited no differences in simple tests of anxiety-related or depression-related behaviors, or spatial or nonspatial working memory. Both GABA-D2R-cKO and Glu-D2R-cKO mice also had normal basal locomotor activity, but GABA-D2R-cKO mice expressed blunted locomotor responses to the psychotomimetic drug MK-801. GABA-D2R-cKO mice exhibited improved motor coordination on a rotarod whereas Glu-D2R-cKO mice were normal. GABA-D2R-cKO mice also exhibited spatial learning deficits without changes in reversal learning on a Barnes maze. At the cellular level, we observed an increase in PV+ cells in the frontal cortex of GABA-D2R-cKO mice and no noticeable changes in Glu-D2R-cKO mice. These data point toward unique and distinct roles for D2Rs within excitatory and inhibitory neurons in the regulation of behavior and interneuron development, and suggest that location-biased D2R pharmacology may be clinically advantageous to achieve higher efficacy and help avoid unwanted effects.

Acute and chronic effects of oral administration of a medium-chain fatty acid, capric acid, on locomotor activity and anxiety-like and depression-related behaviors in adult male C57BL/6J mice.

AimCapric acid (also known as decanoic acid or C10) is one of the fatty acids in the medium‐chain triglycerides (MCTs) commonly found in dietary fats. Although dietary treatment with MCTs is recently of great interest for the potential therapeutic effects on neuropsychiatric disorders, the effects of oral administration of C10 on behavior remain to be examined. This study investigated acute and chronic effects of oral administration of C10 on locomotor activity and anxiety‐like and depression‐related behaviors in adult male C57BL/6J mice.MethodsTo explore the acute effects of C10 administration, mice were subjected to a series of behavioral tests in the following order: light/dark transition, open field, elevated plus maze, Porsolt forced swim, and tail suspension tests, 30 minutes after oral gavage of either vehicle or C10 solution (30 mmol/kg dose in Experiment 1; 0.1, 0.3, 1.0, 3.0 mmol/kg doses in Experiment 2). Next, to examine chronic effects of C10, mice repeatedly administered with either vehicle or C10 solution (0.3, 3.0 mmol/kg doses per day, for 21 days, in Experiment 3) were subjected to behavioral tests without oral administration immediately before each test.ResultsThe mice administrated with the high dose of C10 (30 mmol/kg) showed lower body weights, shorter distance traveled, and more anxiety‐like behavior than vehicle‐treated mice, and the results reached study‐wide statistical significance. The C10 administration at a lower dose of 0.3 mmol/kg had no significant effects on body weights and induced nominally significantly longer distance traveled than vehicle administration. Repeated administration of C10 at a dose of 3.0 mmol/kg for more than 21 days caused lower body weights and decreased depression‐related behavior, although the behavioral differences did not reach study‐wide significance.ConclusionsAlthough these results suggest dose‐dependent effects of oral administration of capric acid on locomotor activity and anxiety‐like and depression‐related behaviors, further study will be needed to replicate the findings and explore the underlying brain mechanisms.

Neuropeptide Y, calcitonin gene-related peptide, and neurokinin A in brain regions of HAB rats correlate with anxiety-like behaviours

Anxiety disorders are pervasive psychiatric disorders causing great suffering. The high (HAB) and low (LAB) anxiety-related behaviour rats were selectively bred to investigate neurobiological correlates of anxiety. We compared the level of neuropeptides relevant for anxiety- and depression-related behaviours in selected brain regions of HAB and LAB rats.Increased anxiety and depression-like behaviours of male and female HAB rats in the elevated plus-maze and forced swim tests were accompanied by elevated levels of neuropeptide Y (NPY) in the prefrontal (PFC), frontal (FC) and cingulate cortex (CCx), the striatum, and periaqueductal grey (PAG). Moreover, HAB rats displayed sex-dependent, elevated levels of calcitonin gene-related peptide (CGRP) in PFC, FC, CCx, hippocampus, and PAG. Higher neurokinin A (NKA) levels were detected in CCx, striatum, and PAG in HAB males and in CCx and hypothalamus in HAB females. Increased neurotensin was detected in CCx and PAG in HAB males and in hypothalamus in HAB females. Elevated corticotropin-releasing hormone (CRH) levels appeared in female HAB hypothalamus. Significant correlations were found between anxiety-like behaviour and NPY, CGRP, NKA, and neurotensin, particularly with NPY in CCx and striatum, CGRP in FC and hippocampus, and NKA in entorhinal cortex.This is the first report of NPY, CGRP, NKA, Neurotensin, and CRH measurements in brain regions of HAB and LAB rats, which showed widespread NPY and CGRP alterations in cortical regions, with NKA and neurotensin changes localised in sub-cortical areas. The results may contribute to elucidate pathophysiological mechanisms underlying anxiety and depression and should facilitate identifying novel therapeutic targets.

Phytoestrogen genistein modulates neuron–microglia signaling in a mouse model of chronic social defeat stress

Microglia, resident immune cells in the brain, are shown to mediate the crosstalk between psychological stress and depression. Interestingly, increasing evidence indicates that sex hormones, particularly estrogen, are involved in the regulation of immune system. In this study, we aimed to understand the potential effects of chronic social defeat stress (CSDS) and genistein (GEN), an estrogenic compound of the plant origin, on neuron–microglia interactions in the mouse hippocampus. The time spent in the avoidance zone in the social interaction test was increased by CSDS 1 day after the exposure, while the avoidance behavior returned to control levels 14 days after the CSDS exposure. Similar results were obtained from the elevated plus-maze test. However, the immobility time in the forced swim test was increased by CSDS 14 days after the exposure, and the depression-related behavior was in part alleviated by GEN. The numerical densities of microglia in the hippocampus were increased by CSDS, and they were decreased by GEN. The voxel densities of synaptic structures and synaptic puncta colocalized with microglia were decreased by CSDS, and they were increased by GEN. Neither CSDS nor GEN affected the gene expressions of major pro-inflammatory cytokines. Conversely, the expression levels of genes related to neurotrophic factors were decreased by CSDS, and they were partially reversed by GEN. These findings show that GEN may in part alleviate stress-related symptoms, and the effects of GEN may be associated with the modulation of neuron–microglia signaling via chemokines and neurotrophic factors in the hippocampus.

A systematic review of studies investigating the acute effects of N-methyl-D-aspartate receptor antagonists on behavioural despair in normal animals suggests poor predictive validity.

The ability of the N-methyl- D -aspartate receptor antagonist ketamine to induce a rapid and sustained antidepressant effect has led to a surge in pre-clinical studies investigating underlying mechanisms and seeking novel treatments. Animal models are key to this research as they can provide a behavioural readout linking underlying mechanisms to clinical benefits. However, quantifying depression-related behaviours in rodents represents a major challenge with the validity of traditional methods such as models of behavioural despair (forced swim test and tail suspension test) a topic of debate. While there is good evidence to support the value of using these behavioural readouts to study the effects of stress, these approaches have largely failed to detect reliable phenotypic effects in other disease models. In this systematic review, we identified publications which had tested N-methyl- D -aspartate receptor antagonists in normal animals using either the forced swim test or tail suspension test. We compared findings for different doses and time points and also drugs with different clinical profiles to investigate how well the outcomes in the rodent model predicted their effects in the clinic. Despite clear evidence that N-methyl- D -aspartate receptor antagonists reduce immobility time and hence exhibit an antidepressant profile in these tasks, we found similar effects with both clinically effective drugs as well as those which have failed to show efficacy in clinical trials. These findings suggest that behavioural despair tests in normal animals do not provide a good method to predict clinical efficacy of N-methyl- D -aspartate receptor antagonists.

Neuroinflammatory transcriptional signatures in the entorhinal cortex based on lipopolysaccharide-induced depression model in mice

The inflammation and immune hypothesis of major depressive disorder (MDD) explains the mechanism of neuroinflammatory response to promote depression-like behaviors and provides targets for immunotherapy. Previous studies revealed that the neuronal function of the entorhinal cortex (EC) was relative to the depression symptoms in MDD. However, it remains largely unknown what role of neuroinflammation plays in the EC. Hence, we used immunofluorescence to determine c-Fos expression in the EC of lipopolysaccharide (LPS)-treated mice. Mice model was constructed of 10-day LPS treatment, and depression-related behaviors were assessed. We used gene expression microarray to determine differentially expressed genes (DEGs) in the EC of LPS group comparing to control group, and molecular verification was performed by quantitative real-time PCR and Western blot. We found that c-Fos expression was significant reduced in the two layers (Lateral 3.25 mm and 3.00 mm) of the EC in LPS-treated mice compared to saline-treated mice. Mice in LPS group exhibited depression- and anxiety-like behaviors in chronic model. Gene expression analyses identified 339 DEGs in the EC between LPS and control group. The molecular verification showed activation of IL-1R1/NF-κB/CCL5 signaling and upregulation of markers of astrocyte (GFAP) and microglia (AIF1 and CD86) in the EC. Our results suggested that LPS-induced neuroinflammation inhibited neuronal activity in the EC of mice, and that activation of IL-1R1/NF-κB/CCL5 signaling could be involved in the neuroinflammation in the EC of LPS-treated depression model.

EFFECT OF SCHOOL-BASED EDUCATIONAL INTERVENTIONS ON DEPRESSION-RELATED HEALTH-SEEKING BEHAVIOUR AMONG IN-SCHOOL ADOLESCENTS IN OGUN STATE, NIGERIA.

Introduction: Depression is one of the most common mental health diseases among adolescents; the repercussions are penetrating and are visible later in life.
 Purpose: To determine the effectiveness of school-based educational interventions on depression-related health-seeking behaviour among in-school adolescents in Ogun state, Nigeria.
 Methodology: A quasi-experimental design comprising of one control group and three experimental groups was conducted. Health Belief Model (HBM) was used for the study. The population of the study was 120 in-school adolescents selected using the multi-stage sampling technique from four (4) selected secondary schools. A validated semi-structured questionnaire was used for data collection. Data collected was coded using IBM® SPSS version 23. Data were analyzed using descriptive and inferential statistics at 0.05 level of significance.
 Findings: The mean±SD ages of the adolescents in the teacher-led, peer-led, teacher-led and peer-led and control groups were 14.43±2.315 years, 14.33±1.605 years, 14.97±1.426 years and 15.43±1.960 years in the teacher-led, peer-led, teacher and peer-led and control groups respectively. Equal number of female and male students were in the teacher-led group but different in other groups 19 (63.3%), 19 (63.3%) and 16 (53.3%). Results established that the students recruited for this study shared similar socio-demographic characteristics. The findings revealed that adolescent’s level of depression health-seeking behaviour significantly increased after the intervention. The teacher-led group had greater health-seeking behaviour scores (mean difference=24.27; effect size=16.04, t = 75.123; p = 0.000).
 Conclusion and Recommendation: The study established that teacher-led educational intervention had the greatest effect size and change in the level depression health-seeking behaviour among adolescents. This reinforces the opinion that teachers are often able to provide adolescents with key support in which they play the role of mentors in schools.
 Contribution to theory, practice and policy: The findings of this study which used the HBM theory support the premise that interventions based on theories are effective in influencing behaviour change in which health educators can utilize. A combination of intervention may also be important in influencing specific changes of adolescents’ mental health behaviours. Policy briefs with the study’s findings and concise summary should be communicated to the policy makers with follow up to aid updating mental health policies available.

Links between peer victimization, dating violence victimization and depression in adolescence: A genetically-informed study

ABSTRACT Peer victimization and dating violence victimization frequently co-occur, with 50.4% of adolescents reporting victimization in both social contexts. A possible explanation for the association between these two negative experiences is offered by interpersonal theories of depression. These theories stipulate that depression might not only be caused by relational stressors but may actually also be causing stressful experiences. Objective The current study aimed to test if individuals with inherent dispositions to depression-related cognitions and behaviors are more at risk of experiencing relational difficulties, such as peer victimization and dating violence victimization. Method This study used a genetically informed design with 806 twins (51.5% girls) to test 1) if at least part of the association between peer victimization in school and dating violence victimization in emerging adulthood can be explained by common underlying heritable factors. Participants provided repeated assessments of their peer victimization in school at ages 13 through 17, their depression symptoms at ages 13 through 19, as well as their victimization in dating relationships at age 19. Results A Cholesky decomposition based on structural equation modeling supported the hypotheses. Specifically, the association between peer victimization and dating violence victimization was to a significant extent explained by common underlying genetic vulnerabilities that were associated with depression symptoms. No sex moderation was found. Conclusions The findings highlight the importance of addressing early indicators of vulnerability toward depression symptoms to prevent victimization by peers or dating partners.

Data-driven analysis of kappa opioid receptor binding in major depressive disorder measured by positron emission tomography

Preclinical studies have implicated kappa opioid receptors (KORs) in stress responses and depression-related behaviors, but evidence from human studies is limited. Here we present results of a secondary analysis of data acquired using positron emission tomography (PET) with the KOR radiotracer [11C]GR103545 in 10 unmedicated, currently depressed individuals with major depressive disorder (MDD; 32.6 ± 6.5 years, 5 women) and 13 healthy volunteers (34.8 ± 10 years, 6 women). Independent component analysis was performed to identify spatial patterns of coherent variance in KOR binding (tracer volume of distribution, VT) across all subjects. Expression of each component was compared between groups and relationships to symptoms were explored using the 17-item Hamilton Depression Rating Scale (HDRS). Three components of variation in KOR availability across ROIs were identified, spatially characterized by [11C]GR103545 VT in (1) bilateral frontal lobe; (2) occipital and parietal cortices, right hippocampus, and putamen; and (3) right anterior cingulate, right superior frontal gyrus and insula, coupled to negative loading in left middle cingulate. In MDD patients, component 3 was negatively associated with symptom severity on the HDRS (r = −0.85, p = 0.0021). There were no group-wise differences in expression of any component between patients and controls. These preliminary findings suggest that KOR signaling in cortical regions relevant to depression, particularly right anterior cingulate, could reflect MDD pathophysiology.

Gut microbiota depletion from early adolescence alters anxiety and depression-related behaviours in male mice with Alzheimer-like disease

The gut-microbiota–brain axis plays an important role in stress-related disorders, and dysfunction of this complex bidirectional system is associated with Alzheimer’s disease. This study aimed to assess the idea that whether gut microbiota depletion from early adolescence can alter anxiety- and depression-related behaviours in adult mice with or without Alzheimer-like disease. Male C57BL/6 mice were treated with an antibiotic cocktail from weaning to adulthood. Adult mice received an intracerebroventricular injection of amyloid-beta (Aβ)1–42, and were subjected to anxiety and depression tests. We measured, brain malondialdehyde and glutathione following anxiety tests, and assessed brain oxytocin and the hypothalamic–pituitary–adrenal (HPA) axis function by measuring adrenocorticotrophic hormone (ACTH) and corticosterone following depression tests. Healthy antibiotic-treated mice displayed significant decreases in anxiety-like behaviours, whereas they did not show any alterations in depression-like behaviours and HPA axis function. Antibiotic treatment from early adolescence prevented the development of anxiety- and depression-related behaviours, oxidative stress and HPA axis dysregulation in Alzheimer-induced mice. Antibiotic treatment increased oxytocin in the brain of healthy but not Alzheimer-induced mice. Taken together, these findings suggest that gut microbiota depletion following antibiotic treatment from early adolescence might profoundly affect anxiety- and depression-related behaviours, and HPA axis function in adult mice with Alzheimer-like disease.

Antidepressant Like Effect of Ascorbic Acid in Mice: Possible Involvement of NO-sGC-cGMP Signaling.

The present study was designed to determine the antidepressant like activity of ascorbic acid (AA) in mice. Further the influence of NO-sGC-cGMP signaling in the antidepressant like effect of AA in mice was determined. Male swiss albino mice were used in the present study. Mice in the control group received saline and fluoxetine (10mg/kg, i.p.) was used as the standard antidepressant drug. AA (50, 100 and 150mg/kg, i.p.) was administered to the mice and depression related behavior were determined using tail suspension test (TST) and forced swim test (FST). Further the whole brain nitrite and serotonin levels were also determined. It was observed that the administration of AA (100mg/kg, i.p.) reversed the depression like behavior in mice in TST and FST. AA (100mg/kg, i.p.) treatment decreased the level of nitrite and increased the level of serotonin in the brain of mice significantly as compared to control. Further the behavioral and neurochemical effect of AA (50mg/kg, i.p) was studied in NO modulator [NO donor: L-Arginine (50mg/kg, i.p); NO-sGC inhibitor: methylene blue (1mg/kg, i.p.) and cGMP modulator: sildenafil (1mg/kg, i.p.)] pretreated mice. It was observed that the pretreatment of NO donor and cGMP modulator counteracted the effect conferred by AA (50mg/kg, i.p). While the pretreatment of NO-sGC inhibitor potentiated the effect conferred by AA (50mg/kg, i.p). The present study suggested that the AA confer antidepressant like effect in mice and NO-sGC-cGMP signaling pathway influence the antidepressant like effect of AA in mice.

Emotion regulation deficits and depression-related maladaptive interpersonal behaviours

ABSTRACT Coyne’s interpersonal theory of depression posits that those with depressive symptoms engage in maladaptive interpersonal behaviours that, although intended to assuage distress, push away social supports and increase depressive symptoms (Coyne, 1976). Excessive reassurance seeking, negative feedback seeking, and conversational self-focus are three behaviours implicated in Coyne’s theory, yet their correlates- apart from depressive symptoms- are poorly understood. The current study considered the potential role of intrapersonal emotion regulation deficits as an additional vulnerability factor for these behaviours. Mediation models further tested whether linkages between emotion regulation deficits and maladaptive interpersonal behaviours helped to explain short-term increases in depressive symptoms, as further suggested by theory. Older adolescents (N = 291, M age = 18.9) completed self-report measures of emotion regulation deficits, depressive symptoms, and the three maladaptive interpersonal behaviours during an initial lab visit and again four weeks later. A series of multiple regression models suggested that emotion regulation difficulties are uniquely associated with each of the behaviours over and above the impact of depressive symptoms. Mediation analyses suggested that only excessive reassurance seeking mediated the association between initial emotion regulation deficits and increased depressive symptoms over time. The clinical implications of these findings are discussed.

Neurobiological effects of a probiotic-supplemented diet in chronically stressed male Long-Evans rats: Evidence of enhanced resilience.

Probiotics that regulate the microbiome-gut-brain axis and provide mental health benefits to the host are referred to as psychobiotics. Preclinical studies have demonstrated psychobiotic effects on early life stress-induced anxiety- and depression-related behavior in rodents; however, the specific mechanisms remain ill-defined. In the current study, we investigated the effects of probiotic supplementation on neurobiological responses to chronic stress in adult male Long-Evans rats. Twenty-four rats were randomly assigned to probiotic (PB) or vehicle control (VEH) groups, then to either chronic unpredictable stress (CUS) or no-stress control (CON) conditions within each group (n = 6/subgroup). We hypothesized that PB supplementation would reduce markers of anxiety and enhance emotional resilience, especially in the CUS animals. In the cognitive uncertainty task, a nonsignificant trend was observed indicating that the PB-supplemented animals spent more time oriented toward the food reward than VEH animals. In the open-field task, CUS-PB animals spent more time in the center of the arena than CUS-VEH animals, an effect not observed between the two CON groups. In the swim task, the PB animals, regardless of stress assignment, exhibited increased floating, suggesting a conserved response in a challenging context. Focusing on the endocrine measures, higher dehydroepiandrosterone (DHEA)-to-corticosterone fecal metabolite ratios, a correlate of emotional resilience, were observed in PB animals. Further, PB animals exhibited reduced microglia immunoreactivity in the basolateral amygdala, possibly indicating a neuroprotective effect of PB supplements in this rodent model. These results provide evidence that PB supplementation interacts with stress exposure to influence adaptive responses associated with endocrine, neural, and behavioral indices of anxiety.

Effects of Radix Polygalae on Cognitive Decline and Depression in Estradiol Depletion Mouse Model of Menopause.

Postmenopausal syndrome refers to symptoms caused by the gradual decrease in female hormones after mid-40 years. As a target organ of estrogen, decrease in estrogen causes various changes in brain function such as a decrease in choline acetyltransferase and brain-derived neurotrophic factor; thus, postmenopausal women experience cognitive decline and more depressive symptoms than age-matched men. Radix Polygalae has been used for memory boosting and as a mood stabilizer and its components have shown neuroprotective, antidepressant, and stress relief properties. In a mouse model of estrogen depletion induced by 4-vinylcyclohexene diepoxide, Radix Polygalae was orally administered for 3 weeks. In these animals, cognitive and depression-related behaviors and molecular changes related to these behaviors were measured in the prefrontal cortex and hippocampus. Radix Polygalae improved working memory and contextual memory and despair-related behaviors in 4-vinylcyclohexene diepoxide-treated mice without increasing serum estradiol levels in this model. In relation to these behaviors, choline acetyltransferase and brain-derived neurotrophic factor in the prefrontal cortex and hippocampus and bcl-2-associated athanogene expression increased in the hippocampus. These results implicate the possible benefit of Radix Polygalae in use as a supplement of estrogen to prevent conditions such as postmenopausal depression and cognitive decline.

Maternal deprivation induces cytoskeletal alterations and depressive-like behavior in adult male rats by regulating the AKT/GSK3β/CRMP2 signaling pathway

Early-life adverse events exert persistent effects on brain functions and may increase the risk of psychopathology in adulthood. However, the underlying mechanism remains unclear. The purpose of our study was to study the long-lasting effects of maternal deprivation (MD) on depression-related behaviors and microtubule dynamics, and to illuminate the underlying molecular mechanism. Rat pups were separated from the dams for 360 min (MD) or 15 min (brief maternal separation) each day from postnatal day 4 through 10. Rats with MD experience showed significant depressive-like behaviors in adulthood, while brief maternal separation did not alter the behaviors. Behavioral alterations in the MD group were accompanied by alterations in the AKT/GSK3β/CRMP2 signaling pathway and hyperphosphorylation of CRMP2. CRMP2 interacted and colocalized with the cytoskeleton in the hippocampus, and the overlap of CRMP2 and tubulin staining in the hippocampus of MD rats was decreased. In MD rats, the expression of the α-tubulin isoforms Acet-tubulin and Tyr-tubulin changed, and the ratio of Tyr/Acet-tubulin, which is an important marker of microtubule dynamics, was decreased, indicating decreased microtubule dynamics. Furthermore, regulation of the AKT/GSK3β/CRMP2 signaling pathway by an LY294002 microinjection in the hippocampus resulted in cytoskeletal alterations and depressive-like behaviors in rats. These findings suggest that early-life MD induces depressive-like behaviors and cytoskeletal alterations in adult male rats and that the effects may be partly mediated by the AKT/GSK3β/CRMP2 signaling pathway. An understanding of the mechanism underlying the effect of MD on behaviors is crucial for developing pharmacological and psychological interventions for childhood neglect.

The effect of URB597, exercise or their combination on the performance of 6-OHDA mouse model of Parkinson disease in the elevated plus maze, tail suspension test and step-down task.

Parkinson disease (PD) is a progressive neurodegenerative disorder that is often accompanied by motor and psychiatric symptoms. Various approaches have been proposed for the treatment of PD. Here, we investigated the effect of a low dose of fatty acid amide hydrolase inhibitor URB597 (as an enhancer of endocannabinoid anandamide levels), exercise or their combination on some behavior alterations in PD mice lesioned by 6-hydroxydopamine (6-OHDA). The impact of swimming exercise (5×/week for 4weeks) and URB597 (0.1mg/kg, 2×/week for 4weeks) on the anxiety-related behavior (elevated plus maze; EPM), depression-related behavior (tail suspension test; TST), and passive avoidance memory (step-down task) was examined in the sham and male NMRI mouse of PD model. The results show that URB597 prevented memory deficits and elicited antidepressant- and anxiolytic-like effects but did not affect hypolocomotion in the PD mice. However, URB597 did not have a significant effect on the performance of the sham mice in the performed tests. Moreover, swimming training abolished depressive- and anxiogenic-like behaviors and increased locomotion without affecting memory deficits in the PD mice. Meanwhile, swimming decreased immobility time and increased locomotion in the sham mice. Furthermore, URB597 in association with swimming training prevented all deficits induced in the PD mice, while this combination impaired memory and produced the positive effects on depression- and anxiety-related behaviors and locomotion of the sham mice. It is concluded that although URB597 or exercise alone had positive effects on most behavioral tests, their combination improved all parameters in the PD mice.

VGF as a biomarker and therapeutic target in neurodegenerative and psychiatric diseases.

Neurosecretory protein VGF (non-acronymic) belongs to the granin family of neuropeptides. VGF and VGF-derived peptides have been repeatedly identified in well-powered and well-designed multi-omic studies as dysregulated in neurodegenerative and psychiatric diseases. New therapeutics is urgently needed for these devastating and costly diseases, as are new biomarkers to improve disease diagnosis and mechanistic understanding. From a list of 537 genes involved in Alzheimer’s disease pathogenesis, VGF was highlighted by the Accelerating Medicines Partnership in Alzheimer’s disease as the potential therapeutic target of greatest interest. VGF levels are consistently decreased in brain tissue and CSF samples from patients with Alzheimer’s disease compared to controls, and its levels correlate with disease severity and Alzheimer’s disease pathology. In the brain, VGF exists as multiple functional VGF-derived peptides. Full-length human VGF1–615 undergoes proteolytic processing by prohormone convertases and other proteases in the regulated secretory pathway to produce at least 12 active VGF-derived peptides. In cell and animal models, these VGF-derived peptides have been linked to energy balance regulation, neurogenesis, synaptogenesis, learning and memory, and depression-related behaviours throughout development and adulthood. The C-terminal VGF-derived peptides, TLQP-62 (VGF554–615) and TLQP-21 (VGF554–574) have differential effects on Alzheimer’s disease pathogenesis, neuronal and microglial activity, and learning and memory. TLQP-62 activates neuronal cell-surface receptors and regulates long-term hippocampal memory formation. TLQP-62 also prevents immune-mediated memory impairment, depression-like and anxiety-like behaviours in mice. TLQP-21 binds to microglial cell-surface receptors, triggering microglial chemotaxis and phagocytosis. These actions were reported to reduce amyloid-β plaques and decrease neuritic dystrophy in a transgenic mouse model of familial Alzheimer’s disease. Expression differences of VGF-derived peptides have also been associated with frontotemporal lobar dementias, amyotrophic lateral sclerosis, Lewy body diseases, Huntington’s disease, pain, schizophrenia, bipolar disorder, depression and antidepressant response. This review summarizes current knowledge and highlights questions for future investigation regarding the roles of VGF and its dysregulation in neurodegenerative and psychiatric disease. Finally, the potential of VGF and VGF-derived peptides as biomarkers and novel therapeutic targets for neurodegenerative and psychiatric diseases is highlighted.

Treadmill exercise sex-dependently alters susceptibility to depression-like behaviour, cytokines and BDNF in the hippocampus and prefrontal cortex of rats with sporadic Alzheimer-like disease

Alzheimer's disease (AD) is associated with increased depression-related behaviours. Previous studies have reported a greater risk of AD and depression in women. In recent years, we and others have provided evidence that exercise during life could be used as a therapeutic strategy for stress-related disorders such as depression. The main goal of the current study was to determine whether treadmill exercise during life can reduce depression-related behaviours in male and female Wistar rats with sporadic Alzheimer-like disease (ALD). Animals were subjected to treadmill exercise eight weeks before and four weeks after ALD induction by streptozocin (STZ). We measured body weight, food intake, and depression-related symptoms in rats using five behavioural tests. We measured brain-derived-neurotrophic factor (BDNF), tumour-necrosis factor (TNF)-α, and interleukin (IL)-10 levels in the hippocampus and prefrontal cortex of animals. Our findings showed that exercise but not ALD induction decreased body weight and food intake in male and female rats. ALD induction increased depression-related symptoms and hippocampal TNF-α in male and female rats. Besides, treadmill exercise alone decreased depression-related behaviours and increased hippocampal BDNF in females but not males. We also found that treadmill exercise decreased depression-related behaviours and TNF-α in the hippocampus and prefrontal cortex, and increased IL-10 in the prefrontal cortex and BDNF in the hippocampus of female ALD-induced rats. However, treadmill exercise only reduced anhedonia-like behaviour and hippocampal TNF-α in male ALD-induced rats. Overall, the evidence from this study suggests that treadmill exercise alters depression-related behaviours, brain BDNF and cytokines in a sex-dependant manner in rats with sporadic Alzheimer-like disease.

Effect of dimethyl fumarate on the changes in the medial prefrontal cortex structure and behavior in the poly(I:C)-induced maternal immune activation model of schizophrenia in the male mice

BackgroundThe link between maternal immune activation (MIA) and the risk of developing schizophrenia (SCZ) later in life has been of major focus in recent years. This link could be bridged by activated inflammatory pathways and excessive cytokine release resulting in adverse effects on behavior, histology, and cytoarchitecture. The down-regulatory effects of immunomodulatory agents on the activated glial cells and their therapeutic effects on schizophrenic patients are consistent with this hypothesis. ObjectiveWe investigated whether treatment with the anti-inflammatory drug dimethyl fumarate (DMF) could rescue impacts of prenatal exposure to polyinosinic:polycytidylic acid [poly (I:C)]. MethodsPregnant dams were administered poly(I:C) at gestational day 9.5. Offspring born from these mothers were treated with DMF for fourteen consecutive days from postnatal day 80 and were assessed behaviorally before and after treatment. The brains were then stained with Cresyl Violet or Golgi-Cox. In addition to the estimation of stereological parameters, cytoarchitectural changes were also evaluated in the medial prefrontal cortex. ResultsMIA caused some abnormalities in behavior, as well as changes in the number of neurons and non-neurons. These alterations were also extended to pyramidal layer III neurons with a significant decrease in dendritic complexity and spine density which DMF treatment could prevent these changes. Furthermore, DMF treatment was also effective against abnormal exploratory and depression-related behavior, but not the changes in the number of cells. ConclusionThese findings support the idea of using anti-inflammatory agents as adjunctive therapy in patients with SCZ.