Nobiletin, an activator of the pyruvate kinase isozyme M1/M2 protein, upregulated the glycolytic signalling pathway and alleviated depressive-like behaviour caused by artificial light exposure at night in zebrafish.

We established a zebrafish model of depression-like behaviour induced by exposure to artificial light at night (ALAN) and found that nobiletin (NOB) alleviated depression-like behaviour. Subsequently, based on the results of a 24-h free movement assay, clock gene expression and brain tissue transcriptome sequencing, the glycolysis signalling pathway was identified as a potential target through which NOB exerted antidepressant effects. Using the ALAN zebrafish model, we found that supplementation with exogenous L-lactic acid alleviated depressive-like behaviour. Molecular docking and molecular dynamics simulations revealed an inter-molecular interaction between NOB and the pyruvate kinase isozyme M1/M2 (PKM2) protein. We then used compound 3 k to construct a zebrafish model in which PKM2 was inhibited. Our analysis of this model suggested that NOB alleviated depression-like behaviour via inhibition of PKM2. In summary, NOB alleviated depressive-like behaviour induced by ALAN in zebrafish via targeting of PKM2 and activation of the glycolytic signalling pathway.

Evidence for the Contribution of the miR-206/BDNF Pathway in the Pathophysiology of Depression.

Depression is a complex disorder with substantial impacts on individual health and has major public health implications. Depression results from complex interactions between genetic and environmental factors. Epigenetic mechanisms, including DNA methylation (DNAm), microRNAs (miRNAs), and histone modifications, can produce heritable phenotypic changes without a change in DNA sequence and have been recently proven to mediate lasting increases in the risk of depression following exposure to adverse life events. Of these, miRNAs are gaining attention for their role in the pathogenesis of many stress-associated mental disorders, including depression. One such miRNA is microRNA-206 (miR-206), which is a critical candidate for increasing the susceptibility to stress. Although miR-206 is thought to be a typical muscle-specific miRNA, it is expressed throughout the brain, particularly in the hippocampus and prefrontal cortex (PFC). Until now, only a few studies have been conducted on rodents to understand its role in stress-related abnormalities in neurogenesis. However, the precise underlying molecular mechanism of miR-206-mediated depression-like behaviours remains largely unknown. Here, we reviewed recent advances in the field of biomedical and clinical research on the role of miR-206 in the pathogenesis of depression from studies using different tissues and various experimental designs, and described how abnormalities in miR-206 expression in these tissues can affect neuronal functions. Moreover, we focused on studies investigating the brain-derived neurotrophic factor (BDNF) as a functional target of miR-206, where miR-206 has been implicated in the pathogenesis of depression by suppressing the expression of the BDNF. In summary, these studies confirm the existence of a tight correlation between the pathogenesis of depression and the miR-206/BDNF pathway.

Catechin Protects against Lipopolysaccharide-induced Depressive-like Behaviour in Mice by Regulating Neuronal and Inflammatory Genes.

BACKGROUND: Many studies have suggested that tea has antidepressant effects; however, the underlying mechanism is not fully studied. As the main anti-inflammatory polyphenol in tea, catechin may contribute to the protective role of tea against depression. OBJECTIVE: The objective of this study is to prove that catechin can protect against lipopolysaccharide (LPS)-induced depressive-like behaviours in mice, and then explore the underlying molecular mechanisms. METHODS: Thirty-one C57BL/6J mice were categorized into the normal saline (NS) group, LPS group, catechin group, and amitriptyline group according to their treatments. Elevated Plus Maze (EPM), Tail Suspension Test (TST), and Open Field Test (OFT) were employed to assess depressive- like behaviours in mice. RNA sequencing (RNA-seq) and subsequent Bioinformatics analyses, such as differential gene analysis and functional enrichment, were performed on the four mouse groups. RESULTS: In TST, the mice in the LPS group exhibited significantly longer immobility time than those in the other three groups, while the immobility times for the other three groups were not significantly different. Similarly in EPM, LPS-treated mice exhibited a significantly lower percentage in the time/path of entering open arms than the mice in the other three groups, while the percentages of the mice in the other three groups were not significantly different. In OFT, LPS-treated mice exhibited significantly lower percentages in the time/path of entering the centre area than those in the other three groups. The results suggested that the LPS-induced depression models were established successfully and catechin can reverse (LPS)-induced depressive-like behaviours in mice. Finally, RNA-seq analyses revealed 57 differential expressed genes (DEGs) between LPS and NS with 19 up-regulated and 38 down-regulated. Among them, 13 genes were overlapped with the DEGs between LPS and cetechin (in opposite directions), with an overlapping p-value < 0.001. The 13 genes included Rnu7, Lcn2, C4b, Saa3, Pglyrp1, Gpx3, Lyz2, S100a8, S100a9, Tmem254b, Gm14288, Hbb-bt, and Tmem254c, which might play key roles in the protection of catechin against LPS-induced depressive-like behaviours in mice. The 13 genes were significantly enriched in defense response and inflammatory response, indicating that catechin might work through counteracting changes in the immune system induced by LPS. CONCLUSION: Catechin can protect mice from LPS-induced depressive-like behaviours through affecting inflammatory pathways and neuron-associated gene ontologies.

Betaine eliminates CFA-induced depressive-like behaviour in mice may be through inhibition of microglia and astrocyte activation and polarization.

Chronic pain can induce not only nociceptive but also depressive emotions. A previous study demonstrated that betaine, a commonly used nutrient supplement, has an anti-nociceptive effect, but whether betaine can alleviate chronic pain-induced depressive emotion is elusive. Our current study found that betaine administration significantly eliminated complete Freund's adjuvant (CFA)-induced pain-related depressive-like behaviour. Mechanistically, betaine treatment inhibited microglia and astrocyte activation. Furthermore, betaine significantly promoted the transition of microglia from the M1 to the M2 phenotype, as well as the transition of astrocytes from the A1 to the A2 phenotype. Additionally, the release of pro-inflammatory factors such as IL-18, IL-1ß and IL-6 and anti-inflammatory factors such as IL-10 in the hippocampus induced by CFA were also reversed by betaine administration. Overall, betaine has therapeutic effects on pain-related depressive-like phenotypes caused by CFA, possibly through altering the polarization of microglia and astrocytes to reduce neuroinflammation.

Involvement of indoleamine 2, 3-dioxygenase (IDO) and brain-derived neurotrophic factor (BDNF) in the neuroprotective mechanisms of ferulic acid against depressive-like behaviour.

OBJECTIVE: Ferulic acid (FA) is a common food ingredient that is abundantly present in various routinely consumed food and beverages. Like many cinnamic acid derivatives, FA produces wide-ranging effects in a dose-dependent manner and various studies link FA consumption with reduced risk of depressive disorders. The aim of this study was to exploit the neuroprotective mechanisms of FA including indoleamine 2,3-dioxygenase (IDO), brain-derived neurotrophic factor (BDNF), and other pro-inflammatory cytokines by employing lipopolysaccharide (LPS)-induced depressive-like behaviour model. METHODS: C57BL/6J male mice were divided into 4 groups consisting of saline (SAL), LPS, FA and Imipramine (IMI). Animals were pretreated orally with FA (10 mg/kg) and IMI (10 mg/kg) for 21 days once daily and all groups except SAL were challenged with LPS (0.83 mg/kg) intraperitoneally on day 21. RESULTS: LPS administration produced a biphasic change in the behaviour of the animals where the animals lost a significant weight and express high immobility time at 24 h. Proinflammatory cytokines including, TNF-α, IL-6, IL-1ß, and IFN-γ were significantly increased along with increased lipid peroxidation and reduced BDNF. Furthermore, the increased kynurenine to tryptophan ratio was indicative of elevated IDO activity. CONCLUSION: The results of this study emphasise that low dose of FA is effective in attenuating depressive-like behaviour by modulating IDO, BDNF and reducing neuroinflammation.

PET imaging of animal models with depressive-like phenotypes.

Major depressive disorder is a growing and poorly understood pathology. Due to technical and ethical limitations, a significant proportion of the research on depressive disorders cannot be performed on patients, but needs to be investigated in animal paradigms. Over the years, animal studies have provided new insight in the mechanisms underlying depression. Several of these studies have used PET imaging for the non-invasive and longitudinal investigation of the brain physiology. This review summarises the findings of preclinical PET imaging in different experimental paradigms of depression and compares these findings with observations from human studies. Preclinical PET studies in animal models of depression can be divided into three main different approaches: (a) investigation of glucose metabolism as a biomarker for regional and network involvement, (b) evaluation of the availability of different neuroreceptor populations associated with depressive phenotypes, and (c) monitoring of the inflammatory response in phenotypes of depression. This review also assesses the relevance of the use of PET imaging techniques in animal paradigms for the understanding of specific aspects of the depressive-like phenotypes, in particular whether it might contribute to achieve a more detailed characterisation of the clinical depressive phenotypes for the development of new therapies for depression.

Impact of genetic deletion of MrgD or Mas receptors in depressive-like behaviour in mice.

OBJECTIVES: To evaluate the impact of genetic deletion of receptors of the counterregulatory arms of the renin-angiotensin system in depressive-like behaviours. METHODS: 8-12 weeks-old male mice wild type (WT, C57BL/6J) and mice with genetic deletion of MrgD (MrgD KO) or Mas receptors (Mas KO) were subjected to the Forced Swim Test (FST) and the Tail Suspension Test (TST). Brain-derived neurotrophic factor (BDNF) levels were measured by enzyme-linked immunosorbent assay (ELISA). Blockade of Mas was performed by acute intracerebroventricular (icv) injection of its selective antagonist, A779. RESULTS: No statistical difference in immobility time was observed between MrgD KO and WT male animals subjected to FST and TST. However, acute icv injection of A779 significantly increased the immobility time of MrgD KO male mice subjected to FST and TST, suggesting the involvement of Mas in preventing depressive-like behaviour. Indeed, Mas KO male animals showed increased immobility time in FST and TST, evidencing a depressive-like behaviour in these animals, in addition to a reduction in BDNF levels in the prefrontal cortex and hippocampus. No changes in BDNF levels were observed in MrgD KO male animals. CONCLUSION: Our data showed that Mas plays an important role in the neurobiology of depression probably by modulating BDNF expression. On the contrary, lack of MrgD did not alter depressive-like behaviour, which was supported by the lack of alterations in BDNF levels.

Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain.

BACKGROUND: Depression is a recurrent and devastating mental disease that is highly prevalent worldwide. Prolonged exposure to stressful events or a stressful environment is detrimental to mental health. In recent years, an inflammatory hypothesis has been implicated in the pathogenesis of stress-induced depression. However, less attention has been given to the initial phases, when a series of stress reactions and immune responses are initiated. Peripheral CD4+ T cells have been reported as the major contributors to the occurrence of mental disorders. Chronic stress exposure-evoked release of cytokines can promote the differentiation of peripheral CD4+ cells into various phenotypes. Among them, Th17 cells have attracted much attention due to their high pathogenic potential in central nervous system (CNS) diseases. Thus, we intended to determine the crucial role of CD4+ Th17 cells in the development of specific subtypes of depression and unravel the underpinnings of their pathogenetic effect. METHODS: In the present research, a daily 6-h restraint stress paradigm was employed in rats for 28 successive days to mimic the repeated mild and predictable, but inevitable environmental stress in our daily lives. Then, depressive-like symptoms, brain-blood barrier (BBB) permeability, neuroinflammation, and the differentiation and functional changes of CD4+ cells were investigated. RESULTS: We noticed that restrained rats showed significant depressive-like symptoms, concomitant BBB disruption and neuroinflammation in the dorsal striatum (DS). We further observed a time-dependent increase in thymus- and spleen-derived naïve CD4+ T cells, as well as the aggregation of inflammatory Th17 cells in the DS during the period of chronic restraint stress (CRS) exposure. Moreover, increased Th17-derived cytokines in the brain can further impair the BBB integrity, thus allowing more immune cells and cytokines to gain easy access to the CNS. Our findings suggested that, through a complex cascade of events, peripheral immune responses were propagated to the CNS, and gradually exacerbated depressive-like symptoms. Furthermore, inhibiting the differentiation and function of CD4+ T cells with SR1001 in the early stages of CRS exposure ameliorated CRS-induced depressive-like behaviour and the inflammatory response. CONCLUSIONS: Our data demonstrated that inflammatory Th17 cells were pivotal in accelerating the onset and exacerbation of depressive symptoms in CRS-exposed rats. This subtype of CD4+ T cells may be a promising therapeutic target for the early treatment of stress-induced depression.

ACTH(6-9)-Pro-Gly-Pro ameliorates anxiety-like and depressive-like behaviour and gut mucosal microbiota composition in rats under conditions of chronic restraint stress.

The effects of the peptide ACTH(6-9)-Pro-Gly-Pro at doses of 5; 50; 500 µg/kg on the Wistar rats' behaviour and gut mucosal microbiota composition under conditions of chronic immobilization stress (CRS) were studied. CRS increased anxiety-like and depressive-like behaviour, disturbances in locomotor activity and gut dysbiosis. Administration of ACTH(6-9)-Pro-Gly-Pro showed many phenotypic results. Peptide demonstrated anti-depressant activity at doses of 5 and 500 µg/kg by a decrease in the total immobile time in the FST. ACTH(6-9)-Pro-Gly-Pro administered at a dose of 50 µg/kg resulted in an anxiolytic effect which is shown by an increase in the time in the open arms of EPM (p < 0.05) and a decrease in the time in the closed arms (p < 0.05). Moreover, the peptide led to a decrease in alpha- and beta-diversity of the gut microbiota (p < 0.01). Correlation and linear regression analysis demonstrated central mechanisms of ACTH(6-9)-Pro-Gly-Pro anxiolytic activity and both central and peripheral ones in an anti-depressant effect. In this way, peptide ACTH(6-9)-Pro-Gly-Pro could prevent the development of behavioural disturbances and gut dysbiosis caused by chronic restraint stress.

Remedial effects of caffeine against depressive-like behaviour in mice by modulation of neuroinflammation and BDNF.

Objective: Caffeine (CAF) is one of the most commonly consumed nutritional stimulant in beverages. Interestingly, CAF produces varied effects in a dose-dependent manner, and that makes it one of the most controversial nutritional ingredients. Various studies have linked CAF consumption and reduced risk of depressive disorders. The aim of this study was to investigate the effect of CAF on lipopolysaccharide (LPS)-induced neuroinflammation and depressive-like behaviour.Methods: C57BL/6J male mice were divided into four groups consisting of saline (SAL), LPS, CAF and Imipramine (IMI). Animals were pretreated orally with CAF (10 mg/kg) and IMI (10 mg/kg) for 14 days once daily and all groups except SAL were challenged with LPS (0.83 mg/kg) intraperitoneally on day 14.Results: LPS produced a biphasic behavioural response with a significantly high immobility time and weight loss after 24 h. The brain cytokines (TNF-α, IL-6, IL-1ß, and IFN-γ) levels were remarkably high, along with increased lipid peroxidation and reduced Brain Derived Neurotrophic Factor (BDNF). These biochemical and behavioural changes were significantly alleviated by CAF and IMI chronic treatment.Conclusion: The results of this study implicate that mild-moderate consumption of CAF could impart anti-inflammatory properties under neuroinflammatory conditions by modulating the cytokine and neurotrophic mechanisms.

Blockade of the kinin B1 receptor counteracts the depressive-like behaviour and mechanical allodynia in ovariectomised mice.

Menopause is related to a decline in ovarian oestrogen production, affecting the perception of the somatosensory stimuli, changing the immune-inflammatory systems, and triggering depressive symptoms. It has been demonstrated that the inhibition of the kinin B1 and B2 receptors (B1R and B2R) prevented the depressive-like behaviour and the mechanical allodynia that was induced by immune-inflammatory mediators in mice. However, there is no evidence regarding the role of the kinin receptors in the depressive-like and nociceptive behaviour in female mice that were subjected to bilateral ovariectomy (OVX). This study has shown that the OVX mice developed time-related mechanical allodynia, together with an increased immobility time as indicative of depression. Both of these changes were reduced by the genetic deletion of B1R, or by the pharmacological blockade of the selective kinin B1R antagonist R-715 (acute, i.p.). The genetic deletion or the pharmacological inhibition of B2R (HOE 140, i.p.) did not prevent the OVX-elicited behavioural changes. The data has suggested a particular modulation of kinin B1R in the nociceptive and depressive-like behaviour in the OVX mice. The selective inhibition of the B1R receptor may be a new pharmacological target for treating pain and depression symptoms in women during the perimenopause/menopause period.

Susceptibility to chronic immobilization stress-induced depressive-like behaviour in middle-aged female mice and accompanying changes in dopamine D1 and GABAA receptors in related brain regions.

BACKGROUND: Middle-aged females, especially perimenopausal females, are vulnerable to depression, but the potential mechanism remains unclear. Dopaminergic and GABAergic system dysfunction is involved in the pathophysiology of depression. In the current study, we used 2-month-old and 11-month-old C57BL/6 mice as young and middle-aged mice, respectively. Chronic immobilization stress (CIS) was used to induce depressive-like behaviour, and the sucrose preference test (SPT), tail suspension test (TST) and forced swim test (FST) were used to assess these behaviours. We then measured the mRNA levels of dopamine receptor D1 (DRD1) and the GABAA receptors GABRA1, GABRB2 and GABRG2 in the nucleus accumbens (NAc) and prefrontal cortex (PFC). RESULTS: We found that immobility time in the FST was significantly increased in the middle-aged mice compared with the middle-aged control mice and the young mice. In addition, the preference for sucrose water was reduced in the middle-aged mice compared with the middle-aged control mice. However, CIS did not induce obvious changes in the performance of the young mice in our behavioural tests. Moreover, the middle-aged mice exhibited equal immobility times as the young mice in the absence of stress. Decreases in the mRNA levels of DRD1, GABRA1, and GABRB2 but not GABRG2 were found in the NAc and PFC in the middle-aged mice in the absence of stress. Further decreases in the mRNA levels of DRD1 in the NAc and GABRG2 in the NAc and PFC were found in the middle-aged mice subjected to CIS. CONCLUSIONS: Our results suggested that ageing could not directly induce depression in the absence of stress. However, ageing could induce susceptibility to depression in middle-aged mice in the presence of stress. CIS-induced decreases in DRD1 and GABRG2 levels might be involved in the increase in susceptibility to depression in this context.

Anti-stress effects of combined block of glucocorticoid and mineralocorticoid receptors in the paraventricular nucleus of the hypothalamus.

BACKGROUND AND PURPOSE: Mineralocorticoid receptors (MRs), glucocorticoid receptors (GRs) and corticotropin-releasing factor (CRF) in the paraventricular nucleus of hypothalamus (PVN) are involved in the response to stress. The present study investigated the role of GRs and MRs in the PVN in regulating depressive and anxiety-like behaviours. EXPERIMENTAL APPROACH: To model chronic stress, rats were exposed to corticosterone treatment via drinking water for 21 days, and GR antagonist RU486 and MR antagonist spironolactone, alone and combined, were directly injected in the PVN daily for the last 7 days of corticosterone treatment. Behavioural tests were run on days 22 and 23. Depressive- and anxiety-like behaviours were evaluated in forced swim test, sucrose preference test, novelty-suppressed feeding test and social interaction test. The expression of GRs, MRs and CRF were detected by western blot. KEY RESULTS: Rats exposed to corticosterone exhibited depressive- and anxiety-like behaviours. The expression of GRs and MRs decreased, and CRF levels increased in the PVN. The intra-PVN administration of RU486 increased the levels of GRs and CRF without influencing depressive- or anxiety-like behaviours. The spironolactone-treated group exhibited an increase in MRs without influencing GRs and CRF in the PVN and improved anxiety-like behaviours. Interestingly, the intra-PVN administration of RU486 and spironolactone combined restored expression of GRs, MRs and CRF and improved depressive- and anxiety-like behaviours. CONCLUSION AND IMPLICATIONS: In this rat model of stress, the simultaneous restoration of GRs, MRs and CRF in the PVN might play an important role in the treatment of depression and anxiety.

Role of the endocannabinoid system in a mouse model of Fragile X undergoing neuropathic pain.

BACKGROUND: Neuropathic pain is a complex condition characterized by sensory, cognitive and affective symptoms that magnify the perception of pain. The underlying pathogenic mechanisms are largely unknown and there is an urgent need for the development of novel medications. The endocannabinoid system modulates pain perception and drugs targeting the cannabinoid receptor type 2 (CB2) devoid of psychoactive side effects could emerge as novel analgesics. An interesting model to evaluate the mechanisms underlying resistance to pain is the fragile X mental retardation protein knockout mouse (Fmr1KO), a model of fragile X syndrome that exhibits nociceptive deficits and fails to develop neuropathic pain. METHODS: A partial sciatic nerve ligation was performed to wild-type (WT) and Fmr1KO mice having (HzCB2 and Fmr1KO-HzCB2, respectively) or not (WT and Fmr1KO mice) a partial deletion of CB2 to investigate the participation of the endocannabinoid system on the pain-resistant phenotype of Fmr1KO mice. RESULTS: Nerve injury induced canonical hypersensitivity in WT and HzCB2 mice, whereas this increased pain sensitivity was absent in Fmr1KO mice. Interestingly, Fmr1KO mice partially lacking CB2 lost this protection against neuropathic pain. Similarly, pain-induced depressive-like behaviour was observed in WT, HzCB2 and Fmr1KO-HzCB2 mice, but not in Fmr1KO littermates. Nerve injury evoked different alterations in WT and Fmr1KO mice at spinal and supra-spinal levels that correlated with these nociceptive and emotional alterations. CONCLUSIONS: This work shows that CB2 is necessary for the protection against neuropathic pain observed in Fmr1KO mice, raising the interest in targeting this receptor for the treatment of neuropathic pain. SIGNIFICANCE: Neuropathic pain is a complex chronic pain condition and current treatments are limited by the lack of efficacy and the incidence of important side effects. Our findings show that the pain-resistant phenotype of Fmr1KO mice against nociceptive and emotional manifestations triggered by persistent nerve damage requires the participation of the cannabinoid receptor CB2, raising the interest in targeting this receptor for neuropathic pain treatment. Additional multidisciplinary studies more closely related to human pain experience should be conducted to explore the potential use of cannabinoids as adequate analgesic tools.

Loss of Brain-Derived Neurotrophic Factor (BDNF) Resulting From Congenital- Or Mild Traumatic Brain Injury-Induced Blood-Brain Barrier Disruption Correlates With Depressive-Like Behaviour.

Brain-derived neurotrophic factor (BDNF) plays an important role in processes associated with neuroplasticity and neuroprotection. Evidence suggests that decreased BDNF levels in the central nervous system (CNS) represent a mechanism underlying the development of mood disorders. We hypothesize that both congenital and traumatic brain injury (mTBI)-induced blood-brain barrier (BBB) breakdown are responsible for brain BDNF depletion that contributes to the development of depressive-like symptoms. We employed a mouse model of innate differences in BBB integrity with high (HA) and low (LA) permeability. Depressive-like behaviours were determined under chronic mild stress (CMS) conditions or following mTBI using the tail suspension test (TST). Microvascular leakage of the BBB was evaluated using the Evans Blue Dye (EBD) extravasation method. BDNF concentrations in the brain and plasma were measured using the ELISA. Control HA mice with congenitally high BBB permeability showed exacerbated depressive-like behaviours compared with LA mice. In LA mice, with normal BBB function, mTBI, but not CMS, facilitated depressive-like behaviours, which correlated with enhanced BDNF efflux from the brain. In addition, mTBI triggered upregulation of the Bdnf gene in LA mice to compensate for BDNF loss. No alterations in BDNF levels were observed in mTBI and CMS-exposed HA mice. Moreover, CMS did not induce BBB damage or affect depressive-like behaviours in HA mice despite downregulating Bdnf gene expression. To conclude, BDNF efflux through the mTBI-disrupted BBB is strongly linked to the development of depressive-like behaviours, while the depressive phenotype in mice with congenital BBB dysfunction is independent of BDNF leakage.

Chronic stress followed by social isolation promotes depressive-like behaviour, alters microglial and astrocyte biology and reduces hippocampal neurogenesis in male mice.

Unpredictable chronic mild stress (UCMS) is one of the most commonly used, robust and translatable models for studying the neurobiological basis of major depression. Although the model currently has multiple advantages, it does not entirely follow the trajectory of the disorder, whereby depressive symptomology can often present months after exposure to stress. Furthermore, patients with depression are more likely to withdraw in response to their stressful experience, or as a symptom of their depression, and, in turn, this withdrawal/isolation can further exacerbate the stressful experience and the depressive symptomology. Therefore, we investigated the effect(s) of 6 weeks of UCMS followed by another 6 weeks of social isolation (referred to as UCMSI), on behaviour, corticosterone stress responsivity, immune system functioning, and hippocampal neurogenesis, in young adult male mice. We found that UCMSI induced several behavioural changes resembling depression but did not induce peripheral inflammation. However, UCMSI animals showed increased microglial activation in the ventral dentate gyrus (DG) of the hippocampus and astrocyte activation in both the dorsal and ventral DG, with increased GFAP-positive cell immunoreactivity, GFAP-positive cell hypertrophy and process extension, and increased s100ß-positive cell density. Moreover, UCMSI animals had significantly reduced neurogenesis in the DG and reduced levels of peripheral vascular endothelial growth factor (VEGF) - a trophic factor produced by astrocytes and that stimulates neurogenesis. Finally, UCMSI mice also had normal baseline corticosterone levels but a smaller increase in corticosterone following acute stress, that is, the Porsolt Swim Test. Our work gives clinically relevant insights into the role that microglial and astrocyte functioning, and hippocampal neurogenesis may play in the context of stress, social isolation and depression, offering a potentially new avenue for therapeutic target.

Environmental enrichment and its influence on rodent offspring and maternal behaviours, a scoping style review of indices of depression and anxiety.

Environmental enrichment is a widely used experimental manipulation that consistently shows measurable effects on rodent behaviour across the lifespan. This scoping review assesses and thematically summarizes the literature of the past decade concerning the effects of environmental enrichment applied during sensitive developmental periods in rodent mothers and offspring. Maternal behaviours as well as maternal and offspring anxiety- and depressive-like behaviours are considered. Relevant terms were searched across five databases (Embase, MEDLINE, PsycINFO, PubMed, Web of Science) and articles were screened with inclusion and exclusion criteria. The remaining articles were thematically analysed. Our results suggest that a greater number of articles reviewed the impacts of environmental enrichment on offspring anxiety-like behaviour (n = 23) rather than on depressive-like behaviour (n = 11) or maternal caregiving behaviour (n = 12). Maternal anxiety- (n = 4) or depressive-like (n = 2) behaviours are not often evaluated for in enrichment studies. The main behavioural tests of anxiety that were reviewed include the elevated plus-maze, the open field test, and the light-dark box whereas those for depression included the forced swim test and the sucrose preference test. Our results yielded mixed findings and significant variation in behavioural responses across all tests. In mothers, trends of increased maternal care behaviours and decreased maternal depressive-like behaviours in enriched mothers were appreciated. Enrichment during the gestational period was identified as pivotal to creating behavioural change in mother subjects. In enriched offspring rodents, a trend towards decreased anxiety-like behaviours was observed most often. Potential confounds inherent in enrichment paradigms and relevant theories of enrichment and their relation to rodent behavioural tests are discussed.

Degree of lipid saturation affects depressive-like behaviour and gut microbiota in mice.

This study explored the effects of the degree of lipid saturation on depressive behaviour and gut microbiota in mice. Thirty-two mice were divided into normal (N), Prozac (NP), lard (L) and fish oil (F) groups. After a 12-week dietary intervention, the open field test (OFT) and the forced swim test (FST) were conducted before sacrifice. The mice in the L group exhibited anxiety-like behaviours in the OFT and depressive-like behaviours in the FST. A significant difference was observed in ß-diversity indices between the L group and the F group. The abundance of Allobaculum and Bifidobacterium was significantly higher in the F group than in the L and N groups. The prefrontal cortex fatty acid composition was altered in various lipid-treated groups and was highly correlated with depressive-like behaviours. In conclusion, the degree of lipid saturation affects depressive-like behaviour, gut microbiota composition, and the prefrontal cortex fatty acid profile in mice.

Sub-chronic celecoxib prevents soluble beta amyloid-induced depressive-like behaviour in rats.

BACKGROUND: Depression and Alzheimer's disease (AD) are co-morbid conditions. Neuropsychiatric symptoms have been reported as prodromal symptoms of AD-like dementia and soluble forms of beta amyloid peptide (Aß), the main constituent of insoluble plaques typical of AD brains, have been implicated in such an effect. We have previously shown that intracerebral injection of Aß can evoke a depressive-like state in rats, accompanied by neurochemical and neuroendocrine alterations reminiscent of depressive symptoms in humans. AD and depression are crucially linked by neuroinflammation and cyclooxygenase II (COX-2) enzyme involvement is an intriguing field of research. Indeed, its pharmacological inhibition has shown both antidepressant and Aß modulating effects. METHODS: Male rats were exposed to sub-chronic celecoxib (15 mg/kg/day sc for 8 days), a selective COX-2 inhibitor or vehicle (saline), starting from the day before central intracerebroventricular injection of Aß peptide (5µL of 4 µM solution or vehicle for sham). Animals were tested for depressive-like behaviour by using the forced swimming test paradigm and prefrontal serotonin (5-HT) content and plasma Aß levels were further evaluated. RESULTS: We found that celecoxib treatment prevented the pro-depressive effects induced by Aß. Moreover, it also prevented the reduction in 5-HT content in prefrontal cortex of Aß-treated rats and decreased their plasma Aß levels. CONCLUSIONS: Taken together, our data indicate that celecoxib could be a suitable pharmaceutical tool for the treatment of depressive state related to increased Aß levels.

Distinct modifications of hippocampal glucocorticoid receptor phosphorylation and FKBPs by lipopolysaccharide in depressive female and male rats.

Inflammation plays a critical role in pathogenesis of depression and can affect the hypothalamic-pituitary-adrenal axis activity. Accordingly, in this study we investigated the role of hippocampal glucocorticoid receptor in mediating the effects of inflammation on behaviour of female and male Wistar rats. We studied the effects of lipopolysaccharide on the levels of glucocorticoid receptors and its co-chaperones FK506 binding protein 52 and FK506 binding protein 51, the levels of glucocorticoid receptor phospho-isoforms, pGR-232 and pGR-246, and glucocorticoid receptor up-stream kinases. In order to assess transcriptional activity of glucocorticoid receptor, we measured mRNA levels of several glucocorticoid receptor-regulated genes. We demonstrated that lipopolysaccharide induced depressive-like behaviour and elevated serum corticosterone in both sexes. However, it affected glucocorticoid receptor signalling in the nucleus of females and males differently - in females it elevated levels of glucocorticoid receptors, pGR-246 and FK506 binding protein 52, while in males it decreased levels of glucocorticoid receptor, both co-chaperons and pGR-246. Alterations in pGR-246 were associated with alterations of c-Jun N-terminal kinases. Altered nuclear levels of total glucocorticoid receptors and pGR-246 were accompanied by sex-specific reduction in brain-derived neurotrophic factor and cyclooxygenase-2 mRNA and sex-unspecific reduction in the expression of p11 and glucocorticoid receptor genes. These alterations may ultimately affect different glucocorticoid receptor -associated processes involved in depressive-like behaviour in males and females.