Depressive-like Phenotype Research Articles

Regulatory effect of lithium on hippocampal blood-brain barrier integrity in a rat model of depressive-like behavior.

Recent evidence has associated mood disorders with blood-brain barrier (BBB)/ neurovascular unit (NVU) dysfunction, and reduction in blood vessels coverage by the water channel aquaporin-4 (AQP4) immunoreactive astrocytes. Lithium is an established treatment for mood disorders, yet, its mechanism of action is partially understood. We investigated the effects of lithium on BBB integrity and NVU-related protein expression in chronic mild stress (CMS) rat model of depressive-like behavior. Male Wistar rats were exposed for 5weeks to unpredictable mild stressors with daily co-administration of lithium chloride to half of the stressed and unstressed groups. Sucrose preference and open field tests were conducted to validate the depressive-like phenotype, and dynamic contrast-enhanced MRI analysis was utilized to assess BBB integrity in brain regions relevant to the pathophysiology of depression. Hippocampal AQP4 and claudin-5 expression were studied using immunofluorescence, western blot, and enzyme-linked immunosorbent assays. Lithium administration to the stressed rats prevented the reductions in sucrose preference and distance traveled in the open field, and normalized the stress-induced hippocampal BBB hyperpermeability, whereas lithium administration to the unstressed rats increased hippocampal BBB permeability. Additionally, lithium treatment attenuated the decrease in hippocampal AQP4 to glial fibrillary acidic protein immunoreactivity ratio in the stressed rats and upregulated hippocampal claudin-5 and BDNF proteins expression. Our findings suggest that lithium administration in a rat CMS model of depressive-like behavior is associated with attenuation of stressed-induced hippocampal BBB/NVU disruption. These protective effects may be relevant to the mode of action of lithium in depression.

Nedd4l downregulation of NRG1 in the mPFC induces depression-like behaviour in CSDS mice

The occurrence of major depressive disorders has been closely related to the vulnerability of stress. The medial prefrontal cortex (mPFC) is involved in regulating pathological reactivity to stress, changes in affective behaviour and cognitive functions by distress. Increasing evidence indicates that neuregulin 1 (NRG1) plays an important role in psychiatric illnesses, including depression, schizophrenia and bipolar disorder. However, whether NRG1 in the mPFC is related to stress vulnerability remains unclear. We here assessed the regulation of NRG1 by the E3 ubiquitin ligase Nedd4l (neural precursor cell expressed developmentally downregulated 4-like) and investigated whether NRG1 changes in the mPFC might lead to vulnerability to depression-like behaviours. We’ve identified a deficiency of NRG1 in the mPFC as a key factor that contributes to the regulation of stress susceptibility in mice, as further suggested by the finding that overexpression of NRG1 attenuated depression-like behaviours in the animal model of chronic social defeat stress (CSDS). Interestingly, RNA sequencing in the mPFC brain region showed no differences in NRG1 mRNA levels between control animals and stress-susceptible (SS) or resilient mice (RES) following CSDS. However, mRNA and protein levels of Nedd4l were markedly increased in SS mice, but not in RES mice compared to controls. Furthermore, ubiquitination of NRG1 was increased in SS mice. Remarkably, overexpression of Nedd4l in mouse mPFC induced a decrease in NRG1 level and caused vulnerability to stress by subthreshold social defeat stress (SSDS), while downregulation of Nedd4l expression in the mPFC rescued the vulnerability to stress-induced social avoidance and anhedonia. Our data strongly indicate that the Nedd4l-mediated downregulation of NRG1 acts as a critical role in depression-like phenotypes of mice in CSDS.

Perinatal fluoxetine treatment and dams\u2019 early life stress history have opposite effects on aggressive behavior while having little impact on sexual behavior of male rat offspring

RationaleMany depressed women continue antidepressant treatment during pregnancy. Selective serotonin reuptake inhibitor (SSRI) treatment during pregnancy increases the risk for abnormal social development of the child, including increased aggressive or defiant behavior, with unknown effects on sexual behavior.ObjectivesOur aim was to investigate the effects of perinatal SSRI treatment and maternal depression, both separately and combined, on aggressive and sexual behavior in male rat offspring.MethodsHeterozygous serotonin transporter (SERT± ) knockout dams exposed to early life stress (ELSD) were used as an animal model of maternal depression. Early life stress consisted of separating litters from their mother for 6 h a day on postnatal day (PND)2–15, resulting in a depressive-like phenotype in adulthood. Depressive-like dams were treated with fluoxetine (FLX, 10 mg/kg) or vehicle throughout pregnancy and lactation (gestational day 1 until PND 21). Male offspring were tested for aggressive and sexual behavior in adulthood. As lifelong reductions in SERT expression are known to alter behavioral outcome, offspring with normal (SERT+/+) and reduced (SERT± ) SERT expression were assessed.ResultsPerinatal FLX treatment reduced offensive behavior and the number of animals attacking and increased the latency to attack, especially in SERT+/+ offspring. Perinatal FLX treatment reduced the mounting frequency in SERT+/+ offspring. ELSD increased offensive behavior, without affecting sexual behavior in SERT± offspring.ConclusionsOverall, our research demonstrates that perinatal FLX treatment and ELSD have opposite effects on aggressive behavior, with little impact on sexual behavior of male offspring.

HUC-MSCs ameliorated CUMS-induced depression by modulating complement C3 signaling-mediated microglial polarization during astrocyte-microglia crosstalk

BackgroundMajor depressive disorder (MDD) has been shown to be related to immune inflammation and the complement system. Previous studies have suggested that human umbilical cord mesenchymal stem cells (hUC-MSCs) play an important role in inflammatory diseases. MethodshUC-MSCs were administered into chronic unpredictable mild stress model (CUMS) mice through the tail vein once a week for 4 weeks. After the administration of hUC-MSCs, the depression-like and anxiety-like phenotypes, neuronal histopathology, synaptic-related protein expression and inflammatory index of the mice were assessed. Microglial M1/M2 polarization and the expression of C3a in astrocytes and C3aR in microglia was detected by immunofluorescence co-localization. Then, CUMS mice were injected with a C3aR antagonist, and the expression of C3a and C3aR and microglial polarization were observed. ResultsBased on the sucrose preference and tail suspension tests, hUC-MSCs ameliorated the depression-like behaviors of CUMS mice. Additionally, the anxiety-like behaviors of CUMS mice in the open-field and plus-maze tests were improved after the administration of hUC-MSCs. hUC-MSCs altered microglia polarization by alleviating complement C3a-C3aR signaling activation, which decreased pro-inflammatory factor levels and increased anti-inflammatory factor levels, alleviating neuronal damage and synaptic deficits. ConclusionhUC-MSCs have therapeutic effects on anxiety-like and depressive-like phenotypes caused by CUMS. They can alter the polarization of microglia by inhibiting C3a-C3aR signaling to reduce neuroinflammation.

Do corticosterone levels predict female depressive-like behavior in rodents?

Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is often linked to the neurobiology of depression, though the presence and type of this dysregulation is not a consistent finding. Meanwhile, significant sex differences exist regarding depression and the HPA axis. Animal models of depression simulate certain aspects of the human disease and aim to advance our knowledge regarding its neurobiology and discover new antidepressant treatments. Most animal models of depression induce a depressive-like phenotype taking advantage of stressful experimental conditions, that also increase corticosterone, the main stress hormone in rodents. In this review we present inconsistent results in male and female rodents regarding the interaction between the depressive-like behavioral phenotype and corticosterone. In commonly used models, the female depressive-like phenotype in rodents seems significantly less dependent on the stress hormone corticosterone, whereas the male behavioral response is more evident and associates with variations of corticosterone. Further research and clarification of this sex-dependent interaction will have significant ramifications on the improvement of the validity of animal models of depression.

Extracellular Matrix and Oxidative Phosphorylation: Important Role in the Regulation of Hypothalamic Function by Gut Microbiota.

BackgroundIn previous studies, our team examined the gut microbiota of healthy individuals and depressed patients using fecal microbiota transplantation of germ-free (GF) mice. Our results showed that depression-like and anxiety-like behavioral phenotypes of host mice were increased, but the molecular mechanism by which gut microbiota regulate host behavioral phenotypes is still unclear.MethodsTo investigate the molecular mechanism by which gut microbiota regulate host brain function, adult GF mice were colonized with fecal samples derived from healthy control (HC) individuals or patients with major depressive disorder (MDD). Transcriptomic profiling of hypothalamus samples was performed to detect differentially expressed genes (DEGs). qRT-PCR was used for validation experiments.ResultsColonization germ-free (CGF) mice had 243 DEGs compared with GF mice. The most enriched KEGG pathways associated with upregulated genes were “protein digestion and absorption,” “extracellular matrix (ECM)-receptor interaction,” and “focal adhesion.” MDD mice had 642 DEGs compared with HC mice. The most enriched KEGG pathways associated with upregulated genes in MDD mice were also “protein digestion and absorption,” “ECM-receptor interaction,” and “focal adhesion.” Meanwhile, the most enriched KEGG pathway associated with downregulated genes in these mice was “oxidative phosphorylation,” and genes related to this pathway were found to be highly correlated in PPI network analysis.ConclusionIn summary, our findings suggested that regulation of ECM is a key mechanism shared by different gut microbiota and that inhibition of energy metabolism in the hypothalamus by gut microbiota derived from MDD patients is a potential mechanism of behavioral regulation and depression.

The role of mitochondrial bioenergetics and oxidative stress in depressive behavior in recurrent concussion model in mice

Traumatic brain injury (TBI) is a public health problem in which even though 80 to 90% of cases are considered mild, usually starts a sequence of neurological disorders that can last a considerable time. Most of the research of this injury has been focused on oxidative stress and functional deficits; however, mechanisms that underlie the development of neuropsychiatric disorders remain little researched. Due to this, the present authors decided to investigate whether recurrent concussion protocols alter depressive-like phenotype behavior, and whether mitochondria play an indispensable role in this behavior or not. The experimental data revealed, for the first time, that the present protocol of recurrent concussions (4, 7, and 10 injuries) in mice did not alter immobility time during tail suspension tests (TSTs), but decreased hippocampal mitochondrial respiration and increased expression of proteins such as nuclear factor erythroid 2-related factor 2 (Nrf2) and superoxide (SOD2). This experimental data suggests that bioenergetic changes elicited by recurrent concussion did not induce depressive-like behavior, but activated the transcription factor of responsive antioxidant elements (ARE) that delay or prevent secondary cascades in this neurological disease.

Imbalance of the oxytocin-vasopressin system contributes to the neuropsychiatric phenotype in the BACHD mouse model of Huntington disease

Neuropsychiatric disturbances with altered social cognition, depression and anxiety are among the most debilitating early features in the fatal neurodegenerative disorder Huntington disease (HD) which is caused by an expanded CAG repeat in the huntingtin gene. The underlying neurobiological mechanisms are not known. Neuropathological analyses of postmortem human HD hypothalamic tissue have demonstrated loss of the neuropeptides oxytocin and vasopressin. The dynamic interplay between these neuropeptides is crucial for modulating emotional and social behavior but its role in HD is unclear. In the present study, we have investigated the effect of expressing the mutant huntingtin gene on the development of behavioral changes using the transgenic BACHD mouse model at different ages. We show for the first time that BACHD mice exhibit deficits in social behavior with parallel aberrations in the balance of the oxytocin-vasopressin system. Importantly, our data also show that restoration of the interplay within the system with an acute dose of intranasal oxytocin immediately prior to behavioral testing can rescue the depressive-like phenotype but not anxiety-like behavior in this transgenic model. These findings demonstrate that imbalances in the oxytocin-vasopressin interplay contribute to the neuropsychiatric component of HD and suggest that interventions aimed at restoring the blunted levels of oxytocin may confer therapeutic benefits for this disease.

A key role of the subdiaphragmatic vagus nerve in the depression-like phenotype and abnormal composition of gut microbiota in mice after lipopolysaccharide administration

The vagus nerve plays a role in the cross talk between the brain and gut microbiota, which could be involved in depression. The subdiaphragmatic vagus nerve serves as a major modulatory pathway between the brain and gut microbiota. Here, we investigated the effects of subdiaphragmatic vagotomy (SDV) on the depression-like phenotype and the abnormal composition of gut microbiota in mice after lipopolysaccharide (LPS) administration. LPS caused a depression-like phenotype, inflammation, increase in spleen weight, and downregulation of synaptic proteins in the medial prefrontal cortex (mPFC) in the sham-operated mice. In contrast, LPS did not produce a depression-like phenotype and downregulated synaptic proteins in the mPFC after SDV. The spleen weight and plasma levels of pro-inflammatory cytokines in the SDV + LPS group were lower than those of the sham + LPS group. Interestingly, there were positive correlations between the plasma levels of pro-inflammatory cytokines and spleen weight, suggesting a relationship between inflammatory events and spleen weight. Furthermore, LPS led to significant alterations in gut microbiota diversity in sham-operated mice, but not SDV-operated mice. In an unweighted UniFrac PCoA, the dots representing the sham + LPS group were located far away from the dots representing the other three groups. Our results suggest that LPS produces a depression-like phenotype, increases spleen weight, triggers inflammation, downregulates synaptic proteins in the mPFC, and leads to abnormal composition of gut microbiota via the subdiaphragmatic vagus nerve. It is likely that the vagus nerve plays a crucial role in the brain–gut–microbiota axis.

Morus nigra leaves extract revokes the depressive-like behavior, oxidative stress, and hippocampal damage induced by corticosterone: a pivotal role of the phenolic syringic acid.

The pathophysiology of depression includes glucocorticoids excess, glutamatergic excitotoxicity, and oxidative stress impairment. Previous study demonstrated Morus nigra L. leaves extract and syringic acid (4-hydroxy-3,5-dimethoxybenzoic acid), its major phenolic compound, administered orally for 7 days, decreased the immobility time in the tail suspension test, without locomotor alteration. Therefore, the purpose of this study was to investigate the antidepressant-like effects, antioxidant effects, and neuroprotective effects of M. nigra leaves extract and syringic acid in an animal model of depression induced by corticosterone. Herein, corticosterone administered in male Swiss mice, 60-90 days of age, at 20 mg/kg, once a day, for 21 days, was effective to induce depressive-like phenotype. This alteration was accompanied by the increase of oxidative stress markers (lipid peroxidation, nitrite, and protein carbonyl) and the decrease in nonprotein thiols level, besides impairment in the hippocampus. Conversely, the treatment with M. nigra leaves extract (10 mg/kg), syringic acid (1 mg/kg), or fluoxetine (10 mg/kg), administered once a day for the last 7 days of the corticosterone treatment, was able to abolish the behavioral alterations elicited by corticosterone, reinforcing evidence of the M. nigra leaves extract and syringic acid having antidepressant-like effect. Both treatments also exerted antioxidant property in the mice's brain, reducing the amount of oxidative stress and abolishing the corticosterone-induced damage in the hippocampal slices. In addition, the treatments protected the hippocampus against the damage induced by the association between corticosterone administration and glutamate excess. In conclusion, M. nigra leaves extract and syringic acid revoke depressive-like behavior induced by corticosterone via inhibition of oxidative stress and hippocampal damage.

Reduction in BDNF from Inefficient Precursor Conversion Influences Nest Building and Promotes Depressive-Like Behavior in Mice.

We generated a knock-in mouse line in which the gene encoding brain-derived neurotrophic factor (Bdnf) was replaced with a sequence for proBDNF containing human single nucleotide polymorphisms encoding arginines proximal to the cleavage site (R125M and R127L). The ratio of the mature form of BDNF (mBDNF) to precursor BDNF (proBDNF) in hippocampal tissue lysates was decreased in a manner dependent on the number of copies of the mutant gene, indicating that the mutations inhibited proteolytic conversion of proBDNF into mBDNF. Although homozygous mice had a proBDNF/mBDNF ratio of ~9:1, they survived until adulthood. The levels of mBDNF were reduced by 57% in heterozygous mutant mice, which exhibited a depressive-like behavior in the tail suspension test and weight gain when housed in social isolation, showing that impaired proBDNF cleavage contributes to stress-induced depressive-like phenotypes. Furthermore, socially isolated heterozygous mice displayed a pronounced deficit in daily nest-building behaviors. These findings suggest that the decreased production of mBDNF by impaired proBDNF cleavage disturbs daily activities in mice.

Flavonoids Ameliorate Stress-Induced Depression by Preventing NLRP3 Inflammasome Priming

Abstract Objectives Chronic stress activates danger-associated molecular patterns (DAMPs), stimulating the NLRP3 inflammasome. NLRP3 activation triggers the release of pro-inflammatory cytokine IL-1β. The activity of the NLRP3 inflammasome propagates pro-inflammatory signaling cascades implicated in the onset of depression. Our previous studies show that polyphenolic compounds were found to ameliorate stress induced depression in mouse models. However, the relevant mechanism has not been identified. This study examined the effect of administering polyphenols on DAMP signaling in enriched mice microglia. Methods This study examined the effect of administering polyphenols on DAMP signaling in mice microglia. To recapitulate stress-induced depression, mice underwent chronic unpredictable stress (CUS). Microglia were isolated at various time points throughout the CUS protocol. We also assessed long-term persistent changes after CUS and susceptibility to subthreshold unpredictable stress (US) re-exposure. Results Interestingly, the development of US – induced depression and anxiety depended upon a previous exposure to CUS. We found that CUS caused robust upregulation of IL-1β mRNA in enriched microglia, an effect that persists for up to 4 weeks following CUS exposure. Following the subthreshold US re-exposure, we observed the upregulation of pro- IL-1β as well as pro-receptor for advanced glycation end products (RAGE). Toll-like receptor 4 (TLR-4) was not. We also observed an increase in RAGE mRNA expression when mice were exposed to US prior to the start of the CUS paradigm. Importantly, a primary exposure to US, was sufficient to increase RAGE mRNA expression. We found that polyphenol administration significantly improved CUS-induced depressive-like phenotypes and also reversed neuroinflammation in mice. Treatment with dietary flavonoids prevented upregulation of IL-1β, RAGE mRNA, which reflects the ability of polyphenols that may have begun following the primary exposure to US. Conclusions Taken all together, the results provide evidence of the role of dietary polyphenols in preventing persistent microglial activation, which has been shown to result in reduced long term vulnerability to depressive-like behaviors following expose to chronic stress. Funding Sources This study was supported by a P50 CARBON Center grant from the NCCIH/ODS.

The Forebrain-Specific Overexpression of Acid Sphingomyelinase Induces Depressive-Like Symptoms in Mice.

Human and murine studies identified the lysosomal enzyme acid sphingomyelinase (ASM) as a target for antidepressant therapy and revealed its role in the pathophysiology of major depression. In this study, we generated a mouse model with overexpression of Asm (Asm-tgfb) that is restricted to the forebrain to rule out any systemic effects of Asm overexpression on depressive-like symptoms. The increase in Asm activity was higher in male Asm-tgfb mice than in female Asm-tgfb mice due to the breeding strategy, which allows for the generation of wild-type littermates as appropriate controls. Asm overexpression in the forebrain of male mice resulted in a depressive-like phenotype, whereas in female mice, Asm overexpression resulted in a social anxiogenic-like phenotype. Ceramides in male Asm-tgfb mice were elevated specifically in the dorsal hippocampus. mRNA expression analyses indicated that the increase in Asm activity affected other ceramide-generating pathways, which might help to balance ceramide levels in cortical brain regions. This forebrain-specific mouse model offers a novel tool for dissecting the molecular mechanisms that play a role in the pathophysiology of major depression.

Anxiety and Depression Are Related to Higher Activity of Sphingolipid Metabolizing Enzymes in the Rat Brain.

Changes in sphingolipid metabolism have been suggested to contribute to the pathophysiology of major depression. In this study, we investigated the activity of acid and neutral sphingomyelinases (ASM, NSM) and ceramidases (AC, NC), respectively, in twelve brain regions of female rats selectively bred for high (HAB) versus low (LAB) anxiety-like behavior. Concomitant with their highly anxious and depressive-like phenotype, HAB rats showed increased activity of ASM and NSM as well as of AC and NC in multiple brain regions associated with anxiety- and depressive-like behavior, including the lateral septum, hypothalamus, ventral hippocampus, ventral and dorsal mesencephalon. Strong correlations between anxiety-like behavior and ASM activity were found in female HAB rats in the amygdala, ventral hippocampus and dorsal mesencephalon, whereas NSM activity correlated with anxiety levels in the dorsal mesencephalon. These results provide novel information about the sphingolipid metabolism, especially about the sphingomyelinases and ceramidases, in major depression and comorbid anxiety.

Antidepressive properties of macrophage-colony stimulating factor in a mouse model of depression induced by chronic unpredictable stress

Previous studies have reported that macrophage-colony stimulating factor (M-CSF), a drug that is used to treat hematological system disease, can ameliorate chronic stress-induced depressive-like behaviors in mice. This indicates that M-CSF could be developed into a novel antidepressant. Here, we investigated the antidepressive properties of M-CSF, aiming to explore its potential values in depression treatment. Our results showed that a single M-CSF injection at the dose of 75 and 100 μg/kg, but not at 25 or 50 μg/kg, ameliorated chronic unpredictable stress (CUS)-induced depressive-like behaviors in mice at 5 h after the drug treatment. In a time-dependent experiment, a single M-CSF injection (100 μg/kg) was found to ameliorate the CUS-induced depressive-like behaviors in mice at 5 and 8 h, but not at 3 h, after the drug treatment. The antidepressant effect of the single M-CSF injection (100 μg/kg) in chronically-stressed mice persisted at least 10 days and disappeared at 14 days after the drug treatment. Moreover, 14 days after the first injection, a second M-CSF injection (100 μg/kg) still produced antidepressant effects at 5 h after the drug treatment in chronically-stressed mice who re-displayed depressive-like phenotypes. The antidepressant effect of M-CSF appeared to be mediated by the activation of the hippocampal microglia, as pre-inhibition of microglia by minocycline (40 mg/kg) or PLX3397 (290 mg/kg) pretreatment prevented the antidepressant effect of M-CSF in CUS mice. These results demonstrate that M-CSF produces rapid and sustained antidepressant effects via the activation of the microglia in the hippocampus in a dose- and time-dependent manner.

Neuroprotective Effects of Fluoxetine Against Chronic Stress-Induced Neural Inflammation and Apoptosis: Involvement of the p38 Activity

Depression is considered a widespread neuropsychiatric disease associated with neuronal injury within specific brain regions. Fluoxetine, a selective serotonin reuptake inhibitor, has been widely used in depressed patients. Recently, fluoxetine has demonstrated neuroprotective effects apart from the effect on serotonin. However, the underlying mechanism involved in this neuroprotection remains unclear, in particular, whether fluoxetine exerts antidepressant effects via protecting against neuronal injury. Here, we found that treatment with fluoxetine (10 mg/kg, i.p.) for 2 weeks ameliorated depression-like behaviors in a chronic unpredictable mild stress (CUMS)-induced rat model of depression and was accompanied with an alleviation of glia activation and inhibition of interleukin-1β (IL-1β), interferon gamma (IFN-γ), and tumor necrosis factor-α (TNF-α) expression in the hippocampal dentate gyrus (DG) region. Meanwhile, CUMS rats treated with fluoxetine showed reductions in neuronal apoptosis and a downregulation of the apoptotic protein Bax, cleaved caspase 3, and caspase 9 levels. These effects appear to involve a downregulation of p38 mitogen-activated protein kinase (MAPK) signaling within the DG hippocampus as the specific inhibitor of p38 MAPK, SB203580, significantly suppressed apoptosis, as well as ameliorated depressive behaviors resulting from CUMS exposure. Moreover, fluoxetine could rescue neuronal deterioration and depression-like phenotypes caused by overexpression of p38 in DG. This finding extends our knowledge on the antidepressant-like effects of fluoxetine, which appear to at least partially profit from neuroprotection against inflammation and neuronal apoptosis via downregulation of the p38 MAPK pathway. The neuroprotective mechanisms of fluoxetine may provide some novel therapeutic avenues for stress-related neurological diseases.

VEGF Treatment Ameliorates Depression-Like Behavior in Adult Offspring After Maternal Immune Activation.

Maternal immune activation (MIA) during pregnancy impacts offspring neurodevelopmental trajectories and induces lifelong consequences, including emotional and cognitive alterations. Using the polyinosinic:polycytidilic acid (PIC) MIA model we have previously demonstrated enhanced depression-like behavior in adult MIA offspring, which was associated with reduced expression of the vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) in the hippocampus. Since VEGF mediates the effects of various antidepressant agents, we here set out to explore whether VEGF administration could rescue the depression-like behavioral deficits in MIA offspring. To test our hypothesis, control and MIA offspring were intracerebroventricularly (i.c.v.) infused with either VEGF or vehicle solution and depression-related behavior was assessed in the sucrose preference test (SPT) and the tail suspension test (TST). As a surrogate of VEGF activity, the phosphorylation of the extracellular signal-regulated kinase (ERK) in hippocampus was quantified. We found that VEGF treatment reduced depression-related behavioral despair in the TST in MIA offspring but had no effect on anhedonia-like behavior in the SPT. While VEGF administration induced the phosphorylation of ERK in the hippocampus of control offspring, this effect was blunted in the MIA offspring. We conclude that VEGF administration, at the dosage tested, beneficially affects some aspects of the depression-like phenotype in the adult MIA offspring, inviting further studies using different dosage regimes to further explore the therapeutic potential of VEGF treatment in MIA-related changes in brain function and behavior.

Chronic depression-like phenotype in male offspring mice following perinatal exposure to naturally contaminated eels with a mixture of organic and inorganic pollutants.

Previously, we demonstrated that maternal exposure to high, intermediate, or lowly contaminated European eels with a mixture of chemicals, during pregnancy and lactation, resulted in adult despair-like behavior, selectively in male offspring mice. Here, we investigate if depression-like behavior in offspring males was transient or permanent by monitoring immobility behavior, a measure of behavioral despair, at three distinct stages of life, including young adult (post-natal day (PND) 55), mature adult (PND 200) and middle (PNDs 335-336) age, in the forced swimming (FST) and the tail suspension (TST) tests. Oxidative stress markers including malondialdehyde (MDA) levels and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities were evaluated in the hippocampus, prefrontal cortex, and cerebellum of middle-aged animals. Findings showed a significant enhancement of immobility behavior in the TST performed at young adult age (all p < 0.05) in the FST carried out at mature adult age (all p < 0.001) and in both behavioral tests realized at middle age (all p < 0.05, except one p = 0.06) in mice perinatally exposed to eels compared with non-exposed controls. Antioxidant-related enzyme activities, including SOD and CAT, were only elevated in the hippocampus of middle-aged males perinatally exposed to the two more polluted eels (all p < 0.05). Further, lipid peroxidation, assessed by MDA levels, was not found to be differentially regulated in the selected areas of middle-aged brains of exposed mice (all p > 0.05). Collectively, this suggested limited oxidative metabolism disturbances in middle-aged brains exposed to eels. In summary, our results highlighted that offspring males perinatally exposed to naturally contaminated reared and river eels with persistent organic pollutants (POPs) and heavy metals displayed chronic depression-like phenotype. As extrapolation of data to humans should be done with precaution, retrospective and prospective epidemiological studies are needed to clarify this potential relationship, stressed in our animal model, between maternal polluted fish consumption and chronically low mood in offspring.

Severe hydroxymethylbilane synthase deficiency causes depression-like behavior and mitochondrial dysfunction in a mouse model of homozygous dominant acute intermittent porphyria

Acute intermittent porphyria (AIP) is an autosomal dominant inborn error of heme biosynthesis due to a pathogenic mutation in the Hmbs gene, resulting in half-normal activity of hydroxymethylbilane synthase. Factors that induce hepatic heme biosynthesis induce episodic attacks in heterozygous patients. The clinical presentation of acute attacks involves the signature neurovisceral pain and may include psychiatric symptoms. Here we used a knock-in mouse line that is biallelic for the Hmbs c.500G > A (p.R167Q) mutation with ~ 5% of normal hydroxymethylbilane synthase activity to unravel the consequences of severe HMBS deficiency on affective behavior and brain physiology. Hmbs knock-in mice (KI mice) model the rare homozygous dominant form of AIP and were used as tool to elucidate the hitherto unknown pathophysiology of the behavioral manifestations of the disease and its neural underpinnings. Extensive behavioral analyses revealed a selective depression-like phenotype in Hmbs KI mice; transcriptomic and immunohistochemical analyses demonstrated aberrant myelination. The uncovered compromised mitochondrial function in the hippocampus of knock-in mice and its ensuing neurogenic and neuroplastic deficits lead us to propose a mechanistic role for disrupted mitochondrial energy production in the pathogenesis of the behavioral consequences of severe HMBS deficiency and its neuropathological sequelae in the brain.

Ketamine relieves depression-like behaviors induced by chronic postsurgical pain in rats through anti-inflammatory, anti-oxidant effects and regulating BDNF expression.

Clinically, chronic postsurgical pain (CPSP) is very common. Many CPSP patients may experience depression. Thus far, little is known about the mechanism of the comorbidity of CPSP and depression. Ketamine has been confirmed to possess analgesic and rapid antidepressant effects, but it is unclear whether ketamine can relieve the comorbidity of CPSP and depression. The present study evaluated the effects of ketamine in rats with the comorbidity of CPSP and depression. We induced CPSP in rats by thoracotomy and screened for rats with or without depression-like phenotype by hierarchical cluster analysis based on the results of depression-related behavioral experiments. Subsequently, rats were intraperitoneally injected with ketamine (20mg/kg) and were evaluated by mechanical withdrawal threshold, cold hyperalgesia test, sucrose preference test, forced swimming test, and open field test. The inflammatory-related cytokines (IL-1, IL-6, TNF-α, nuclear factor-kappaB), oxidative stress parameters (superoxide dismutase, malondialdehyde, glutathione, catalase), and brain-derived neurotrophic factor (BDNF) in rat hippocampus were detected. In the hippocampus of rats with the comorbidity of CPSP and depression, IL-1, IL-6, TNF-α, nuclear factor-kappaB, and malondialdehyde were significantly increased, while superoxide dismutase, glutathione, catalase, and BDNF were significantly decreased. Ketamine relieved depression but did not attenuate hyperalgesia in CPSP rats. Additionally, ketamine reduced proinflammatory cytokines, inhibited oxidative stress, and elevated BDNF levels in rat hippocampus. Ketamine can rapidly relieve CPSP-induced depression in rats, which may be related to the reduction of proinflammatory cytokines, regulating oxidative stress and increasing BDNF in the hippocampus.