Imbalance in Sirt1 Alternative Splicing in Response to Chronic Stress during the Adolescence Period in Female Mice

Stressful unpredictable life events have been implicated in numerous diseases. It is now becoming clear that some life periods are more vulnerable than others. As adolescence is a sensitive period in brain development, the long-term effects of stress during this period could be significant. We investigated the long-term effects of exposure to unpredictable chronic mild stress in adolescent mice on alternative splicing of Sirtuin 1. One-month-old mice were exposed to 4 weeks of UCMS and examined for anxiety and cognition at the age of 2, 4 and 6 months. We found a rise in anxious behavior immediately after the exposure to stress. Notably, there was a long-term impairment of performance in cognitive tasks and an imbalance in Sirtuin 1 and TrkB receptor alternative splicing in the stress-exposed mice compared with controls. To conclude, our results show that exposure to unpredictable chronic mild stress during adolescence affects cognition in adulthood. Understanding pathways affiliated with stress may help minimize the long-term emotional effects of an unpredictable, stressful event.     

Effect of δ-Opioid Receptor Activation on BDNF-TrkB vs. TNF-α in the Mouse Cortex Exposed to Prolonged Hypoxia

We investigated whether δ-opioid receptor (DOR)-induced neuroprotection involves the brain-derived neurotrophic factor (BDNF) pathway. We studied the effect of DOR activation on the expression of BDNF and other proteins in the cortex of C57BL/6 mice exposed to hypoxia (10% of oxygen) for 1–10 days. The results showed that: (1) 1-day hypoxia had no appreciable effect on BDNF expression, while 3- and 10-day hypoxia progressively decreased BDNF expression, resulting in 37.3% reduction (p < 0.05) after 10-day exposure; (2) DOR activation with UFP-512 (1 mg/kg, i.p., daily) partially reversed the hypoxia-induced reduction of BDNF expression in the 3- or 10-day exposed cortex; (3) DOR activation partially reversed the hypoxia-induced reduction in functional TrkB (140-kDa) and attenuated hypoxia-induced increase in truncated TrkB (90-kDa) in the 3- or 10-day hypoxic cortex; and (4) prolonged hypoxia (10 days) significantly increased TNF-α level and decreased CD11b expression in the cortex, which was completely reversed following DOR activation; and (5) there was no significant change in pCREB and pATF-1 levels in the hypoxic cortex. We conclude that prolonged hypoxia down-regulates BDNF-TrkB signaling leading to an increase in TNF-α in the cortex, while DOR activation up-regulates BDNF-TrkB signaling thereby decreasing TNF-α levels in the hypoxic cortex.     

Effects of Chronic LY341495 on Hippocampal mTORC1 Signaling in Mice with Chronic Unpredictable Stress-Induced Depression

In several rodent models, acute administration of the metabotropic glutamate 2/3 (mGlu2/3) receptor antagonist LY341495 induced antidepressant-like effects via a mechanism of action similar to that of ketamine. However, the effects of chronic mGlu2/3 antagonism have not yet been explored. Therefore, we investigated the effects of chronic LY341495 treatment on the mechanistic target of rapamycin complex 1 (mTORC1) signaling and the levels of synaptic proteins in mice subjected to chronic unpredictable stress (CUS). LY341495 (1 mg/kg) was administered daily for 4 weeks to mice with and without CUS exposure. After the final treatment, the forced swimming test (FST) was used to assess antidepressant-like effects. The hippocampal levels of mTORC1-related proteins were derived by Western blotting. Chronic LY341495 treatment reversed the CUS-induced behavioral effects of FST. CUS significantly reduced the phosphorylation of mTORC1 and downstream effectors [eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP-1) and small ribosomal protein 6 (S6)], as well as the expression of synaptic proteins postsynaptic density-95 (PSD-95) and AMPA receptor subunit GluR1 (GluA1) in the hippocampus. However, chronic LY341495 treatment rescued these deficits. Our results suggest that the activation of hippocampal mTORC1 signaling is related to the antidepressant effect of chronic LY341495 treatment in an animal model of CUS-induced depression.     

Neuropeptide Trefoil Factor 3 Reverses Depressive-Like Behaviors by Activation of BDNF-ERK-CREB Signaling in Olfactory Bulbectomized Rats

The trefoil factors (TFFs) are a family of three polypeptides, among which TFF1 and TFF3 are widely distributed in the central nervous system. Our previous study indicated that TFF3 was a potential rapid-onset antidepressant as it reversed the depressive-like behaviors induced by acute or chronic mild stress. In order to further identify the antidepressant-like effect of TFF3, we applied an olfactory bulbectomy (OB), a classic animal model of depression, in the present study. To elucidate the mechanism underlying the antidepressant-like activity of TFF3, we tested the role of brain-derived neurotrophic factor (BDNF)-extracellular signal-related kinase (ERK)-cyclic adenosine monophosphate response element binding protein (CREB) signaling in the hippocampus in the process. Chronic systemic administration of TFF3 (0.1 mg/kg, i.p.) for seven days not only produced a significant antidepressant-like efficacy in the OB paradigm, but also restored the expression of BDNF, pERK, and pCREB in the hippocampal CA3. Inhibition of BDNF or extracellular signal-related kinase (ERK) signaling in CA3 blocked the antidepressant-like activity of TFF3 in OB rats. Our findings further confirmed the therapeutic effect of TFF3 against depression and suggested that the normalization of the BDNF-ERK-CREB pathway was involved in the behavioral response of TFF3 for the treatment of depression.     

High,in Contrast to Low Levels of Acute Stress Induce Depressive-like Behavior by Involving Astrocytic,in Addition to Microglial P2X7 Receptors in the Rodent Hippocampus

Extracellular adenosine 5′-triphosphate (ATP) in the brain is suggested to be an etiological factor of major depressive disorder (MDD). It has been assumed that stress-released ATP stimulates P2X7 receptors (Rs) at the microglia, thereby causing neuroinflammation; however, other central nervous system (CNS) cell types such as astrocytes also possess P2X7Rs. In order to elucidate the possible involvement of the MDD-relevant hippocampal astrocytes in the development of a depressive-like state, we used various behavioral tests (tail suspension test [TST], forced swim test [FST], restraint stress, inescapable foot shock, unpredictable chronic mild stress [UCMS]), as well as fluorescence immunohistochemistry, and patch-clamp electrophysiology in wild-type (WT) and genetically manipulated rodents. The TST and FST resulted in learned helplessness manifested as a prolongation of the immobility time, while inescapable foot shock caused lower sucrose consumption as a sign of anhedonia. We confirmed the participation of P2X7Rs in the development of the depressive-like behaviors in all forms of acute (TST, FST, foot shock) and chronic stress (UCMS) in the rodent models used. Further, pharmacological agonists and antagonists acted in a different manner in rats and mice due to their diverse potencies at the respective receptor orthologs. In hippocampal slices of mice and rats, only foot shock increased the current responses to locally applied dibenzoyl-ATP (Bz-ATP) in CA1 astrocytes; in contrast, TST and restraint depressed these responses. Following stressful stimuli, immunohistochemistry demonstrated an increased co-localization of P2X7Rs with a microglial marker, but no change in co-localization with an astroglial marker. Pharmacological damage to the microglia and astroglia has proven the significance of the microglia for mediating all types of depression-like behavioral reactions, while the astroglia participated only in reactions induced by strong stressors, such as foot shock. Because, in addition to acute stressors, their chronic counterparts induce a depressive-like state in rodents via P2X7R activation, we suggest that our data may have relevance for the etiology of MDD in humans.     

Myricetin Attenuates Depressant-Like Behavior in Mice Subjected to Repeated Restraint Stress

Increasing evidence has shown that oxidative stress may be implicated in chronic stress-induced depression. Several flavonoids with anti-oxidative effects have been proved to be anti-depressive. Myricetin is a well-defined flavonoid with the anti-oxidative, anti-inflammatory, anti-apoptotic, and neuroprotective properties. The aim of the present study is to investigate the possible effects of chronic administration of myricetin on depressant-like behaviors in mice subjected to repeated restraint (4 h/day) for 21 days. Our results showed that myricetin administration specifically reduced the immobility time in mice exposed to chronic stress, as tested in both forced swimming test and tail suspension test. Myricetin treatment improved activities of glutathione peroxidase (GSH-PX) in the hippocampus of stressed mice. In addition, myricetin treatment decreased plasma corticosterone levels of those mice subjected to repeated restraint stress. The effects of myricetin on the brain-derived neurotrophic factor (BDNF) levels in hippocampus were also investigated. The results revealed that myricetin normalized the decreased BDNF levels in mice subjected to repeated restraint stress. These findings provided more evidence that chronic administration of myricetin improves helpless behaviors. The protective effects of myricetin might be partially mediated by an influence on BDNF levels and might be attributed to myricetin-mediated anti-oxidative stress in the hippocampus.     

mTOR Knockdown in the Infralimbic Cortex Evokes A Depressive-like State in Mouse

Fast and sustained antidepressant effects of ketamine identified the mammalian target of rapamycin (mTOR) signaling pathway as the main modulator of its antidepressive effects. Thus, mTOR signaling has become integral for the preclinical evaluation of novel compounds to treat depression. However, causality between mTOR and depression has yet to be determined. To address this, we knocked down mTOR expression in mice using an acute intracerebral infusion of small interfering RNAs (siRNA) in the infralimbic (IL) or prelimbic (PrL) cortices of the medial prefrontal cortex (mPFC), and evaluated depressive- and anxious-like behaviors. mTOR knockdown in IL, but not PrL, cortex produced a robust depressive-like phenotype in mice, as assessed in the forced swimming test (FST) and the tail suspension test (TST). This phenotype was associated with significant reductions of mTOR mRNA and protein levels 48 h post-infusion. In parallel, decreased brain-derived neurotrophic factor (BDNF) expression was found bilaterally in both IL and PrL cortices along with a dysregulation of serotonin (5-HT) and glutamate (Glu) release in the dorsal raphe nucleus (DRN). Overall, our results demonstrate causality between mTOR expression in the IL cortex and depressive-like behaviors, but not in anxiety.     

Music-Based Intervention Ameliorates Mecp2-Loss-Mediated Sociability Repression in Mice through the Prefrontal Cortex FNDC5/BDNF Pathway

Patients with Rett syndrome (RTT) show severe difficulties with communication, social withdrawl, and learning. Music-based interventions improve social interaction, communication skills, eye contact, and physical skills and reduce seizure frequency in patients with RTT. This study aimed to investigate the mechanism by which music-based interventions compromise sociability impairments in mecp2 ^null/y mice as an experimental RTT model. Male mecp2 ^null/y mice and wild-type mice (24 days old) were randomly divided into control, noise, and music-based intervention groups. Mice were exposed to music or noise for 6 h/day for 3 consecutive weeks. Behavioral patterns, including anxiety, spontaneous exploration, and sociability, were characterized using open-field and three-chamber tests. BDNF, TrkB receptor motif, and FNDC5 expression in the prefrontal cortex (PFC), hippocampus, basal ganglia, and amygdala were probed using RT-PCR or immunoblotting. mecp2 ^null/y mice showed less locomotion in an open field than wild-type mice. The social novelty rather than the sociability of these animals increased following a music-based intervention, suggesting that music influenced the mecp2-deletion-induced social interaction repression rather than motor deficit. Mechanically, the loss of BDNF signaling in the prefrontal cortex and hippocampal regions, but not in the basal ganglia and amygdala, was compromised following the music-based intervention in mecp2 ^null/y mice, whereas TrkB signaling was not significantly changed in either region. FNDC5 expression in the prefrontal cortex region in mecp2 ^null/y mice also increased following the music-based intervention. Collective evidence reveals that music-based interventions improve mecp2-loss-induced social dysfunction. BDNF and FNDC5 signaling in the prefrontal cortex region mediates the music-based-intervention promotion of social interactions. This study gives new insight into the mechanisms underlying the improvement of social behaviors in mice suffering from experimental Rett syndrome following a music-based intervention.     

Escitalopram Targets Oxidative Stress,Caspase-3, BDNF and MeCP2 in the Hippocampus and Frontal Cortex of a Rat Model of Depression Induced by Chronic Unpredictable Mild Stress

In recent years, escitalopram (ESC) has been suggested to have different mechanisms of action beyond its well known selective serotonin reuptake inhibition. The aim of this study is to investigate the effects of escitalopram on oxidative stress, apoptosis, brain-derived neurotrophic factor (BDNF), Methyl-CpG-binding protein 2 (MeCP2), and oligodendrocytes number in the brain of chronic unpredictable mild stress-induced depressed rats. The animals were randomised in four groups (8 in each group): control, stress, stress + ESC 5 and stress + ESC 5/10. ESC was administered for 42 days in a fixed dose (5 mg/kg b.w.) or in an up-titration regimen (21 days ESC 5 mg/kg b.w. then 21 days ESC 10 mg/kg b.w.). Sucrose preference test (SPT) and elevated plus maze (EPM) were also performed. ESC improved the percentage of sucrose preference, locomotion and anxiety. ESC5/10 reduced the oxidative damage in the hippocampus and improved the antioxidant defence in the hippocampus and frontal lobe. ESC5/10 lowered caspase 3 activity in the hippocampus. Escitalopram had a modulatory effect on BDNF and the number of oligodendrocytes in the hippocampus and frontal lobe and also improved the MeCP2 expressions. The results confirm the multiple pathways implicated in the pathogenesis of depression and suggest that escitalopram exerts an antidepressant effect via different intricate mechanisms.     

Hippocampal Over-Expression of Cyclooxygenase-2 (COX-2) Is Associated with Susceptibility to Stress-Induced Anhedonia in Mice

The phenomenon of individual variability in susceptibility/resilience to stress and depression, in which the hippocampus plays a pivotal role, is attracting increasing attention. We investigated the potential role of hippocampal cyclooxygenase-2 (COX-2), which regulates plasticity, neuroimmune function, and stress responses that are all linked to this risk dichotomy. We used a four-week-long chronic mild stress (CMS) paradigm, in which mice could be stratified according to their susceptibility/resilience to anhedonia, a key feature of depression, to investigate hippocampal expression of COX-2, a marker of microglial activation Iba-1, and the proliferation marker Ki67. Rat exposure, social defeat, restraints, and tail suspension were used as stressors. We compared the effects of treatment with either the selective COX-2 inhibitor celecoxib (30 mg/kg/day) or citalopram (15 mg/kg/day). For the celecoxib and vehicle-treated mice, the Porsolt test was used. Anhedonic (susceptible) but not non-anhedonic (resilient) animals exhibited elevated COX-2 mRNA levels, increased numbers of COX-2 and Iba-1-positive cells in the dentate gyrus and the CA1 area, and decreased numbers of Ki67-positive cells in the subgranular zone of the hippocampus. Drug treatment decreased the percentage of anhedonic mice, normalized swimming activity, reduced behavioral despair, and improved conditioned fear memory. Hippocampal over-expression of COX-2 is associated with susceptibility to stress-induced anhedonia, and its pharmacological inhibition with celecoxib has antidepressant effects that are similar in size to those of citalopram.     

Regulation of Neuroinflammatory Signaling by PPARγ Agonist in Mouse Model of Diabetes

Many relevant studies, as well as clinical practice, confirm that untreated diabetes predisposes the development of neuroinflammation and cognitive impairment. Having regard for the fact that PPARγ are widely distributed in the brain and PPARγ ligands may regulate the inflammatory process, the anti-inflammatory potential of the PPARγ agonist, pioglitazone, was assessed in a mouse model of neuroinflammation related with diabetes. In this regard, the biochemical and molecular indicators of neuroinflammation were determined in the hippocampus and prefrontal cortex of diabetes mice. The levels of cytokines (IL-1β, IL-6, and TNF) and the expression of genes (Tnfrsf1a and Cav1) were measured. In addition, behavioral tests such as the open field test, the hole-board test, and the novel object recognition test were conducted. A 14-day treatment with pioglitazone significantly decreased IL-6 and TNFα levels in the prefrontal cortex and led to the downregulation of Tnfrsf1a expression and the upregulation of Cav1 expression in both brain regions of diabetic mice. Pioglitazone, by targeting neuroinflammatory signaling, improved memory and exploratory activity in behavioral tests. The present study provided a potential theoretical basis and therapeutic target for the treatment of neuroinflammation associated with diabetes. Pioglitazone may provide a promising therapeutic strategy in diabetes patients with muffled of behavioral activity.     

Brain Proteome and Behavioural Analysis in Wild Type,BDNF+/− and BDNF−/− Adult Zebrafish (Danio rerio) Exposed to Two Different Temperatures

Experimental evidence suggests that environmental stress conditions can alter the expression of BDNF and that the expression of this neurotrophin influences behavioural responses in mammalian models. It has been recently demonstrated that exposure to 34 °C for 21 days alters the brain proteome and behaviour in zebrafish. The aim of this work was to investigate the role of BDNF in the nervous system of adult zebrafish under control and heat treatment conditions. For this purpose, zebrafish from three different genotypes (wild type, heterozygous BDNF^+/− and knock out BDNF^−/−) were kept for 21 days at 26 °C or 34 °C and then euthanized for brain molecular analyses or subjected to behavioural tests (Y-maze test, novel tank test, light and dark test, social preference test, mirror biting test) for assessing behavioural aspects such as boldness, anxiety, social preference, aggressive behaviour, interest for the novel environment and exploration. qRT-PCR analysis showed the reduction of gene expression of BDNF and its receptors after heat treatment in wild type zebrafish. Moreover, proteomic analysis and behavioural tests showed genotype- and temperature-dependent effects on brain proteome and behavioural responding. Overall, the absent expression of BDNF in KO alters (1) the brain proteome by reducing the expression of proteins involved in synapse functioning and neurotransmitter-mediated transduction; (2) the behaviour, which can be interpreted as bolder and less anxious and (3) the cellular and behavioural response to thermal treatment.     

BDNF Overexpression in the Ventral Hippocampus Promotes Antidepressant- and Anxiolytic-Like Activity in Serotonin Transporter Knockout Rats

BDNF plays a pivotal role in neuroplasticity events, vulnerability and resilience to stress-related disorders, being decreased in depressive patients and increased after antidepressant treatment. BDNF was found to be reduced in patients carrying the human polymorphism in the serotonin transporter promoter region (5-HTTLPR). The serotonin knockout rat (SERT^−/−) is one of the animal models used to investigate the underlying molecular mechanisms of depression in humans. They present decreased BDNF levels, and anxiety- and depression-like behavior. To investigate whether upregulating BDNF would ameliorate the phenotype of SERT^−/− rats, we overexpressed BDNF locally into the ventral hippocampus and submitted the animals to behavioral testing. The results showed that BDNF overexpression in the vHIP of SERT^−/− rats promoted higher sucrose preference and sucrose intake; on the first day of the sucrose consumption test it decreased immobility time in the forced swim test and increased the time spent in the center of a novel environment. Furthermore, BDNF overexpression altered social behavior in SERT^−/− rats, which presented increased passive contact with test partner and decreased solitary behavior. Finally, it promoted decrease in plasma corticosterone levels 60 min after restraint stress. In conclusion, modulation of BDNF IV levels in the vHIP of SERT^−/− rats led to a positive behavioral outcome placing BDNF upregulation in the vHIP as a potential target to new therapeutic approaches to improve depressive symptoms.     

Environmental Enrichment Induces Meningeal Niche Remodeling through TrkB-Mediated Signaling

Neural precursors (NPs) present in the hippocampus can be modulated by several neurogenic stimuli, including environmental enrichment (EE) acting through BDNF-TrkB signaling. We have recently identified NPs in meninges; however, the meningeal niche response to pro-neurogenic stimuli has never been investigated. To this aim, we analyzed the effects of EE exposure on NP distribution in mouse brain meninges. Following neurogenic stimuli, although we did not detect modification of the meningeal cell number and proliferation, we observed an increased number of neural precursors in the meninges. A lineage tracing experiment suggested that EE-induced β3-Tubulin⁺ immature neuronal cells present in the meninges originated, at least in part, from GLAST⁺ radial glia cells. To investigate the molecular mechanism responsible for meningeal reaction to EE exposure, we studied the BDNF-TrkB interaction. Treatment with ANA-12, a TrkB non-competitive inhibitor, abolished the EE-induced meningeal niche changes. Overall, these data showed, for the first time, that EE exposure induced meningeal niche remodeling through TrkB-mediated signaling. Fluoxetine treatment further confirmed the meningeal niche response, suggesting it may also respond to other pharmacological neurogenic stimuli. A better understanding of the neurogenic stimuli modulation for meninges may be useful to improve the effectiveness of neurodegenerative and neuropsychiatric treatments.     

Exercise Training Enhances BDNF/TrkB Signaling Pathway and Inhibits Apoptosis in Diabetic Cerebral Cortex

This study aimed to clarify the therapeutic effects of exercise training on neural BDNF/TrkB signaling and apoptotic pathways in diabetic cerebral cortex. Thirty-six male C57BL/6JNarl mice were randomly divided into three groups: control (CON-G), diabetic group (DM-G, 100 mg/kg streptozotocin, i.p.), and diabetic with exercise training group (DMEX-G, Swim training for 30 min/day, 5 days/week). After 12 weeks, H&E staining, TUNEL staining, and Western blotting were performed to detect the morphological changes, neural apoptosis, and protein levels in the cerebral cortex. The Bcl2, BclxL, and pBad were significant decreased in DM-G compared with CON-G, whereas they (excluded the Ras and pRaf1) were increased in DMEX-G. In addition, interstitial space and TUNEL(+) apoptotic cells found increased in DM-G with increases in Fas/FasL-mediated (FasL, Fas, FADD, cleaved-caspase-8, and cleaved-caspase-3) and mitochondria-initiated (tBid, Bax/Bcl2, Bak/BclxL, Bad, Apaf1, cytochrome c, and cleaved-caspase-9) apoptotic pathways. However, diabetes-induced neural apoptosis was less in DMEX-G than DM-G with observed raises in the BDNF/TrkB signaling pathway as well as decreases in Fas/FasL-mediated and mitochondria-initiated pathways. In conclusion, exercise training provided neuroprotective effects via enhanced neural BDNF/TrkB signaling pathway and prevent Fas/FasL-mediated and mitochondria-initiated apoptotic pathways in diabetic cerebral cortex.     

Short Daily Exposure to Environmental Enrichment,Fluoxetine, or Their Combination Reverses Deterioration of the Coat and Anhedonia Behaviors with Differential Effects on Hippocampal Neurogenesis in Chronically Stressed Mice

Depression is a neuropsychiatric disorder with a high impact on the worldwide population. To overcome depression, antidepressant drugs are the first line of treatment. However, pre-clinical studies have pointed out that antidepressants are not entirely efficacious and that the quality of the living environment after stress cessation may play a relevant role in increasing their efficacy. As it is unknown whether a short daily exposure to environmental enrichment during chronic stress and antidepressant treatment will be more effective than just the pharmacological treatment, this study analyzed the effects of fluoxetine, environmental enrichment, and their combination on depressive-associated behavior. Additionally, we investigated hippocampal neurogenesis in mice exposed to chronic mild stress. Our results indicate that fluoxetine reversed anhedonia. Besides, fluoxetine reversed the decrement of some events of the hippocampal neurogenic process caused by chronic mild stress. Conversely, short daily exposure to environmental enrichment changed the deterioration of the coat and anhedonia. Although, this environmental intervention did not produce significant changes in the neurogenic process affected by chronic mild stress, fluoxetine plus environmental enrichment showed similar effects to those caused by environmental enrichment to reverse depressive-like behaviors. Like fluoxetine, the combination reversed the declining number of Ki67, doublecortin, calretinin cells and mature newborn neurons. Finally, this study suggests that short daily exposure to environmental enrichment improves the effects of fluoxetine to reverse the deterioration of the coat and anhedonia in chronically stressed mice. In addition, the combination of fluoxetine with environmental enrichment produces more significant effects than those caused by fluoxetine alone on some events of the neurogenic process. Thus, environmental enrichment improves the benefits of pharmacological treatment by mechanisms that need to be clarified.     

N-Acetylcysteine and Aripiprazole Improve Social Behavior and Cognition and Modulate Brain BDNF Levels in a Rat Model of Schizophrenia

Treatment of negative symptoms and cognitive disorders in patients with schizophrenia is still a serious clinical problem. The aim of our study was to compare the efficacy of chronic administration of the atypical antipsychotic drug aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy}-3,4-dihydro-2(1H)-quinolinone; ARI) and the well-known antioxidant N-acetylcysteine (NAC) both in alleviating schizophrenia-like social and cognitive deficits and in reducing the decreases in the levels of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC) and hippocampus (HIP) of adult Sprague-Dawley rats, that have been induced by chronic administration of the model compound L-buthionine-(S, R)-sulfoximine (BSO) during the early postnatal development (p5–p16). ARI was administered at doses of 0.1 and 0.3 mg/kg while NAC at doses of 10 and 30 mg/kg, alone or in combination. Administration of higher doses of ARI or NAC alone, or co-treatment with lower, ineffective doses of these drugs significantly improved social and cognitive performance as assessed in behavioral tests. Both doses of NAC and 0.3 mg/kg of ARI increased the expression of BDNF mRNA in the PFC, while all doses of these drugs and their combinations enhanced the levels of BDNF protein in this brain structure. In the HIP, only 0,3 mg/kg ARI increased the levels of both BDNF mRNA and its protein. These data show that in the rat BSO-induced neurodevelopmental model of schizophrenia, ARI and NAC differently modulated BDNF levels in the PFC and HIP.     

2-Phenylethylamine (PEA) Ameliorates Corticosterone-Induced Depression-Like Phenotype via the BDNF/TrkB/CREB Signaling Pathway

Depression is a serious medical illness that is one of the most prevalent psychiatric disorders. Corticosterone (CORT) increases depression-like behavior, with some effects on anxiety-like behavior. 2-Phenethylamine (PEA) is a monoamine alkaloid that acts as a central nervous system stimulant in humans. Here, we show that PEA exerts antidepressant effects by modulating the Brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element binding protein (CREB) signaling pathway in CORT-induced depression. To investigate the potential effects of PEA on CORT-induced depression, we first treated CORT (50 μM)-induced hippocampal neurons with 100 μM PEA for 24 h. We found that treatment with CORT altered dendritic spine architecture; however, treatment with PEA rescued dendritic spine formation via regulation of BDNF/TrkB/CREB signaling. Next, we used a mouse model of CORT-induced depression. Mice were treated with CORT (20 mg/kg) for 21 days, followed by assessments of a battery of depression-like behaviors. During the final four days of CORT exposure, the mice were treated with PEA (50 mg/kg). We found that CORT injection promoted depression-like behavior and significantly decreased BDNF and TrkB expression in the hippocampus. However, treatment with PEA significantly ameliorated the behavioral and biochemical changes induced by CORT. Our findings reveal that PEA exerts antidepressant effects by modulating the BDNF/TrkB/CREB signaling pathway in a mouse model of CORT-induced depression.     

Joint Degeneration in a Mouse Model of Pseudoachondroplasia: ER Stress,Inflammation, and Block of Autophagy

Pseudoachondroplasia (PSACH), a short limb skeletal dysplasia associated with premature joint degeneration, is caused by misfolding mutations in cartilage oligomeric matrix protein (COMP). Here, we define mutant-COMP-induced stress mechanisms that occur in articular chondrocytes of MT-COMP mice, a murine model of PSACH. The accumulation of mutant-COMP in the ER occurred early in MT-COMP articular chondrocytes and stimulated inflammation (TNFα) at 4 weeks, and articular chondrocyte death increased at 8 weeks while ER stress through CHOP was elevated by 12 weeks. Importantly, blockage of autophagy (pS6), the major mechanism that clears the ER, sustained cellular stress in MT-COMP articular chondrocytes. Degeneration of MT-COMP articular cartilage was similar to that observed in PSACH and was associated with increased MMPs, a family of degradative enzymes. Moreover, chronic cellular stresses stimulated senescence. Senescence-associated secretory phenotype (SASP) may play a role in generating and propagating a pro-degradative environment in the MT-COMP murine joint. The loss of CHOP or resveratrol treatment from birth preserved joint health in MT-COMP mice. Taken together, these results indicate that ER stress/CHOP signaling and autophagy blockage are central to mutant-COMP joint degeneration, and MT-COMP mice joint health can be preserved by decreasing articular chondrocyte stress. Future joint sparing therapeutics for PSACH may include resveratrol.     

Aversive Learning Deficits and Depressive-Like Behaviors Are Accompanied by an Increase in Oxidative Stress in a Rat Model of Fetal Alcohol Spectrum Disorders: The Protective Effect of Rapamycin

Fetal alcohol spectrum disorders (FASDs) are one of the most common consequences of ethanol exposure during pregnancy. In adulthood, these disorders can be manifested by learning and memory deficits and depressive-like behavior. Ethanol-induced oxidative stress may be one of the factors that induces FASD development. The mammalian target of the Rapamycin (mTOR) signaling pathway that acts via two distinct multiprotein complexes, mTORC1 and mTORC2, can affect oxidative stress. We investigated whether mTOR-dependent or mTOR-independent mechanisms are engaged in this phenomenon. Thus, Rapamycin—a selective inhibitor of mTORC1, Torin-2—a non-selective mTORC1/mTORC2 inhibitor, and FK-506—a drug that impacts oxidative stress in an mTOR-independent manner were used. Behavioral tests were performed in adult (PND60-65) rats using a passive avoidance (PA) task (aversive learning and memory) and forced swimming test (FST) (depressive-like behaviors). In addition, the biochemical parameters of oxidative stress, such as lipid peroxidation (LPO), as well as apurinic/apyrimidinic (AP)-sites were determined in the hippocampus and prefrontal cortex in adult (PND65) rats. The rat FASD model was induced by intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4–9 (an equivalent to the third trimester of human pregnancy). All substances (3 mg/kg) were given 30 min before ethanol. Our results show that neonatal ethanol exposure leads to deficits in context-dependent fear learning and depressive-like behavior in adult rats that were associated with increased oxidative stress parameters in the hippocampus and prefrontal cortex. Because these effects were completely reversed by Rapamycin, an mTORC1 inhibitor, this outcome suggests its usefulness as a preventive therapy in disorders connected with prenatal ethanol exposure.