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The neurocircuitry that contributes to the pathophysiology of posttraumatic stress disorder and major depressive disorder, psychiatric conditions that exhibit a high degree of comorbidity, likely involves both overlapping and unique structural and functional changes within multiple limbic brain regions. In this review, we discuss neurobiological alterations that are associated with posttraumatic stress disorder and major depressive disorder and highlight both similarities and differences that may exist between these disorders to argue for the existence of a shared neurobiology. We highlight the key contributions based on preclinical studies, emerging from the late Professor Ronald Duman's research, that have shaped our understanding of the neurocircuitry that contributes to both the etiopathology and treatment of major depressive disorder and posttraumatic stress disorder.

Introduction Major depressive disorder is the leading source of disability globally and current pharmacological treatments are less than adequate. Animal models such as the Flinders Sensitive Line (FSL) rats are used to mimic aspects of the phenotype in the human disorder and to characterise candidate antidepressant agents. Communication between the gut microbiome and the brain may play an important role in psychiatric disorders such as depression. Interventions targeting the gut microbiota may serve as potential treatments for depression, and this drives increasing research into the effect of probiotics and prebiotics in neuropsychiatric disorders. Prebiotics, galacto-oligosaccharides and fructooligosaccharides that stimulate the activity of gut bacteria have been reported to have a positive impact, reducing anxiety and depressive-like phenotypes and stress-related physiology in mice and rats, as well as in humans. Bimuno, the commercially available beta-galacto-oligosaccharide, has been shown to increase gut microbiota diversity. Aim Here, we aim to investigate the effect of Bimuno on rat anxiety-like and depressive-like behaviour and gut microbiota composition in the FSL model, a genetic model of depression, in comparison to their control, the Flinders Resistant Line (FRL) rats. Methods Sixty-four male rats aged 5–7 weeks, 32 FSL and 32 FRL rats, will be randomised to receive Bimuno or control (4 g/kg) daily for 4 weeks. Animals will be tested by an experimenter unaware of group allocation on the forced swim test to assessed depressive-like behaviour, the elevated plus maze to assess anxiety-like behaviour and the open field test to assess locomotion. Animals will be weighed and food and water intake, per kilogram of bodyweight, will be recorded. Faeces will be collected from each animal prior to the start of the experiment and on the final day to assess the bacterial diversity and relative abundance of bacterial genera in the gut. All outcomes and statistical analysis will be carried out blinded to group allocation, group assignments will be revealed after raw data have been uploaded to Open Science Framework. Two-way analysis of variance will be carried out to investigate the effect of treatment (control or prebiotic) and strain (FSL or FRL) on depressive-like and anxiety-like behaviours.

Multiple studies on the pathomechanisms of depressive disorder and antidepressants have been reported. However, literature involving scientometric analysis of depressive disorder is sparse. Here, we use scientometric analysis and a historical review to highlight recent research on depression. We use the former to examine research on depressive disorders from 1998 to 2018. The latter is used to identify the most frequent keywords in keyword analysis, as well as explore hotspots and depression trends. Scientometric analysis uncovered field distribution, knowledge structure, research topic evolution, and topics emergence as main explorations in depressive disorder. Induction factor, comorbidity, pathogenesis, therapy and animal models of depression help illustrate occurrence, development and treatment of depressive disorder. Scientometric analysis found 231,270 research papers on depression, a 4-fold increase over the last 20 years. These findings offer a vigorous roadmap for further studies in this field.

Inhalation therapy involves two types of adherence: adherence to the drug and adherence to the procedures for the inhalation device. Recent increases in the range of inhaled medications available have expanded treatment options

Background: Despite the availability of vast group of drugs, treatment of depression still remains unsatisfactory, largely due to differential efficacy of antidepressants at adequate doses resulting in treatment refractive depression. In addition, serious adverse effects of anti-depressants also lead to early withdrawal from treatment. One more important concern is the therapeutic lag of nearly 3-4 weeks, before some appreciable clinical effect. Therefore, newer agents with good safety profile, rapid onset of action and with substantial benefits in treating patients who are either refractory or resistant to conventional therapy, need to be explored. Methods: 8 groups of 6 mice each were evaluated for anti-depressant effect in Tail Suspension Test and Forced Swim Test. Treatment used was normal saline (control), citalopram, ketamine and combination of ketamine with citalopram. Results: Citalopram decreased the immobility time in both models but it was not significant in FST. Significant decrease in immobility time was observed in ketamine treated mice in both models. Ketamine and citalopram combination also decreased the immobility time significantly. Conclusion: Ketamine have an antidepressant activity of its own, as shown in both TST & FST models. Additionally, it also potentiated the antidepressant effect of citalopram, which could be attributed to possible involvement of NMDA receptors and its interaction with the monoaminergic system.

Antidepressant doses of ketamine rapidly facilitate synaptic plasticity and modify neuronal function within prefrontal and hippocampal circuits. However, most studies have demonstrated these effects in animal models and translational studies in humans are scarce. A recent animal study showed that ketamine restored dendritic spines in the hippocampal CA1 region within 1 h of administration. To translate these results to humans, this randomized, double-blind, placebo-controlled, crossover magnetic resonance imaging (MRI) study assessed ketamine’s rapid neuroplastic effects on hippocampal subfield measurements in healthy volunteers. S-Ketamine vs. placebo data were analyzed, and data were also grouped by brain-derived neurotrophic factor (BDNF) genotype. Linear mixed models showed that overall hippocampal subfield volumes were significantly larger (p = 0.009) post ketamine than post placebo (LS means difference=0.008, standard error=0.003). Post-hoc tests did not attribute effects to specific subfields (all p > 0.05). Trend-wise volumetric increases were observed within the left hippocampal CA1 region (p = 0.076), and trend-wise volumetric reductions were obtained in the right hippocampal—amygdaloid transition region (HATA) (p = 0.067). Neither genotype nor a genotype–drug interaction significantly affected the results (all p > 0.7). The study provides evidence that ketamine has short-term effects on hippocampal subfield volumes in humans. The results translate previous findings from animal models of depression showing that ketamine has pro-neuroplastic effects on hippocampal structures and underscore the importance of the hippocampus as a key region in ketamine’s mechanism of action.

Depressive disorder is one of the most widespread forms of psychiatric pathology, worldwide. According to a report by the World Health Organization, the number of people with depression, globally, is increasing dramatically with each year. Previous studies have demonstrated that various factors, including genetics and environmental stress, contribute to the risk of depression. As such, it is crucial to develop a detailed understanding of the pathogenesis of depressive disorder and animal studies are essential for identifying the mechanisms and genetic disorders underlying depression. Recently, many researchers have reported on the pathology of depression via various models of depressive disorder. Given that different animal models of depression show differences in terms of patterns of depressive behavior and pathology, the comparison between depressive animal models is necessary for progress in the field of the depression study. However, the various animal models of depression have not been fully compared or evaluated until now. In this paper, we reviewed the pathophysiology of the depressive disorder and its current animal models with the analysis of their transcriptomic profiles. We provide insights for selecting different animal models for the study of depression., Experimental models for the study of depression.

Ulcerative colitis (UC) is a chronic and recurrent gastrointestinal (GI) disorder with an unknown aetiology and pathogenesis. Regarding the effectiveness of antidepressants on UC in animal models of depression and the known anti-inflammatory effects of escitalopram this study was conducted to evaluate the beneficial effects of escitalopram on an acetic acid-induced UC model without depression. UC model was induced by intra rectal (i.r.) administration of 4% acetic acid in rats after 24 hours of fasting. Animals were treated with three doses of escitalopram (5, 10 and 20 mg/kg). Prednisolone (4 mg/kg) was used as a reference drug in UC. Histological and oxidative stress markers were measured in all groups. Results showed significant increase in superoxide dismutase (SOD) activity and glutathione (GSH) levels, as well as significant decrease in myeloperoxidase (MPO) activity, malondialdehyde (MDA) levels, macroscopic factors (ulcer surface area, ulcer severity and weight-to-colon ratio) and microscopic and histological parameters (severity and extent of inflammation, cryptic destruction and severity of tissue involvement) in escitalopram treated rats (10, 20 mg/kg) compared to the UC group. In conclusion, the results of our study are in support of beneficial anti-inflammatory and antioxidant effects of escitalopram in UC.

Background: Depression refers to a wide range of mental health problems characterized by the loss of interest in routine activities, low mood and a range of associated emotional, cognitive, physical and behavioral symptoms. It is one of the major causes of mortality as tendency of suicidal attacks are exhibited in these patients. The diagnosis of depressive patients is very complicated in many cases and they do not respond to rational clinical prescription. In traditional medicine, Nardostachys jatamansi has been used as stimulant, antispasmodic, laxative and antiepileptic in ayurvedic and unani systems of medicine. The objective of our study was to evaluate and compare the antidepressant activity of N. jatamansi extract with fluoxetine in animal models of depression. Methodology: It was a preclinical experimental study in which Total 100 BALB/c mice divide into 14 groups i.e. Group 1 & 2 control 0.9% NaCl i.p for forced swimming test (FST) and tail suspension test (TST) respectively, Group 3 & 4 Fluoxetine 0.5 mg/kg i.p for FST and TST respectively, Group 5, 6 & 7 of N. jatamansi 125, 250 and 500 mg/kg respectively for FST, Group 8, 9 & 10 N. jatamansi 125, 250 and 500 mg/kg respectively for TST, Group 11 N. jatamansi (most effective dose) for Locomotor Test, Group 12 NaCl 0.9% for Yohimbine Potentiation Test (YPT), Group 13 Fluoxetine 0.5 mg/kg for YPT and Group 14 Received extract of N. jatamansi (most effective dose) for YPT. Antidepressant activity of N. jatamansi extract at different doses after induction of depression via FST and TST was recorded. Moreover the antidepressant effect was confirmed by locomotor test. YPT was also applied to comment on possible underlying mechanism. Results: In our study 250 mg/kg and 500 mg/kg doses of N. jatamansi showed significant reduction in immobility time when compared to controls and 500 mg/kg showed significant reduction as compared to group given fluoxetine in FST model. All the groups in TST model showed significant reduction in immobility time when compared to controls and fluoxetine given group. N. jatamansi at the dose of 500 mg/kg was found to be most effective in both the models. No significant change in locomotor activity was found in locomotor test. The percentage mortality of 50% was observed in N. jatamansi group using yohimbine potentiation test. Conclusion: In our study Nardostachys jatamansi showed significant reduction in immobility time when compared to controls and fluoxetine.

Objectives Despite recent advances in depression treatment, many patients still do not respond to serial conventional therapies and are considered "treatment resistant." Deep brain stimulation (DBS) has therapeutic potential in this context. This comprehensive review of recent studies of DBS for depression in animal models identifies potential biomarkers for improving therapeutic efficacy and predictability of conventional DBS to aid future development of closed-loop control of DBS system. Materials and methods A systematic search was performed in Pubmed, EMBASE, and Cochrane Review using relevant keywords. In overall, 56 animal studies satisfied the inclusion criteria. Results Outcomes were divided into biochemical/physiological, electrophysiological, and behavioral categories. Promising biomarkers include biochemical assays (in particular, microdialysis and electrochemical measurements), which provide real-time results in awake animals. Electrophysiological tests, showing changes at both the target site and downstream structures also revealed characteristic changes at several anatomic targets (such as the medial prefrontal cortex and locus coeruleus). However, the substantial range of models and DBS targets limits the ability to draw generalizable conclusions in animal behavioral models. Conclusions Overall, DBS is a promising therapeutic modality for treatment-resistant depression. Different outcomes have been used to assess its efficacy in animal studies. From the review, electrophysiological and biochemical markers appear to offer the greatest potential as biomarkers for depression. However, to develop closed-loop DBS for depression, additional preclinical and clinical studies with a focus on identifying reliable, safe, and effective biomarkers are warranted.

Depression affects both women and men, but women are 2 times more susceptible to the incidence of depression. Although a number of studies report sex differences in stress responses, it remains unclear which animal models of depression can better mimic the sex difference in human depression. The majority of stress models used male rodents whereas fewer studies included females. The aims of this study were to determine which rat stress models mimic the sex difference in depression and to identify sex-specific risk factors for depression model-induced depression-like behaviors. Here, we compared subchronic variable stress (SCVS) and chronic unpredictable mild stress (CUMS) models to evaluate the susceptibility versus resilient phenotypes in male and female rats. SCVS induced depression-like behaviors in female rats only. The CUMS paradigm was more likely to induce depression-like behaviors in male rats. Furthermore, to explore the underlying mechanisms, we used quantitative reverse transcriptase polymerase chain reaction to examine and compare the messenger RNA (mRNA) levels of various transcripts previously shown to be involved in psychiatric disorders in RNA-sequencing/microarray studies including serotonin receptor-7, early growth response-2, histone deacetylase-2, roundabout guidance receptor-2 (Robo2), serum/glucocorticoid regulated kinase-2, orthodenticle homeobox-2, parathyroid hormone-2 receptor, and neuronal PAS domain protein-4 in the hippocampus after exposure of rats to SCVS and CUMS. Our results showed that SCVS significantly altered the mRNA levels of neuronal PAS domain protein-4, orthodenticle homeobox-2, Robo2, parathyroid hormone-2 receptor, and serum/glucocorticoid regulated kinase-2 in the female hippocampus only, and histone deacetylase-2 in only the male hippocampus. CUMS significantly changed the mRNA levels of one transcript (Robo2) in the female hippocampus only when compared with SCVS. Overall, this study shows that SCVS can be used to study sex differences in depression-like behaviors in rats. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Our understanding of the molecular mechanisms of depression remains largely unclear. Previous studies have shown that the prefrontal cortex (PFC) is among most important brain regions that exhibits metabolic changes in depression. A comprehensive analysis based on candidate metabolites in the PFC of animal models of depression will provide valuable information for understanding the pathogenic mechanism underlying depression. Candidate metabolites that are potentially involved in the metabolic changes of the PFC in animal models of depression were retrieved from the Metabolite Network of Depression Database. The significantly altered metabolic pathways were revealed by canonical pathway analysis, and the relationships among altered pathways were explored by pathway crosstalk analysis. Additionally, drug-associated pathways were investigated using drug-associated metabolite set enrichment analysis. The interrelationships among metabolites, proteins, and other molecules were analyzed by molecular network analysis. Among 88 candidate metabolites, 87 altered canonical pathways were identified, and the top five ranked pathways were tRNA charging, the endocannabinoid neuronal synapse pathway, (S)-reticuline biosynthesis II, catecholamine biosynthesis, and GABA receptor signaling. Pathway crosstalk analysis revealed that these altered pathways were grouped into three interlinked modules involved in amino acid metabolism, nervous system signaling/neurotransmitters, and nucleotide metabolism. In the drug-associated metabolite set enrichment analysis, the main enriched drug pathways were opioid-related and antibiotic-related action pathways. Furthermore, the most significantly altered molecular network was involved in amino acid metabolism, molecular transport, and small molecule biochemistry. This study provides important clues for the metabolic characteristics of the PFC in depression.

A significant number of adolescents are considered insufficiently active. This is of concern considering the negative association between physical activity and major depressive disorder (MDD). There is a lack of approved pharmacological treatment options in this population partly due to limited information on the risks associated with lasting effects during early life. Therefore, interest in non-pharmacological strategies is gaining popularity with low- to moderate-intensity exercise being especially attractive for its antidepressant-like effects and augmentation properties in combination with antidepressants. Early-life development might present a unique "window of opportunity" to induce long-term beneficial effects in individuals treated with central acting drugs, such as antidepressants. Therefore, we investigated the bio-behavioural effects of pre-pubertal, low-intensity exercise (EXE) and/or venlafaxine (VEN) on depressive-like behaviour in juvenile (postnatal day 35 (PND35)) and young adult (PND60) stress-sensitive Flinders sensitive line (FSL) rats. Interventions were introduced during pre-pubertal development, that is PND21-34, followed by a 26-day washout/sedentary period, when bio-behavioural analyses were performed in the early adulthood group. VEN, alone or in combination with EXE, proved ineffective in inducing any bio-behavioural changes in either age group. EXE did not induce early-life antidepressant-like effects, despite increasing frontal serotonin (5-HT) and noradrenaline (NA) levels. Later in life (PND60), pre-pubertal exercise reduced immobility and increased coping behaviours, together with increased cortical 5-HT levels, despite a significant reduction in locomotor activity. These findings emphasize a strong serotonergic basis to the observed delayed antidepressant effects of EXE later in life.

Animal experimental studies suggest that 5-HT4 receptor activation holds promise as a novel target for the treatment of depression and cognitive impairment. 5-HT4 receptors are post-synaptic receptors that are located in striatal and limbic areas known to be involved in cognition and mood. Consistent with this, 5-HT4 receptor agonists produce rapid antidepressant effects in a number of animal models of depression, and pro-cognitive effects in tasks of learning and memory. These effects are accompanied by molecular changes, such as the increased expression of neuroplasticity-related proteins that are typical of clinically useful antidepressant drugs. Intriguingly, these antidepressant-like effects have a fast onset of their action, raising the possibility that 5-HT4 receptor agonists may be a particularly useful augmentation strategy in the early stages of SSRI treatment. Until recently, the translation of these effects to humans has been challenging. Here, we review the evidence from animal studies that the 5-HT4 receptor is a promising target for the treatment of depression and cognitive disorders, and outline a potential pathway for the efficient and cost-effective translation of these effects into humans and, ultimately, to the clinic.

Evidence demonstrates that chronic caffeine exposure, primarily through consumption of coffee or tea, leads to increased alertness and anxiety. Preclinical and clinical studies showed that caffeine induced beneficial effects on mood and cognition. Other studies using molecular techniques have reported that caffeine exhibited neuroprotective effects in animal models by protecting dopaminergic neurons. Moreover, caffeine interacts with dopaminergic system, which leads to improvements in neurobehavioral measures in animal models of depression or attention deficit hyperactivity disorder (ADHD). Glutamatergic receptors have been found to be involved on the neurobiological effects of caffeine. Additionally, caffeine has been found to suppress the inhibitory (GABAergic) activity and modulate GABA receptors. Studies have also found that modulating these neurotransmitters leads to neurobehavioral effects. The linkage between the modulatory role of caffeine on neurotransmitters and neurobehavioral effects has not been fully discussed. The purpose of this review is to discuss in detail the role of neurotransmitters in the effects of caffeine on neurobehavioral disorders. Keywords: Caffeine, Neurobehavioral effects, Neurotransmitters, Dopamine, Glutamate, GABA

Optimal acetylcholine (ACh) signaling is important for sustained attention and facilitates learning and memory. At the same time, human and animal studies have demonstrated increased levels of ACh in the brain during depressive episodes and increased symptoms of anxiety, depression, and reactivity to stress when ACh breakdown is impaired. While it is possible that the neuromodulatory roles of ACh in cognitive and affective processes are distinct, one possibility is that homeostatic levels of ACh signaling are necessary for appropriate learning, but overly high levels of cholinergic signaling promote encoding of stressful events, leading to the negative encoding bias that is a core symptom of depression. In this review, we outline this hypothesis and suggest potential neural pathways and underlying mechanisms that may support a role for ACh signaling in negative encoding bias.

Neuronal injury within specific brain regions is considered a critical risk factor in the pathophysiology of depression. However, the underlying mechanisms of this process, and thus the potential for development of novel therapeutic strategies in the treatment of depression, remain largely unknown. Here, we report that Il-6 protects against neuronal anomalies related with depression, in part, by suppressing oxidative stress and consequent autophagic and apoptotic hyperactivity. Specifically, we show that IL-6 is downregulated within the CA1 hippocampus in two animal models of depression and upregulated by antidepressants. Increasing levels of IL-6 in the CA1 region result in pleiotropic protective actions including reductions in oxidative stress and modulation of autophagy, anti-immuno-inflammatory activation and anti-apoptotic effects in CA1 neurons, all of which are associated with the rescue of depression-like behaviors. In contrast, IL-6 downregulation exacerbates neuronal anomalies within the CA1 region and facilitates the genesis of depression phenotypes in rats. Interestingly, in addition to attenuating oxidative damage, the antioxidant, N-acetylcysteine (NAC), is also associated with significantly decreased neuronal deficits and the display of depressive behaviors in rats. These results suggest that IL-6 may exert neuroprotection within CA1 neurons via pleiotropic mechanisms and may serve as a potential therapeutic target for the treatment of depression.

Major depressive disorder (MDD) is a prevalent condition associated with high rates of disability, as well as suicidal ideation and behavior. Current treatments for MDD have significant limitations in efficacy and side effect burden. FDA-approved devices for MDD are burdensome (due to repeated in-office procedures) and are most suitable for severely ill subjects. There is a critical need for device-based treatments in MDD that are efficacious, well-tolerated, and easy to use. In this paper, we review a novel neuromodulation strategy, transcranial photobiomodulation (t-PBM) with near-infrared light (NIR). The scope of our review includes the known biological mechanisms of t-PBM, as well as its efficacy in animal models of depression and in patients with MDD. Theoretically, t-PBM penetrates into the cerebral cortex, stimulating the mitochondrial respiratory chain, and also significantly increases cerebral blood flow. Animal and human studies, using a variety of t-PBM settings and experimental models, suggest that t-PBM may have significant efficacy and good tolerability in MDD. In aggregate, these data support the need for large confirmatory studies for t-PBM as a novel, likely safe, and easy-to-administer antidepressant treatment.

Nociceptin/orphanin FQ (N/OFQ) and its receptor, nociceptin opioid peptide (NOP) receptor, are localized in brain areas implicated in depression including the amygdala, bed nucleus of the stria terminalis, habenula, and monoaminergic nuclei in the brain stem. N/OFQ inhibits neuronal excitability of monoaminergic neurons and monoamine release from their terminals by activation of G protein-coupled inwardly rectifying K+ channels and inhibition of voltage sensitive calcium channels, respectively. Therefore, NOP receptor antagonists have been proposed as a potential antidepressant. Indeed, mounting evidence shows that NOP receptor antagonists have antidepressant-like effects in various preclinical animal models of depression, and recent clinical studies again confirmed the idea that blockade of NOP receptor signaling could provide a novel strategy for the treatment of depression. In this review, we describe the pharmacological effects of N/OFQ in relation to depression and explore the possible mechanism of NOP receptor antagonists as potential antidepressants.

Major depression can be triggered by stressful events that promote deregulation of the hypothalamic-pituitary-adrenal axis response and, in some circumstances, persistent elevation of circulating glucocorticoid levels. Animal models are widely used to investigate the mechanisms responsible for the etiology and treatment of major depression. However, to mimic the dysfunction of the hypothalamic-pituitary-adrenal axis in rodents, animals should be exposed to sustained physical and psychological stressful situations. These animal models of depression are labor intensive and impact individual animals differently. Aiming to add evidence for a new acute neuroendocrine model of depression, male and female mice were treated with a single administration of dexamethasone, and behavioral effects were evaluated in the presence and absence of the antidepressants nortriptyline and venlafaxine. Male and female Swiss mice were treated with dexamethasone (0.07 mg/kg, subcutaneously) and the mouse behavior was assessed in the tail suspension and open field tests at 4 h, 24 h, and 7 days after administration. Dexamethasone induced depressogenic-like states in both sexes at 4 and 24 h after injection. Additionally, acute dexamethasone increased latency to body fur licking, thus corroborating the depressive-like behavior. The treatment with nortriptyline and venlafaxine (both at 30 mg/kg, intraperitoneally) blocked dexamethasone-induced increase in the immobility time and the latency to self-care. In conclusion, the present findings suggest that a single administration of dexamethasone induces depressive-like states in male and female mice, and these behavioral alterations are counteracted by conventional antidepressants. Ultimately, these data provide new evidence for an acute neuroendocrine model of depression. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

In the past decades, the improving knowledge of genes implicated in the pathogenesis of psychiatric disorders together with the advancements in genetic engineering has led to the creation of mice in which one or more genes are inactivated or 'knocked out'. Knockout mice are extensively used to better investigate the molecular and cellular mechanisms underlying these diseases as well as the biological role of specific genes. Moreover, they are also useful tools for developing new therapeutic strategies. The success of using knockout mice is possible due to availability of several models used to mimic some clinical manifestations reported in psychiatric patients. In the present review, we will give an update of the most used gene knockout models in the field of psychiatric disorders including depression, anxiety, and obsessive-compulsive disorder.

Converging clinical and preclinical evidence demonstrates that depressive phenotypes are associated with synaptic dysfunction and dendritic simplification in cortico-limbic glutamatergic areas. On the other hand, the rapid antidepressant effect of acute ketamine is consistently reported to occur together with the rescue of dendritic atrophy and reduction of spine number induced by chronic stress in the hippocampus and prefrontal cortex of animal models of depression. Nevertheless, the molecular mechanisms underlying these morphological alterations remain largely unknown. Here, we found that miR-9-5p levels were selectively reduced in the hippocampus of rats vulnerable to Chronic Mild Stress (CMS), while acute subanesthetic ketamine restored its levels to basal condition in just 24h; miR-9-5p expression inversely correlated with the anhedonic phenotype. A decrease of miR-9-5p was reproduced in an in vitro model of stress, based on primary hippocampal neurons incubated with the stress hormone corticosterone. In both CMS animals and primary neurons, decreased miR-9-5p levels were associated with dendritic simplification, while treatment with ketamine completely rescued the changes. In vitro modulation of miR-9-5p expression showed a direct role of miR-9-5p in regulating dendritic length and spine density in mature primary hippocampal neurons. Among the putative target genes tested, Rest and Sirt1 were validated as biological targets in primary neuronal cultures. Moreover, in line with miR-9-5p changes, REST protein expression levels were remarkably increased in both CMS vulnerable animals and corticosterone-treated neurons, while ketamine completely abolished this alteration. Finally, the shortening of dendritic length in corticosterone-treated neurons was shown to be partly rescued by miR-9-5p overexpression and dependent on REST protein expression. Overall, our data unveiled the functional role of miR-9-5p in the remodeling of dendritic arbor induced by stress/corticosterone in vulnerable animals and its rescue by acute antidepressant treatment with ketamine., Highlights • miR-9-5p is reduced in the hippocampus of stress-vulnerable rats. • miR-9-5p is reduced in primary neurons treated with corticosterone. • Acute ketamine restores stress-induced morphological changes and miR-9-5p levels. • miR-9-5p directly modulates dendritic length and spine number in primary neurons. • REST is a validated target of miR-9-5p.

Major depressive disorder is one of the most prevalent forms of mental illnesses and causes tremendous individual suffering and socioeconomic burden. Despite its importance, current pharmacological treatment is limited, and novel treatment options are urgently needed. One key factor in the search for potential new drugs is evaluating their anti-depressive potency in appropriate animal models. The classical Porsolt forced swim test was used for this purpose for decades to induce and assess a depressive-like state. It consists of two short periods of forced swimming: the first to induce a depressed state and the second on the following day to evaluate the antidepressant effect of the agent given in between the two swim sessions. This model might be suitable as a screening tool for potential antidepressive agents but ignores the delayed onset of action of many antidepressants. The CDM was recently established and represented a modification of the classical test with notable differences. Mice are forced to swim for 5 consecutive days, following the idea that in humans, depression is induced by chronic rather than by acute stress. In a resting period of several days (1-3 weeks), animals develop sustained behavioral despair. The standard read-out method is the measurement of immobility time in an additional delayed swim session, but several alternative methods are proposed to get a broader view of the mood status of the animal. Multiple analysis tools can be used targeting behavioral, molecular, and electrophysiological changes. The depressed phenotype is stable for at least 4 weeks, providing a time window for rapid but also subchronic antidepressant treatment strategies. Furthermore, alterations in the development of a depressive-like state can be addressed using this approach. CDM, therefore, represents a useful tool to better understand depression and to develop novel treatment interventions.

Medicinal plants are a great source of medicines, being used by the population, and their biological activities are attributed to a great diversity of secondary metabolites. The species Citrus sinensis (Rutaceae) is known as “sweet orange”, it has been traditionally used to treat various disorders, including mental disorders. Depression is a chronic, multifactorial psychiatric disorder characterized by symptoms such as low mood and/or anhedonia, which may be accompanied by cognitive, neurovegetative deficits. Approximately 85% of patients with depression also have significant anxiety symptoms. The essential oil of C. sinensis has biological activities, such as antimicrobials, antioxidants, and is widely studied for having anxiolytic activity. Based on this, the work aimed to carry out the chemical characterization of the constituents present in the essential oil of C. sinensis, obtained from three (3) different suppliers, and to evaluate the antidepressant and antioxidant effect of the essential oil. Chemical characterization was performed using GC-MS, where five components were identified in the essential oil sample, with limonene being the major compound. For pharmacological tests, a dexamethasone-type behavior induction protocol was used. The project was approved by the Ethics Committee on the use of animals (CEUA/UFPB) of the Federal University of Paraíba, with approval certificate nº 8690120320. The Swiss mice were divided into six groups of 6 to 8 animals and submitted to behavioral tests as forced swimming, tail suspension and open field and after that, in vivo antioxidant tests were performed. In the forced swim test there was no difference between the groups treated with essential oil at doses 25, 50 and 100 mg/kg and the control group. In the tail suspension test, it was observed that CS 75 and CS 100 increased the immobility time when compared to the group treated with imipramine and there was no significant difference in the immobility time between the EO concentrations and the control. In the open field test the groups treated with CS 75 and CS 100 doses of essential oil also reduced the number of crossings when compared to the control group. The dexamethasone groups, CS 50, CS 75 and CS 100, increased the number of rearing when compared to the imipramine group. In the grooming parameter, there was a significant reduction in the frequency of self-cleaning between the dexamethasone, imipramine, CS 75 and CS 100 groups compared to the control group. The results found suggest that the groups treated with the EO of C. sinensis did not show an antidepressant effect when submitted to behavioral tests. In the in vivo antioxidant test, the essential oil showed an antioxidant effect in the glutathione reductase (GSH) test, as it significantly increased the GSH concentration in the CS 75 treated group when compared to the control and imipramine group. In the nitrite concentration, a significant increase was observed in the concentration of nitrite in the group treated with imipramine and CS 50, compared to the control group, suggesting that this increase leads to oxidation of cellular lipids, formation of free radicals and generation of reactive species of oxygen (ROS). Nenhuma As plantas medicinais são uma grande fonte de medicamentos, sendo utilizada pela população, e suas atividades biológicas são atribuídas a grande diversidade de metabólitos secundários. A espécie Citrus sinensis (Rutaceae) é conhecida como “laranja doce”, tem sido usado tradicionalmente para tratar diversos distúrbios, dentre eles distúrbios mentais. A depressão é um transtorno psiquiátrico crônico, multifatorial, caracterizada por sintomas como baixo humor e/ou anedonia, que podem ser acompanhados por déficits cognitivos, neurovegetativos. Aproximadamente 85% dos pacientes com depressão também apresentam sintomas significativos de ansiedade. O óleo essencial de C. sinensis apresentam atividades biológicas, tais como antimicrobianas, antioxidantes, e é amplamente estudado por possuir atividade ansiolítica. Com base nisso, o trabalho teve como objetivo realizar a caracterização química dos constituintes presentes no óleo essencial de C. sinensis, obtidos de três (3) diferentes fornecedores, e avaliar o efeito antidepressivo e antioxidante do óleo essencial. A caracterização química foi realizada através de CG-EM, onde foram identificados cinco componentes na amostra do óleo essencial, sendo o limoneno o composto majoritário. Para os testes farmacológicos, foi utilizado um protocolo de indução do comportamento do tipo depressivo por dexametasona. O projeto foi aprovado pelo Comitê de Ética no uso de animais (CEUA/UFPB) da Universidade Federal da Paraíba, com a certidão de aprovação nº 8690120320. Os camundongos Swiss foram divididos em seis grupos de 6 a 8 animais e submetidos à testes comportamentais como nado forçado, suspensão da cauda e campo aberto e após isso, foram realizados os testes antioxidantes in vivo. No teste de nado forçado não houve diferença entre os grupos tratados com o óleo essencial nas doses 25, 50 e 100 mg/kg e o grupo controle. No teste de suspensão da cauda, foi observado que CS 75 e CS 100 aumentaram o tempo de imobilidade, quando comparado com o grupo tratado com imipramina e não houve diferença significativa do tempo de imobilidade entre as concentrações do OE e o controle. No teste de campo aberto os grupos tratados com as doses CS 75 e CS 100 do óleo essencial, também reduziram o número de cruzamentos quando comparados com o grupo de controle. Os grupos dexametasona, CS 50, CS 75 E CS 100, aumentaram o número de rearing quando comparados com o grupo imipramina. No parâmetro de grooming houve uma redução na frequência de autolimpeza significativa entre o grupo dexametasona, imipramina, CS 75 e CS 100 em relação ao grupo controle. Os resultados encontrados sugerem que os grupos tratados com o OE de C. sinensis não apresentaram efeito antidepressivo quando submetido aos testes comportamentais. No teste antioxidante in vivo, o óleo essencial apresentou efeito antioxidante no teste de glutationa redutase (GSH), pois aumentou significativamente a concentração de GSH no grupo tratado CS 75 quando comparado ao grupo controle e imipramina. Já na concentração de nitrito foi observado um aumento significativo na concentração de nitrito no grupo tratado com imipramina e CS 50, em comparação com o grupo controle, sugerindo que esse aumento leva a oxidação de lipídios celulares, formação de radicais livres e geração de espécies reativas de oxigênio (ROS).

The neuroinflammatory basis of depression encompasses the detrimental role of otherwise supportive non-neuronal cells and neuroinflammation in hampering neuronal function, leading to depressive behavior. Animals subjected to different stress paradigms show glial cell activation and a surge in proinflammatory cytokines in various brain regions. The concept of sterile inflammation observed in animal models of depression has intrigued many researchers to determine the possible triggers of central immune cell activation. Notably, microglial activation and subsequent phenotypic polarization in depression have been strongly advocated by the wealth of recent preclinical studies; however, findings from human studies have shown contradictory results. Despite intensive investigation, many research gaps still exist to elucidate the molecular mechanisms of neuroinflammatory cascades underlying the pathophysiology of depression. In this mini-review, recent progress in understanding neuroinflammatory mechanisms in light of experimental models of depression will be thoroughly discussed. The challenges of mirroring depression in animal and in vitro models will also be highlighted. Furthermore, prospects of targeting neuroinflammation to treat depressive disorder will be covered.

The olfactory bulbectomized rodent has long been one of the preferred animal models of depression and certain other neuropsychiatric diseases. In fact, it is considered unparalleled, by some, in the search for antidepressant medication and the literature generated about the model is prodigious. We have revisited the "syndrome" of behavioral sequela following bulbectomy choosing ecologically valid tests likely to be underpinned with evolutionarily preserved neural circuits. Our test battery included measurements of activity, intermale aggression, pleasure seeking, stress/fear and non-spatial memory. The emphasis was on the timetable of syndrome emergence, since this has been understudied and bears on the widely held belief that non-olfactory effects dominate. Our results largely agree with previous reports describing the behavioral syndrome in that we document bulbectomized mice as hyperactive, non-aggressive and fearless. However, we did not find deficits in memory as have frequently been reported in previous studies. Notably, our results revealed that some syndrome behaviors-including the hallmark of hyperactivity-appear immediately or soon after surgery. This rapid appearance casts doubt on the widely held view that compensatory reorganization of limbic and prefrontal cortical areas following bulbectomy underlies the syndrome. Rather, hyperactivity, non-aggressiveness, reduced fear and diminished sucrose preference in the olfactory bulbectomized mouse find ready explanations in the loss of smell that is the immediate and irreversible outcome of bulbectomy. Finally, after a critical consideration of the literature and our results, we conclude that the olfactory bulbectomy model lacks the validity and simplicity previously credited to it. Indeed, we deem this lesion unsuitable as a model of most neuropsychiatric diseases since its effects are at least as complex and misunderstood as the disorders it is purported to model.

Objective:Ginsenosides, biologically active components of the root of Panax ginseng, have been reported to have therapeutic benefits in a number of disease states including psychiatric conditions such as major depressive disorder. Our objective was to determine if a standardised commercial ginseng extract, G115®, could reduce the signs of behavioural despair commonly observed in animal models of depression either alone or in combination with the selective serotonin reuptake inhibitor (SSRI) fluoxetine.Methods:Male Sprague-Dawley (SD) rats (N = 51) were divided into four groups: vehicle control, G115® ginseng root extract, fluoxetine and fluoxetine plus G115®. Rats were trained to voluntarily consume treatments twice daily for 14 days and were then tested in an open field (OF), elevated plus maze (EPM) and forced swim test (FST). Post-mortem hippocampal and prefrontal cortex tissue was analysed for expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) by western blot.Results:One-way Analysis of Variance revealed no significant group differences in the OF or plus-maze performance on any variable examined. In the FST, fluoxetine significantly reduced immobility time and increased latency to immobility. The effects of fluoxetine were further significantly potentiated by co-administration of G115®. Post-mortem tissue analysis revealed significant group differences in BDNF expression in the left hippocampus and left prefrontal cortex without any accompanying changes in TrkB expression.Conclusions:We conclude that oral G115® significantly potentiates the antidepressant-like effect of fluoxetine in the FST in the absence of potentially confounding effects on locomotion and anxiety.

According to the WHO, major depressive disorder is the leading cause of disability worldwide, and it is a major contributor to the overall global burden of disease. The pathophysiology of this common and chronic disease is still not completely understood. The gut microbiome is an increasingly recognized environmental factor that can have a role in depression, acting through the gut–microbiota–brain axis. The available treatment for depression is still insufficient since 30% of patients are treatment-resistant. There is an unquestionable need for novel strategies. Ketamine is an effective antidepressant in treatment-resistant patients. It is suggested that the antidepressant effect of ketamine may be partially mediated by the modification of gut microbiota. In this study, we presented a review of data on gut microbiota in depression with special attention to the effect of ketamine on the microbiome in animal models of depression. Earlier reports are preliminary and are still insufficient to draw firm conclusion, but further studies in this field might help to understand the role of the gut–brain axis in the treatment of depression and might be the ground for developing new effective treatment strategies.

Increasing evidence has shown that adult hippocampal neurogenesis is closely related to the pathophysiological condition of depressive disorders. Recently, chronic social defeat stress paradigms have been regarded as important animal models of depression, accompanied with neural plastic changes in the hippocampus. However, little is known about influences of non-physical stress on neurogenesis. In the present study, we focused on the chronic vicarious social defeat stress paradigm and examined the effect of psychological stress on mouse hippocampal neurogenesis. Immediately after the chronic psychological stress, the cell survival rate in the dentate gyrus of the hippocampus was significantly diminished without modifying the cell proliferation rate. The decreased ratio in cell survival persisted for 4 weeks after the stress-loading period, while the differentiation and maturity of new-born neurons were identical to control groups. Furthermore, treatment with the chronic antidepressant fluoxetine reversed the social behavioral deficits and promoted new-born neurons survival. These results demonstrate that emotional stress in the vicarious social defeat stress paradigm influences neuronal cell survival in the hippocampus, which reinforces its validity as an animal model of depression.

Despite the severity and the high prevalence of depression and anxiety and the efforts that have been done to improve their treatment, the available pharmacotherapy still has several limitations. Therefore, the investigation of novel agents and the characterization of the molecular signaling pathways underlying their effects are needed. The organoselenium compound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI) has emerged as a promising antidepressant and anxiolytic molecule in several animal models of depression through the modulation of neuroinflammation and oxidative stress. In light of this, the present study aimed to dive into the mechanism of action of CMI in ameliorating anhedonic- and anxiogenic-like behaviors induced by repeated corticosterone administration in mice. A single administration of CMI (1 ​mg/kg, i.g.) abrogated the behavioral alterations induced by corticosterone in the open field test, splash test, and elevated plus maze test. Additionally, CMI treatment decreased the levels of reactive species and lipid peroxidation in the plasma of corticosterone-treated mice and normalized the expression of GR, BDNF, synaptophysin, GSK-3β, Nrf2, and IDO in the hippocampi of stressed mice. Noteworthy, the pre-treatment of mice with LY294002 (PI3K inhibitor) and rapamycin (mTOR inhibitor) abrogated the anti-anhedonic- and anxiolytic-like effects elicited by CMI in corticosterone-treated mice, while ZnPP (HO-1 inhibitor) counteracted the anxiolytic-like effect of CMI. These findings suggest that CMI might ameliorate behavioral and biochemical alterations in the depression-anxiety comorbidity induced by corticosterone, highlighting the potential of CMI as a possible adjuvant therapy.

Background Current antidepressant therapy remains unsatisfactory due to its delayed clinical onset of action and the heterogeneity of depression. Targeting disturbed neurometabolic pathways could provide a novel therapeutic approach for the treatment of depression. Albiflorin is a phytomedicine isolated from the root of Peony (Paeonia albiflora Pall) with excellent clinical tolerance. Until now, the antidepressant-like activities of albiflorin in different subtypes of depression and its effects on neurometabolism are unknown. Purpose The objective of this study was to investigate the rapid antidepressant-like effects of albiflorin in three common animal models of depression and elucidate the pharmaco-metabolic mechanisms of its action using a multi-omics approach. Results We found that albiflorin produces rapid antidepressant-like effects in chronic unpredictable mild stress (CUMS), olfactory bulbectomy (OBX), and lipopolysaccharide (LPS)-induced murine models of depression. Using a system-wide approach combining metabolomics, lipidomics, and transcriptomics, we showed that the therapeutic effects of albiflorin are highly associated with the rapid restoration of a set of common metabolic abnormities in the hippocampus across all three depression models, including phospholipid and tryptophan metabolism. Further mechanistic analysis revealed that albiflorin normalized the metabolic dysregulation in phospholipid metabolism by suppressing hippocampal cytosolic phospholipases A2 (cPLA2). Additionally, inhibition of cPLA2 overexpression by albiflorin corrects abnormal kynurenine pathway of tryptophan metabolism via the cPLA2-protein kinase B (Akt1)-indoleamine 2,3-dioxygenase 1(IDO1) regulatory loop and directs tryptophan catabolism towards more hippocampal serotonin biosynthesis. Conclusion Our study contributed to a better understanding of the homogeneity in the metabolic mechanisms of depression and established a proof-of-concept for rapid treatment of depression through targeting dysregulated neurometabolic pathways.

Unregulated stress during critical periods of development is proposed to drive deficits consistent with schizophrenia in adults. If accurate, reopening the critical period could make the adult susceptible to pathology. We evaluated the impact of early adolescent and adult stress exposure (combination of daily footshock for 10 days and 3 restraint sessions) on (1) midbrain dopamine (DA) neuron activity, (2) ventral hippocampal (vHipp) pyramidal neuron activity, and (3) the number of parvalbumin (PV) interneurons in the vHipp and their associated perineuronal nets (PNNs). Ventral tegmental area (VTA) DA neuron population activity and vHipp activity was increased 1–2 and 5–6 weeks post-adolescent stress, along with a decrease in the number of PV+, PNN+, PV + /PNN + cells in the vHipp, which are consistent with the MAM model of schizophrenia. In contrast, adult stress decreased VTA DA neuron population activity only at 1–2 weeks post stress, which is consistent with what has been observed in animal models of depression, without impacting vHipp activity and PV/PNN expression. Administration of valproate (VPA), which can re-instate the critical period of plasticity via histone deacetylase (HDAC) inhibition, caused adult stress to produce changes similar to those induced by adolescent stress, presumably by increasing stress vulnerability to early adolescent levels. Our findings indicate that timing of stress is a critical determinant of the pathology produced in the adult: adolescent stress led to circuit deficits that recapitulates schizophrenia, whereas adult stress induced a depression-like hypodopaminergic state. Reopening the critical period in the adult restores vulnerability to stress-induced pathology resembling schizophrenia.

Introduction: Tryptophan hydroxylase 2 (TPH2) is the key, rate-limiting enzyme of serotonin (5-HT) synthesis in the brain. Some polymorphic variants of the human Tph2 gene are associated with psychiatric disorders. Area covered: This review focuses on the mechanisms underlying the association between the TPH2 activity and behavioral disturbances in models of psychiatric disorders. Specifically, it discusses: 1) genetic and posttranslational mechanisms defining the TPH2 activity, 2) behavioral effects of knockout and loss-of-function mutations in the mouse Tph2 gene, 3) pharmacological inhibition and the activation of the TPH2 activity and 4) alterations in the brain TPH2 activity in animal models of psychiatric disorders. We show the dual role of the TPH2 activity: both deficit and excess of the TPH2 activity cause significant behavioral disturbances in animal models of depression, anxiety, aggression, obsessive-compulsive disorders, schizophrenia, and catalepsy. Expert opinion: Pharmacological chaperones correcting the structure of the TPH2 molecule are promising tools for treatment of some hereditary psychiatric disorders caused by loss-of-function mutations in the human Tph2 gene; while some stress-induced affective disorders, associated with the elevated TPH2 activity, may be effectively treated by TPH2 inhibitors. This dual role of TPH2 should be taken into consideration during therapy of psychiatric disorders.

Neuropeptide Y is a peptide neuromodulator with protective roles including anxiolytic and antidepressant-like effects in animal models of depression and post-traumatic stress disorder. The lateral habenula (LHb) is a brain region that encodes aversive information and is closely related with mood disorders. Although LHb neurons express NPY receptors, the physiological roles of NPY in this region remain uninvestigated. In this study, we examined the actions of NPY on synaptic transmission in the LHb using whole cell patch clamp recording. We observed that NPY inhibited excitatory neurotransmission in a subset of LHb neurons whereas potentiating in a small population of neurons. Inhibitory transmission remained unchanged by NPY application in a subset of neurons but was reduced in the majority of LHb neurons recorded. The overall outcome of NPY application was a decrease in the spontaneous firing rate of the LHb, leading to hypoactivation of the LHb. Our observations indicate that although NPY has divergent effects on excitatory and inhibitory transmission, NPY receptor activation decreases LHb activity, suggesting that the LHb may partly mediate the protective roles of NPY in the central nervous system.