The dangerous "West Coast Swing" by hyperglycaemia and chronic stress in the mouse hippocampus: Role of kynurenine catabolism.

Growing epidemiological studies highlight a bi-directional relationship between depressive symptoms and diabetes mellitus. However, the detrimental impact of their co-existence on mental health suggests the need to treat this comorbidity as a separate entity rather than the two different pathologies. Herein, we characterized the peculiar mechanisms activated in mouse hippocampus from the concurrent development of hyperglycaemia, characterizing the different diabetes subtypes, and chronic stress, recognized as a possible factor predisposing to major depression. Our work demonstrates that kynurenine overproduction, leading to apoptosis in the hippocampus, is triggered in a different way depending on hyperglycaemia or chronic stress. Indeed, in the former, kynurenine appears produced by infiltered macrophages whereas, in the latter, peripheral kynurenine preferentially promotes resident microglia activation. In this scenario, QA, derived from kynurenine catabolism, appears a key mediator causing glutamatergic synapse dysfunction and apoptosis, thus contributing to brain atrophy. We demonstrated that the coexistence of hyperglycaemia and chronic stress worsened hippocampal damage through alternative mechanisms, such as GLUT-4 and BDNF down-expression, denoting mitochondrial dysfunction and apoptosis on one hand and evoking the compromission of neurogenesis on the other. Overall, in the degeneration of neurovascular unit, hyperglycaemia and chronic stress interacted each other as the partners of a "West Coast Swing" in which the leading role can be assumed alternatively by each partner of the dance. The comprehension of these mechanisms can open novel perspectives in the management of diabetic/depressed patients, but also in the understanding the pathogenesis of other neurodegenerative disease characterized by the compromission of hippocampal function.

Chronic Stress Impairs the Structure and Function of Astrocyte Networks in an Animal Model of Depression.

Now astrocytes appear to be the key contributors to the pathophysiology of major depression. Evidence in rodents shows that chronic stress is associated with a decreased expression of astrocytic GFAP-immunoreactivity within the cortex in addition to changes in the complexity and length of astrocyte processes. Furthermore, postmortem brains of individuals with depression have revealed a decrease in astrocyte density. Notably, astrocytes are extensively coupled to one another through gap junctions to form a network, or syncytium, and we have previously demonstrated that syncytial isopotentiality is a mechanism by which astrocytes function as an efficient system with respect to brain homeostasis. Interestingly, the question of how astrocyte network function changes following chronic stress is yet to be elucidated. Here, we sought to examine the effects of chronic stress on network-level astrocyte (dys)function. Using a transgenic aldh1l1-eGFP astrocyte reporter mouse, a six-week unpredictable chronic mild stress (UCMS) paradigm as a rodent model of major depression, and immunohistochemical approaches, we show that the morphology of individual astrocytes is altered by chronic stress exposure. Additionally, in astrocyte syncytial isopotentiality measurement, we found that UCMS impairs the syncytial coupling strength of astrocytes within the hippocampus and prefrontal cortex-two brain regions that have been implicated in the regulation of mood. Together, these findings reveal that chronic stress leads to astrocyte atrophy and impaired gap junction coupling, raising the prospect that both individual and network-level astrocyte functionality are important in the etiology of major depression and other neuropsychiatric disorders.

Effects of unpredictable chronic mild stress on the cellular redox state and mitochondrial energy homeostasis in rat adipose tissue: A comprehensive metabolic study.

Unpredictable chronic mild stress (UCMS) leads to variable metabolic effects. Oxidative stress (OS) of adipose tissue (AT) and mitochondrial energy homeostasis is little investigated. This work studied the effects of UCMS on OS and the antioxidant/redox status in AT and mitochondrial energy homeostasis in rats. Twenty-four male Wistar rats (180-220 g) were divided into two equal groups; the normal control (NC) group and the UCMS group which were exposed to various stresses for 28 days. An indirect calorimetry machine was used to measure volumes of respiratory gases (VO2 & VCO2 ), total energy expenditure (TEE), and food intake (FI). The AT depots were collected, weighed, and used for measuring activities and gene expression of key antioxidant enzymes (GPx1, SOD, CAT, GR, GCL, and GS), OS marker levels including superoxide anion (SA), peroxynitrite radical (PON), nitric oxide (NO), hydrogen peroxide (H2 O2 ), lipid peroxides (LPO), t-protein carbonyl content (PCC), and reduced/oxidized glutathione levels (GSH, GSSG). Additionally, AT mitochondrial fractions were used to determine the activities of the tricarboxylic acid cycle (TCA) cycle enzymes (CS, α-KGDH, ICDH, SDH, MDH), respiratory chain complexes I-III, II-III, IV, the nicotinamide coenzymes NAD+ , NADH, and ATP/ADP levels. Compared with the NC group, the UCMS group showed very significantly increased OS marker levels, lowered antioxidant enzyme activities and gene expression, as well as lowered TCA cycle and respiratory chain activity and NAD+ , NADH, and ATP levels (p < .001 for all comparisons). Besides, the UCMS group had lowered TEE and insignificant FI and weight gain. In conclusion, AT of the UCMS-subjected rats showed a state of disturbed redox balance linked to disrupted energy homeostasis producing augmentation of AT.

High and fluctuating levels of ovarian hormones induce an anxiogenic effect, which can be modulated under stress conditions: Evidence from an assisted reproductive rodent model.

Elevated levels of endogenous ovarian hormones are conditions commonly experienced by women undergoing assisted reproductive technologies (ART). Additionally, infertility-associated stress and treatment routines are factors that together may have a highly negative impact on female emotionality, which can be aggravated when several cycles of ART are needed to attempt pregnancy. This study aimed to investigate the effect of high and fluctuating levels of gonadal hormones induced by repeated ovarian stimulation on the stress response in rodents. To mimic the context of ART, female rats were exposed to an unpredictable chronic mild stress (UCMS) paradigm for four weeks. During this time, three cycles of ovarian stimulation (superovulation) (150 IU/Kg of PMSG and 75 IU/Kg of hCG) were applied, with intervals of two estrous cycles between them. The rats were distributed into four groups: Repeated Superovulation/UCMS; Repeated Superovulation/No Stress; Saline/UCMS; and Saline/No Stress. Anxiety-like and depressive-like behaviors were evaluated in a light-dark transition box and by splash test, respectively. Corticosterone, estradiol, progesterone, and biometric parameters were assessed. Data were analyzed using a two-way Generalized Linear Model (GzLM). Our results showed that repeated ovarian stimulation exerts by itself an expressive anxiogenic effect. Surprisingly, when high and fluctuating levels of ovarian hormones were combined with chronic stress, anxiety-like behavior was no longer observed, and a depressive-like state was not detected. Our findings suggest that females subjected to emotional overload induced by repeated ovarian stimulation and chronic stress seem to trigger the elaboration of adaptive coping strategies.

Effects of the Bark Resin Extract of Garcinia nigrolineata on Chronic Stress-Induced Memory Deficit in Mice Model and the In Vitro Monoamine Oxidases and ß-Amyloid Aggregation Inhibitory Activities of Its Prenylated Xanthone Constituents.

The present study describes investigation of the effects of the bark resin extract of Garcinia nigrolineata (Clusiaceae) on the cognitive function and the induction of oxidative stress in both frontal cortex and hippocampus by unpredictable chronic mild stress (UCMS). By using behavioral mouse models, i.e., the Y-maze test, the Novel Object Recognition Test (NORT), and the Morris Water Maze Test (MWMT), it was found that the negative impact of repeated mild stress-induced learning and memory deficit through brain oxidative stress in the UCMS mice was reversed by treatment with the bark resin extract G. nigrolineata. Moreover, the prenylated xanthones viz. cowagarcinone C, cowaxanthone, α-mangostin, cowaxanthone B, cowanin, fuscaxanthone A, fuscaxanthone B, xanthochymusxanthones A, 7-O-methylgarcinone E, and cowagarcinone A, isolated from the bark resin of G. nigrolineata, were assayed for their inhibitory activities against ß-amyloid (Aß) aggregation and monoamine oxidase enzymes (MAOs).

Brain immune cells characterization in UCMS exposed P2X7 knock-out mouse.

BACKGROUND: Several lines of evidence suggest that neuroinflammation might be a key neurobiological mechanism of depression. In particular, the P2X7 receptor (P2X7R), an ATP-gated ion channel involved in activation of the pro-inflammatory interleukin IL-1ß, has been shown to be a potential new pharmacological target in depression. The aim of this study was to explore the impact of unpredictable chronic mild stress (UCMS) on behavioural changes, hippocampal neurogenesis, and cellular characterisation of brain immune cells, in P2X7R Knock-Out (KO) mice. METHODS: P2X7R KO and wild-type (WT) mice were subjected to a 6-week UCMS protocol and received a conventional oral antidepressant (15 mg.kg-1 fluoxetine) or water per os. The mice then underwent behavioural tests consisting of the tail suspension test (TST), the elevated plus maze (EPM) test, the open field test, the splash test and the nest building test (week 7). Doublecortin immunostaining (DCX) of brain slices was used to assess neurogenesis in the dentate gyrus. Iba1 and TMEM119 immunostaining was used to characterise brain immune cells, Iba1 as a macrophage marker (including microglial cells) and TMEM119 as a potential specific resident microglial cells marker. RESULTS: After a 6-week UCMS exposure, P2X7R KO mice exhibited less deterioration of their coat state, spent a significantly smaller amount of time immobile in the TST and spent a larger amount of time in the open arms of the EPM. As expected, adult ventral hippocampal neurogenesis was significantly decreased by UCMS in WT mice, while P2X7R KO mice maintained ventral hippocampal neurogenesis at similar levels in both control and UCMS conditions. In stress-related brain regions, P2X7R KO mice also exhibited less recruitment of Iba1+/TMEM119+ and Iba1+/TMEM119- cells in the brain. The ratio between these two staining patterns revealed that brain immune cells were mostly composed of Iba1+/TMEM119+ cells (87 to 99%), and this ratio was affected neither by P2X7R genetic depletion nor by antidepressant treatment. DISCUSSION: Behavioural patterns, neurogenesis levels and density of brain immune cells in P2X7R KO mice after exposure to UCMS significantly differed from control conditions. Brain immune cells were mostly increased in brain regions known to be sensitive to UCMS exposure in WT but not in P2X7R KO mice. Considering Iba1+/TMEM119- staining might characterize peripheral immune cells, the ratio between Iba1+/TMEM119+ cells and IBA1+/TMEM119- cells, suggests that the rate of peripheral immune cells recruitment may not be modified neither by P2X7R gene expression nor by antidepressant treatment.

Desvenlafaxine prevents white matter injury and improves the decreased phosphorylation of the rate-limiting enzyme of cholesterol synthesis in a chronic mouse model of depression.

Serotonin/norepinephrine reuptake inhibitors antidepressants exert their effects by increasing serotonin and norepinephrine in the synaptic cleft. Studies show it takes 2-3 weeks for the mood-enhancing effects, which indicate other mechanisms may underlie their treatment effects. Here, we investigated the role of white matter in treatment and pathogenesis of depression using an unpredictable chronic mild stress (UCMS) mouse model. Desvenlafaxine (DVS) was orally administrated to UCMS mice at the dose of 10 mg/kg/day 1 week before they went through a 7-week stress procedure and lasted for over 8 weeks before the mice were killed. No significant changes were found for protein markers of neurons and astrocytes in UCMS mice. However, myelin and oligodendrocyte-related proteins were significantly reduced in UCMS mice. DVS prevented the stress-induced injury to white matter and the decrease of phosphorylated 5'-AMP-activated protein kinase and 3-hydroxy-3-methyl-glutaryl-CoA reductase protein expression. DVS increased open arm entries in an elevated plus-maze test, sucrose consumption in the sucrose preference test and decreased immobility in tail suspension and forced swimming tests. These findings suggest that stress induces depression-like behaviors and white matter deficits in UCMS mice. DVS may ameliorate the oligodendrocyte dysfunction by affecting cholesterol synthesis, alleviating the depression-like phenotypes in these mice. We examined the possible role of oligodendrocyte and myelin in the pathological changes of depression with an unpredictable chronic mild stress (UCMS) mouse model. Oligodendrocyte-related proteins in the mouse brain were specifically changed during the stress period. The depressive-like behaviors and oligodendrocyte deficits could be prevented by the administration of desvenlafaxine. Oligodendrocyte and myelin may be an essential target of desvenlafaxine for the treatment of depression.

A Comparison of Isolation Stress and Unpredictable Chronic Mild Stress for the Establishment of Mouse Models of Depressive Disorder.

This study aimed to help to understand the influence of stress on depression, which reflects the social environments of especially solitary life and the increasing prevalence of depressive disorders. To determine the distinguishable features of two-representative animal models of stress-induced depressive disorder, we compared isolation stress (IS) and unpredictable chronic mild stress (UCMS). After 4-week of stress, both models showed significant depressive- and anxiety-like behaviors in an open field test (OFT; p < 0.01 for IS, p < 0.01 for UCMS), forced swimming test (FST; p < 0.01 for IS, p < 0.01 for UCMS), and tail suspension test (TST; p < 0.01 for IS, p < 0.05 for UCMS) along with alterations in serum corticosterone levels, serotonin activity in the dorsal raphe nuclei (DRN) and microglial activity in the dentate gyrus of the hippocampus (p < 0.05 for both parameters). In a comparison of the two stress models, IS strongly induced depressive and anxiety features, as indicated by all parameters: behavior test scores (p < 0.05 for OFT, FST, and TST), serum corticosterone levels (p < 0.05), immunohistological alterations for serotonin activity (p < 0.05) and microglial activity (p = 0.072). Our results indicate the suitability of IS for the development of animal models of depressive disorders and may reveal the medical impact of social isolation environment in modern society.

Cerebral MAO Activity Is Not Altered by a Novel Herbal Antidepressant Treatment.

Inhibition of monoamine oxidase (MAO)-A/B can ameliorate depressive- and anxiety-related symptoms via increase of monoamine extracellular levels. However, such inhibition can also instigate hypertensive response following exposure to dietary tyramine (i.e., "the cheese effect"). Novel herbal treatment (NHT) is an herbal formula that has been demonstrated to reduce depressive- and anxiety-like symptoms in pre-clinical studies. The aim of the current study was to examine whether the therapeutic potential of NHT is underlain by inhibition of MAO-A/B and whether NHT poses a risk for tyramine hyper-potentiation. Unpredictable chronic mild stress (UCMS)-exposed mice and naïve mice were treated for 3 weeks with NHT (30 mg/kg; i.p.), the selective serotonin reuptake inhibitor (SSRI) escitalopram (15 mg/kg; i.p.), or saline. Subsequently, MAO-A/B activities in the hypothalamus, striatum, and prefrontal cortex (PFC) were assessed. Exposure to UCMS led to significant increases in both MAO-A and MAO-B activities in the hypothalamus (p < 0.001) and in the PFC (p < 0.01 for MAO-A; p < 0.001 for MAO-B). Neither NHT nor escitalopram had any notable effects. Treatment with NHT was supported as safe in terms of risk for inducing a hypertensive response. The antidepressant- and anxiolytic-like effects of NHT are mediated via pathways other than MAO-A/B inhibition.

A P2X7 receptor antagonist reverses behavioural alterations, microglial activation and neuroendocrine dysregulation in an unpredictable chronic mild stress (UCMS) model of depression in mice.

A polymorphism in the P2RX7 gene that encodes for the P2X7 ionotropic ATP-gated receptor (P2X7R) protein has been shown to be associated with an increased risk for developing depressive illnesses. However, the role of P2X7R in depression is still unclear. To better understand the role of P2X7R and its subsequent impact on microglial activation, we compared the effect of the P2X7R antagonist Brilliant Blue G (BBG) with that of fluoxetine in an unpredictable chronic mild stress (UCMS) model of depression in mice. Our results indicate that BBG (50 mg/kg body weight in 0.9% NaCl, 10 ml/kg/day) successfully reversed the degradation of coat states and nest-building scores induced by exposure to UCMS, similar to the conventional antidepressant fluoxetine (15 mg/kg body weight in 0.9% NaCl, 10 ml/kg/day). BBG also reversed the UCMS-induced microglial activation in cortical and hippocampal regions and the basal nuclei of mouse brains and corrected the UCMS-induced hypothalamo-pituitary-adrenal (HPA) axis dysregulation. In contrast to fluoxetine, however, BBG treatment did not increase the density of doublecortin-positive cells in the dentate gyrus, indicating that BBG had no impact on hippocampal neurogenesis. These results suggest that P2X7R is involved in recovery from depressive-like states caused by exposure to UCMS in a mechanism that involves restoration of the HPA axis but not hippocampal neurogenesis. These results add to the evidence that P2X7R antagonist agents may have potential value in the pharmacological management of depression.