Chronic Stress-induced Depression-like Behaviors Research Articles

Antidepressant-like effects of agmatine and NOS inhibitors in chronic unpredictable mild stress model of depression in rats: The involvement of NLRP inflammasomes

Innate immunity activation in the central nervous system (CNS) is known to contribute to the development of depression through NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasome assembly. Furthermore, administration of agmatine (AGM), a nitric oxide synthase (NOS) inhibitor, reverses stress-induced NLRP3 inflammasome activation in rats. We examined the effects of chronically-administered nitric oxide (NO) pathway modulating drugs on NLRP1/3-mediated neuroinflammatory responses and depressive-like behaviors in chronic unpredictable mild stress (CUMS) depression model of rats. CUMS model was applied to the adult male Sprague-Dawley rats for 6 weeks and the treatments were daily administered via intraperitoneal route in the last 3 weeks of CUMS procedure. Depressive-like behaviors were assessed by sucrose preference and forced swimming tests. The levels of NLRP inflammasome components (NLRP1, NLRP3, ASC, caspase-1 and IL-1β) were investigated in the prefrontal cortex by real time PCR and western blot methods. CUMS-induced depressive-like behaviors were coupled with the overactivation of NLRP1 and NLRP3 inflammasome sensors and increased levels of IL-1β. Depressive-like behaviors were ameliorated by chronic AGM and NOS inhibitor treatments. AGM and other NOS inhibitor treatments were found to be more effective in suppressing NLRP3 and NLRP1, respectively. All inhibitor reagents downregulated inflammasome components and IL-1β. These results suggest that both neuronal NLRP1 and microglial NLRP3 inflammasomes are involved in chronic stress-induced depressive-like behaviors. The antidepressant effects of AGM, iNOS and nNOS inhibitors are associated with the downregulation of CNS inflammasome expression levels. NO-pathway modulating drugs might provide novel therapeutic strategies for depression.

Effects of Acupuncture on Chronic Stress-Induced Depression-Like Behavior and Its Central Neural Mechanism.

Depression is a serious psychiatric disorder with an enormous socioeconomic burden, and it is commonly comorbid with pain, chronic fatigue, or other inflammatory diseases. Recent studies have shown that acupuncture is an effective therapeutic method for reducing depressive symptoms; however, the underlying mechanism remains unknown. In this study, we investigated the effects of acupuncture on chronic stress-induced depression-like behavior and its central neural mechanisms in the brain. We induced chronic restraint stress (CRS) in male C57BL/6 mice for 14 or 28 consecutive days. Acupuncture treatment was performed at KI10·LR8·LU8·LR4 or control points for 7 or 14 days. Depression-like behavior was assessed with the open field test. Then, brain neural activity involving c-Fos and serotonin-related mechanisms via the 5-HT1A and 5-HT1B receptors were investigated. Acupuncture treatment at KI10·LR8·LU8·LR4 points rescued the depressive-like behavior, while control points (LU8·LR4·HT8·LR2) and non-acupoints on the hips did not. Brain neural activity was changed in the hippocampus, cingulate cortex, motor cortex, insular cortex, thalamus, and the hypothalamus after acupuncture treatment. Acupuncture treatment increased expression of 5-HT1A receptor in the cortex, hippocampus, thalamus, and the hypothalamus, and of 5-HT1B in the cortex and thalamus. In conclusion, acupuncture treatment at KI10·LR8·LU8·LR4 was effective in alleviating the depressive-like behavior in mice, and this therapeutic effect was produced through central brain neural activity and serotonin receptor modulation.

Increased Homer1-mGluR5 mediates chronic stress-induced depressive-like behaviors and glutamatergic dysregulation via activation of PERK-eIF2α

Glutamatergic dysregulation has served as one common pathophysiology of major depressive disorder (MDD) and a promising target for treatment intervention. Previous studies implicate neurotransmission via metabotropic glutamate receptors (mGluRs) and Homer1 in stress-induced anhedonia, but the mechanisms have not been well elucidated. In the present study, we used two different animal models of depression, chronic social defeat stress (CSDS) and chronic restraint stress (CRS), to investigate the expression of Homer1 isoforms and functional interaction with mGluRs. We found that chronic stress selectively upregulated the expression of Homer1b/c in the hippocampus, whereas the level of Homer1a was unchanged. Additionally, there was a significant negative correlation between the levels of Homer1-mGluR5 signaling and depressive-like behaviors. Both application of paired-pulse low-frequency stimulation (PP-LFS) and the selective group 1 mGluRs agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) significantly enhanced mGluR-dependent long-term depression (LTD) at CA3-CA1 pyramidal cell synapses in slices from susceptible mice, whereas there was no change in NMDAR-dependent LTD induced by LFS. Furthermore, these effects were associated with the internalization of surface AMPARs in hippocampal pyramidal neurons, including reduced the expression of AMPARs and amplitude of AMPARs-mediated mEPSC. Finally, we found that chronic stress activated the KR-like ER kinase-eukaryotic initiation factor 2α (PERK-eIF2α) signaling pathway, subsequently phosphorylated cAMP response element binding protein (CREB) at the S129 and reduced the BDNF level, eventually leading to the impairment of synaptic transmission and depressive-like behaviors. Therefore, our study suggests that PERK-eIF2α acts as a critical target downstream of Homer1-mGluR5 complex to mediate chronic stress-induced depressive-like behaviors, and highlights them as a potential target for the treatment of mood disorder.

The chemokine CXCL1 and its receptor CXCR2 contribute to chronic stress-induced depression in mice.

Depression is increasingly recognized as an inflammatory disease, with inflammatory crosstalk in the brain contributing its pathogenesis. Life stresses may up-regulate inflammatory processes and promote depression. Although cytokines are central to stress-related immune responses, their contribution to stress-induced depression remains unclear. Here, we used unpredictable chronic mild stress (UCMS) to induce depression-like behaviors in mice, as assessed through a suite of behavioral tests. C-X-C motif chemokine ligand 1 (CXCL1)-related molecular networks responsible for depression-like behaviors were assessed through intrahippocampal microinjection of lenti-CXCL1, the antidepressant fluoxetine, the C-X-C motif chemokine receptor 2 (CXCR2) inhibitor SB265610, and the glycogen synthase kinase-3β (GSK3β) inhibitor AR-A014418. Modulation of apoptosis-related pathways and neuronal plasticity were assessed via quantification of cleaved caspase-3, B-cell lymphoma 2-associated X protein, cAMP response element-binding protein (CREB), and brain-derived neurotrophic factor (BDNF) protein expression. CXCL1/CXCL2 expression was correlated with depression-like behaviors in response to chronic stress or antidepressant treatment in the UCMS depression model. Intrahippocampal microinjection of lenti-CXCL1 increased depression-like behaviors, activated GSK3β, increased apoptosis pathways, suppressed CREB activation, and decreased BDNF. Administration of the selective GSK3β inhibitor AR-A014418 abolished the effects of lenti-CXCL1, and the CXCR2 inhibitor SB265610 prevented chronic stress-induced depression-like behaviors, inhibited GSK3β activity, blocked apoptosis pathways, and restored BDNF expression. The CXCL1/CXCR2 axis appears to play a critical role in stress-induced depression, and CXCR2 is a potential novel therapeutic target for patients with depression.-Chai, H.-H., Fu, X.-C., Ma, L., Sun, H.-T., Chen, G.-Z., Song, M.-Y., Chen, W.-X., Chen, Y.-S., Tan, M.-X., Guo, Y.-W., Li, S.-P. The chemokine CXCL1 and its receptor CXCR2 contribute to chronic stress-induced depression in mice.

Chronic Stress Disturbs Metabolome of Blood Plasma and Urine in Diabetic Rats.

About 30% of diabetes patients suffer from varying degrees of depression. Diabetes itself is associated with abnormal carbohydrate and energy metabolism. Whether chronic stress-induced depression-like behavior impacts the metabolome of blood plasma and urine in diabetes is not clear. This study aimed to investigate the effect of chronic stress on metabolome of plasma and urine in spontaneously diabetic Goto-Kakizaki (GK) rats. The GK rats were subjected to 8 weeks' chronic unpredictable mild stress (CUMS) to induce depression-like behavior. Metabolome analysis of blood plasma and urine using liquid chromatography mass spectrometry (LC/MS) was performed. Multivariate data analysis was used to evaluate the data. Behavior and biochemical assay confirmed the successful establishment of CUMS-induced depression-like behavior model in rats. Disturbance of 20 plasma metabolites and 16 urine metabolites were altered in CUMS-induced depression GK rats as compared to control ones. These disturbed metabolites were involved in fatty acid metabolism, sphingolipid metabolism, phenylalanine metabolism, citrate cycle, glycolysis, glutathione metabolism, and nicotinate and nicotinamide metabolism. This study suggest that chronic stress-induced depression-like behavior may further disturb diabetes-itself energy metabolome. The plasma and urine lipid metabolites monitoring may be useful for early detection of depression in patients with diabetes mellitus.

(2R,6R)-hydroxynorketamine rescues chronic stress-induced depression-like behavior through its actions in the midbrain periaqueductal gray

It has been widely reported that ketamine rescues chronic stress-induced depression-like behavior, but the underlying cellular mechanisms of the rapid antidepressant actions of ketamine remain largely unclear. Both male and female Sprague-Dawley rats were used and received modified learned helplessness paradigm to induce depression-like behavior. Depression-like behavior was assayed and manipulated using forced swim tests, sucrose preference tests and pharmacological microinjection. We conducted whole-cell patch-clamp electrophysiological recordings in the midbrain ventrolateral periaqueductal gray (vlPAG) neurons. Surface and cytosolic glutamate receptor 1 (GluR1) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression were analyzed using Western blotting. Phosphorylated GluR1 expression was quantified using Western blotting analysis. The results showed that a single systemic administration of a ketamine metabolite (2R,6R)-hydroxynorketamine (2R,6R-HNK) rapidly rescued chronic stress-induced depression-like behavior and persisted for up to 21 days. Consistently, the chronic stress-induced diminished glutamatergic transmission and surface GluR1 expression in the vlPAG were also reversed by a single systemic injection of (2R,6R)-HNK. Furthermore, bath application of (2R,6R)-HNK increased the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in the vlPAG. Further evidence for the antidepressant action of (2R,6R)-HNK is provided by the finding that microinjection of (2R,6R)-HNK into the vlPAG exhibited a rapid-acting and long-lasting antidepressant effect. This antidepressant effect of (2R,6R)-HNK was prevented by the intra-vlPAG microinjection of AMPA receptor antagonist CNQX. Together, the current results provide evidence that (2R,6R)-HNK rescues chronic stress-induced depression-like behavior with rapid-acting and long-lasting antidepressant effects through enhancement of AMPA receptor-mediated transmission in the vlPAG.

Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors

BackgroundIn recent years, proinflammatory cytokine interleukin-1β (IL-1β) was considered to play a critical role in the pathogenesis of depression. In addition, P2X7 receptor (P2X7R), a member of the purinergic receptor family, which is predominantly present on microglia, as well as on astrocytes and neurons in lesser amounts in the central nervous system, was suggested to be involved in the processing and releasing of IL-1β. Here, we investigated the role of P2X7R in the pathogenesis of depression.MethodsMale Sprague-Dawley rats were subjected to chronic unpredictable stressors (CUS) for 3 weeks. At the end of week 1, 2, and 3, extracellular ATP, caspase 1, IL-1β, and components and activation of NLRP3 inflammasome (nucleotide-binding, leucine-rich repeat, pyrin domain containing 3) were evaluated as biomarker of neuroinflammation. In separate experiments, the rats were microinjected with P2X7R agonists ATP, BzATP, and saline into the hippocampus, respectively, or exposed to CUS combined with hippocampal microinjection with P2X7R antagonist, BBG and A438079, and saline, respectively, for 3 weeks, followed by exposed to forced swimming test and open-field test. Moreover, we also evaluated the depressive and anxiety-like behavior of P2X7-null mice in forced swimming test, open-field test, and elevated plus maze.ResultsAlong with stress accumulation, extracellular ATP, cleaved-caspase 1, IL-1β, and ASC were significantly enhanced in the hippocampus, but P2X7R and NLRP3 were not. Immunoprecipitation assay indicated that along with the accumulation of stress, assembly of NLRP3 inflammasome and cleaved caspase 1 in NLRP3 inflammasome were significantly increased. Moreover, antagonists of P2X7R, either BBG or A438079, prevented the development of depressive-like behaviors induced by chronic unpredictable stress in rats. Meanwhile, we could not observe any depressive-like or anxiety-like behaviors of P2X7-null mice after they had been exposed to CUS. The results implied that P2X7 knockout could impede the development of depressive-like and anxiety-like behaviors induced by CUS. In contrast, chronic administration of agonists of P2X7R, either ATP or BzATP, could induce depressive-like behaviors.ConclusionsThe activation of P2X7R and subsequent NLRP3 inflammasome in hippocampal microglial cells could mediate depressive-like behaviors, which suggests a new therapeutic target for the prevention and treatment of depression.

Gene deficiency and pharmacological inhibition of caspase-1 confers resilience to chronic social defeat stress via regulating the stability of surface AMPARs

Both inflammatory processes and glutamatergic systems have been implicated in the pathophysiology of mood-related disorders. However, the role of caspase-1, a classic inflammatory caspase, in behavioral responses to chronic stress remains largely unknown. To address this issue, we examined the effects and underlying mechanisms of caspase-1 on preclinical murine models of depression. We found that loss of caspase-1 expression in Caspase-1−/− knockout mice alleviated chronic stress-induced depression-like behaviors, whereas overexpression of caspase-1 in the hippocampus of wild-type (WT) mice was sufficient to induce depression- and anxiety-like behaviors. Furthermore, chronic stress reduced glutamatergic neurotransmission and decreased surface expression of glutamate receptors in hippocampal pyramidal neurons of WT mice, but not Caspase-1−/− mice. Importantly, pharmacological inhibition of caspase-1-interleukin-1β (IL-1β) signaling pathway prevented the depression-like behaviors and the decrease in surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in stressed WT mice. Finally, the effects of chronic stress on both depression- and anxiety-like behaviors can be mimicked by exogenous intracerebroventricular (i.c.v.) administration of IL-1β in both WT and Caspase-1−/− mice. Taken together, our findings demonstrate that an increase in the caspase-1/IL-1β axis facilitates AMPAR internalization in the hippocampus, which dysregulates glutamatergic synaptic transmission, eventually resulting in depression-like behaviors. These results may represent an endophenotype for chronic stress-induced depression.

Cav1.2 channels mediate persistent chronic stress-induced behavioral deficits that are associated with prefrontal cortex activation of the p25/Cdk5-glucocorticoid receptor pathway

Chronic stress is known to precipitate and exacerbate neuropsychiatric symptoms, and exposure to stress is particularly pathological in individuals with certain genetic predispositions. Recent genome wide association studies have identified single nucleotide polymorphisms (SNPs) in the gene CACNA1C, which codes for the Cav1.2 subunit of the L-type calcium channel (LTCC), as a common risk variant for multiple neuropsychiatric conditions. Cav1.2 channels mediate experience-dependent changes in gene expression and long-term synaptic plasticity through activation of downstream calcium signaling pathways. Previous studies have found an association between stress and altered Cav1.2 expression in the brain, however the contribution of Cav1.2 channels to chronic stress-induced behaviors, and the precise Cav1.2 signaling mechanisms activated are currently unknown. Here we report that chronic stress leads to a delayed increase in Cav1.2 expression selectively within the prefrontal cortex (PFC), but not in other stress-sensitive brain regions such as the hippocampus or amygdala. Further, we demonstrate that while Cav1.2 heterozygous (Cav1.2+/−) mice show chronic stress-induced depressive-like behavior, anxiety-like behavior, and deficits in working memory 1–2 days following stress, they are resilient to the effects of chronic stress when tested 5–7 days later. Lastly, molecular studies find a delayed upregulation of the p25/Cdk5-glucocorticoid receptor (GR) pathway in the PFC when examined 8 days post-stress that is absent in Cav1.2+/− mice. Our findings reveal a novel Cav1.2-mediated molecular mechanism associated with the persistent behavioral effects of chronic stress and provide new insight into potential Cav1.2 channel mechanisms that may contribute to CACNA1C-linked neuropsychiatric phenotypes.

Hippocampal MicroRNA-124 Enhances Chronic Stress Resilience in Mice.

Chronic stress-induced aberrant gene expression in the brain and subsequent dysfunctional neuronal plasticity have been implicated in the etiology and pathophysiology of mood disorders. In this study, we examined whether altered expression of small, regulatory, noncoding microRNAs (miRNAs) contributes to the depression-like behaviors and aberrant neuronal plasticity associated with chronic stress. Mice exposed to chronic ultra-mild stress (CUMS) exhibited increased depression-like behaviors and reduced hippocampal expression of the brain-enriched miRNA-124 (miR-124). Aberrant behaviors and dysregulated miR-124 expression were blocked by chronic treatment with an antidepressant drug. The depression-like behaviors are likely not conferred directly by miR-124 downregulation because neither viral-mediated hippocampal overexpression nor intrahippocampal infusion of an miR-124 inhibitor affected depression-like behaviors in nonstressed mice. However, viral-mediated miR-124 overexpression in hippocampal neurons conferred behavioral resilience to CUMS, whereas inhibition of miR-124 led to greater behavioral susceptibility to a milder stress paradigm. Moreover, we identified histone deacetylase 4 (HDAC4), HDAC5, and glycogen synthase kinase 3β (GSK3β) as targets for miR-124 and found that intrahippocampal infusion of a selective HDAC4/5 inhibitor or GSK3 inhibitor had antidepressant-like actions on behavior. We propose that miR-124-mediated posttranscriptional controls of HDAC4/5 and GSK3β expressions in the hippocampus have pivotal roles in susceptibility/resilience to chronic stress. Depressive disorders are a major public health concern worldwide. Although a clear understanding of the etiology of depression is still lacking, chronic stress-elicited aberrant neuronal plasticity has been implicated in the pathophysiology of depression. We show that the hippocampal expression of microRNA-124 (miR-124), an endogenous small, noncoding RNA that represses gene expression posttranscriptionally, controls resilience/susceptibility to chronic stress-induced depression-like behaviors. These effects on depression-like behaviors may be mediated through regulation of the mRNA or protein expression levels of histone deacetylases HDAC4/5 and glycogen synthase kinase 3β, all highly conserved miR-124 targets. Moreover, miR-124 contributes to stress-induced dendritic hypotrophy and reduced spine density of dentate gyrus granule neurons. Modulation of hippocampal miR-124 pathways may have potential antidepressant effects.

Exercise amelioration of depression-like behavior in OVX mice is associated with suppression of NLRP3 inflammasome activation in hippocampus

Exercise has benefit for perimenopause women in many ways, such as affective disorders. Our previous study has demonstrated that inflammation in hippocampus contributes to development of depression-like behavior in ovariectomized (OVX) rats. Recently, oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has been implicated to be involved in lipopolysaccharide (LPS)- and chronic stress-induced depression-like behavior in rodents. We sought to investigate whether ovariectomy-induced depression-like behavior is associated with NLRP3 inflammasome activation in brain and the effect of exercise on NLRP3 inflammasome activation in this model. The results showed that ovariectomy resulted in depression-like behavior in mice and an increase in levels of IL-1β and IL-18 in hippocampus. Exercise ameliorated the depression-like behavior and decreased levels of IL-1β and IL-18 in hippocampus. The level of IL-1β and IL-18 in hippocampus correlated to depression-like behavior in OVX mice. The levels of NLRP3, cleaved caspase-1 P10 and CD11b in hippocampus were increased in OVX mice compared with control group. Exercise could reduce the levels of NLRP3, cleaved caspase-1 P10 and CD11b in OVX mice. Our study suggests that NLRP3 inflammasome activation contribute to inflammation in hippocampus upon to deprivation of ovary. Exercise amelioration of depression-like behavior is associated with suppression of NLRP3 inflammasome activation in hippocampus of this model.

Orbitofrontal cortex 5-HT2A receptor mediates chronic stress-induced depressive-like behaviors and alterations of spine density and Kalirin7

Neuroimaging studies show that patients with major depression have reduced volume of the orbitofrontal cortex (OFC). Although the serotonin (5-HT) 2A receptor, which is abundant in the OFC, has been implicated in depression, the underlying mechanisms in the development of stress-induced depression remain unclear. Kalirin-7 (Kal7) is an essential component of mature excitatory synapses for maintaining dendritic spines density, size and synaptic functions. The aim of this study was to investigate the role of orbitofrontal 5-HT and 5-HT2A receptors in depressive-like behaviors and their associations with Kal7 and dendritic spines using chronic unpredictable mild stress (CUMS), an established animal model of depression. CUMS had no effect on the levels of 5-HT or the 5-HT2A receptor in the OFC. However, CUMS or microinjection of the 5-HT2A/2C receptor agonist (±)-1-(2, 5-Dimethoxy-4-iodophenyl)- 2-aminopropane hydrochloride (DOI, 5 μg/0.5 μL) into the OFC induced depressive-like behaviors, including anhedonia in the sucrose preference test and behavioral despair in the tail suspension test, a significant reduction in body weight gain and locomotor activity in the open field test, which were accompanied by decreased expression of Kal7 and PSD95 as well as decreased density of dendritic spines in the OFC. These alterations induced by CUMS were reversed by pretreatment with the 5-HT2A receptor antagonist Ketanserin (Ket, 5 μg/0.5 μL into the OFC). These results suggest that CUMS alters structural plasticity through activation of the orbital 5-HT2A receptor and is associated with decreased expression of Kal7, thereby resulting in depressive-like behaviors in rats, suggesting an important role of Kal7 in the OFC in depression.

Lipopolysaccharide-induced depressive-like behavior is associated with α₁-adrenoceptor dependent downregulation of the membrane GluR1 subunit in the mouse medial prefrontal cortex and ventral tegmental area.

Background:Chronic stress-induced depressive-like behavior is relevant to inflammatory immune activation. However, the neurobiological alterations in the brain following the central inflammatory immune activation remain elusive.Methods:Therefore, we investigated the neurobiological alterations during depressive-like behavior induced in mice by systemic administration of lipopolysaccharide (LPS; 1.2mg/kg administered twice at a 30-min interval via intraperitoneal injection).Results:At 24h after the second administration of LPS, an increased immobility time in the tail suspension test and the forced swimming test were observed, as well as reduced sucrose preference. Protein levels of the AMPA receptor GluR1 were significantly decreased at the plasma membrane in the medial prefrontal cortex (mPFC) and ventral tegmental area (VTA), while levels of the GluR2 were increased at the plasma membrane in the nucleus accumbens (NAc) at 24h after LPS. However, total GluR1 and GluR2 protein levels in the mPFC, VTA, and NAc were not affected by LPS. Moreover, LPS facilitated release of noradrenaline in the mPFC and VTA, but not in the NAc. Consistently, systemic administration of prazosin, an α1-adrenoceptor antagonist, blocked the LPS-induced downregulation of the membrane GluR1 subunit in both the mPFC and VTA and also blocked the upregulation of the membrane GluR2 subunit in the NAc. Intracerebroventricular administration of prazosin 30min before LPS injection abrogated the LPS-induced depressive-like behaviors. In opposition, administration of propranolol, a β-adrenoceptor antagonist, did not affect the LPS-induced downregulation of GluR1, the upregulation of GluR2, or the depressive-like behavior.Conclusions:These results suggest that LPS-activated α1-adrenoceptor-induced downregulation of membrane GluR1 in the mPFC and VTA is associated with inflammation-induced depressive-like behavior.

SSRI or CRF antagonism partially ameliorate depressive-like behavior after adolescent social defeat

Depression and anxiety during adolescence are complex disorders due to persistent effects on physiology and behavior. Selective-serotonin reuptake inhibitors (SSRI) are currently the most widely used pharmacological intervention for depression. Corticotropin-releasing factor one (CRF1) receptor antagonists represent a novel class of compounds that may have efficacy for depressive and anxiety disorders. This study used an animal model of chronic adolescent stress to determine the efficacy of the SSRI fluoxetine, and a novel CRF1 receptor antagonist, GSK876008, on prevention of the behavioral effects of chronic adolescent stress. Male rats were exposed to chronic social defeat stress, fluoxetine, and/or GSK876008 from postnatal day 28-50. Chronic stress-induced depressive-like behaviors were partially attenuated by either concurrent fluoxetine or GSK876008. Fluoxetine blunted body mass gain in the adolescents exposed to chronic stress. The collective data demonstrate similar efficacy between a SSRI and a CRF1 receptor antagonist in the attenuation of stress-induced anhedonia but fewer side effects were observed in those rats treated with the CRF1 receptor antagonist. These data suggest that CRF1 receptor antagonists may be a viable alternative for treatment of depressive behaviors in adolescents.

Monoacylglycerol Lipase Inhibition Blocks Chronic Stress-Induced Depressive-Like Behaviors via Activation of mTOR Signaling

The endocannabinoid (eCB) system regulates mood, emotion, and stress coping, and dysregulation of the eCB system is critically involved in pathophysiology of depression. The eCB ligand 2-arachidonoylglycerol (2-AG) is inactivated by monoacylglycerol lipase (MAGL). Using chronic unpredictable mild stress (CUS) as a mouse model of depression, we examined how 2-AG signaling in the hippocampus was altered in depressive-like states and how this alteration contributed to depressive-like behavior. We report that CUS led to impairment of depolarization-induced suppression of inhibition (DSI) in mouse hippocampal CA1 pyramidal neurons, and this deficiency in 2-AG-mediated retrograde synaptic depression was rescued by MAGL inhibitor JZL184. CUS induced depressive-like behaviors and decreased mammalian target of rapamycin (mTOR) activation in the hippocampus, and these biochemical and behavioral abnormalities were ameliorated by chronic JZL184 treatments. The effects of JZL184 were mediated by cannabinoid CB1 receptors. Genetic deletion of mTOR with adeno-associated viral (AAV) vector carrying the Cre recombinase in the hippocampus of mTORf/f mice recapitulated depressive-like behaviors induced by CUS and abrogated the antidepressant-like effects of chronic JZL184 treatments. Our results suggest that CUS decreases eCB-mTOR signaling in the hippocampus, leading to depressive-like behaviors, whereas MAGL inhibitor JZL184 produces antidepressant-like effects through enhancement of eCB-mTOR signaling.

Regular Moderate or Intense Exercise Prevents Depression-Like Behavior without Change of Hippocampal Tryptophan Content in Chronically Tryptophan-Deficient and Stressed Mice

Regular exercise has an antidepressant effect in human subjects. Studies using animals have suggested that the antidepressant effect of exercise is attributable to an increase of brain 5-hydroxytryptamine (5-HT); however, the precise mechanism underlying the antidepressant action via exercise is unclear. In contrast, the effect of 5-HT on antidepressant activity has not been clarified, in part because the therapeutic response to antidepressant drugs has a time lag in spite of the rapid increase of brain 5-HT upon administration of these drugs. This study was designed to investigate the contribution of brain 5-HT to the antidepressant effect of exercise. Mice were fed a tryptophan-deficient diet and stressed using chronic unpredictable stress (CUS) for 4 weeks with or without the performance of either moderate or intense exercise on a treadmill 3 days per week. The findings demonstrated that the onset of depression-like behavior is attributable not to chronic reduction of 5-HT but to chronic stress. Regular exercise, whether moderate or intense, prevents depression-like behavior with an improvement of adult hippocampal cell proliferation and survival and without the recovery of 5-HT. Concomitantly, the mice that exercised showed increased hippocampal noradrenaline. Regular exercise prevents the impairment of not long-term memory but short-term memory in a 5-HT-reduced state. Together, these findings suggest that: (1) chronic reduction of brain 5-HT may not contribute to the onset of depression-like behavior; (2) regular exercise, whether moderate or intense, prevents the onset of chronic stress-induced depression-like behavior independent of brain 5-HT and dependent on brain adrenaline; and (3) regular exercise prevents chronic tryptophan reduction-induced impairment of not long-term but short-term memory.

Chronic stress-induced depression-like behavior of rats accompanied by microbial translocation the blood-brain barrier and persistent activation the inducible nitric oxide synthase in mitochondria of cortico-limbic brain

Chronic stress may affect brain-gut axis and compromise blood-brain barrier (BBB) causing bacterial invasion and mounting nitrergic response that might be involved in stress-induced depression via direct impact on mitochondrial function in brain. The objectives of this study are to examine microbial composition in gut, blood and brain and assess a contribution of functionally different constitutive and inducible forms of nitric oxide synthase (cNOS and iNOS, respectively) to nitric oxide (NO) production in cytoplasm and mitochondria of cortico-limbic brain following chronic stress-induced depression. Depression-like behavior of early adolescent male rats - resembling human depression - was developed by exposure to 2 weeks of chronic variable physical stress (CVS) (forced swimming, ether, restraint, cold, orthostatic shock andfood deprivation).CVS induces in the rat gut a substantial enhancement the number of resident Candida albicans and manifestation of Staphylococcus aureus accompanied by a reduced number of obligate microbes immediately after CVS (stress group) and four days later (post-stress group). S. aureus and C. albicans were also detected in bloodstream and brain of CVS-treated rats. Simultaneously, the levels of L-arginine, L-citrulline and reactive nitrogen species were remarkably elevated in cytoplasm and mitochondria of the prefrontal cortex, striatum, hippocampus, and hypothalamus. We have found for the first time that CVS causes a persistent activation the iNOS in mitochondria of the mentioned brain regions, as well as in cytoplasm of the hypothalamus, while the cNOS activity was not significantly changed in mitochondria of the regions studied, with exception for the hypothalamic mtcNOS which reduced twice. We have also found a concurrent down-regulation the cNOS in cytoplasm of all the mentioned regions and a long-term up-regulation the iNOS in cytoplasm of the hypothalamus. CVS-induced opposite changes in the subcellular activity of distinct NOSs in cortico-limbic brain appear to be involved in the mitochondrial dysfunction leading to disturbances in neurotransmission, hemodynamic and energy impairment, pathophysiological pathways relevant to depression. We emphasize a role of gut microbiota in the persistent activation the mitochondrial iNOS in cortico-limbic brain and therefore the importance of origin the mitochondrial dysfunction involved in the pathological processes manifested during chronic stress-induced depression. This study would be helpful in understanding both brain-gut-microbiota communications and intracellular processes in the brain at depression, and therapeutic targeting of microbiome and nitrergic response might be included in future strategies in prevention and treatment of depression/anxiety.

The effect of citalopram on chronic stress-induced depressive-like behavior in rats through GSK3β/β-catenin activation in the medial prefrontal cortex

Antidepressant treatments enhance synaptic connectivity in stress-sensitive brain regions such as the medial prefrontal cortex (mPFC). The mPFC plays a key role in controlling cognition and emotion. While several signaling pathways are involved in this enhancement process, the exact mechanisms are not fully established. In the present study, we evaluated the role of the glycogen synthase kinase 3β (GSK3β)/β-catenin signaling pathway in the antidepressant effect of citalopram in rats exposed to forced swim stress. The acute stress group received the classic, two-day variant of the forced swimming test (FST), whereas the chronic stress group received swim stress for 14 consecutive days. We found that rats exposed to acute swim stress showed depressive-like behaviors and expressed normal GSK3β and β-catenin levels in the mPFC. Chronic swim stress, also induced a significant behavior changes but was associated with decreased levels of phosphorylated GSK3β and β-catenin in the rat's mPFC. Chronic citalopram treatment alleviated these behavioral changes in chronically stressed rats and normalized the downregulation of GSK3β/β-catenin signaling. Our results suggest that GSK3β/β-catenin signaling plays an important role in chronic but not acute stress-related depression and contributes, at least in part, to the antidepressant effects of citalopram in distinct brain regions associated with mood regulation.

Region-specific nitric oxide production in cytosolic and mitochondrial compartments of the rat brain tissues following chronic stress-induced depression-like behavior

Keywords: L-arginine, brain, chronic stress, depression-like behavior, mitochondria, nitric oxide synthase

Prevention of chronic stress-induced depression-like behavior by inducible nitric oxide inhibitor

Depression is associated with significant morbidity and functional disability, and it is thus important to reveal the mechanism of depression. A variety of studies suggest an involvement of neuronal nitric oxide synthase in the pathophysiological mechanism of none-stress-associated depression-like behavior in rodents. It is unknown, however, whether inducible nitric oxide synthase (iNOS) also makes contributions to the mechanism of depression. Here we show that intra-hippocampal injections of the iNOS inhibitor aminoguanidine during chronic unexpected mild stress (CUMS) suppressed CUMS-induced depression-like behavioral changes, including a reduction in sucrose preference, body weight, locomotor activity, rearing and grooming in open field test, and increased duration of immobility in forced swimming test. Thus, inhibition of hippocampal iNOS may prevent the development of CUMS model of depression.