Chronic Stress Rat Research Articles

Exploring the potential role of sonic hedgehog cell signalling pathway in antidepressant effects of nicotine in chronic unpredictable mild stress rat model

Nicotine is the most common and highly addictive drug of abuse, associated with several life-threatening diseases and high mortality. Nicotine abuse is the concerted effort to feel reward and fight depression in depressed individuals. The underlying mechanism of nicotine is to activate the brain reward system in the central nervous system and provide an antidepressant effect. Antidepressants provide their therapeutic effect by stimulating hippocampal neurogenesis, which can be correlated with brain derived neurotrophic factor (BDNF) expression in the hippocampus. BDNF interacts with Wnt/β-catenin and sonic hedgehog (Shh) signalling cascade to stimulate hippocampal neurogenesis. Shh is the marker of hippocampal neurogenesis and also involved in the neuropathology of depression. But knowledge in this area to identify the potential therapeutic target is limited. In our study, we explored the role of BDNF, Wnt/β-catenin and Shh signalling in depression and the involvement of these signalling pathways in providing an antidepressant effect by nicotine. Our investigations showed that chronic unpredictable mild stress induced depression results declined expression of BDNF, Wnt/β-catenin, Shh and its downstream transcription factors GLI1/2/3 and NKX2.2 in the hippocampus of male Wistar rat. Moreover, we also observed that nicotine administration increased the expression of these signalling molecules in providing the antidepressant effects.

The antidepressant effect of bone marrow mononuclear cell transplantation in chronic stress.

Inflammation could be a risk factor for the development of depression and change the outcome of this common chronic-recurrent mental disorder. This study aimed to investigate if bone marrow mononuclear cell (BMMC) transplantation is effective in restoring sucrose preference in rats subjected to chronic stress (CS), if it has an anti-inflammatory effect and is able to restore damaged DNA. The effect of BMMC transplantation was studied in a controlled protocol (compared with a control group and a selective serotonin reuptake inhibitor escitalopram group) involving sucrose preference in CS in rats. Measurements were taken of the amygdala, hippocampus, frontal cortex, and other brain areas, the spleen and blood pro-inflammatory cytokines, namely interleukin-1β, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma, as well as anti-inflammatory cytokine interleukin-10. Finally, 8-hydroxy-2'-deoxyguanosine (a DNA damage marker) was determined. BMMC transplantation was as effective as escitalopram in restoring sucrose preference. It also had an anti-inflammatory effect and slightly improved damaged DNA after one week. These findings suggest administration of BMMC in rats subjected to CS restores sucrose preference, resolves inflammation in both the peripheral and central nervous system, as well as diminishes DNA damage. This effect was similar to that of escitalopram, which is effective in the treatment of depressive patients.

Acupuncture improves hippocampal apoptosis state by reducing expression of ROS and Cytochrome C and Caspase-3 in Chronic Restraint Stress Rats

The depressant-like effects of albiflorin (AF) were studied on stressed chronic restraint stress (CRS) rats. Experimental rats were subjected to immobilization stress for a daily 6 h-restraining in a plastic restrainer for continuous 21 d and were treated with 30 or 15 mg·kg−1 of AF for 21 d. Control rats were maintained in completely non stressed conditions. Behavioral tests and biochemical analysis were applied to investigating a regulatory mechanism of anti-stress of AF. Treatment with AF significantly restored the depressant-like behaviors. Besides, AF increased the levels of 5-hydroxytryptophan (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NE) and dopamine (DA) in the hippocampus and increased the level of brain-derived neurotrophic factor (BDNF) in serum and protein expression in hippocampus. In addition, AF decreased the levels of hypothalamo-pituitary-adrenal (HPA) cascade, reduced the level of NO and cGMP in serum and inhibited the overexpression of 5-HT2AR mRNA and protein expression. Taken together, AF can modulate the NO-mediated network pathway in the hippocampus against stress-induced depressive-like behaviors. These physiological and behavioral changes allow rats to avoid potential deleterious effects of stress that may result from chronically elevated levels of glucocorticosteroids over days.

Pharmacokinetics-pharmacodynamics and tissue distribution analysis of Low Polar extract of Xiaoyao Powder combined with rat model of chronic unpredictable mild stress

Xiaoyao powder (XYP) is a valuable traditional Chinese Medicine (TCM) prescription developed for depression. Previous findings have suggested that the low polar extract of XYP (XYP-A) was more effect than other parts and its main ingredients included ligustilide, (2Z,8Z,10E)-pentadecatriene-4,6-diyn-1-ol (RB-1), (2Z,8E,10E)-pentadecatriene-4,6-diyn-1-ol (RB-2), (2Z,8Z,10E)-heptadecatriene-4,6-diyn-1-ol (RB-3), and bupleurynol (RB-4). However, the correlation between concentration of main ingredients and effects is still indeterminate. This study developed an ultra performance lipid chromatography combined with photo-diode array detector (UPLC-PDA) method to determine the contents of main ingredients in serum and tissues for pharmacokinetics and tissue distribution analysis. And, norepinephrine (NE) and 5-hydroxytryptamine (5-HT) were selected as the pharmacodynamic index and determined using the method of high performance lipid chromatography combined with fluorescence detector (HPLC-FD) in the serum for pharmacodynamics analysis. The DAS3.0 software was used to fit the pharmacokinetics-pharmacodynamics (PK-PD) model. The pharmacokinetic assay revealed that the absorption of polyacetylene compound was more favorable under pathological status. And, the result of tissue distribution showed that RB-2 and RB-4 were rapidly and widely distributed in tissues, and easy to cross the blood-brain barrier. The comparison of the value of NE and 5-HT in chronic unpredictable mild stress (CUMS) and control group rats suggested that 5-HT might be the main targets for the four polyacetylene compounds. The present study demonstrated that XYP-A showed the certain therapeutic effect of for depression safely and that polyacetylene compounds might be active ingredient for depression.

Integrated Metabolomics and Proteomics Analysis Revealed Second Messenger System Disturbance in Hippocampus of Chronic Social Defeat Stress Rat.

Depression is a common and disabling mental disorder characterized by high disability and mortality, but its physiopathology remains unclear. In this study, we combined a non-targeted gas chromatography-mass spectrometry (GC-MS)-based metabolomic approach and isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis to elucidate metabolite and protein alterations in the hippocampus of rat after chronic social defeat stress (CSDS), an extensively used animal model of depression. Ingenuity pathway analysis (IPA) was conducted to integrate underlying relationships among differentially expressed metabolites and proteins. Twenty-five significantly different expressed metabolites and 234 differentially expressed proteins were identified between CSDS and control groups. IPA canonical pathways and network analyses revealed that intracellular second messenger/signal transduction cascades were most significantly altered in the hippocampus of CSDS rats, including cyclic adenosine monophosphate (cAMP), phosphoinositol, tyrosine kinase, and arachidonic acid systems. These results provide a better understanding of biological mechanisms underlying depression, and may help identify potential targets for novel antidepressants.

A Resting-State Functional MR Imaging and Spectroscopy Study of the Dorsal Hippocampus in the Chronic Unpredictable Stress Rat Model

Exposure to chronic stress leads to an array of anatomical, functional, and metabolic changes in the brain that play a key role in triggering psychiatric disorders such as depression. The hippocampus is particularly well known as a target of maladaptive responses to stress. To capture stress-induced changes in metabolic and functional connectivity in the hippocampus, stress-resistant (low-responders) or -susceptible (high-responders) rats exposed to a chronic unpredictable stress paradigm (categorized according to their hormonal and behavioral responses) were assessed by multimodal neuroimaging; the latter was achieved by using localized 1H MR spectroscopy and resting-state functional MRI (fMRI) at 11,7T data from stressed (n = 25) but also control (n = 15) male Wistar rats.Susceptible animals displayed increased GABA-glutamine (+19%) and glutamate-glutamine (+17%) ratios and decreased levels of macromolecules (-11%); these changes were positively correlated with plasma corticosterone levels. In addition, the neurotransmitter levels showed differential associations with functional connectivity between the hippocampus and the amygdala, the piriform cortex and thalamus between stress-resistant and -susceptible animals. Our observations are consistent with previously reported stress-induced metabolomic changes that suggest overall neurotransmitter dysfunction in the hippocampus. Their association with the fMRI data in this study reveals how local adjustments in neurochemistry relate to changes in the neurocircuitry of the hippocampus, with implications for its stress-associated dysfunctions.SIGNIFICANCE STATEMENT Chronic stress disrupts brain homeostasis, which may increase the vulnerability of susceptible individuals to neuropsychiatric disorders such as depression. Characterization of the differences between stress-resistant and -susceptible individuals on the basis of noninvasive imaging tools, such as magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI), contributes to improved understanding of the mechanisms underpinning individual differences in vulnerability and can facilitate the design of new diagnostic and intervention strategies. Using a combined functional MRI/MRS approach, our results demonstrate that susceptible- and non-susceptible subjects show differential alterations in hippocampal GABA and glutamate metabolism that, in turn, associate with changes in functional connectivity.

Minocycline ameliorates anxiety-related self-grooming behaviors and alters hippocampal neuroinflammation, GABA and serum cholesterol levels in female Sprague-Dawley rats subjected to chronic unpredictable mild stress

Neuroinflammation induced by stress results in aberrant neurotransmission and dyslipidemia, which can trigger depression- and anxiety-like behaviors. Gamma-aminobutyric acid (GABA) and cholesterol play a crucial role in anxiety-like states, including self-grooming - a common stress-evoked rodent behavior. However, the interaction between neuroinflammation, GABA and cholesterol under stress, and their effects on grooming, remain unclear. Here, we utilize the chronic unpredictable mild stress (CUMS) rat cohort used previously in our Zhang et al. (2019) study, to examine whether CUMS affects grooming behavior, and whether minocycline, a microglia antagonist, can correct these behavioral deficits, accompanied by altering hippocampal neuroinflammation, GABA and serum cholesterol levels. Female Sprague-Dawley rats underwent a 6-week CUMS and received daily minocycline (40 mg/kg, i.p.) during this period, followed by behavioral testing in the open field test. Serum cholesterol, inflammatory cytokines and GABA levels in hippocampus were assayed by ELISA. CUMS significantly decreased locomotion, rearing, central zone entries and time spent in the open field center compared to unstressed controls. CUMS also strongly affected self-grooming behaviors, increasing the frequency of grooming episodes, the number of transitions, interruptions and individual elements of various grooming phases. However, these CUMS-induced behavioral abnormalities were corrected by minocycline. Likewise, CUMS elevated total serum cholesterol and lowered serum high-density lipoprotein cholesterol, whereas minocycline ameliorated these responses. CUMS also lowered hippocampal GABA, whereas minocycline normalized CUMS-induced GABA in the hippocampus. We also found significant correlations between neuroinflammation and GABA, neuroinflammation and cholesterol, GABA and grooming, as well as cholesterol and grooming measures, further implicating stress-evoked neuroinflammation, GABA and cholesterol in the regulation of complex rodent behaviors. In summary, minocycline ameliorated CUMS-induced aberrant self-grooming behaviors in rats by altering hippocampal neuroinflammation, GABA and serum cholesterol levels.

Neuroprotective Effects of Curcumin on IL-1β-Induced Neuronal Apoptosis and Depression-Like Behaviors Caused by Chronic Stress in Rats.

Depression is suggested to be a neuropsychiatric disease resulting from neuroinflammation within specific brain regions. Curcumin, a potential neuroprotective agent extracted from curcuma loga, exerts antidepressant-like effects in various animal models of depression. However, the underlying mechanisms, in particular whether curcumin may exert neuroprotection through suppression of inflammatory pathway activity in depression remains largely unknown. In the present study, we examined the molecular events of curcumin as related to its capacity for neuroprotection against inflammation-induced neuronal apoptosis and depression-like behaviors in a rat model of depression. Our results show that chronic administration of curcumin (40 mg/kg, i.p., 5 weeks) prior to stress exposure significantly alleviated depression-like behaviors, expression of the proinflammatory cytokine interleukin-1β (IL-1β) and inhibited neuronal apoptosis within neurons of the ventromedial prefrontal cortex (vmPFC). Within the vmPFC of stressed rats, an intracerebral infusion of an RNAi form of IL-1β in adenovirus associated virus (AAV-IL-1β RNAi) significantly ameliorated depression-like behaviors, neuronal apoptosis and reduced phosphorylated-p38 mitogen-activated protein kinase (p-p38 MAPK) expression levels. More important, within the vmPFC of wild type rats, overexpression of IL-1β via intracerebral infusion of AAV-IL-1β induced p38 MAPK phosphorylation and neuronal apoptosis, which could be significantly prevented by chronic treatment of curcumin. Collectively, these findings reveal that curcumin protects against IL-1β-induced neuronal apoptosis, which may be related to the display of depression-like behaviors in stressed rats. Moreover, they provide new insights into the mechanisms and therapeutic potential for curcumin in the treatment of inflammation-related neuronal deterioration in this disorder.

Research on the establishment of chronic stress-induced premature ovarian failure the rat model and effects of Chinese medicine Muniziqi treatment.

The purposes of this study were to establish and to explore the biological basis of the chronic stress-induced premature ovarian failure (POF) model and to explore the therapeutic effects of the traditional Chinese medicine Muniziqi. Sexually matured female Sprague-Dawley rats were fed with spinach and cilantro in cold and wet conditions for about 20 weeks until a chronic stress (CS) model was established. The CS rats were divided into a POF stress model group and a stress model group according to weekly biological characteristics and hormone level detection ( luteinizing hormone [LH], follicle stimulating hormone [FSH], and estrogen [E2]). To investigate the therapeutic effect of Muniziqi, the POF disease stress model group was divided into the high-, medium-, and low-drug intervention groups. The results showed that chronic stresses (special food, cold, damp) can lead to POF disease. The traditional Chinese medicine Muniziqi could not only improve the reproductive hormone level disorder, but also improve the function of the hypothalamus-pituitary-ovarian axis. The underlying mechanism may be a change in the E2, LH, and FSH hormone levels in serum and lower expression of ovarian premature aging-related protein PFN-1.

Pterostilbene, an active component of the dragon's blood extract, acts as an antidepressant in adult rats.

Hippocampal neurogenesis has been widely considered as one of the potential biological mechanisms for the treatment of depression caused by chronic stress. Many natural products have been reported to be beneficial for neurogenesis. The present study is designed to investigate the effect of dragon's blood extract (DBE) and its biologically active compound, pterostilbene (PTE), on hippocampal neurogenesis. The male Sprague-Dawley (SD) rats were used in this study, which were maintained on the normal, DBE and PTE diet groups for 4 weeks before dissection in the normal rat model and behavioral testing in the CUS depression rat model. Meanwhile, DMI-treated rats are subcutaneously injected with DMI (10 mg/kg, i.p.). Results revealed that DBE and PTE have the ability to promote hippocampal neurogenesis. DBE and PTE also promoted the proliferation of neural stem cells isolated from the brain of suckling rats. Oral administration of DBE and PTE induced the proliferation, migration, and differentiation of neural progenitor cells (NPCs) in chronic unexpected stressed (CUS) model rats, and improved the behavioral ability and alleviated depress-like symptoms of CUS rats. It was also observed that PTE treatment significantly induced the expression of neurogenesis-related factors, including BDNF, pERK, and pCREB. Oral administration of PTE could affect neurogenesis and it is likely to be achieved via BDNF/ERK/CREB-associated signaling pathways.

Impact of traditional Chinese medicine treatment on chronic unpredictable mild stress-induced depression-like behaviors: intestinal microbiota and gut microbiome function.

Gut microbiota dysbiosis is a recognized contributing factor to many noncommunicable diseases, but more evidence is still needed to illustrate its causative impact on mental and brain health disorders and mechanism(s) for targeted mitigation. Traditional Chinese Medicine (TCM) has been used in the management of neuropsychiatric diseases for many years in China. In this study, a randomized, controlled trial was conducted to examine the impact of stress on gut microbiota dysbiosis and depression, and TCM in alleviating the damage using Chronic Unpredictable Mild Stress (CUMS) rats, a well-established rodent model for depression. The behaviors of rats and the profiles of the fecal microbiota were assessed by an array of behavioral tests and 16S rRNA gene sequencing, and the intestinal microbial function was assessed by shotgun sequencing-based metagenomic analysis of microbial DNA from fecal samples. Data on brain targeted metabolites by liquid chromatography-mass spectrometry (LC-MS) were also discussed. Depressive and anxiety-like behaviors and changes in the fecal microbiota profile were observed in CUMS rats, which were then significantly reversed in CUMS rats that received TCM. Specifically, TCM treatment reduced the levels of Firmicutes, and Ruminococcus, and increased the abundance of Bacteroidetes and Roseburia, reportedly being associated with relieving psychiatric disorders. Furthermore, the levels of brain metabolites perturbed by CUMS were reversed by TCM treatment, and Spearman's correlation analysis illustrated strong correlation between brain metabolites and perturbed fecal microbiota genera. Finally, the fecal microbiome of CUMS rats was characterized by alterations in amino acid metabolism and evaluation of bile acid biosynthesis, and TCM-treated rats showed elevation of cysteine and methionine metabolism. Overall, these results indicated that administration of the TCM may mitigate CUMS-induced depression-behaviors, and it is correlated with reversing CUMS-induced intestinal microbiota dysbiosis; evidence also supported related changes in brain metabolites. These findings set up the foundation to further reveal the exact causal relationship among the TCM formula, host responses, gut microbiota dysbiosis and the levels of brain metabolites, and enabled scientific interpretation of the therapeutic function of the TCM.

Effects of escitalopram and ibuprofen on a depression-like phenotype induced by chronic stress in rats

Clinical and preclinical studies have reported that co-administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and antidepressant drugs are effective in patients with depression and in animal models of depression. However, several studies have suggested that NSAIDs inhibit the antidepressant effects of selective serotonin reuptake inhibitors in humans and mice. The present study investigated the effects of escitalopram (ESC) and ibuprofen (IBU), alone or in combination, on the stress-induced behavior and expression of brain-derived neurotrophic factor (BDNF) and p11, markers of depression and antidepressant action, in chronically stressed rats. Rats were subjected to chronic restraint stress (CRS) for 3 weeks and administered the following drugs: single administration of ESC or IBU or co-administration of ESC and IBU (ESC + IBU). Immobility time was measured by the forced swimming test (FST), and hippocampal BDNF and p11 levels were analyzed by quantitative real-time polymerase chain reaction and Western blotting. CRS increased immobility time on the FST. Administration of ESC, IBU, or ESC + IBU significantly attenuated the stress-induced increase in immobility time. CRS also significantly increased plasma corticosterone concentration by 169%. This effect was significantly recovered by administering ESC, IBU, or ESC + IBU. The levels of BDNF and p11 in the hippocampus decreased significantly in response to CRS. These decreases were prevented by administering ESC, IBU, or ESC + IBU. These findings suggest that both single and co-administration of ESC and IBU exerts antidepressant effects. These effects were associated with upregulation of BDNF and p11 expression.

Neuroprotective Effects of Ginsenoside-Rg1 Against Depression-Like Behaviors via Suppressing Glial Activation, Synaptic Deficits, and Neuronal Apoptosis in Rats.

Depression is considered a neuropsychiatric disease associated with various neuronal changes within specific brain regions. We previously reported that ginsenoside-Rg1, a potential neuroprotective agent extracted from ginseng, significantly alleviated depressive-like disorders induced by chronic stress in rats. However, the mechanisms by which ginsenoside-Rg1 exerts its neuroprotective effects in depression remain largely uncharacterized. In the present study we confirm that ginsenoside-Rg1 significantly prevented the antidepressant-like effects in a rat model of chronic unpredictable mild stress (CUMS) and report on some of the underlying mechanisms associated with this effect. Specifically, we found that chronic pretreatment with ginsenoside-Rg1 prior to stress exposure significantly suppressed inflammatory pathway activity via alleviating the overexpression of proinflammatory cytokines and the activation of microglia and astrocytes. These effects were accompanied with an attenuation of dendritic spine and synaptic deficits as associated with an upregulation of synaptic-related proteins in the ventral medial prefrontal cortex (vmPFC). In addition, ginsenoside-Rg1 inhibited neuronal apoptosis induced by CUMS exposure, increased Bcl-2 expression and decreased cleaved Caspase-3 and Caspase-9 expression within the vmPFC region. Furthermore, ginsenoside-Rg1 could increase the nuclear factor erythroid 2-related factor (Nrf2) expression and inhibit p38 mitogen-activated protein kinase (p-p38 MAPK) and nuclear factor κB (NF-κB) p65 subunit activation within the vmPFC. Taken together, these results suggest that the neuroprotective effects of ginsenoside-Rg1, which may assume the antidepressant-like effect in this animal model of depression, appears to result from amelioration of a CUMS-dependent neuronal deterioration within the vmPFC. Moreover, they also provide support for the therapeutic potential of ginsenoside-Rg1 in the treatment of stress-related mental disorders.

Phyllanthus emblica leaf extract ameliorates testicular damage in rats with chronic stress.

Stress affects the male reproductive system and can cause sub-fertility or infertility. Although Phyllanthus emblica L. (PE) extract has been shown to have high antioxidant capacity and protective properties in damaged tissue, the preventive effects of PE extract on testicular function from stress-related impairment have never been demonstrated. This study aimed to investigate the effects of PE aqueous leaf extract on testicular impairment and protein marker changes in rats suffering from chronic stress. Adult male rats were divided into four groups: a control group, a chronic stress (CS) group, and two groups with CS that received different doses of PE extract (50 or 100 mg/kg body weight (BW)). In the treatment groups, the animals were given PE extract daily before stress induction for 42 consecutive days. Stress was induced through immobilization (4 h/d) followed by forced cold swimming (15 min/d). Sperm quality and the histology of the testes and caudal epididymis were examined, as were levels of serum corticosterone, testosterone, and malondialdehyde (MDA). The expressions of testicular steroidogenic acute regulatory (StAR) and tyrosine-phosphorylated proteins were investigated using immuno-Western blot analysis, as these proteins are assumed to play important roles in spermatogenesis and androgen synthesis. The results showed that PE (50 mg/kg BW) significantly increased sperm concentration and testosterone levels, while decreasing corticosterone levels, MDA levels, sperm head abnormalities, and acrosome-reacted sperm in CS rats. In addition, PE at both doses was found to diminish testicular histopathology in the CS rats. We also found that 50 mg/kg BW of PE significantly improved StAR protein expression and altered the intensities of some tyrosine-phosphorylated proteins in testis. We conclude that PE leaf extract at 50 mg/kg BW can prevent testicular damage in rats with CS.

Apelin-13 ameliorates chronic water-immersion restraint stress-induced memory performance deficit through upregulation of BDNF in rats

A large number of studies have demonstrated that the hippocampus has important influences on stress response and memory. The abundant expressions of apelin and its receptor APJ in the hippocampus may imply potential involvement of apelin/APJ signaling in modulating stress-related memory performance deficit. In our previous study, apelin-13 ameliorates memory performance deficit in acute stressed rats. Here, we further examined whether apelin-13 can ameliorate memory performance deficit in chronic stressed rats. Rats were exposed to chronic water-immersion restraint stress (CWIRS) for 4 weeks. After stress withdrawal, apelin-13 was intracerebroventricularly infused once a day for one week. The novel object recognition test (NORT) and Y-maze test (YMT), two hippocampus-dependent memory tasks, were performed to assess memory performance. We found that apelin-13 restored CWIRS-induced decline in the discrimination index and alternation ratio in NORT and YMT, respectively. Furthermore, apelin-13 ameliorated CWIRS-induced hippocampal BDNF expression deficit, and the TrkB receptor antagonist ANA-12 blocked the ameliorative effect of apelin-13 on memory performance deficit in CWIRS rats. The current observations indicate that apelin-13 ameliorates CWIRS-induced memory performance deficit through upregulation of BDNF in rats.

L-theanine ameliorate depressive-like behavior in a chronic unpredictable mild stress rat model via modulating the monoamine levels in limbic-cortical-striatal-pallidal-thalamic-circuit related brain regions.

L-theanine, originally found in green tea, elicits various physiological effects, such as promoting relaxation, improving concentration and learning ability, and providing antianxiety-like and antidepressant-like properties. This study aims to investigate the effects of L-theanine (2mg/kg) on monoamine levels in an animal model of depression. The effect of l-theanine on the symptoms of depression was examined through the open-field test, sucrose preference test, and forced swim test. The monoamine neurotransmitters that involve serotonin (5-HT), norepinephrine (NE), and dopamine (DA) were measured in the limbic-cortical-striatal-pallidal-thalamic (LCSPT)-circuit related brain regions, including the prefrontal cortex (PFC), nucleus accumbens (NAC), striatum (ST), amygdala, and hippocampus (HIP). L-theanine ameliorated the depressive-like behaviors in the chronic unpredictable mild stress (CUMS) rat model. In the PFC, NAC, and HIP, L-theanine administration significantly increased the levels of 5-HT, NE, and DA. In the ST, the levels of 5-HT and DA were increased after the administration of L-theanine. However, in the HIP, only the level of DA significantly changed after the treatment of L-theanine. Taken together, these results indicated that L-theanine has possibly antidepressant-like effects in the CUMS rat model, which could be mediated by the monoamine neurotransmitters in the LCSPT-circuit related brain regions.

Hippocampal orexin receptor blocking prevented the stress induced social learning and memory deficits.

Stress as a homeostatic challenge leads to the malfunction of learning and memory processes, namely social learning and memory. The orexin system is involved in stress responses through connections to the hypothalamic-pituitary axis (HPA). In addition, the hippocampus, a structure vulnerable to stress-induced changes, expresses orexin receptors 1 and 2 (OXr1 and OXr2) in various sub-regions. The present study is aimed at assessing the effects of hippocampal orexin receptor blockade on social learning and memory impairments and anxiety development following stress. Male Wistar rats (220-250 g) underwent cannula implantation in the hippocampus. Acute (two mild electric shocks, 5.5 mA) and chronic stresses (ten days of restraint, 6 h daily) were applied with or without injection of orexin receptor antagonists (SB-334867 or TCS OX 29). Sociability and social novelty in animals were assessed in a three-chamber social maze at the end of stress application. Anxiety and exploratory behavior of animals were then examined, with 20 min intervals, using the open field (OF) and elevated plus maze (EPM) tests, respectively. Cisterna Magna cerebro-spinal fluid (CSF) was drained, before sacrifice, for orexin (OX) assay and trunk blood was collected to measure the plasma corticosterone (CRT). Neither the acute nor the chronic stress could affect the sociability. The acute but not chronic stress prevented the animal from sniffing the familiar caged rat in the novelty session, a response which was reversed following the blockade of both OXRs. Furthermore, acute but not chronic stress, led to increased anxiety and immobility behavior which were both impeded by blocking the orexin receptor (OXR). Conversely, OX content in CSF increased due to chronic restraint stress, an effect that was reversed by orexin blockade. Finally, elevated plasma CRT was recorded in response to both acute and chronic stresses. The observed increase in plasma CRT in chronically-stressed rats was abolished following inhibition of OXRs, however a similar effect was not seen in the acute-stress group. Our results identify hippocampal OXRs as potential candidates capable of preventing acute stress-induced impairments of social novelty and anxiety behavior, and chronic stress-induced plasma CRT and CSF orexin, changes. OXR manipulation may improve adaptation to stress pathophysiology.

ITRAQ-Based Quantitative Proteomics Suggests Synaptic Mitochondrial Dysfunction in the Hippocampus of Rats Susceptible to Chronic Mild Stress.

Mounting studies show that hippocampal synaptic transmission and plasticity are abnormal in depression. It has been suggested that impairment of synaptic mitochondrial functions potentially occurs in the hippocampus. Thus, the synaptic mitochondria may be a crucial therapeutic target in the course of depression. Here, we investigated the potential dysregulation of synaptic mitochondrial proteins in the hippocampus of a chronic mild stress (CMS) rat model. Proteomic changes of hippocampal synaptosomes containing synaptic mitochondria were quantitatively examined using the isobaric tag for relative and absolute quantitation labeling combined with tandem mass spectrometry. 45 Proteins were identified to be differentially expressed, of which 21 were found to be putative synaptic mitochondrial proteins based on gene ontology component and SynaptomeDB analyses. Detailed investigations of protein functions and disease relevance support the importance of hippocampal synaptic mitochondria as a key substrate contributing to impairment in synaptic plasticity of stress-related disorders. Interestingly, eight synaptic mitochondrial proteins were specifically associated to the susceptible group, and might represent part of molecular basis of depression. Further analysis indicated that the synaptic mitochondrial oxidative phosphorylation (OXPHOS) system was heavily affected by CMS in the susceptible rats. The present results provide novel insights into the disease mechanism underlying the abnormal OXPHOS that is responsible for energy-demanding synaptic plasticity, and thereby increase our understanding of the role of hippocampal synaptic mitochondrial dysfunction in depression.

Sexual Dimorphism of the Neuroendocrine-Immune Complex and its Reactions to Chronic Stress in Rats

Sexual Dimorphism of the Neuroendocrine-Immune Complex and its Reactions to Chronic Stress in Rats

Carob (Ceratonia siliqua L.) Prevents Short-Term Memory Deficit Induced by Chronic Stress in Rats.

Long-term exposure to stressful conditions could impair the normal brain structure and function, specifically the hippocampus-dependent memory. This impairment could be attributed to a decrease in brain-derived neurotrophic factor (BDNF) levels during chronic stress. Knowing that carob [Ceratonia siliqua L. (Fabaceae)] is rich in a wide variety of polyphenols with a high antioxidant value, we hypothesized that the methanolic carob extract (C. siliqua) pods will prevent stress-induced memory impairment. Hence, the methanolic extract of carob pods was investigated for its ability to enhance learning and memory as well as to protect from memory impairment in normal stressed animals. Rats were chronically stressed for 7weeks via the intruder stress model. Carob extract was administered to animals via intraperitoneal (i.p.) route at a daily dose of 50mg/kg. Radial arm water maze (RAWM) was utilized to test for spatial learning and memory. In addition, brain tissues were dissected to determine BDNF levels. Chronic stress (CS) impaired short-term spatial memory (number of committed errors: P < 0.05, days to criterion (DTC): P < 0.001). Animal treatment with carob pod extract prevented the short-term memory impairment induced by CS (P < 0.05), while such treatment showed no effect on memory functions of unstressed rats. Moreover, carob pod extract prevented the reduction in the hippocampal BDNF (P < 0.05) induced by chronic stress exposure. In conclusion, CS impaired short-term memory function, while methanolic extract of carob pods prevented this impairment, probably as a result of preventing reduction in BDNF levels in the hippocampus.