Changes in SLITRK1 Level in the Amygdala Mediate Chronic Neuropathic Pain-Induced Anxio-Depressive Behaviors in Mice.

BACKGROUND: Comorbid chronic neuropathic pain (NPP) and anxio-depressive disorders (ADD) have become a serious global public-health problem. The SLIT and NTRK-like 1 (SLITRK1) protein is important for synaptic remodeling and is highly expressed in the amygdala, an important brain region involved in various emotional behaviors. We examined whether SLITRK1 protein in the amygdala participates in NPP and comorbid ADD. METHODS: A chronic NPP mouse model was constructed by L5 spinal nerve ligation; changes in chronic pain and ADD-like behaviors were measured in behavioral tests. Changes in SLITRK1 protein and excitatory synaptic functional proteins in the amygdala were measured by immunofluorescence and Western blot. Adeno-associated virus was transfected into excitatory synaptic neurons in the amygdala to up-regulate the expression of SLITRK1. RESULTS: Chronic NPP-related ADD-like behavior was successfully produced in mice by L5 ligation. We found that chronic NPP and related ADD decreased amygdalar expression of SLITRK1 and proteins important for excitatory synaptic function, including Homer1, postsynaptic density protein 95 (PSD95), and synaptophysin. Virally-mediated SLITRK1 overexpression in the amygdala produced a significant easing of chronic NPP and ADD, and restored the expression levels of Homer1, PSD95, and synaptophysin. CONCLUSION: Our findings indicated that SLITRK1 in the amygdala plays an important role in chronic pain and related ADD, and may prove to be a potential therapeutic target for chronic NPP-ADD comorbidity.

Day-to-day regularity and diurnal switching of physical activity reduce depression-related behaviors: a time-series analysis of wearable device data.

BACKGROUND: Wearable devices have been widely used in research to understand the relationship between habitual physical activity and mental health in the real world. However, little attention has been paid to the temporal variability in continuous physical activity patterns measured by these devices. Therefore, we analyzed time-series patterns of physical activity intensity measured by a wearable device and investigated the relationship between its model parameters and depression-related behaviors. METHODS: Sixty-six individuals used the wearable device for one week and then answered a questionnaire on depression-related behaviors. A seasonal autoregressive integral moving average (SARIMA) model was fitted to the individual-level device data and the best individual model parameters were estimated via a grid search. RESULTS: Out of 64 hyper-parameter combinations, 21 models were selected as optimal, and the models with a larger number of affiliations were found to have no seasonal autoregressive parameter. Conversely, about half of the optimal models indicated that physical activity on any given day fluctuated due to the previous day's activity. In addition, both irregular rhythms in day-to-day activity and low-level of diurnal variability could lead to avoidant behavior patterns. CONCLUSION: Automatic and objective physical activity data from wearable devices showed that diurnal switching of physical activity, as well as day-to-day regularity rhythms, reduced depression-related behaviors. These time-series parameters may be useful for detecting behavioral issues that lie outside individuals' subjective awareness.

Timing matters: the interval between acute stressors within chronic mild stress modifies behavioral and physiologic stress responses in male rats.

Chronic mild stress can lead to negative health outcomes. Frequency, duration, and intensity of acute stressors can affect health-related processes. We tested whether the temporal pattern of daily acute stressors (clustered or dispersed across the day) affects depression-related physiology. We used a rodent model to keep stressor frequency, duration, and intensity constant, and experimentally manipulated the temporal pattern of acute stressors delivered during the active phase of the day. Adult male Sprague-Dawley rats were exposed to one of three chronic mild stress groups: Clustered: stressors that occurred within 1 hour of each other (n = 21), Dispersed: stressors that were spread out across the active phase (n = 21), and Control: no stressors presented (n = 21). Acute mild stressors included noise, strobe lights, novel cage, cage tilt, wet bedding, and water immersion. Depression-related outcomes included: sucrose preference, body weight, circulating glucocorticoid (corticosterone) concentration after a novel acute stressor and during basal morning and evening times, and endotoxin-induced circulating interleukin-6 concentrations. Compared to control rats, those in the Clustered group gained less weight, consumed less sucrose, had a blunted acute corticosterone response, and an accentuated acute interleukin-6 response. Rats in the Dispersed group had an attenuated corticosterone decline during the active period and after an acute stressor compared to the Control group. During a chronic mild stress experience, the temporal distribution of daily acute stressors affected health-related physiologic processes. Regular exposure to daily stressors in rapid succession may predict more depression-related symptoms, whereas exposure to stressors dispersed throughout the day may predict diminished glucocorticoid negative feedback.

Maternal separation increases later immobility during forced swim in guinea pig pups: evidence for sensitization of a depressive-like state.

Early-life stress is thought to increase later vulnerability for developing depressive illness by sensitizing underlying stress-responsive systems. Guinea pig pups separated from their mother and isolated in a novel cage for 3 hr exhibit a sensitized depressive-like behavioral response when separated again the following day as well as weeks later. The behavioral response and its sensitization appear to be mediated by inflammatory factors. To determine if this sensitization is specific to the separation response or if it reflects a broader underlying depressive-like state, guinea pig pups that had either been separated for 3 hr or remained with their mothers were observed in the forced swim test the following 3 days. Earlier separation was found to increase the duration of immobility, a measure sensitive to antidepressant treatment. These results support the use of the guinea pig as a model for examining mechanisms of inflammatory-mediated sensitization of depression following stress in early life.

NMDA receptor-dependent LTD is required for consolidation but not acquisition of fear memory.

NMDA receptor-dependent long-term depression (NMDAR-LTD) is a form of synaptic plasticity leading to long-lasting decreases in synaptic strength. NMDAR-LTD is essential for spatial and working memory, but its role in hippocampus-dependent fear memory has yet to be determined. Induction of NMDAR-LTD requires the activation of caspase-3 by cytochrome c. Cytochrome c normally resides in mitochondria and during NMDAR-LTD is released from mitochondria, a process promoted by Bax (Bcl-2-associated X protein). Bax induces cell death in apoptosis, but it plays a nonapoptotic role in NMDAR-LTD. Here, we investigated the role of NMDAR-LTD in fear memory in CA1-specific Bax knock-out mice. In hippocampal slices from these knock-out mice, while long-term potentiation of synaptic transmission, basal synaptic transmission, and paired-pulse ratio are intact, LTD in both young and fear-conditioned adult mice is obliterated. Interestingly, in CA1-specific Bax knock-out mice, long-term contextual fear memory is impaired, but the acquisition of fear memory and innate fear are normal. Moreover, these conditional Bax knock-out mice exhibit less behavioral despair. These findings indicate that NMDAR-LTD is required for consolidation, but not the acquisition of fear memory. Our study also shows that Bax plays an important role in depressive behavior.

Nonylphenol induces depressive behavior in rats and affects gut microbiota: A dose-dependent effect.

Nonylphenol (NP), an endocrine disruptor absorbed through food intake, was investigated in this study for its potential dose-response relationship with the manifestation of depression-like behavior in rats. Based on this, the mechanisms of NP-induced depressive behavior, encompassing neurotransmitters, gut barrier function, inflammatory response, gut microbiota composition and metabolites were further explored. At medium and high NP doses, both mRNA and protein levels of zonula occludens protein-1 and claudin-1 were considerably downregulated, concomitant with an elevation in tumor necrosis factor-α and interleukin-1ß expression in a dose-dependent effect, resulting in damage to the gut mucosa. Despite a minimal impact on behavior and gut barriers at low NP doses, alterations in gut microbiota composition were observed. During NP exposure, dose-dependent changes in the gut microbiota revealed a decline in microbial diversity linked to the synthesis of short-chain fatty acids. NP not only adversely affected the gut microbiota structure but also exacerbated central nervous system damage through the gut-brain axis. The accumulation of NP may cause neurotransmitter disturbances and inflammatory responses in the hippocampus, which also exacerbate depressed behavior in rats. Therefore, NP could exacerbate the inflammatory response in the hippocampus and colon by compromising intestinal barrier integrity, facilitating the proliferation of pathogenic bacteria, impairing butyrate metabolism, and perturbing neurotransmitter homeostasis, thus aggravating the depressive behavior of rats. It is noteworthy that the changes in these indicators were related to the NP exposure dose.

Phenylpropanoid-rich maize root extract serves as a natural antidepressant.

BACKGROUND: Depression is a serious and complex mental disease that has attracted worldwide attention because of its high incidence rate, high disability rate and high mortality. Excitotoxicity is one of the most important mechanisms involved in the pathophysiological process of depression. In our previous studies, n-butanol extract from maize roots was found to have good neuroprotective effects due to its antioxidative activity. However, the antidepressive effective constituents, efficacy in vivo and mechanism of action of maize root extracts have not been determined. PURPOSE: This study aimed to determine the main active neuroprotective compound in maize root extract and investigate its antidepressant effects and possible underlying mechanism in vitro and in vivo. METHODS: Sixteen extracts were isolated and purified from maize roots. The active components of the most active extracts of maize roots (hereafter referred to as EM 2) were identified using UF-HPLC-QTOF/MS. In vitro cell models of NMDA-induced excitotoxicity in SH-SY5Y cells were used to analyze the anti-excitatory activity of the extracts. The MTT assay and Annexin V-FITC/PI Apoptosis Detection were used to evaluate cell viability. Several network pharmacological strategies have been employed to investigate the potential mechanism of action of EM 2. The effects of EM 2 on depressive-like behaviors were evaluated in CUMS mice. Changes in the levels of related proteins were detected via western blotting. RESULTS: Among the 16 extracts extracted by n-butanol, EM 2 was determined to be the most active extract against NMDA-induced excitotoxicity by n-butanol extraction. Meanwhile, seventeen compounds were further identified as the main active components of EM 2. Mechanistically, EM 2 inhibited NMDA-induced excitatory injury in SH-SY5Y cells and alleviated the depressive-like behaviors of CUMS mice by suppressing NR2B and subsequently mediating the downstream CREB/TRKB/BDNF, PI3K/Akt and MAPK pathways, as well as the Nrf2/HO-1 antioxidant signaling pathway. CONCLUSION: The study indicated that EM 2 could potentially be developed as a potential therapeutic candidate to cure depression in NMDA-induced excitatory damage.

LQFM212, a piperazine derivative, exhibits potential antioxidant effect as well as ameliorates LPS-induced behavioral, inflammatory and oxidative changes.

AIMS: Oxidative stress, impaired antioxidant defense and neuroinflammation are often associated with the onset and progression of neuropsychiatric diseases. Conversely, several piperazine compounds presents beneficial neuropharmacological effects as well as antioxidant activity, and some derivatives combine both activities. LQFM212 (2,6-di-tert-butyl-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenol) was synthesized to produce effects on CNS and to have an additional antioxidant effect. Previous preclinical tests have been shown anxiolytic- and antidepressant-like effects of LQFM212 in mice. Herein, the main objective was to verify the possible antioxidant potential and the effects of LQFM212 against behavioral changes, inflammatory and oxidative markers induced by lipopolysaccharide (LPS). MAIN METHODS: Initially, antioxidant potential of LQFM212 was evaluated by electrochemical assays. Afterwards, the effects of oral treatment with LQFM212 were evaluated in mice using LPS-induced models of systemic or local inflammation. KEY FINDINGS: In LPS-induced neuroinflammation, LQFM212 treatment reverted changes caused by LPS, demonstrated by attenuated anxiogenic- and depressive-like behaviors, reduced pro-inflammatory cytokines (TNF-α and IL-1ß) and increased anti-inflammatory cytokines (IL-4 and IL-10) on serum, and also improved oxidative stress-related changes (levels of nitrite, malondialdehyde, glutathione and carbonylated protein, and superoxide dismutase, catalase, myeloperoxidase and cholinesterase activities) on brain cortex and hippocampus. However, LQFM212 treatment did not attenuate the inflammatory changes in LPS-induced pleurisy model. SIGNIFICANCE: LQFM212 presents antioxidant activity and ameliorates behavioral, inflammatory and oxidative changes after LPS-induced neuroinflammation model. These effects do not seem to be secondary to a peripheral anti-inflammatory action of LQFM212, since this compound failed to attenuate the inflammatory changes in LPS-induced pleurisy model.

Liquiritin apioside alleviates colonic inflammation and accompanying depression-like symptoms in colitis by gut metabolites and the balance of Th17/Treg.

BACKGROUND: Inflammatory bowel disease (IBD) is a significant global health concern that can lead to depression in affected patients. Liquiritin apioside (LA) possesses anti-oxidative and anti-inflammatory properties. However, its anti-inflammatory mechanism in IBD has not been extensively studied. PURPOSE: This study elucidates the pivotal role of LA in alleviating inflammation by regulating gut metabiota-derived metabolites and evaluating its regulative effects on promoting a balance of Th17/Treg cells in colitis mice. METHODS: To evaluate the effect of LA on IBD,16S rRNA gene sequencing and UPLC-QTOF-MS analysis were used to identify the changes of intestinal bacteria and their metabolites. Cytokines levels were determined by ELISA and qPCR, while immune cell ratios were evaluated via flow cytometry. RESULTS: Our findings revealed that LA treatment ameliorated general states of DSS-induced colitis mice and their accompanying depressive behaviors. Moreover, LA restricted the expression of pro-inflammatory cytokines and revised the imbalanced Treg/Th17 differentiation, while promoting SCFAs production in inflamed colon tissues. Fecal microbiota transplantation from LA-fed mice also corrected the imbalanced Treg/Th17 differentiation, indicating that LA-mediated restoration of the colonic Treg/Th17 balance mainly depends on the changes in gut metabolites. CONCLUSION: These results provide scientific evidence explaining the apparent paradox of low bioavailability and high bioactivity in polyphenols, and suggesting that LA could be used as a potential dietary supplement for the prevention and improvement of IBD.

Inflammatory Immune Process and Depression-like Behavior in Hypothyroid Rats: A [18F] DPA-714 Micro Positron Emission Tomography Study.

Hypothyroidism is closely related to mental disorders, mainly depression, through an as-yet-unknown mechanism. The cerebral inflammatory immune process has been implied to play a pivotal role in the onset of affective symptoms in several conditions. In order to gain insight into the mechanism underlying the depressive behaviors in hypothyroid rats, brain microglial activation was evaluated using micro positron emission tomography imaging with a translocator protein (TSPO) radioligand. Hypothyroidism was induced in adult male Wistar rats by administration of 0.05% propylthiouracil in drinking water for five weeks. Open field, forced swimming and tail suspension tests were employed to evaluate the depressive behavior in hypothyroid rats, and the relationship between the behavioral changes and brain microglial activation was evaluated using [18F] DPA-714 micro positron emission tomography imaging. The open field test revealed significantly reduced first-minute activity and rearing behavior in the hypothyroid group, as well as significantly increased immobility in the forced swimming test and the tail suspension test. Hypothyroidism induced significantly increased microglial activation in the hippocampus. The radioligand uptake in the hippocampus correlated negatively with first-minute activity in the open field test (p < 0.05), and the radioligand uptake in the hippocampus correlated positively with changes in the immobility time in the forced swimming test and the tail suspension test (p < 0.05). Immunohistochemistry also confirmed the activation of microglia and inflammatory bodies in hypothyroid rats. The results indicate that hypothyroidism can induce depressive behavior in adult Wistar rats, microglial activation in the hippocampus plays an important role in the depressive behavior in hypothyroid rats and the inflammatory immune mechanism may underlie the behavioral abnormalities in thyroid dysfunction. Furthermore, the findings in the present study suggest there might be a common mechanism underlying depressive behavior in adult-onset hypothyroidism and depression.

The food preservative sodium propionate induces hyperglycaemic state and neurological disorder in zebrafish.

Propionate is an effective mould inhibitor widely used as a food preservative. In this study, we used zebrafish to explore the adverse effects of long-term exposure to low concentrations of sodium propionate and the underlying molecular mechanisms (from larvae to adult). When exposed for 3 months, we found that blood glucose, total cholesterol, and triglyceride levels increased, and zebrafish developed a hyperglycaemic state. New tank test results showed depression in zebrafish reduced 5-hydroxytryptamine levels in the brain and damaged the dopamine system. At the same time, the results of the color preference test showed that zebrafish had cognitive impairments. In addition, Hypothalamic-Pituitary-Adrenal axis analysis revealed abnormal gene expression, increased cortisol levels, and reduced glucocorticoid receptor mRNA levels, which were consistent with depressive behavior. We also observed abnormal transcription of inflammatory and apoptotic factors. Overall, we found that chronic exposure to sodium propionate induces depressive symptoms. This may be related to the activation of the HPA axis by the hyperglycaemic state, thereby inducing inflammation and disrupting the dopaminergic system. In summary, this study provides theoretical and technical support for the overlap of the emotional pathogenesis associated with diabetes.

Lipidomics Changes in a Murine Model of Neuropsychiatric Lupus.

Purpose: Neuropsychiatric lupus (NPSLE) is one of the important manifestations of systemic lupus erythematosus. Previous studies mainly focused on the disruption of the blood-brain barrier and the production of brain-reactive autoantibodies, However, there is no comprehensive lipidomic analysis in NPSLE. Therefore, this research evaluated the lipidomic analysis in the hippocampus and liver of NPSLE mice with mood disorders, to explore the influence of the liver-brain axis on this disease. Methods: MRL/lpr mice and MRL/mpj mice were respectively used as NPSLE and control groups. Behavioral tests and systemic disease characteristics of mice were assessed at the age of 18 weeks. Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) was used for lipid metabolite determination. Multivariate statistical analysis was used to identify lipid metabolites that were differentially expressed in two groups. Results: Our results showed that 355 and 405 lipid metabolites were differentially expressed between the NPSLE and control groups in the hippocampus and liver. According to the pathway enrichment analysis, several pathways were affected, and the glycerophospholipid metabolism pathway was most relevant to the mouse's depressive behavior. Conclusion: Based on UPLC-MS/MS, the results provide evidence for how the liver-brain axis affects NPSLE and improve the understanding of NPSLE pathogenesis.

The Effect of Earthing Mat on Stress-Induced Anxiety-like Behavior and Neuroendocrine Changes in the Rat.

Grounding is a therapeutic technique that involves doing activities that "ground" or electrically reconnect us to the earth. The physiological effects of grounding have been reported from a variety of perspectives such as sleep or pain. However, its anti-stress efficacy is relatively unknown. The present study investigated the stress-related behavioral effects of earthing mat and its neurohormonal mechanisms in the Sprague−Dawley male rat. Rats were randomly divided into four groups: the naïve normal (Normal), the 21 days immobilization stressed (Control), the 21 days stressed + earthing mat for 7 days (A7) or 21 days (A21) group. The depressive-and anxiety like behaviors were measured by forced swimming test (FST), tail suspension test (TST) and elevated plus maze (EPM). Using immunohistochemistry, the expression of corticotrophin-releasing factor (CRF) and c-Fos immunoreactivity were analyzed in the brain. In the EPM, time spent in the open arm of the earthing mat groups was significantly increased compared to the Control group (p < 0.001), even though there were without effects among groups in the FST and TST. The expression of CRF immunoreactive neurons in the earthing mat group was markedly decreased compared to the Control group. Overall, the earthing mat reduced stress-induced behavioral changes and expression of c-Fos and CRF immunoreactivity in the brain. These results suggest that the earthing mat may have the potential to improve stress-related responses via the regulation of the corticotrophinergic system.

Effects of semi-purified diet on depressive behaviors in aged mice.

Diet is a key modifiable factor influencing the composition of gut microbiota. There are two types of commercially available diets for experimental animals: non-purified and semi-purified diets. Non-purified diets are composed of complex ingredients from multiple sources, while semi-purified diets are formulated with refined ingredients. Accumulating evidence has demonstrated a link between the gut microbiota and depression, and feed ingredients may influence depressive physiology and behaviors. To test this hypothesis, we examined how chronic non-purified (CRF-1) and semi-purified (AIN-93G) diets affected phenotypes, including depressive behaviors, plasma corticosterone levels, and small-intestine microbiota in young (2 months old) and aged (22 months old) inbred C57BL/JJcl mice. In young mice, similar phenotypes were associated with non-purified and semi-purified diets. However, in aged mice, semi-purified diets increased depressive behaviors in the tail suspension (P < 0.05) and forced swimming tests (P < 0.01). The corticosterone levels were similar between the two diets under normal rearing conditions. However, immediately after exposure to the stressful conditions of the forced swimming test, the corticosterone levels in the aged mice fed the semi-purified diet were higher than those of mice fed the non-purified diet (P < 0.05). There were fewer Lactobacillales in the small intestines of aged mice fed the semi-purified diet compared to those fed the non-purified diet (P < 0.01). Further, α-diversity was lower in aged mice fed the semi-purified versus non-purified diet (P < 0.01). Our results indicate that host physiology and gut microbiota differed according to whether the aged mice were fed a non-purified or semi-purified diet. Specifically, those fed the semi-purified diet were more vulnerable to stress than age-matched mice fed the non-purified diet. Our findings indicate that researchers should consider the effects of feed ingredients on depressive physiology and behaviors, and select diets that are appropriate for their particular research design. Further, identification of the ingredients in non-purified diets could facilitate examination of the mechanisms by which gut microbiota composition might increase resistance to stress and depression.

Salidroside Improves Chronic Stress Induced Depressive Symptoms Through Microglial Activation Suppression.

Depression is a severe neurological disorder highly associated with chronic mental stress stimulation, which involves chronic inflammation and microglial activation in the central nervous system (CNS). Salidroside (SLDS) has been reported to exhibit anti-neuroinflammatory and protective properties on neurological diseases. However, the mechanism underlying the effect of SLDS on depressive symptoms has not been well elaborated. In the present study, the effects of SLDS on depressive behaviors and microglia activation in mice CNS were investigated. Behavioral tests, including Forced swimming test (FST), Open field test (OFT) and Morris water maze (MWM) revealed that SLDS treatment attenuated the depressive behaviors in stress mice. SLDS treatment significantly reduced the microglial immunoreactivity for both Iba-1 and CD68, characteristic of deleterious M1 phenotype in hippocampus of stress mice. Additionally, SLDS inhibited microglial activation involving the suppression of ERK1/2, P38 MAPK and p65 NF-κB activation and thus reduced the expression and release of neuroinflammatory cytokines in stress mice as well as in lipopolysaccharide (LPS)-induced primary microglia. Also, SLDS changed microglial morphology, attachment and reduced the phagocytic ability in LPS-induced primary microglia. The results demonstrated that SLDS treatment could improve the depressive symptoms caused by unpredictable chronic stress, indicating a potential therapeutic application of SLDS in depression treatment by interfering microglia-mediated neuroinflammation.

Exo- and Endo-cannabinoids in Depressive and Suicidal Behaviors.

Cannabis (marijuana) has been known to humans for thousands of years but its neurophysiological effects were sparsely understood until recently. Preclinical and clinical studies in the past two decades have indisputably supported the clinical proposition that the endocannabinoid system plays an important role in the etiopathogeneses of many neuropsychiatric disorders, including mood and addictive disorders. In this review, we discuss the existing knowledge of exo- and endo-cannabinoids, and role of the endocannabinoid system in depressive and suicidal behavior. A dysfunction in this system, located in brain regions such as prefrontal cortex and limbic structures is implicated in mood regulation, impulsivity and decision-making, may increase the risk of negative mood and cognition as well as suicidality. The literature discussed here also suggests that the endocannabinoid system may be a viable target for treatments of these neuropsychiatric conditions.

Animal models for the study of depressive disorder.

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.

Neuromodulatory peptides: Orally active anxiolytic-like and antidepressant-like peptides derived from dietary plant proteins.

Mental disorders are a severe health problem, and the number of patients is growing worldwide. Increased anxiety and decreased motivation due to excessive mental stress further accelerated the severity of the problem. Enzymatic digestion of food proteins produces bioactive peptides with various physiological functions, some of which exhibit neuromodulatory effects with oral administration. Recently, studies reported that some peptides produced from plant proteins such as soybeans, leaves, and grains exhibit emotional regulatory functions such as strong anxiolytic-like and antidepressant-like effects comparable to pharmaceuticals. Conventionally, researchers investigated bioactive peptides by fractionation of protein hydrolysates and structure-activity relationship. As a novel methodology for analyzing bioactive peptides, the information obtained by peptidomics simultaneous analysis of the digested fractions of proteins using mass spectrometry has been effectively utilized. Some small-sized peptides such as dipeptides and tripeptides released food-derived proteins show emotional regulating effects. Moreover, some middle-sized peptides produced after intestinal digestion may exhibit the emotional regulating effect via the vagus nerve, and the importance of the gut-brain axis is also focused. As the central mechanism of emotional regulation, it has been found that these plant-derived peptides regulated monoamine neurotransmitter signaling and hippocampal neurogenesis.

Dual pharmacological inhibitor of endocannabinoid degrading enzymes reduces depressive-like behavior in female rats.

Major depressive disorder (MDD) is common, often under-treated and a leading cause of disability and mortality worldwide. The causes of MDD remain unclear, including the role of the endocannabinoid system. Intriguingly, the prevalence of depression is significantly greater in women than men. In this study we examined the role of endocannabinoids in depressive behavior. The levels of endocannabinoids, N-arachidonoyl ethanolamide (AEA) and 2-arachidonoyl glycerol (2-AG) were measured along with brain derived neurotrophic factor (BDNF) in postmortem ventral striata of female patients with MDD and non-psychiatric controls, and in Wistar Kyoto (WKY) rat, a selectively inbred strain of rat widely used for testing the depressive behavior. The effect of pharmacological elevation of endocannabinoids through inhibition of their catabolizing enzymes (fatty acid amide hydrolase [FAAH] and monoacyl glycerol lipase [MAGL]) on depressive-like phenotype was also assessed in WKY rat. The findings showed lower levels of endocannabinoids and BDNF in the ventral striata of MDD patients and WKY rats. A dual inhibitor of FAAH and MAGL, JZL195, elevated the endocannabinoids and BDNF levels in ventral striatum, and reduced the depressive-like phenotype in female WKY rats. Collectively, our study suggests a blunted ventral striatal endocannabinoid and BDNF signaling in depressive behavior and concludes that endocannabinoid enhancing agents may have an antidepressant effect.

Activation of NPY receptor subtype 1 by [D-His26]NPY is sufficient to prevent development of anxiety and depressive like effects in the single prolonged stress rodent model of PTSD.

The neuropeptide Y (NPY) system plays an important role in mediating resilience to the harmful effect of stress in post-traumatic stress disorder (PTSD). It can mediate its effects via several G-protein coupled receptors: Y1R, Y2R, Y4R and Y5R. To investigate the role of individual NPY receptors in the resilience effects of NPY to traumatic stress, intranasal infusion of either Y1R agonists [D-His26]NPY, [Leu31Pro34]NPY, Y2R agonist NPY (3-36) or NPY were administered to male Sprague-Dawley rats immediately following the last stressor of the single prolonged stress (SPS) protocol, a widely used PTSD animal model. After 7 or 14 days, effects of the treatments were measured on the elevated plus maze (EPM) for anxiety, in forced swim test (FST) for development of depressive-like or re-experiencing behavior, in social interaction (SI) test for impaired social behavior, and acoustic startle response (ASR) for hyperarousal. [D-His26]NPY, but not [Leu31Pro34]NPY nor NPY (3-36) Y2R, was effective in preventing the SPS-elicited development of anxiety. Y1R, but not Y2R agonists prevented development of depressive- feature on FST, with [D-His26]NPY superior to NPY. The results demonstrate that [D-His26]NPY was sufficient to prevent development of anxiety, social impairment and depressive symptoms, and has promise as an early intervention therapy following traumatic stress.