Ketamine, a dissociative anesthetic with well documented abuse liability, can also provide rapid-onset and persistent antidepressant effects and is currently used for the management of treatment-resistant depression. Although the precise neurobiological mechanisms underlying its antidepressant actions are not fully determined, a critical feature of ketamine's clinical efficacy may be its antianhedonic action. Anhedonia is an endophenotype of depression defined by decreased responsivity to previously rewarding stimuli and is generally not ameliorated by conventional antidepressants, emphasizing the need to examine underlying behavioral mechanisms of action. In this study, the probabilistic reward task, a reverse-translated assay originally designed to objectively quantify anhedonic phenotypes in human subjects, was used in rats to examine ketamine's effects on reward responsiveness under conditions without programmed stressors (3.2-32.0 mg/kg) or during ongoing chronic exposure to ecologically relevant stress (10.0 mg/kg). Results showed that under conditions without programmed stress, ketamine produced significant prohedonic effects in the probabilistic reward task, defined by increases in reward responsiveness that dissipated within 24 hours. In rats exposed to ongoing chronic stress, ketamine produced significant antianhedonic effects, defined by the rescue of blunted reward responsiveness, that persisted for nearly 1 week. Taken together, the prolonged antianhedonic effects of ketamine in rats experiencing chronic stress, compared with the shorter-lived prohedonic effects in subjects without exposure to programmed stressors, are striking and highlight the role of environmental determinants in the effects of ketamine on behavioral processes. Moreover, the translational nature of this experimental design may offer the opportunity to accelerate development of novel antianhedonic therapeutics. SIGNIFICANCE STATEMENT: Although ketamine is used for the management of treatment-resistant depression, its precise behavioral mechanisms of action are not fully delineated. Emerging evidence suggests the attenuation of anhedonia plays a key role in its rapid-acting therapeutic efficacy. To evaluate this possibility, the effects of ketamine were studied using a reverse-translated assay of reward responsiveness in rats and documented to be short-lived (prohedonic) under nonstressful conditions and persistent (antianhedonic) under stressful conditions, informing ketamine effects in healthy versus depressed individuals.

Chronic stress is a major risk factor for depression, a leading cause of disability and suicide. Because current antidepressants work slowly, have common side effects, and are only effective in a minority of patients, there is an unmet need to identify the underlying molecular mechanisms. Here, we identify the receptor for neuropeptides B and W, Npbwr1, as a key regulator of depressive-like symptoms. Npbwr1 is increased in the nucleus accumbens of chronically stressed mice and postmortem in patients diagnosed with depression. Using viral-mediated gene transfer, we demonstrate a causal link between Npbwr1, dendritic spine morphology, the biomarker Bdnf, and depressive-like behaviors. Importantly, microinjection of the synthetic antagonist of Npbwr1, CYM50769, rapidly ameliorates depressive-like behavioral symptoms and alters Bdnf levels. CYM50769 is selective, well tolerated, and shows effects up to 7 days after administration of a single dose. In summary, these findings advance our understanding of mood and chronic stress and warrant further investigation of CYM50769 as a potential fast-acting antidepressant.

Qingyangshen (Cynanchum otophyllum C.K. Schneid) is a folk drug for treating depression and other mental disorders induced by social defeat stress. Neuroplasticity in the hippocampus is essential for the modulation of cognition and emotion, and its impairment may contribute to the development and progression of depression. Our previous studies have found that Qingyangshen glycosides (QYS) can improve depression-like behavior in social failure mouse models, mainly through PGC-1α/FNDC5/BDNF signaling pathways activation, but its effects and mechanisms on hippocampal neuroplasticity remain unknown.

Chronic social defeat stress (CSDS) was used to induce social defeat in mice. Morphological changes in the hippocampus were observed by H&E staining and Golgi staining. Immunofluorescence double staining was used to detect the expression of synaptophysin (SYN) and postsynaptic density protein-95 (PSD-95), while western blot was employed to evaluate PSD-95, SYN, and doublecortin (DCX) proteins. The pathological processing of social defeat and the therapeutic effects of QYS on it was confirmed through behavioral assessment associated with morphologic observation.

During the whole study, the sucrose preference indices and OFT activity time of CSDS mice were significantly decreased (p ≤ 0.05), and the tail suspension immobility time was significantly increased (p ≤ 0.05), suggesting that the mice had significant depressive symptoms. Treatment with QYS (25, 50, and 100 mg/kg) significantly alleviated depressive symptoms in CSDS mice, which was demonstrated by significantly (p ≤ 0.05 or p ≤ 0.01) reducing the duration of tail-hanging immobility and increasing the tendency of sucrose preference indices and OFT activity time. QYS treatment also significantly increased the expression of DCX, PSD-95, and SYN proteins, which play a crucial role in depression.

QYS alleviated these symptoms by enhancing hippocampal neuroplasticity through upregulating the expression of synapse-associated proteins (SAPs). The therapeutic mechanism of QYS may involve modulating the neuroplasticity of hippocampus neurons by altering the expression of SAPs.

The treatment of stress-related disorders such as anxiety and depression is still challenging. One potential therapeutical option are neurosteroids. Their synthesis is promoted by ligands of the mitochondrial translocator protein 18 kDa (TSPO). We tested the TSPO ligand etifoxine (ETX) in a rat model of hyper-anxiety and depression-like behavior, i.e., in female and male HAB (high anxiety-related behavior) rats, as well as in respective low anxiety (LAB) and non-selected control (NAB) rats for behavioral, molecular, cellular, and physiological parameters. Daily acute i.p. treatment with ETX or vehicle over 5 or 9 days revealed that ETX was most effective in female HAB rats; it reduced anxiety levels (5 days) and OXT-R binding brain site-specifically (5 and 9 days), and increased spine density (5 days). The behavioral ETX effect exclusively found in female HABs was accompanied by increased 3β5α-THDOC levels, without any effect in female LABs and NABs and on other neurosteroids. In males of all breeding lines, ETX changed a total of 10 out of 23 brain steroids. Passive stress-coping during 10-min forced swimming was not affected by 9-day treatment with ETX, the resulting stress-induced plasma corticosterone levels were higher in ETX-treated NAB rats of both sexes compared with their VEH-treated groups. The fecal bacterial composition was similar but beta diversity differed between HABs and LABs and from NABs independent of sex; ETX treatment had no effect. Therefore, we propose considering the aspect of sex in treatment strategies for anxiety disorders. This is particularly important to establish better treatment regimens for women.

Early protein malnutrition has been shown to affect the brain reward circuitry, leading to enduring molecular, neurochemical, and behavioral alterations. This study explored how maternal protein restriction contributes to anhedonia, a key depression symptom, focusing on the hippocampal BDNF-TrkB signaling and structural plasticity changes in the CA1 subregion of the dorsal hippocampus (DH). To achieve our goal, adult rats submitted to a protein restriction schedule from the 14th day of gestation up to 30 days of age (PR-rats) were subjected to the sucrose preference test (SPT) and compared with animals fed a normoprotein diet. Immediately after SPT, we assessed the levels of BDNF and its receptor TrkB and structural plasticity changes. Interestingly, PR-rats showed a significant decrease in sucrose preference. Furthermore, perinatal protein-restriction-induced anhedonia correlated with decreased BDNF and p-TrkB levels in the DH, alongside reduced dendritic spine density in CA1 pyramidal neurons, particularly mature spines (i.e., stubby and mushroom spines). These findings suggest that decreased hippocampal BDNF-TrkB signaling accompanied by structural remodeling in the CA1 pyramidal neurons may contribute to the reduced ability of undernourished animals to respond to rewarding stimuli, increasing their vulnerability to anhedonia later in life.

Chronic cocaine use triggers inflammatory and oxidative processes in the central nervous system, resulting in impaired microglia. Mesenchymal stem cells, known for their immunomodulatory properties, have shown promise in reducing inflammation and enhancing neuronal survival. The study employed the cocaine self-administration model, focusing on ionized calcium-binding adaptor protein 1 (Iba-1) and cell morphology as markers for microglial impairment and PLX-PAD cells as a treatment for attenuating cocaine craving. The results revealed an addiction-stage and region-specific impairment in microglia following chronic cocaine exposure, with deficits observed in the Nucleus Accumbens (NAc) during the maintenance stage and in both the NAc and Dentate Gyrus (DG) during the extinction and reinstatement stages. Furthermore, PLX-PAD cell therapy demonstrated a significant reduction in cocaine craving and seeking behavior, interestingly accompanied by the prevention of Iba-1 level decrease and restoration of microglial activity in the NAc and DG. These findings highlight the unique role of microglia in modulating cocaine addiction behaviors through their influence on synaptic plasticity and neuronal remodeling associated with memory formation. They also suggest that PLX-PAD therapy may mitigate the detrimental effects of chronic cocaine exposure on microglia, underscoring the importance of incorporating microglia in comprehensive addiction rehabilitation strategies.

Spatially heterogeneous synapse loss is a characteristic of many psychiatric and neurological disorders, but the underlying mechanisms are unclear. Here, we show that spatially-restricted complement activation mediates stress-induced heterogeneous microglia activation and synapse loss localized to the upper layers of the medial prefrontal cortex (mPFC) in male mice. Single cell RNA sequencing also reveals a stress-associated microglia state marked by high expression of the apolipoprotein E gene (Apoehigh) localized to the upper layers of the mPFC. Mice lacking complement component C3 are protected from stress-induced layer-specific synapse loss, and the Apoehigh microglia population is markedly reduced in the mPFC of these mice. Furthermore, C3 knockout mice are also resilient to stress-induced anhedonia and working memory behavioral deficits. Our findings suggest that region-specific complement and microglia activation can contribute to the disease-specific spatially restricted patterns of synapse loss and clinical symptoms found in many brain diseases.

The development of novel radiotracers for Positron Emission Tomography (PET) imaging agents targeting the synaptic vesicle glycoprotein 2 A (SV2A), an integral glycoprotein present in the membrane of all synaptic vesicles throughout the central nervous system, provides a method for the in vivo quantification of synaptic density. This is of particular interest in neuropsychiatric disorders given that synaptic alterations appear to underlie disease progression and symptom severity. In this review, we briefly describe the development of these SV2A tracers and the evaluation of quantification methods. Next, we discuss application of SV2A PET imaging to the study of depression, including a review of our findings demonstrating lower SV2A synaptic density in people with significant depressive symptoms and the use of a ketamine drug challenge to examine synaptogenesis in vivo. We then highlight the importance of performing translational PET imaging in animal models in conjunction with clinical imaging. We consider the ongoing challenges, possible solutions, and present preliminary findings from our lab demonstrating the translational benefit and potential of in vivo SV2A imaging in animal models of chronic stress. Finally, we discuss methodological improvements and future directions for SV2A imaging, potentially in conjunction with other neural markers.

Nymphaea candida Presl (NC), traditionally used in medicine for heat syndrome-related ailments, possesses antioxidative, anti-inflammatory, hepatoprotective, and neuroprotective properties. This research investigates the antidepressant and neuroprotective effects and mechanisms of Nymphaea candida Presl ethyl acetate (NCEA). Primary components of NCEA were identified as phenolic acids and flavonoids through UPLC-MS/MS analysis. The depression mouse model was induced via intracerebroventricular injection of Lipopolysaccharide (LPS), followed by oral administration of fluoxetine and NCEA for one week. Biochemical assays and HE staining confirmed NCEA's non-toxicity and protective effects on the liver and lungs. NCEA administration mitigated LPS-induced depressive behaviors, decreased IL-1β, TNF-α levels in the hippocampus, suppressed microglial activation, reduced Iba-1 expression, and increased NA, brain-derived neurotrophic factor (BDNF), and dendritic spine density in the hippocampus. Furthermore, NCEA enhanced cell viability in a CORT-induced PC12 cell model, decreased lactate dehydrogenase (LDH) release rate, total superoxide dismutase (SOD) inhibition rate, intracellular nitric oxide (NO) release, and reduced reactive oxygen species (ROS) production. Our research findings suggest that NCEA exhibits significant antidepressant effects, which may be attributed to its reduction of neuroinflammation, improvement in neurotransmitter levels, neuronal protection, and antioxidative stress properties.

Over 300 million people worldwide suffer from major depressive disorder (MDD). Unfortunately, only 30-40% of patients with MDD achieve complete remission after conventional monoamine antidepressant therapy. In recent years, ketamine has revolutionized the treatment of MDD, with its rapid antidepressant effects manifesting within a few hours as opposed to weeks with conventional antidepressants. Many research endeavors have sought to identify ketamine's mechanism of action in mood disorders; while many studies have focused on ketamine's role in glutamatergic modulation, several studies have implicated its role in regulating neuroinflammation. The complement system is an important component of the innate immune response vital for synaptic plasticity. The complement system has been implicated in the pathophysiology of depression, and studies have shown increases in complement component 3 (C3) expression in the prefrontal cortex of suicidal individuals with depression. Given the role of the complement system in depression, ketamine and the complement system's abilities to modulate glutamatergic transmission, and our current understanding of ketamine's anti-inflammatory properties, there is reason to suspect a common link between the complement system and ketamine's mechanism of action. This review will summarize ketamine's anti- inflammatory roles in the periphery and central nervous system, with an emphasis on complement system regulation.

Neurodevelopmental disorders such as autism spectrum disorder (ASD) have a heterogeneous etiology but are largely associated with genetic factors. Robust evidence from recent human genetic studies has linked mutations in the Shank2 gene to idiopathic ASD. Modeling these Shank2 mutations in animal models recapitulates behavioral changes, e.g. impaired social interaction and repetitive behavior of ASD patients. Shank2-deficient mice exhibit NMDA receptor (NMDAR) hypofunction and associated behavioral deficits. Of note, NMDARs are strongly implicated in cognitive flexibility. Their hypofunction, e.g. observed in schizophrenia, or their pharmacological inhibition leads to impaired cognitive flexibility. However, the association between Shank2 mutations and cognitive flexibility is poorly understood. Using Shank2-deficient mice, we explored the role of Shank2 in cognitive flexibility measured by the attentional set shifting task (ASST) and whether ASST performance in Shank2-deficient mice can be modulated by treatment with the partial NMDAR agonist D-cycloserine (DCS). Furthermore, we investigated the effects of Shank2 deficiency, ASST training, and DCS treatment on the expression level of NMDAR signaling hub components in the orbitofrontal cortex (OFC), including NMDAR subunits (GluN2A, GluN2B, GluN2C), phosphoglycerate dehydrogenase and serine racemase. Surprisingly, Shank2 deficiency did not affect ASST performance or alter the expression of the investigated NMDAR signaling hub components. Importantly, however, DCS significantly improved ASST performance, demonstrating that positive NMDAR modulation facilitates cognitive flexibility. Furthermore, DCS increased the expression of GluN2A in the OFC, but not that of other NMDAR signaling hub components. Our findings highlight the potential of DCS as a pharmacological intervention to improve cognitive flexibility impairments downstream of NMDAR modulation and substantiate the key role of NMDAR in cognitive flexibility.

Habits are familiar behaviors triggered by cues, not outcome predictability, and are insensitive to changes in the environment. They are adaptive under many circumstances but can be considered antecedent to compulsions and intrusive thoughts that drive persistent, potentially maladaptive behavior. Whether compulsive-like and habit-like behaviors share neural substrates is still being determined. Here, we investigated mice bred to display inflexible reward-seeking behaviors that are insensitive to action consequences. We found that these mice demonstrate habitual response biases and compulsive-like grooming behavior that was reversible by fluoxetine and ketamine. They also suffer dendritic spine attrition on excitatory neurons in the orbitofrontal cortex (OFC). Nevertheless, synaptic melanocortin 4 receptor (MC4R), a factor implicated in compulsive behavior, is preserved, leading to the hypothesis that Mc4r+ OFC neurons may drive aberrant behaviors. Repeated chemogenetic stimulation of Mc4r+ OFC neurons triggered compulsive and not inflexible or habitual response biases in otherwise typical mice. Thus, Mc4r+ neurons within the OFC appear to drive compulsive-like behavior that is dissociable from habitual behavior. Understanding which neuron populations trigger distinct behaviors may advance efforts to mitigate harmful compulsions.

Glutamate is the main excitatory neurotransmitter in the brain wherein it controls cognitive functional domains and mood. Indeed, brain areas involved in memory formation and consolidation as well as in fear and emotional processing, such as the hippocampus, prefrontal cortex, and amygdala, are predominantly glutamatergic. To ensure the physiological activity of the brain, glutamatergic transmission is finely tuned at synaptic sites. Disruption of the mechanisms responsible for glutamate homeostasis may result in the accumulation of excessive glutamate levels, which in turn leads to increased calcium levels, mitochondrial abnormalities, oxidative stress, and eventually cell atrophy and death. This condition is known as glutamate-induced excitotoxicity and is considered as a pathogenic mechanism in several diseases of the central nervous system, including neurodevelopmental, substance abuse, and psychiatric disorders. On the other hand, these disorders share neuroplasticity impairments in glutamatergic brain areas, which are accompanied by structural remodeling of glutamatergic neurons. In the current narrative review, we will summarize the role of glutamate-induced excitotoxicity in both the pathophysiology and therapeutic interventions of neurodevelopmental and adult mental diseases with a focus on autism spectrum disorders, substance abuse, and psychiatric disorders. Indeed, glutamatergic drugs are under preclinical and clinical development for the treatment of different mental diseases that share glutamatergic neuroplasticity dysfunctions. Although clinical evidence is still limited and more studies are required, the regulation of glutamate homeostasis is attracting attention as a potential crucial target for the control of brain diseases.

Astrocyte dysfunctions have been consistently observed in patients affected with depression and other psychiatric illnesses. Although over the years our understanding of these changes, their origin, and their consequences on behavior and neuronal function has deepened, many aspects of the role of astroglial dysfunction in major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) remain unknown. In this review, we summarize the known astroglial dysfunctions associated with MDD and PTSD, highlight the impact of chronic stress on specific astroglial functions, and how astroglial dysfunctions are implicated in the expression of depressive- and anxiety-like behaviors, focusing on behavioral consequences of astroglial manipulation on emotion-related and fear-learning behaviors. We also offer a glance at potential astroglial functions that can be targeted for potential antidepressant treatment.

The neuronal cell adhesion molecule (NrCAM) is widely expressed and has important physiological functions in the nervous system across the lifespan, from axonal growth and guidance to spine and synaptic pruning, to organization of proteins at the nodes of Ranvier. NrCAM lies at the core of a functional protein network where multiple targets (including NrCAM itself) have been associated with schizophrenia. Here we investigated the effects of chronic unpredictable stress on latent inhibition, a measure of selective attention and learning which shows alterations in schizophrenia, in NrCAM knockout (KO) mice and their wild-type littermate controls (WT). Under baseline experimental conditions both NrCAM KO and WT mice expressed robust latent inhibition (p = 0.001). However, following chronic unpredictable stress, WT mice (p = 0.002), but not NrCAM KO mice (F < 1), expressed latent inhibition. Analyses of neuronal activation (c-Fos positive counts) in key brain regions relevant to latent inhibition indicated four types of effects: a single hit by genotype in IL cortex (p = 0.0001), a single hit by stress in Acb-shell (p = 0.031), a dual hit stress x genotype in mOFC (p = 0.008), vOFC (p = 0.020), and Acb-core (p = 0.032), and no effect in PrL cortex (p > 0.141). These results indicating a pattern of differential effects of genotype and stress support a complex stress × genotype interaction model and a role for NrCAM in stress-induced pathological behaviors relevant to schizophrenia and other psychiatric disorders.

Depression is a prevalent mental illness, affecting a significant portion of the global population. Recent research has highlighted the crucial role of the gut microbiota in both metabolic and central nervous health. By reviewing literature from various databases, including Pubmed, Science Direct, Web of Science, and Scopus, spanning the years 2005-2023, a comprehensive search was conducted using keywords such as "Depression" and "Gut Microbiota". The gut microbiota acts as a "second brain" in humans and can communicate bidirectionally with the brain through the Brain-gut-microbiota axis pathway. This communication involves the immune and nervous systems. However, there are challenges in detecting and treating depression effectively. To address these limitations, researchers have been exploring the relationship between gut microbiota and depression. Studies have shown that gut microbial metabolites, such as lipopolysaccharides and short-chain fatty acids, can induce pro-inflammatory cytokines that contribute to neuroinflammation and increase the risk of depression. The kynurenine pathway, triggered by gut microbial metabolites, has also been associated with neuroinflammation. Thus, investigating these microbial metabolites can provide insights into depression treatment. This review focuses on analyzing the connection between gut microbial metabolites, inflammation, and depression. It explores novel mechanisms contributing to depression, specifically focusing on the mediation of inflammation through the release of pro-inflammatory cytokines. The objective is to provide valuable insights into the mechanisms underlying depression and to propose potential treatments.

Stress disorders are psychiatric disorders arising following stressful or traumatic events. They could deleteriously affect an individual's health because they often co-occur with mental illnesses. Considerable attention has been focused on neurons when considering the neurobiology of stress disorders. However, like other mental health conditions, recent studies have highlighted the importance of astrocytes in the pathophysiology of stress-related disorders. In addition to their structural and homeostatic support role, astrocytes actively serve several functions in regulating synaptic transmission and plasticity, protecting neurons from toxic compounds, and providing metabolic support for neurons. The astrocyte-neuron lactate shuttle model sets forth the importance of astrocytes in providing lactate for the metabolic supply of neurons under intense activity. Lactate also plays a role as a signaling molecule and has been recently studied regarding its antidepressant activity. This review discusses the involvement of astrocytes and brain energy metabolism in stress and further reflects on the importance of lactate as an energy supply in the brain and its emerging antidepressant role in stress-related disorders.

Alzheimer's disease (AD), the most common neurodegenerative disease, is characterized by accumulated amyloid-β (Aβ) plaques, aggregated phosphorylated tau protein, gliosis-associated neuroinflammation, synaptic dysfunction, and cognitive impairment. Many cohort studies indicate that tooth loss is a risk factor for AD. The detailed mechanisms underlying the association between AD and tooth loss, however, are not yet fully understood.

We explored the involvement of early tooth loss in the neuropathogenesis of the adult AppNL-G-F mouse AD model. The maxillary molars were extracted bilaterally in 1-month-old male mice soon after tooth eruption.

Plasma corticosterone levels were increased and spatial learning memory was impaired in these mice at 6 months of age. The cerebral cortex and hippocampus of AD mice with extracted teeth showed an increased accumulation of Aβ plaques and phosphorylated tau proteins, and increased secretion of the proinflammatory cytokines, including interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α), accompanied by an increased number of microglia and astrocytes, and decreased synaptophysin expression. AD mice with extracted teeth also had a shorter lifespan than the control mice.

These findings revealed that long-term tooth loss is a chronic stressor, activating the recruitment of microglia and astrocytes; exacerbating neuroinflammation, Aβ deposition, phosphorylated tau accumulation, and synaptic dysfunction; and leading to spatial learning and memory impairments in AD model mice.

Post-traumatic stress disorder (PTSD) is a highly prevalent psychiatric disorder that can become chronic and debilitating when left untreated. Available pharmacotherapies are limited, take weeks to show modest benefit and remain ineffective for up to 40% of patients. Methylone is currently in clinical development for the treatment of PTSD. Preclinical studies show rapid, robust and long-lasting antidepressant-like and anxiolytic effects. The mechanism of action underlying these effects is not yet fully understood. This study investigated the downstream gene expression changes and signaling pathways affected by methylone in key brain areas linked to PTSD and MDD. It also sought to determine whether neuroplasticity-related genes were involved. We compared effects of methylone with MDMA to explore similarities and differences in their brain effects because MDMA-assisted psychotherapy has recently shown benefit in clinical trials for PTSD and methylone is a structural analog of MDMA.

Monoamine binding, uptake and release studies were performed and a high-throughput-screen evaluated agonist/antagonist activities at 168 GPCRs in vitro. We used RNA sequencing (RNA-seq) to probe drug-induced gene expression changes in the amygdala and frontal cortex, two brain areas responsible for emotional learning that are affected by PTSD and MDD. Rats were treated with methylone or MDMA (both 10 mg/kg, IP), and their responses were compared with controls. We performed functional enrichment analysis to identify which pathways were regulated by methylone and/or MDMA. We confirmed changes in gene expression using immunohistochemistry.

Methylone, a monoamine uptake inhibitor and releaser, demonstrated no off-target effects at 168 GPCRs, unlike MDMA, which showed activity at 5HT2A and 5HT2C receptors. RNA-seq results revealed significant regulation of myelin-related genes in the amygdala, confirmed by immunohistochemistry. In the frontal cortex, methylone significantly upregulated genes implicated in neuroplasticity.

Results suggest that (1) methylone is a rapid-acting neuroplastogen that affects key brain substrates for PTSD and MDD and that (2) methylone appears to exhibit higher specificity and fewer off-target effects than MDMA. Together, these results are consistent with the reported clinical experiences of methylone and MDMA and bolster the potential use of methylone in the treatment of PTSD and, potentially, other neuropsychiatric disorders.

Altered mood and psychiatric disorders are commonly associated with chronic pain conditions; however, brain mechanisms linking pain and comorbid clinical depression are still largely unknown. In this study, we aimed to identify whether key genes/cellular mechanisms underlie susceptibility/resiliency to development of depressive-like behaviors during chronic pain state. Genome-wide RNA-seq analysis was used to examine the transcriptomic profile of the hippocampus, a limbic brain region that regulates mood and stress responses, from male rats exposed to chronic inflammatory pain. Pain-exposed animals were separated into either 'resilient' or 'susceptible' to development of enhanced behavioral emotionality based on behavioral testing. RNA-seq bioinformatic analysis, followed by validation using qPCR, revealed dysregulation of hippocampal genes involved in neuroinflammation, cell cycle/neurogenesis and blood-brain barrier integrity. Specifically, ADAM Metallopeptidase Domain 8 (Adam8) and Aurora Kinase B (Aurkb), genes with functional roles in activation of the NLRP3 inflammasome and microgliosis, respectively, were significantly upregulated in the hippocampus of 'susceptible' animals expressing increased behavioral emotionality. In addition, genes associated with blood-brain barrier integrity, such as the Claudin 4 (Cldn4), a tight junction protein and a known marker of astrocyte activation, were also significantly dysregulated between 'resilient' or 'susceptible' pain groups. Furthermore, differentially expressed genes (DEGs) were further characterized in rodents stress models to determine whether their hippocampal dysregulation is driven by common stress responses vs. affective pain processing. Altogether these results continue to strengthen the connection between dysregulation of hippocampal genes involved in neuroinflammatory and neurodegenerative processes with increased behavioral emotionality often expressed in chronic pain state.

Approximately one-third of Gulf War veterans suffer from Gulf War Illness (GWI), which encompasses mood disorders and depressive symptoms. Deployment-related exposure to organophosphate compounds has been associated with GWI development. Epigenetic modifications have been reported in GWI veterans. We previously showed that epigenetic histone dysregulations were associated with decreased brain-derived neurotrophic factor (BDNF) expression in a GWI rat model. GWI has no effective therapies. Ketamine (KET) has recently been approved by the Food and Drug Administration for therapy-resistant depression. Interestingly, BDNF upregulation underlies KET's antidepressant effect in GWI-related depression. Here, we investigated whether KET's effect on histone mechanisms signals BDNF upregulations in GWI. Male Sprague-Dawley rats were injected once daily with diisopropyl fluorophosphate (DFP; 0.5 mg/kg, s.c., 5 days). At 6 months following DFP exposure, KET (10 mg/kg, i.p.) was injected, and brains were dissected 24 hours later. Western blotting was used for protein expression, and epigenetic studies used chromatin immunoprecipitation methods. Dil staining was conducted for assessing dendritic spines. Our results indicated that an antidepressant dose of KET inhibited the upregulation of histone deacetylase (HDAC) enzymes in DFP rats. Furthermore, KET restored acetylated histone occupancy at the Bdnf promoter IV and induced BDNF protein expression in DFP rats. Finally, KET treatment also increased the spine density and altered the spine diversity with increased T-type and decreased S-type spines in DFP rats. Given these findings, we propose that KET's actions involve the inhibition of HDAC expression, upregulation of BDNF, and dendritic modifications that together ameliorates the pathologic synaptic plasticity and exerts an antidepressant effect in DFP rats. SIGNIFICANCE STATEMENT: This study offers evidence supporting the involvement of epigenetic histone pathways in the antidepressant effects of ketamine (KET) in a rat model of Gulf War Illness (GWI)-like depression. This effect is achieved through the modulation of histone acetylation at the Bdnf promoter, resulting in elevated brain-derived neurotrophic factor expression and subsequent dendritic remodeling in the hippocampus. These findings underscore the rationale for considering KET as a potential candidate for clinical trials aimed at managing GWI-related depression.

The role of death-associated protein kinase1 (DAPK1) in post-stroke functional recovery is controversial, as is its mechanism of action and any neural remodeling effect after ischemia. To assess the debatable role of DAPK1, we established the middle cerebral artery occlusion (MCAo) model in DAPK1 knockout mice and Sprague-Dawley (SD) rats. We identified that the genetic deletion of the DAPK1 as well as pharmacological inhibition of DAPK1 showed reduced brain infarct volume and neurological deficit. We report that DAPK1 inhibition (DI) reduces post-stroke neuronal death by inhibiting BAX/BCL2 and LC3/Beclin1 mediated apoptosis and autophagy, respectively. Histological analysis displayed a reduction in nuclear condensation, neuronal dissociation, and degraded cytoplasm in the DI group. The DI treatment showed enhanced dendrite spine density and neurite outgrowth, upregulated neural proliferation marker proteins like brain-derived neurotrophic factor, and reduced structural abnormalities of the cortical pyramidal neurons. This research shows that DAPK1 drives cell death, its activation exacerbates functional recovery after cerebral ischemia and shows that oxazolone-based DI could be an excellent candidate for stroke and ischemic injury intervention.

Reductions of astroglia expressing glial fibrillary acidic protein (GFAP) are consistently found in the prefrontal cortex (PFC) of patients with depression and in rodent chronic stress models. Here, we examine the consequences of PFC GFAP+ cell depletion and cell activity enhancement on depressive-like behaviors in rodents. Using viral expression of diphtheria toxin receptor in PFC GFAP+ cells, which allows experimental depletion of these cells following diphtheria toxin administration, we demonstrated that PFC GFAP+ cell depletion induced anhedonia-like behavior within 2 days and lasting up to 8 days, but no anxiety-like deficits. Conversely, activating PFC GFAP+ cell activity for 3 weeks using designer receptor exclusively activated by designer drugs (DREADDs) reversed chronic restraint stress-induced anhedonia-like deficits, but not anxiety-like deficits. Our results highlight a critical role of cortical astroglia in the development of anhedonia and further support the idea of targeting astroglia for the treatment of depression.

N-methyl-D-aspartate receptors (NMDARs) are ion channels that respond to the neurotransmitter glutamate, playing a crucial role in the permeability of calcium ions and excitatory neurotransmission in the central nervous system (CNS). Composed of various subunits, NMDARs are predominantly formed by two obligatory GluN1 subunits (with eight splice variants) along with regulatory subunits GluN2 (GluN2A-2D) and GluN3 (GluN3A-B). They are widely distributed throughout the CNS and are involved in essential functions such as synaptic transmission, learning, memory, plasticity, and excitotoxicity. The presence of GluN2A and GluN2B subunits is particularly important for cognitive processes and has been strongly implicated in neurodegenerative diseases like Parkinson's disease and Alzheimer's disease. Understanding the roles of GluN2A and GluN2B NMDARs in neuropathologies provides valuable insights into the underlying causes and complexities of major nervous system disorders. This knowledge is vital for the development of selective antagonists targeting GluN2A and GluN2B subunits using pharmacological and molecular methods. Such antagonists represent a promising class of NMDA receptor inhibitors that have the potential to be developed into neuroprotective drugs with optimal therapeutic profiles.

Introduction: Natural products such as phytoestrogens-enriched foods or supplements have been considered as an alternative therapy to reduce depressive symptoms associated with menopause. It is known that the aqueous extract of Punica granatum (AE-PG) exerts antidepressant-like effects by activating β-estrogen receptors and facilitates the antidepressant response of the clinical drug citalopram (CIT). However, the effects on neuroplasticity are unknown. Objectvie investigated the antidepressant-like response of combining AE-PG and CIT at sub-optimal doses, analyzing their effects on the formation and maturation of dendrite spines in granule cells as well as on the dendrite complexity. Methods: Ovariectomized Wistar rats (3-month-old) were randomly assigned to one of the following groups: A) control (saline solution as vehicle of CIT and AE-PG, B) AE-PG at a sub-threshold dose (vehicle of CIT plus AE-PG at 0.125 mg/kg), C) CIT at a sub-threshold dose (0.77 mg/kg plus vehicle of AE-PG), and D) a combination of CIT plus AE-PG (0.125 mg/kg and 0.77 mg/kg, respectively). All rats were treated intraperitoneally for 14 days. Antidepressant-like effects were evaluated using the force swimming test test (FST). The complexity of dendrites and the number and morphology of dendrite spines of neurons were assessed in the dentate gyrus after Golgi-Cox impregnation. The expressions of the mature brain-derived neurotrophic factor (mBDNF) in plasma and of mBDNF and synaptophysin in the hippocampus, as markers of synaptogenesis, were also determined. Results: Administration of CIT combined with AE-PG, but not alone, induced a significant antidepressant-like effect in the FST with an increase in the dendritic complexity and the number of dendritic spines in the dentate gyrus (DG) of the hippocampus, revealed by the thin and stubby categories of neurons at the granular cell layer. At the same time, an increase of mBDNF and synaptophysin expression was observed in the hippocampus of rats that received the combination of AE-PG and CIT.

Spatially heterogeneous synapse loss is a characteristic of many psychiatric and neurological disorders, but the underlying mechanisms are unclear. Here, we show that spatially-restricted complement activation mediates stress-induced heterogeneous microglia activation and synapse loss localized to the upper layers of the mouse medial prefrontal cortex (mPFC). Single cell RNA sequencing also reveals a stress-associated microglia state marked by high expression of the apolipoprotein E gene (ApoE high ) localized to the upper layers of the mPFC. Mice lacking complement component C3 are protected from stress-induced layer-specific synapse loss, and the ApoE high microglia population is markedly reduced in the mPFC of these mice. Furthermore, C3 knockout mice are also resilient to stress-induced anhedonia and working memory behavioral deficits. Our findings suggest that region-specific complement and microglia activation can contribute to the disease-specific spatially restricted patterns of synapse loss and clinical symptoms found in many brain diseases.

Depression is the most common affective disorder worldwide, accounting for 4.4% of the global population, a figure that could increase in the coming decades. In depression, there exists a reduction in the availability of dendritic spines in the frontal cortex (FC) and hippocampus (Hp). In addition, histone modification and DNA methylation are also dysregulated epigenetic mechanisms in depression. Repetitive transcranial magnetic stimulation (rTMS) is a technique that is used to treat depression. However, the epigenetic mechanisms of its therapeutic effect are still not known. Therefore, in this study, we evaluated the antidepressant effect of 5 Hz rTMS and examined its effect on dendritic remodeling, immunoreactivity of synapse proteins, histone modification, and DNA methylation in the FC and Hp in a model of chronic mild stress. Our data indicated that stress generated depressive-like behaviors and that rTMS reverses this effect, romotes the formation of dendritic spines, and favors the presynaptic connection in the FC and DG (dentate gyrus), in addition to increasing histone H3 trimethylation and DNA methylation. These results suggest that the antidepressant effect of rTMS is associated with dendritic remodeling, which is probably regulated by epigenetic mechanisms. These data are a first approximation of the impact of rTMS at the epigenetic level in the context of depression. Therefore, it is necessary to analyze in future studies as to which genes are regulated by these mechanisms, and how they are associated with the neuroplastic modifications promoted by rTMS.

The endocannabinoid system (eCS) is widely distributed in mammalian tissues and it is classically formed by cannabinoid receptors, endogenous bioactive lipids and its synthesis and degradation enzymes. Due to the modulatory role of eCS in synaptic activity in the Central Nervous System (CNS), phytocannabinoids have been increasingly used for the treatment of neurological disorders, even though little is known in terms of the long-term effect of these treatments on CNS development, mainly in the timeframe that comprises childhood and adolescence. Furthermore, an increased number of clinical trials using full-spectrum Cannabis extracts has been seen, rather than the isolated form of phytocannabinoids, when exploring the therapeutical benefits of the Cannabis plant. Thus, this study aims to evaluate the effect of cannabidiol (CBD)-enriched Cannabis extract on synaptic components in the hippocampus of rats from adolescence to early adulthood (postnatal day 45 to 60). Oral treatment of healthy male Wistar rats with a CBD-enriched Cannabis extract (3 mg/kg/day CBD) during 15 days did not affect food intake and water balance. There was also no negative impact on locomotor behaviour and cognitive performance. However, the hippocampal protein levels of GluA1 and GFAP were reduced in animals treated with the extract, whilst PSD95 levels were increased, which suggests rearrangement of glutamatergic synapses and modulation of astrocytic features. Microglial complexity was reduced in CA1 and CA3 regions, but no alterations in their phagocytic activity have been identified by Iba-1 and LAMP2 co-localization. Collectively, our data suggest that CBD-enriched Cannabis treatment may be safe and well-tolerated in healthy subjects, besides acting as a neuroprotective agent against hippocampal alterations related to the pathogenesis of excitatory and astrogliosis-mediated disorders in CNS.

Reductions of astroglia expressing glial fibrillary acidic protein (GFAP) are consistently found in the prefrontal cortex (PFC) of patients with depression and in rodent chronic stress models. Here, we examine the consequences of PFC GFAP+ cell depletion and cell activity enhancement on depressive-like behaviors in rodents. Using viral expression of diphtheria toxin receptor in PFC GFAP+ cells, which allows experimental depletion of these cells following diphtheria toxin administration, we demonstrated that PFC GFAP+ cell depletion induced anhedonia-like behavior within 2 days and lasting up to 8 days, but no anxiety-like deficits. Conversely, activating PFC GFAP+ cell activity for 3 weeks using designer receptor exclusively activated by designer drugs (DREADDs) reversed chronic restraint stress-induced anhedonia-like deficits, but not anxiety-like deficits. Our results highlight a critical role of cortical astroglia in the development of anhedonia and further support the idea of targeting astroglia for the treatment of depression.

Depression is a neuropsychiatric disease resulting from deteriorations of molecular networks and synaptic injury induced by stress. Traditional Chinese formula Xiaoyaosan (XYS) exert antidepressant effect, which was demonstrated by a great many of clinical and basic investigation. However, the exact mechanism of XYS has not yet been fully elucidated.

In this study, chronic unpredictable mild stress (CUMS) rats were used as a model of depression. Behavioral test and HE staining were used to detect the anti-depressant effects of XYS. Furthermore, whole transcriptome sequencing was employed to establish the microRNA (miRNA), long non-coding RNA (lncRNA), circular RNA (circRNA), and mRNA profiles. The biological functions and potential mechanisms of XYS for depression were gathered from the GO and KEGG pathway. Then, constructed the competing endogenous RNA (ceRNA) networks to illustrate the regulatory relationship between non-coding RNA (ncRNA) and mRNA. Additionally, longest dendrite length, total length of dendrites, number of intersections, and density of dendritic spines were detected by Golgi staining. MAP2, PSD-95, SYN were detected by immunofluorescence respectively. BDNF, TrkB, p-TrkB, PI3K, Akt, p-Akt were measured by Western Blotting.

The results showed that XYS could increase the locomotor activity and sugar preference, decreased swimming immobility time as well as attenuate hippocampal pathological damage. A total of 753 differentially expressed lncRNAs (DElncRNAs), 28 circRNAs (DEcircRNAs), 101 miRNAs (DEmiRNAs), and 477 mRNAs (DEmRNAs) were identified after the treatment of XYS in whole transcriptome sequencing analysis. Enrichment results revealed that XYS could regulate multiple aspects of depression through different synapse or synaptic associated signal, such as neurotrophin signaling and PI3K/Akt signaling pathways. Then, vivo experiments indicated that XYS could promote length, density, intersections of synapses and also increase the expression of MAP2 in hippocampal CA1, CA3 regions. Meanwhile, XYS could increase the expression of PSD-95, SYN in the CA1, CA3 regions of hippocampal by regulating the BDNF/trkB/PI3K signal axis.

The possible mechanism on synapse of XYS in depression was successfully predicted. BDNF/trkB/PI3K signal axis were the potential mechanism of XYS on synapse loss for its antidepressant. Collectively, our results provided novel information about the molecular basis of XYS in treating depression.

We aimed to dissect the complex relations between depressive symptoms, antidepressant use, and constituent metabolic syndrome (MetS) components in a representative U.S. population sample. A total of 15,315 eligible participants were included from 2005 to March 2020. MetS components were defined as hypertension, elevated triglycerides, reduced high-density lipoprotein cholesterol, central obesity, and elevated blood glucose. Depressive symptoms were classified as mild, moderate, or severe. Logistic regression was used to evaluate the relationship between depression severity, antidepressant use, individual MetS components and their degree of clustering. Severe depression was associated with the number of MetS components in a graded fashion. ORs for severe depression ranged from 2.08 [95%CI, 1.29-3.37] to 3.35 [95%CI, 1.57-7.14] for one to five clustered components. Moderate depression was associated with hypertension, central obesity, raised triglyceride, and elevated blood glucose (OR = 1.37 [95%CI, 1.09-1.72], 1.82 [95%CI, 1.21-2.74], 1.63 [95%CI, 1.25-2.14], and 1.37 [95%CI, 1.05-1.79], respectively). Antidepressant use was associated with hypertension (OR = 1.40, 95%CI [1.14-1.72]), raised triglyceride (OR = 1.43, 95%CI [1.17-1.74]), and the presence of five MetS components (OR = 1.74, 95%CI [1.13-2.68]) after adjusting for depressive symptoms. The depression severity and antidepressant use were associated with individual MetS components and their graded clustering. Metabolic abnormalities in patients with depression need to be recognized and treated.

Abnormal expression of long non-coding RNAs (lncRNAs) has been correlated with depressive disorders, but limited data are available on the lncRNA-microRNA (miRNA/miR)-messenger RNA (mRNA) competitive endogenous RNA (ceRNA) mechanism in depression. Herein, we address this issue based on transcriptome sequencing and in vitro experiments. Mouse hippocampus tissues were obtained from chronic unpredictable mild stress (CUMS)-induced mice to screen out differentially expressed mRNAs and lncRNAs based on the transcriptome sequencing. Next, the depression-related differentially expressed genes (DEGs) were obtained, followed by Gene Ontology (GO) and Kyoto Encylopedia of Genes and Genomes (KEGG) enrichment analysis. A total of 1018 differentially expressed mRNAs, 239 differentially expressed lncRNAs, and 58 DEGs related to depression were acquired. The miRNAs targeting Harvey rat sarcoma virus oncogene (Hras) and miRNAs sponged by Hras-related lncRNA were intersected to identify the ceRNA regulatory network. In addition, the synapse-related genes related to depression were acquired by bioinformatics analysis. Hras was identified as the core gene related to depression, mainly related to neuronal excitation. We also found that 2210408F21Rik competitively bound to miR-1968-5p that targeted Hras. The effects of 2210408F21Rik/miR-1968-5p/Hras axis on neuronal excitation were verified in primary hippocampal neurons. The experimental data indicated that the downregulation of 2210408F21Rik increased the level of miR-1968-5p to diminish Hras expression, thereby affecting neuronal excitation in CUMS mice. In conclusion, the 2210408F21Rik/miR-1968-5p/Hras ceRNA network can potentially affect the expression of synapsia-related proteins and is a promising target for preventing and treating depression.

Persistent and negative stress stimulation is one of the most important factors leading to anxiety and depression in individuals, and it can negatively affect the normal function and structure of brain-related regions. However, the maladaptive changes of brain neural networks in anxiety and depression induced by chronic stress have not been explored in detail. In this study, we analyzed the changes in global information transfer efficiency, stress related blood oxygen level dependent (BOLD)- and diffusion tensor imaging (DTI)- signals and functional connectivity (FC) in rat models based on resting-state functional magnetic resonance imaging (rs-fMRI). The results showed that compared to control group, rats treated with chronic restraint stress (CRS) for 5 weeks had reconstructed the small-world network properties. In addition, CRS group had increased coherence and activity in bilateral Striatum (ST_R & L), but decreased coherence and activity in unilateral (left) Frontal Association Cortex (FrA_L) and unilateral (left) Medial Entorhinal Cortex (MEC_L). DTI analysis and correlation analysis confirmed the disrupted integrity of MEC_L and ST_R & L and their correlation to anxiety- and depressive-liked behaviors. Functional connectivity further showed these regions of interest (ROI) had decreased positive correlations with several brain areas, respectively. Our study comprehensively revealed the adaptive changes of brain neural networks induced by chronic stress and emphasized the abnormal activity and functional connectivity of ST_R & L and MEC_L in the pathological condition.

Major depressive disorder (MDD) is a complex illness that is arising as a growing public health concern. Although several brain areas are related to this type of disorders, at the cellular level, the parvalbumin-positive cells of the hippocampus interplay a very relevant role. They control pyramidal cell bursts, neuronal networks, basic microcircuit functions, and other complex neuronal tasks involved in mood disorders. In resistant depressions, the efficacy of current antidepressant treatments drops dramatically, so the new rapid-acting antidepressants (RAADs) are being postulated as novel treatments. Ketamine at subanesthetic doses and its derivative metabolites have been proposed as RAADs due to their rapid and sustained action by blocking N-methyl-d-aspartate (NMDA) receptors, which in turn lead to the release of brain-derived neurotrophic factor (BDNF). This mechanism produces a rapid plasticity activation mediated by neurotransmitter homeostasis, synapse recovery, and increased dendritic spines and therefore, it is a promising therapeutic approach to improve cognitive symptoms in MDD.

This theoretical article revives a classical bridging construct, canalization, to describe a new model of a general factor of psychopathology. To achieve this, we have distinguished between two types of plasticity, an early one that we call 'TEMP' for 'Temperature or Entropy Mediated Plasticity', and another, we call 'canalization', which is close to Hebbian plasticity. These two forms of plasticity can be most easily distinguished by their relationship to 'precision' or inverse variance; TEMP relates to increased model variance or decreased precision, whereas the opposite is true for canalization. TEMP also subsumes increased learning rate, (Ising) temperature and entropy. Dictionary definitions of 'plasticity' describe it as the property of being easily shaped or molded; TEMP is the better match for this. Importantly, we propose that 'pathological' phenotypes develop via mechanisms of canalization or increased model precision, as a defensive response to adversity and associated distress or dysphoria. Our model states that canalization entrenches in psychopathology, narrowing the phenotypic state-space as the agent develops expertise in their pathology. We suggest that TEMP - combined with gently guiding psychological support - can counter canalization. We address questions of whether and when canalization is adaptive versus maladaptive, furnish our model with references to basic and human neuroscience, and offer concrete experiments and measures to test its main hypotheses and implications. This article is part of the Special Issue on "National Institutes of Health Psilocybin Research Speaker Series".

Stress represents a main risk factor for psychiatric disorders. Whereas it is known that even a single trauma may induce psychiatric disorders in humans, the mechanisms of vulnerability to acute stressors have been little investigated. In this study, we generated a new animal model of resilience/vulnerability to acute footshock (FS) stress in rats and analyzed early functional, molecular, and morphological determinants of stress vulnerability at tripartite glutamate synapses in the prefrontal cortex (PFC). We found that adult male rats subjected to FS can be deemed resilient (FS-R) or vulnerable (FS-V), based on their anhedonic phenotype 24 h after stress exposure, and that these two populations are phenotypically distinguishable up to two weeks afterwards. Basal presynaptic glutamate release was increased in the PFC of FS-V rats, while depolarization-evoked glutamate release and synapsin I phosphorylation at Ser⁹ were increased in both FS-R and FS-V. In FS-R and FS-V rats the synaptic expression of GluN2A and apical dendritic length of prelimbic PFC layers II-III pyramidal neurons were decreased, while BDNF expression was selectively reduced in FS-V. Depolarization-evoked (carrier-mediated) glutamate release from astroglia perisynaptic processes (gliosomes) was selectively increased in the PFC of FS-V rats, while GLT1 and xCt levels were higher and GS expression reduced in purified PFC gliosomes from FS-R. Overall, we show for the first time that the application of the sucrose intake test to rats exposed to acute FS led to the generation of a novel animal model of resilience/vulnerability to acute stress, which we used to identify early determinants of maladaptive response related to behavioral vulnerability to stress.

Chronic stress can produce reward system deficits (i.e., anhedonia) and other common symptoms associated with depressive disorders, as well as neural circuit hypofunction in the medial prefrontal cortex (mPFC). However, the molecular mechanisms by which chronic stress promotes depressive-like behavior and hypofrontality remain unclear. We show here that the neuronal activity-regulated transcription factor, NPAS4, in the mPFC is regulated by chronic social defeat stress (CSDS), and it is required in this brain region for CSDS-induced changes in sucrose preference and natural reward motivation in the mice. Interestingly, NPAS4 is not required for CSDS-induced social avoidance or anxiety-like behavior. We also find that mPFC NPAS4 is required for CSDS-induced reductions in pyramidal neuron dendritic spine density, excitatory synaptic transmission, and presynaptic function, revealing a relationship between perturbation in excitatory synaptic transmission and the expression of anhedonia-like behavior in the mice. Finally, analysis of the mice mPFC tissues revealed that NPAS4 regulates the expression of numerous genes linked to glutamatergic synapses and ribosomal function, the expression of upregulated genes in CSDS-susceptible animals, and differentially expressed genes in postmortem human brains of patients with common neuropsychiatric disorders, including depression. Together, our findings position NPAS4 as a key mediator of chronic stress-induced hypofrontal states and anhedonia-like behavior.

Stress is a key risk factor in the onset of neuropsychiatric disorders. The study of the mechanisms underlying stress response is important to understand the etiopathogenetic mechanisms and identify new putative therapeutic targets. In this context, microRNAs (miRNAs) have emerged as key regulators of the complex patterns of gene/protein expression changes in the brain, where they have a crucial role in the regulation of neuroplasticity, neurogenesis, and neuronal differentiation. Among them, miR-135a-5p has been associated with stress response, synaptic plasticity, and the antidepressant effect in different brain areas. Here, we used acute unavoidable foot-shock stress (FS) and chronic mild stress (CMS) on male rats to study whether miR-135a-5p was involved in stress-induced changes in the prefrontal cortex (PFC). Both acute and chronic stress decreased miR-135a-5p levels in the PFC, although after CMS the reduction was induced only in animals vulnerable to CMS, according to a sucrose preference test. MiR-135a-5p downregulation in the primary neurons reduced dendritic spine density, while its overexpression exerted the opposite effect. Two bioinformatically predicted target genes, Kif5c and Cplx1/2, were increased in FS rats 24 h after stress. Altogether, we found that miR-135a-5p might play a role in stress response in PFC involving synaptic mechanisms.