Maternal separation during lactation affects recognition memory, emotional behaviors, hippocampus and gut microbiota composition in C57BL6J adolescent female mice.

BACKGROUND: Maternal separation (MS) in rodents is a paradigm of early life events that affects neurological development in depression. Adolescence is a time of dramatic increases in psychological vulnerability, and being female is a depression risk factor. However, data on whether different MS scenarios affect behavioral deficits and the potential mechanisms in adolescent female mice are limited. METHODS: C57BL/6 J female pups were exposed to different MS (no MS, NMS; MS for 15 min/day, MS15; or 180 min/day, MS180) from postnatal day (PND)1 to PND21 and subjected for behavioral tests during adolescence. Behavioural tests, specifically the open field test (OFT), novel object recognition test (NOR) test and tail suspension test (TST), were performed. The expression of proinflammatory cytokines, hippocampal neurogenesis, neuroinflammation, and gut microbiota were also assessed. RESULTS: The results showed that MS180 induced emotional behavioral deficits and object recognition memory impairment; however, MS15 promoted object recognition memory in adolescent females. MS180 decreased hippocampal neurogenesis of adolescent females, induced an increase in microgliosis, and increased certain inflammatory factors in the hippocampus, including TNF-α, IL-1ß, and IL-6. Furthermore, different MS altered gut microbiota diversity, and alpha diversity in the Shannon index was negatively correlated with the peripheral inflammatory factors TNF-α, IL-1ß, and IL-6. Species difference analysis showed that the gut microbiota composition of the phyla Desulfobacterota and Proteobacteria was affected by the MS. LIMITATIONS: The sex differences in adolescent animal and causality of hippocampal neurogenesis and gut microbiota under different MS need to be further analyzed in depression. CONCLUSION: This study indicates different MS affect recognition memory and emotional behaviors in adolescent females, and gut microbiota-neuroinflammation and hippocampal neurogenesis may be a potential site of early neurodevelopmental impairment in depression.

Brief Pup Separation in Lactation Confers Stress Resistance with Increased Prolactin and Adult Hippocampal Neurogenesis in Postpartum C57BL/6J Dams.

Prolactin (PRL) assumes a pivotal role during the postpartum phase, particularly within the hippocampus-a region densely populated with receptors for stress hormones, where stress significantly inhibits adult hippocampal neurogenesis (AHN). The reduction in neurogenesis is implicated in the pathogenesis of anxiety and depression. Mothers are at an increased risk of developing depression when exposed to chronic stress. Therefore, it is imperative to investigate the potential role of PRL in depression-like behaviors stemming from prolonged postpartum stress, and to explore any underlying mechanisms. Despite pup separation (PS) being a natural postpartum care practice, the impact of various PS methods on lactating dams remains uncertain. Lactating C57BL/6J mice, from postpartum day (PPD) 1 to PPD 21, underwent no PS (NPS), brief PS (15 min per day, PS15), or long PS (180 min per day, PS180), followed by 21 days of chronic restraint stress (CRS). Behavioral tests were conducted, and measurements included serum PRL concentration, PRL-R expression, and AHN in the hippocampus. Dams with CRS exhibited cognitive decline, depressive- and anxiety-like behaviors, and reduced PRL secretion, correlating with lower levels of AHN. PS15 dams displayed lower levels of depressive- and anxiety-like behaviors and cognitive decline compared to NPS and PS180 dams. Significantly, PS15 dams exhibited higher levels of AHN, PRL-R expression in the hippocampus, and serum PRL concentration. This study collectively reveals reduced serum PRL and AHN in dams with cognitive decline and depressive- and anxiety-like behaviors after CRS. Brief PS confers resistance to behavioral deficits after CRS, increasing serum PRL concentration and reversing AHN decrease in dams.

Brief pup separation during lactation confers resilience in behavioural deficits induced by chronic restraint stress in postpartum C57BL/6J dams.

BACKGROUND: The postpartum period is a complex time for females that affects health recovery. Stress during this period is one of the main risk factors for depression. Therefore, preventing stress-induced depression in the postpartum period is of great importance. Pup separation (PS) is a natural paradigm of postpartum care; however, the effect of different PS protocols during lactation on stress-induced depressive behaviours in dams is unknown. METHODS: Lactating C57BL/6J mice were subjected to no pup separation (NPS), brief PS (15 min/day, PS15) or long PS (180 min/day, PS180) from postpartum day 1 to postpartum day 21 and were then subjected to chronic restraint stress (CRS) for 21 days. Behavioural tests, specifically the open field test (OFT), elevated plus maze (EPM) test and tail suspension test (TST), were performed. The expression of mRNA and protein in the hippocampus and microbiota composition were also assessed. RESULTS: We observed CRS-induced anxiety- and depression-like behaviours in NPS dams. In addition, in NPS dams, microglial activation and the levels of NOD-like receptor pyrin domain containing 3, caspase-1 and interleukin-1ß were increased, whereas expression levels of collapsing response mediator protein 2 (CRMP2) and α-tubulin were decreased. However, immobility time in the TST was lower in PS15+CRS dams than in NPS+CRS dams, and time spent in the centre during the OFT and in the open arms during the EPM test was higher in PS15+CRS dams, indicating resilience. Expression of hippocampal biomarkers of neuroinflammation was inhibited and levels of CRMP2-mediated neuroplasticity were increased in PS15+CRS dams. Notably, we observed taxonomic changes in the cecal microbiota across different PS groups, as well as relationships between gut microbiota composition and some biomarkers of hippocampal neuroinflammation and neuroplasticity. LIMITATIONS: The sample size for gut microbiota analysis in this study was small. CONCLUSION: Collectively, the results of this study confirm that brief PS confers stress resilience in CRS-induced behavioural deficits and reverses hippocampal neuroinflammation-neuroplasticity injury and gut microbiota imbalance.

Intermittent hypoxia exacerbated depressive and anxiety-like behaviors in the bleomycin-induced pulmonary fibrosis mice.

Depression and anxiety are prevalent in patients with idiopathic pulmonary fibrosis (IPF). Recent researchers reveal that intermittent hypoxia (IH) increases the severity of bleomycin (BLM)-induced lung injury. However, experimental studies dealing with anxiety- and depression-like behavior in animal models of BLM-induced pulmonary fibrosis in a combination of IH are lacking, hence, this study aimed to investigate that. In this study, 80 C57BL/6J male mice were intratracheally injected with BLM or normal saline at day0 and then exposed to IH (alternating cycles of FiO2 21 % for 60 s and FiO2 10 % for 30 s, 40 cycles/hour, 8 h/day) or intermittent air (IA) for 21 days. Behavioral tests, including open field test (OFT), sucrose preference test (SPT) and tail suspension test (TST), were detected from day22 to day26. This study found that pulmonary fibrosis developed and lung inflammation were activated in BLM-induced mice, which were potentiated by IH. Significant less time in center and less frequency of entries in the centre arena in OFT were observed in BLM treated mice, and IH exposure further decreased that. Marked decreased percent of sucrose preference in SPT, and significant increased immobility time of the TST were detected in BLM treated mice and IH widen the gaps. The expression of ionized calcium-binding adaptor molecule (Iba1) was activated in the hippocampus of BLM instillation mice and IH enlarged it. Moreover, a positive correlation between hippocampal microglia activation and inflammatory factors was observed. Our results demonstrated that IH exacerbated depressive and anxiety-like behaviors in the BLM-induced pulmonary fibrosis mice. The changes in pulmonary inflammation-hippocampal microglia activation may be a potential mechanism in this phenomenon, which can be researched in future.

Brief Maternal Separation Promotes Resilience to Anxiety-like and Depressive-like Behaviors in Female C57BL/6J Offspring with Imiquimod-Induced Psoriasis.

BACKGROUND: Psoriasis is a common chronic inflammatory skin disease that often causes depression. Early life experience affects brain development and relates to depression. Whether the effect of different MS protocols in early life on anxiety-like and depressive-like behaviors in female offspring with imiquimod (IMQ)-induced psoriasis is unknown. METHODS: C57BL/6J mice were subjected to no separation (NMS), brief MS (15 min/day, MS15) or long MS (180 min/day, MS180) from postpartum days (PPD) 1 to PPD21. Then, 5% imiquimod cream was applied for 8 days in adults. Behavioral tests, skin lesions and hippocampal protein expression were also assessed. RESULTS: We found significant psoriasis-like skin lesions in female mice following IMQ application, and mice showed anxiety-like and depressive-like behaviors. Further, increased microglial activation and decreased expression of neuroplasticity were detected in mice following IMQ application. However, after MS15 in early life, mice showed decreased anxiety-like and depressive-like behaviors, indicating resilience. Further, inhibited hippocampal neuroinflammation and increased neuroplasticity were detected. CONCLUSIONS: Collectively, this study confirms that brief MS confers resilience to the behavior deficits in female offspring with IMQ-induced psoriasis and reverses the activation of neuroinflammation and the damage of neuroplasticity injury.

Swimming exercise reverses chronic unpredictable mild stress-induced depression-like behaviors and alleviates neuroinflammation and collapsing response mediator protein-2-mediated neuroplasticity injury in adult male mice.

OBJECTIVE: Impaired neuroplasticity and neuroinflammation are vital in the mechanisms of depression. Exercise alleviates depressive symptoms and ameliorates body functions. Swimming is one of the most common exercises; however, whether swimming alters depressive behaviors and the underlying mechanism has not been fully elucidated. METHODS: Male C57/BL6J mice were exposed to chronic unpredictable mild stress (CUMS) for 6 weeks and then were subjected to a 5-week swimming program. Behavioral test, including sucrose preference test (SPT), open field test (OFT), elevated plus-maze (EPM) test, and tail suspension test (TST), was conducted to assess the anxiety-like and depressive behaviors. Western blotting and immunofluorescence staining were carried out after tissue collection. RESULTS: This study showed that CUMS-induced depressive behaviors but swimming exercise increased sucrose preference in SPT, increased time and velocity in the center on OFT, decreased time in the closed arm, increased time in the open arm in EPM, and decreased immobility time in TST. We further found swimming exercise increased hippocampal collapsing response mediator protein-2 (CRMP2) expression and decreased p-CRMP2 expression in CUMS mice. CUMS inhibited the levels of α-tubulin and CRMP2, and the expression of ionized calcium-binding adaptor molecule 1 and caspase-1, whereas swimming reversed them in CUMS-exercised mice. CONCLUSION: Our study confirmed that swimming exercise reverses CUMS-induced depressive behaviors, and neuroinflammation and CRMP2-mediated neuroplasticity are involved, which may provide a new insight into the antidepression therapy of exercise.

Swimming Exercise Modulates Gut Microbiota in CUMS-Induced Depressed Mice.

Background: Gut microbiota is associated with anxiety and depression, while exercise has been proved to alleviate depressive symptoms. However, the interaction of exercise, depression, and gut microbiota remains unclear. Methods: Male C57/BL6J mice were exposed to chronic unpredictable mild stress (CUMS) for 6 weeks and then were subjected to a 5-week swimming program. Behavioral tests, including sucrose preference test (SPT), open field test (OFT), elevated plus-maze (EPM) test, and tail suspension test (TST), were conducted to assess the anxiety-like and depressive behaviors. Gut microbiota analysis was carried out after sample collection. Results: This study showed that CUMS induced depressive behaviors, but swimming exercise increased sucrose preference rate in the SPT, increased time in the center and number of rearing in the OFT, decreased time in the closed arm and increased time in the open arm in EPM, and decreased immobility time in the TST. Firmicutes were the predominant phylum in the gut microbiome, followed by the phyla Bacteroidetes and Proteobacteria. We further found that CUMS and swimming influenced the relative abundance of the genus Desulfovibrio, genus Streptococcus, genus p-75-a5. Among the metabolic pathways, aromatic biogenic amine degradation (PWY-7431), mono-trans and polycis decaprenyl phosphate biosynthesis (PWY-6383), chlorosalicylate degradation (PWY-6107), mycothiol biosynthesis (PWY1G-0), mycolyl-arabinogalactan-peptidoglycan complex biosynthesis (PWY-6397), toluene degradation I (aerobic) (via o-cresol) (PWY-5180), toluene degradation II (aerobic) (via 4-methylcatechol) (PWY-5182), and starch degradation III (PWY-6731) may be related to the mechanism of anti-depression effect. Conclusion: Swimming exercise reverses CUMS-induced depressive behaviors, and the alteration of gut microbiota composition and regulation of microbiota metabolic pathways are involved.

The Effects and Mechanisms of Exercise on the Treatment of Depression.

Background: It is necessary to seek alternative therapies for depression, because side effects of medications lead to poor adherence and some patients do not achieve a clinical treatment effect. Recently the role of exercise as a low-cost and easy-to-use treatment for depression has gained attention with a number of studies showing that exercise is effective at reducing depressive symptoms and improving body functions such as cardiorespiratory system and cognitive function. Because of the heterogeneity of exercise therapy programs, there is no standardized and unified program. Few studies have summarized the specific properties of exercise programs (type, intensity, duration, and frequency) and clinical prescriptions for exercise are not mentioned in most articles. Aims: This study aimed to investigate the feasibility and efficacy of exercise therapy for patients with depression, in order to appraise the evidence and outline accepted guidelines to direct individualized treatment plans for patients with depression based on their individual situations. Methods: A systematic review of English language literature including papers published from 2010 to present in PubMed was performed. Given the feasibility of prescribing exercise therapy for patients with depression, nearly 3 years of clinical studies on the treatments of depressive symptoms with exercise were first reviewed, comparing the exercise programs utilized. Conclusions: Exercise has therapeutic effects on depression in all age groups (mostly 18-65 years old), as a single therapy, an adjuvant therapy, or a combination therapy, and the benefits of exercise therapy are comparable to traditional treatments for depression. Moderate intensity exercise is enough to reduce depressive symptoms, but higher-dose exercise is better for overall functioning. Exercise therapy has become more widely used because of its benefits to the cardiovascular system, emotional state, and systemic functions. Recommendations: Aerobic exercise/mind-body exercise (3-5 sessions per week with moderate intensity lasting for 4-16 weeks) is recommended. Individualized protocols in the form of group exercise with supervision are effective at increasing adherence to treatment.

Maternal deprivation induces cytoskeletal alterations and depressive-like behavior in adult male rats by regulating the AKT/GSK3ß/CRMP2 signaling pathway.

Early-life adverse events exert persistent effects on brain functions and may increase the risk of psychopathology in adulthood. However, the underlying mechanism remains unclear. The purpose of our study was to study the long-lasting effects of maternal deprivation (MD) on depression-related behaviors and microtubule dynamics, and to illuminate the underlying molecular mechanism. Rat pups were separated from the dams for 360 min (MD) or 15 min (brief maternal separation) each day from postnatal day 4 through 10. Rats with MD experience showed significant depressive-like behaviors in adulthood, while brief maternal separation did not alter the behaviors. Behavioral alterations in the MD group were accompanied by alterations in the AKT/GSK3ß/CRMP2 signaling pathway and hyperphosphorylation of CRMP2. CRMP2 interacted and colocalized with the cytoskeleton in the hippocampus, and the overlap of CRMP2 and tubulin staining in the hippocampus of MD rats was decreased. In MD rats, the expression of the α-tubulin isoforms Acet-tubulin and Tyr-tubulin changed, and the ratio of Tyr/Acet-tubulin, which is an important marker of microtubule dynamics, was decreased, indicating decreased microtubule dynamics. Furthermore, regulation of the AKT/GSK3ß/CRMP2 signaling pathway by an LY294002 microinjection in the hippocampus resulted in cytoskeletal alterations and depressive-like behaviors in rats. These findings suggest that early-life MD induces depressive-like behaviors and cytoskeletal alterations in adult male rats and that the effects may be partly mediated by the AKT/GSK3ß/CRMP2 signaling pathway. An understanding of the mechanism underlying the effect of MD on behaviors is crucial for developing pharmacological and psychological interventions for childhood neglect.

Swimming exercise reduces the vulnerability to stress and contributes to the AKT/GSK3ß/CRMP2 pathway and microtubule dynamics mediated protective effects on neuroplasticity in male C57BL/6 mice.

While swimming exercise has been shown to positively affect the development of the nervous system, it still remains unclear whether it reduces the vulnerability to stress. In this study, male C57BL/6 mice were exposed to swimming training for 5 weeks, and then subjected to chronic unpredictable mild stress (CUMS) for 4 weeks. We found that swimming exercise prevented anxiety-like and depressive phenotypes induced by CUMS, including increased anxiety-like behavior in the open field test (OFT) and elevated plus-maze (EPM) test and increased despair behavior in the tail suspension test (TST). Moreover, the control+stress group showed reduced expression of phosphorylated AKT kinase (p-AKT), phosphorylated glycogen synthase kinase-3ß (p-GSK3ß), and tubulin-tyrosine ligase (Tyr-tubulin) and increased protein expression of phosphorylated collapsin response mediator protein 2 (p-CRMP-2); the control+control, swim+control, and swim+stress groups exhibited higher expression of these proteins than the control+stress group. This study confirmed that swimming exercise could reduce the vulnerability of individuals to stress and that it contributes to the AKT/GSK-3ß/CRMP-2 pathway and microtubule dynamics mediated protective effects on neuroplasticity. The AKT/GSK-3ß/CRMP-2 pathway and microtubule dynamics may be involved in resilience to stress.

Neuroinflammation decreased hippocampal microtubule dynamics in the acute behavioral deficits induced by intracerebroventricular injection of lipopolysaccharide in male adult rats.

Neuroinflammation plays a vital role in the pathology of depression. Microtubule dynamics produces an immediate response to stress, but the effect of microtubule dynamics in the rats with acute behavioral deficits following a central immune challenge remains elusive. Adult male Sprague-Dawley rats were subjected to the intracerebroventricular (icv) injection of lipopolysaccharide (. Behavioral tests, including bodyweight, sucrose preference test (SPT), forced swimming test (FST) and open field test (OFT), were performed to evaluate anxiety-like and depressive-like phenotypes at 24 h after injection, and some neuroinflammation biomarkers and microtubule dynamics in the hippocampus were detected. Lipopolysaccharide decreased the bodyweight, sucrose preference in SPT (depressive-like behavior), spontaneous activity in OFT (anxiety-like behavior) and increased the immobility time in FST (depressive-like behavior). Besides, lipopolysaccharide increased the mRNA levels of hippocampal CD11b and ionized calcium binding adaptor molecule (Iba1), which suggest microglial activation, and also upregulated hippocampal NLR Family Pyrin Domain Containing 3 inflammasome/interleukin-18/nuclear factor kappa-B mRNA. Lipopolysaccharide injection(icv) reduced the ratio of Tyr-/Acet-tubulin, an important marker of microtubule dynamics, in the acute behavioral deficit rats. Specifically, a decrease in Tyr-tubulin and an increase in the expression of Acet-tubulin were observed, indicating weakened microtubule dynamics. Pearson correlation analysis further showed that there was a significant negative correlation between hippocampal microtubule dynamics and neuroinflammatory activity. This study confirmed that hippocampal microtubule dynamics was decreased in the rats with acute behavioral deficits following a central immune challenge.

Neurogenic hypothesis of positive psychology in stress-induced depression: Adult hippocampal neurogenesis, neuroinflammation, and stress resilience.

Stress is an important risk factor for depression. Emerging evidence supports the hypothesis that stress-mediated neuroinflammation destroys brain function and leads to anxiety-like and depression-like behaviors. Previous studies of stress-induced depression have mainly focused on pathological damage; however, the rise of positive psychology has attracted the interest of many researchers in environmental enrichment to promote stress resilience. The hippocampus is one of the most severely damaged brain regions in stress-induced depression. In addition, the hippocampus is one of the most unique regions in the brain, as new neurons are produced in the adult hippocampus, a process known as adult hippocampal neurogenesis (AHN). AHN is an important core component of the neurogenic hypothesis and has also become a major innovative breakthrough in positive psychology, in which environmental enrichment mediates stress resilience. Neuroinflammation, by activating microglia and releasing some proinflammatory cytokines, is increasingly shown to be one of the key determinant pathophysiological factors that negatively affects AHNand cognitive reserve. AHN is mainly related to remodeling stress response mechanisms, such as memory clearing, emotional control, and pattern separation, suggesting that a correlation may exist between neuroinflammation and AHN in stress resilience. Therefore, we summarized the previous research results to systematically expound on the relationship between AHN, stress resilience, and neuroinflammation. We hope this neurogenic hypothesis of positive psychology in stress-induced depression will provide a new perspective for the study of depression and antidepressant therapy.

Brief postpartum separation from offspring promotes resilience to lipopolysaccharide challenge-induced anxiety and depressive-like behaviors and inhibits neuroinflammation in C57BL/6J dams.

Emerging evidence indicates an important role for neuroinflammation in depression. Brief maternal separation promotes resilience to depression in offspring, but relatively little is known about the effects of different durations of postpartum separation (PS) from offspring on anxiety and depressive-like behaviors in dams following immune challenge. Lactating C57BL/6J mice were subjected to no separation (NPS), brief PS (15 min/day, PS15) or prolonged PS (180 min/day, PS180) from postpartum day (PPD) 1 to PPD21 and then injected with lipopolysaccharide (LPS). Behavioral tests, including the open field test (OFT) and forced swimming test (FST), were carried out at 24 h after the injection. LPSresulted in anxiety and depressive-like behaviors in NPS dams and activated ionized calcium-binding adaptor molecule (Iba1), an important biomarker of microglia, in the hippocampus. However, compared with NPS + LPS dams, PS15 + LPS dams spent significantly more time in the center of the OFT (anxiety-like behavior) and exhibited lower immobility time in the FST (depressive-like behavior), which indicated a phenomenon of resilience. Furthermore, the activation of neuroinflammation was inhibited in PS15 dams. Specifically, levels of the Iba1 mRNA and protein were decreased, while the mRNA expression of NLR family pyrin domain containing 3 (NLRP3) inflammasome/interleukin-18 (IL-18)/nuclear factor kappa-B (NF-κB) was decreased in the hippocampus. Furthermore, positive linear correlations were observed between microglial activation and LPS-induced depressive-like behaviors in dams. Collectively, the findings of this study confirm that brief PS from offspring promotes resilience to LPS immune challenge-induced behavioral deficits and inhibits neuroinflammation in dams separated from their offspring during lactation.

Resilience in the LPS-induced acute depressive-like behaviors: Increase of CRMP2 neuroprotection and microtubule dynamics in hippocampus.

Depressive-like behaviors occur at 24 h after lipopolysaccharide (LPS) injection, but whether the animals have resilience has not been reported. This study is to explore the existence of resilience in the LPS-induced acute depressive-like behaviors and its biological changes in the neuroprotection and microtubule dynamics. The behavioral tests of Sprague-Dawley male rats, including body weight (BW), sucrose preference test (SPT), forced swimming test (FST) and open field test (OFT), which are used to explore depressive and anxiety-like behaviors, were detected at 24 h after intraperitoneal injection of LPS. In the LPS-induced depression group, body weight and sucrose preference index in SPT were decreased, the immobility time in FST was increased, total distance, time in central zone and frequency of rearing in OFT were decreased. However, there was not any difference in behavioral phenotypes between the resilient animals and the saline control group. The activity of collapsing response mediator protein 2 (CRMP2), which is related to neuronal plasticity and neuroprotection, was increased in resilient rats. The brain-derived neurotrophic factor (BDNF) mRNA expression was also increased. The ratio of Tyr/Acet-tubulin in hippocampus, which is an important marker of microtubule dynamics, was increased without alpha-tubulin. In addition, the expression of CRMP2 and alpha-tubulin in dentate gyrus (DG) region increased in resilient animals, but not in CA1 and CA3 regions. This study firstly confirms the phenomenon of resilience in the LPS-induced acute depressive-like behaviors animal model. CRMP2 neuroprotection and microtubule dynamics in hippocampus are enhanced in this phenomenon of resilience, which may functionally contribute to resilience but need further research.

Long-term maternal separation potentiates depressive-like behaviours and neuroinflammation in adult male C57/BL6J mice.

Early life experience is closely related to depression caused by stress in adulthood. Early life experience, including maternal separation (MS), has been shown to evoke stress sensitivity to depression upon re-exposure to stress in adults. However, MS has also been shown to lead to resilience to stress-induced depression, which is contradictory and rarely studied. To investigate the effects of MS on depression in adults and the related mechanism, male C57/BL6J mouse pups were exposed to different MS procedures from postnatal day (PD)1 to PD21. Body weight (BW) measurements and behavioural tests (the forced swimming test (FST) and open field test (OFT)) were performed on PD41 to explore depressive and anxiety-like behaviours. Then, as adults, the mice were exposed to chronic unpredictable mild stress (CUMS) for 28 days, and then behavioural tasks were recorded. After CUMS exposure, the mice in the MS180 group (which were separated from their mothers for 3 h on PD1-PD21) showed significantly decreased time spent in the centre of the open field and reduced velocity in the OFT, a reduced latency to immobility in the FST, and decreased BW. However, the mice in the MS15 group (which were separated from their mothers for 15 min on PD1-PD21) performed similarly to NSNC mice (which were not separated from their mothers) in the behavioural tests. We further found that the expression of Iba1, a marker of neuroinflammation, was increased in the MS180 group but not in the MS15 group. In addition, our study showed decreased mRNA and protein expression of CRMP2, an important neuroprotective factor, in the MS180 group, but CRMP2 expression was unchanged in the MS15 group. This study confirmed the generation of different behavioural responses to stress exposure in adulthood due to different degrees of MS. Neuroinflammation and neuroprotection are involved, which requires further research.

Fluoxetine exposure for more than 2 days decreases the neuronal plasticity mediated by CRMP2 in differentiated PC12 cells.

BACKGROUND: Recent studies indicate that antidepressants treatment restores neuronal plasticity. In contrast, some researchers claim that serotonergic antidepressants, including fluoxetine (FLU), may exacerbate neuronal plasticity, which is contradictory and rarely studied. Since almost those studies exposed cells with drugs for 1-2 days as treatment models of antidepressants, it is possible that FLU exposure for longer periods would have opposite effects on neuronal plasticity. RESULTS: In the present study, we examined the effects of FLU exposure (up to 3 days) on the neuronal plasticity in differentiated PC12 cells. The cell viability shown a slight decrease at day 2 (93.5 ± 3.5 %), followed by a highly significant decrease at day 3(71.4 ± 4.4 %). As previously reported, neuronal plasticity was significantly upregulated by FLU exposure at day 1. However, the neurite length, activity-regulated cytoskeleton-associated protein (Arc) and c-Fos mRNA were inhibited with FLU exposure at day 3. Similarly, the expression of tubulin, which play important roles in the neuronal plasticity, was the same result. Furthermore, we found α-tubulin interacted with collapsing response mediator protein 2(CRMP2), which is related to neuronal plasticity, and the regulation of CRMP2 activity influenced the neurite length, Arc, c-Fos and tubulin expression. CONCLUSIONS: The results demonstrated that neuronal plasticity was increased by FLU exposure at day 1, but exposure with FLU for more than 2 days had opposite effect on it. The reduction in neuronal plasticity with FLU exposure for more than 2 days might be involved in some aspects of the therapeutic effect of antidepressant on depression.

PI3K/AKT/GSK3ß/CRMP-2-mediated neuroplasticity in depression induced by stress.

Early neurodevelopmental dysplasia or disorder is an important stimulus for depression, but early stress can easily damage nerve development and lead to decreased neural plasticity. Because of the characteristics of nerve cell, nerve loop, structure instability and so on, stress can often lead to the occurrence and recurrence of depression. Stress is often associated with the release of inflammatory factors in the central nervous system. Recent studies suggest that neuroinflammatory factors are most likely involved in the occurrence and development of stress-induced depression, attacking neuronal cells through central inflammatory factors. The changes in neural plasticity, such as microtubule system of nerve scaffold, extension of axonal dendrites, regeneration of nerve junctions, disturbance of neurotransmitter synthesis, transmission and release, and abnormal synapses, cause abnormal transmission of information between nerve cells and cause symptoms of depression. The changes in the structure of neural stent microtubules are closely related to the neuroplastic damage of depression induced by stress. Our previous studies and current studies have found that the AKT/GSK3ß/CRMP-2 pathway mediates the changes in neural stent microtubule plasticity. There is an interaction between central inflammatory factors and this pathway. Therefore, from the point of view of neuritis injury and the plasticity change of nerve scaffold, it can be concluded that after the activation and release of central inflammatory factor under stress, the possible mechanism of depression is mediated by the AKT/GSK3ß/CRMP-2 pathway by changing the normal structure and function of the central nervous cell scaffold microtubule system.

Sex-dependent impact of different degrees of maternal separation experience on OFT behavioral performances after adult chronic unpredictable mild stress exposure in rats.

Early-life social-environmental factors are important for normal development, and different degrees of early-life stress experience have different impacts on adult behaviors and stress responsiveness. The aim of present study was to investigate the long-term effects of different degrees of maternal separation (MS) on male and female rats and subsequent responsiveness to chronic unpredictable mild stress (CUMS) exposure in adults. Sprague-Dawley (SD) newborn pups were exposed to either 15 min/day of MS (MS15), 360 min/day of MS (MS360) or no separation (NS) during postnatal day (PND)4-PND10. At PND56, behavioral tasks, including sucrose preference test (SPT), forced swimming test (FST) and open field test (OFT), were used to explore depressive and anxiety-like behaviors. Then the rats received a series of CUMS for 28 days, behavioral tasks were recorded after CUMS. Prior to CUMS, the behavioral performances in male and female rats were consistent, MS360 led to increased immobile time in FST and decreased activity in OFT, while MS15 rats exhibited behavioral performances similar to NS group. After CUMS, sexual dimorphism was observed in the OFT behavioral responses to adult stress re-exposure, but no differences in FST were observed. CUMS male rats with MS360 experiences showed the worst behavioral performances in OFT compared to those of the other male rats groups, while CUMS female rats without MS experience showed the worst behavioral performances in OFT compared to those of the other female rats groups. Both CUMS male and female rats with MS15 experiences showed better trend in OFT performances than those of CUMS rats with MS360 experience and without MS experiences. These results suggest that brief MS experiences increase the OFT behavioral resilience of rats to adult stress re-exposure, and prolonged MS promotes OFT behavioral resilience of female rats to adult stress re-exposure, while increases vulnerability of male rats to adult stress re-exposure.