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/6J female pups were exposed to different MS (no MS, NMS; MS for 15min/day, MS15; or 180min/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.

Network pharmacology- and molecular docking-based investigation on the mechanism of action of Si-ni San in the treatment of depression combined with anxiety and experimental verification in adolescent rats.

Background: The incidence rate of adolescent depression and anxiety has been increasing since the outbreak of COVID-19, which there are no effective therapeutic drugs available. Si-ni San is commonly used in traditional Chinese medicine for the treatment of depression-like as well as anxiety-like behavior, but its mechanism for treating depression combined with anxiety during adolescence is not yet clear. Methods: Network pharmacology was used to explore potential drug molecules and related targets, molecular docking and molecular dynamics (MD) simulation were used to evaluate the interaction between the potential drug molecules and related targets, and a model of anxiety combined with depression in adolescent rats as well as the following behavioral tests and molecular biology tests were used to verify the results from network pharmacology and molecular docking. Results: As a result, 256 active ingredients of Si-ni San and 1128 potential targets were screened out. Among them, quercetin, Luteolin, kaempferol, 7-Methoxy-2-methyl isoflavone, formononetin showed to be the most potential ingredients; while STAT3, IL6, TNF, AKT1, AKT1, TP53, IL1B, MAPK3, VEGFA, CASP3, MMP9 showed to be the most potential targets. AGE-RAGE signaling pathway in diabetic complications, IL-17 signaling pathway, HIF-1 signaling pathway, PI3K-Akt signaling pathway and TNF signaling pathway, which are involved in anti-inflammation processes, showed to be the most probable pathways regulated by Si-ni San. Molecular docking and MD simulation between the compounds to inflammation-associated targets revealed good binding abilities of quercetin, Luteolin, kaempferol, nobiletin and formononetin to PTGS2 and PPARγ. In the experiment with adolescent rats, Si-ni San markedly suppressed early maternal separation (MS) combined with adolescent chronic unpredictable mild stress (CUMS)-induced depression combined with anxiety. The qPCR results further indicated that Si-ni San regulated the oxidative stress and inflammatory response. Conclusion: This study demonstrates that adolescent anxiety- and depression-like behavior induced by MS combined CUMS can be ameliorated by Si-ni San by improved inflammation in hippocampus via targeting TNF pathway and Nrf2 pathway, helping to reveal the mechanism of Si-ni San in treating adolescent depression combined with anxiety.

Effects of double neonatal stress on female rat sexual behaviour.

Neonatal stress affects psychological and physiological development and may be associated with affective disorders. The aim was to examine the effects of double neonatal stress (DNS) - a combination of limited bedding and nesting (LBN) and repeated maternal separation (MS) - on the oestrous cycle and sexual behaviour of adult female rats. LBN was achieved by removing part of the wood shavings from the boxes. In the control group, each box was lined with 100 g of wood shavings, while in the experimental group there were only 10 g of wood shavings. MS was performed from P1 (P0 = day of birth) to P15. At P90, the sexual response of females in oestrus was evaluated. Statistical analysis was performed using two-way analysis of variance followed by Tukey's test. The size and profile of the oestrous cycle and the sexual behaviour of female rats submitted to the DNS were considered, as well as the influence of female behaviour on the sexual response of male rats. Female rats submitted to DNS showed a reduction in the lordosis quotient, suggesting a reduction in female receptivity. These rats also showed a reduction in the number of hops and darts, the number of ear wiggles, and the genital exploration time rate, suggesting a reduction in proceptivity. The males that interacted with the females of the DNS group showed a reduction in intromission ratio. Experimental model that mimics neonatal factors that affect adult female sexual response will allow more effective interventions to prevent and treat such changes. In addition, analysis of the female sexual response makes it possible to assess the general state of health and quality of life. In female rats, DNS exerted inhibitory effects on sexual behaviour. LBN was probably the most important factor. In conclusion, combating childhood poverty can be a key measure to prevent problems in the sex life of adults and improve overall health.

Analysis of hippocampal synaptic function in a rodent model of early life stress.

Background: Early life stress (ELS) is an important risk factor in the aetiology of depression. Developmental glucocorticoid exposure impacts multiple brain regions with the hippocampus being particularly vulnerable. Hippocampal mediated behaviours are dependent upon the ability of neurones to undergo long-term potentiation (LTP), an N-methyl-D-aspartate receptor (NMDAR) mediated process. In this study we investigated the effect of ELS upon hippocampal NMDAR function. Methods: Hooded Long-Evans rat pups (n=82) were either undisturbed or maternally separated for 180 minutes per day (MS180) between post-natal day (PND) 1 and PND14. Model validation consisted of sucrose preference (n=18) and novelty supressed feeding (NSFT, n=34) tests alongside assessment of corticosterone (CORT) and paraventricular nucleus (PVN) cFos reactivity to stress and hippocampal neurogenesis (all n=18). AMPA/NMDA ratios (n=19), miniEPSC currents (n=19) and LTP (n=15) were assessed in whole-cell patch clamp experiments in CA1 pyramidal neurones. Results: MS180 animals showed increased feeding latency in the NSFT alongside increased overall CORT in the restraint stress experiment and increased PVN cFos expression in males but no changes in neurogenesis or sucrose preference. MS180 was associated with a lower AMPA/NMDA ratio with no change in miniEPSC amplitude or area. There was no difference in short- or long-term potentiation between MS180 and control animals nor were there any changes during the induction protocol. Conclusions: The MS180 model showed a behavioural phenotype consistent with previous work. MS180 animals showed increased NMDAR function with preliminary evidence suggesting that this was not concurrent with an increase in LTP.

Highly stressful early life events are the biggest risk factor for developing depression in adulthood. The hippocampus is a brain region that is highly susceptible to this stress and is crucial for coordinating learning and memory which underpins many aspects of cognitive function. Our study investigated if changes in the way that the neurons in the hippocampus communicate could provide explanations as to why early life stress predisposes to depression. We used an animal model of early life stress where rat pups are separated from their mother for three hours per day during their early life. Upon adulthood this resulted in the rats being slower to eat food in a new environment, a standard test of anxiety behaviour. We then used a technique called ex-vivo patch clamp electrophysiology to study how the individual neurons in their hippocampi and their connections functioned after early life stress. We measured the relative power of the signals from two key synaptic receptors essential for communication between neurons: AMPA and NMDA receptors. AMPA receptors are the key receptors enabling communication between neurons at synapses whereas NMDA receptors allow a neuron to become more sensitive to input signals and adapt synaptic strength. Animals with early life stress had more NMDA receptor function relative to AMPA function compared to control animals. We used a technique called miniEPSC recordings to rule out any change in AMPA receptor function in ELS animals meaning an effect specific to NMDA receptors. However, we found no changes to the ability for synapses to adapt their strength between groups. This work presents evidence for changes in hippocampal neurons and synapses caused by early life stress but further work is needed to understand how this relates to depression.

Comparison of CUMS at different pregnancy stages, maternal separation, and their effects on offspring in postpartum depression mouse models.

Due to the diversity of postpartum depression (PPD) patients and the complexity of associated pathophysiological changes, most current animal models cannot accurately simulate PPD-like symptoms. In this study, we established a reliable animal model for PPD by inducing chronic unpredictable mild stress (CUMS) at different stages (pre-pregnancy, pregnancy, or postnatal) in female mice, followed by maternal separation (MS) from day 2-21 after delivery. The results for female mice subjected to pre-pregnancy stress were not statistically significant due to a lower conception rate. However, female mice exposed to CUMS during either the gestational or postnatal stage, followed by MS, successfully exhibited PPD-like symptoms. The models were deemed effective based on observed behavioral abnormalities, impaired hippocampal neuron functioning, and reduced serum concentrations of neurotransmitters (5-HT, GABA, and NE). Additionally, mice that underwent gestational CUMS followed by MS displayed a more dysfunctional hypothalamic-pituitary-adrenal (HPA) axis and more severe uterine inflammation. The study also investigated the impact of PPD on the behavior and neurodevelopment of adolescent offspring through behavioral tests, enzyme-linked immunosorbent assay (ELISA), hematoxylin-eosin (HE) staining, and western blotting (WB). The results indicated that adolescent offspring of mothers with PPD exhibited behavioral and neurodevelopmental disorders, with male offspring being more susceptible than females. Female mice exposed to both CUMS and MS during the postnatal period had more severe adverse effects on their offspring compared to the other model groups.

Lateral habenula IL-10 controls GABAA receptor trafficking and modulates depression susceptibility after maternal separation.

Maternal separation (MS), a form of early life adversity, increases the risk of psychiatric disorders in adulthood by intricately linking cytokines and mood-regulating brain circuits. The Lateral Habenula (LHb) encodes aversive experiences, contributes to negative moods, and is pivotal in depression development. However, the precise impact of MS on LHb cytokine signaling and synaptic plasticity remains unclear. We reported that adolescent MS offspring mice displayed susceptibility to depression behavioral phylotypes, with neuronal hyperactivity and an imbalance in pro-inflammatory and anti-inflammatory cytokines in the LHb. Moreover, the decreased IL-10 level negatively correlated with depressive-like behaviors in susceptible mice. Functionally, LHb IL-10 overexpression restored decreased levels of PI3K, phosphorylated AKT (pAKT), gephyrin, and membrane GABAA receptor proteins while reducing abnormally elevated GSK3ß and Fos expression, rescuing the MS-induced depression. Conversely, LHb neuronal IL-10 receptor knockdown in naive mice increased Fos expression and elicited depression-like symptoms, potentially through impaired membrane GABAA receptor trafficking by suppressing the PI3K/pAKT/gephyrin cascades. Hence, this work establishes a mechanism by which MS promotes susceptibility to adolescent depression by impeding the critical role of IL-10 signaling on neuronal GABAA receptor function.

Maternal separation as early-life stress: Mechanisms of neuropsychiatric disorders and inspiration for neonatal care.

The establishment of positive early parent-infant relationships provide essential nourishment and social stimulation for newborns. During the early stages of postnatal brain development, events such as synaptogenesis, neuronal maturation and glial differentiation occur in a highly coordinated manner. Maternal separation, as an early-life stress introducer, can disrupt the formation of parent-child bonds and exert long-term adverse effects throughout life. When offspring are exposed to maternal separation, the body regulates the stress of maternal separation through multiple mechanisms, including neuroinflammatory responses, neuroendocrinology, and neuronal electrical activity. In adulthood, early maternal separation has long-term effects, such as the induction of neuropsychiatric disorders such as anxiety, depression, and cognitive dysfunction. This review summarized the application of maternal separation models and the mechanisms of stress system response in neuropsychiatric disorders, serving as both a reminder and inspiration for approaches to improve neonatal care, "from bench to bedside".

Microglia: The Drunken Gardeners of Early Adversity.

Early life adversity (ELA) is a heterogeneous group of negative childhood experiences that can lead to abnormal brain development and more severe psychiatric, neurological, and medical conditions in adulthood. According to the immune hypothesis, ELA leads to an abnormal immune response characterized by high levels of inflammatory cytokines. This abnormal immune response contributes to more severe negative health outcomes and a refractory response to treatment in individuals with a history of ELA. Here, we examine this hypothesis in the context of recent rodent studies that focus on the impact of ELA on microglia, the resident immune cells in the brain. We review recent progress in our ability to mechanistically link molecular alterations in microglial function during a critical period of development with changes in synaptic connectivity, cognition, and stress reactivity later in life. We also examine recent research showing that ELA induces long-term alterations in microglial inflammatory response to "secondary hits" such as traumatic brain injury, substance use, and exposure to additional stress in adulthood. We conclude with a discussion on future directions and unresolved questions regarding the signals that modify microglial function and the clinical significance of rodent studies for humans.

Late maternal separation provides resilience to chronic variable stress-induced anxiety- and depressive-like behaviours in male but not female mice.

Maternal separation can have long-lasting effects on an individual's susceptibility to stress later in life. Maternal separation during the postnatal period is a commonly used paradigm in rodents to investigate the effects of early life stress on neurobehavioural changes and stress responsiveness. However, maternal separation during stress hyporesponsive and responsive periods of postnatal development may differ in its effects on stress resilience. Therefore, we hypothesised that late maternal separation (LMS) from postnatal day 10 to 21 in mice may have different effect on resilience than early maternal separation during the first week of postnatal life. Our results suggested that male LMS mice are more resilient to chronic variable stress (CVS)-induced anxiety and depressive-like behaviour as confirmed by the open field, light-dark field, elevated plus maze, sucrose preference and tail suspension tests. In contrast, female LMS mice were equally resilient as non-LMS female mice. We found increased expression of NPY, NPY1R, NPY2R, NPFFR1, and NPFFR2 in the hypothalamus of male LMS mice whereas the opposite effect was observed in the hippocampus. LMS in male and female mice did not affect circulating corticosterone levels in response to psychological or physiological stressors. Thus, LMS renders male mice resilient to CVS-induced neurobehavioural disorders in adulthood.

Sexual dimorphism exists in the effects of late maternal separation (LMS)LMS provides resilience to stress-induced anxiety and depression in male miceLMS upregulates NPY and NPVF system in the hypothalamus of male miceNo effect of LMS on stress-induced corticosterone levels.

Early Life Stress Influences Oxidative Stress Enzyme Activities in Liver, Heart, Kidney, Suprarenal Glands, and Pancreas in Male and Female Rat Pups.

Early life stress (ELS) is a risk factor for the development of chronic diseases resulting from functional alterations of organs in the cardiorespiratory and renal systems. This work studied the changes in oxidative stress enzyme activities (EAs) of SOD, CAT, GPX, GR, GST, NOS, MDA, and FRAP in different organs (heart, liver, kidney, adrenal glands (AGs), and pancreas) of male and female Sprague-Dawley rat pups on postnatal day (PN) 15, immediately after basal and acute or chronic stress conditions were accomplished, as follows: basal control (BC; undisturbed maternal pups care), stress control (SC; 3 h maternal separation on PN15), basal maternal separation (BMS; daily 3 h maternal separation on PN 1-14), and stress maternal separation (SMS; daily 3 h maternal separation on PN 1-14 and 3 h maternal separation on PN15). Acute or long-term stress resulted in overall oxidative stress, increase in EA, and reduced antioxidant capacity in these organs. Some different response patterns, due to precedent SMS, were observed in specific organs, especially in the AGs. Acute stress exposure increases the EA, but chronic stress generates a response in the antioxidant system in some of the organs studied and is damped in response to a further challenge.

Coping with the experience of frustration throughout life: Sex- and age-specific effects of early life stress on the susceptibility to reward devaluation.

Early life stress may lead to lifelong impairments in psychophysiological functions, including emotional and reward systems. Unpredicted decrease in reward magnitude generates a negative emotional state (frustration) that may be involved with susceptibility to psychiatric disorders. We evaluated, in adolescents and adult rats of both sexes, whether maternal separation (MS) alters the ability to cope with an unexpected reduction of reward later in life. Litters of Wistar rats were divided into controls (non handled - NH) or subjected to MS. Animals were trained to find sugary cereal pellets; later the amount was reduced. Increased latency to reach the reward-associated area indicates higher inability to regulate frustration. The dorsal hippocampus (dHC) and basolateral amygdala (BLA) were evaluated for protein levels of NMDA receptor subunits (GluN2A/GluN2B), synaptophysin, PSD95, SNAP-25 and CRF1. We found that adult MS males had greater vulnerability to reward reduction, together with decreased GluN2A and increased GluN2B immunocontent in the dHC. MS females and adolescents did not differ from controls. We concluded that MS enhances the response to frustration in adult males. The change in the ratio of GluN2A and GluN2B subunits in dHC could be related to a stronger, more difficult to update memory of the aversive experience.

Gas5 regulates early-life stress-induced anxiety and spatial memory.

Early-life stress (ES) induced by maternal separation (MS) remains a proven causality of anxiety and memory deficits at later stages of life. Emerging studies have shown that MS-induced gene expression in the hippocampus is operated at the level of transcription. However, the extent of involvement of non-coding RNAs in MS-induced behavioural deficits remains unexplored. Here, we have investigated the role of synapse-enriched long non-coding RNAs (lncRNAs) in anxiety and memory upon MS. We observed that MS led to an enhancement of expression of the lncRNA growth arrest specific 5 (Gas5) in the hippocampus; accompanied by increased levels of anxiety and deficits in spatial memory. Gas5 knockdown in early life was able to reduce anxiety and partially rescue the spatial memory deficits of maternally separated adult mice. However, the reversal of MS-induced anxiety and memory deficits is not attributed to Gas5 activity during neuronal development as Gas5 RNAi did not influence spine development. Gene Ontology analysis revealed that Gas5 exerts its function by regulating RNA metabolism and translation. Our study highlights the importance of MS-regulated lncRNA in anxiety and spatial memory.

Developmental functions of microglia: Impact of psychosocial and physiological early life stress.

Microglia play numerous important roles in brain development. From early embryonic stages through adolescence, these immune cells influence neuronal genesis and maturation, guide connectivity, and shape brain circuits. They also interact with other glial cells and structures, influencing the brain's supportive microenvironment. While this central role makes microglia essential, it means that early life perturbations to microglia can have widespread effects on brain development, potentially resulting in long-lasting behavioral impairments. Here, we will focus on the effects of early life psychosocial versus physiological stressors in rodent models. Psychosocial stress refers to perceived threats that lead to stress axes activation, including prenatal stress, or chronic postnatal stress, including maternal separation and resource scarcity. Physiological stress refers to physical threats, including maternal immune activation, postnatal infection, and traumatic brain injury. Differing sources of early life stress have varied impacts on microglia, and these effects are moderated by factors such as developmental age, brain region, and sex. Overall, these stressors appear to either 1) upregulate basal microglia numbers and activity throughout the lifespan, while possibly blunting their responsivity to subsequent stressors, or 2) shift the developmental curve of microglia, resulting in differential timing and function, impacting the critical periods they govern. Either could contribute to behavioral dysfunctions that occur after the resolution of early life stress. Exploring how different stressors impact microglia, as well as how multiple stressors interact to alter microglia's developmental functions, could deepen our understanding of how early life stress changes the brain's developmental trajectory. This article is part of the Special Issue on "Microglia".

The Impact of Abrupt and Fenceline-Weaning Methods on Cattle Stress Response, Live Weight Gain, and Behaviour.

The impact of abrupt (AB) and fenceline (FL) weaning methods on cattle stress response, live weight gain, and behaviour were determined across 14 days. Thirty-two cow-calf pairs were fitted with ear tag sensors (to continuously record behaviour) and allocated to two weaning treatments. After separation, FL calves were maintained in a pen adjacent to the FL cow paddock. The AB calves were transported to a pen removing all contact with the cows. After 7 d, FL cows were transported away from all calf pens. Body weights and salivary samples were collected for all animals on experimental days 0, 7, and 14. Fenceline-weaned calves had a greater duration of rest and rumination with reduced high activity across the first 3 days after separation as compared to abruptly weaned calves in line with the greater occurrences of pacing observed for AB calves. Fenceline-separated cows had greater levels of rest across the first 7 days but similar levels of rumination compared to abruptly separated cows. Fenceline-separated cow activity levels tended to be greater and eating levels were similar across the first three days. Body weight (BW) and cortisol concentrations were similar for AB and FL cattle, but FL cows had lower overall weight gain than the abrupt cows likely due to reduced eating time on days four to seven. Together, these results suggest that calves be fenceline-weaned for three days followed by total separation.

Scopoletin mitigates maternal separation-induced anxiety-like and depression-like behaviors in male mice through modulation of the Sirt1/NF-κB pathway.

RATIONALE: Early-life maternal separation can lead to anxiety-like and depression-like behaviors in mice reared under maternal separation conditions. Scopoletin, a compound with anti-inflammatory and antidepressant properties, may offer therapeutic benefits, but its effectiveness against behaviors induced by maternal separation during adulthood remains unexplored. OBJECTIVES: This study investigates scopoletin's efficacy in alleviating anxiety-like and depression-like phenotypes in male mice subjected to early-life maternal separation. METHODS: Male C57BL/6J mice experienced daily maternal separation for 4 h from postnatal day (PND) 2 to 21. From postnatal day 61(PND 61), scopoletin was administered intraperitoneally at 20 mg/kg/day for four weeks. Behavioral and biochemical assessments were conducted at postnatal day 95 (PND 95). RESULTS: Maternally separated mice displayed marked anxiety-like and depression-like behaviors, evident in behavioral tests like the open field and elevated plus maze. These mice also showed increased immobility in the forced swimming and tail suspension tests. Biochemically, there were elevated levels of IL-1ß, IL-6, and TNF-α in the hippocampus, with a decrease in Sirt1 and upregulation in NF-κB p65 expression. Scopoletin treatment significantly mitigated these behavioral abnormalities, normalizing both anxiety-like and depression-like behaviors. Correspondingly, it reduced the levels of pro-inflammatory cytokines and reinstated the expression of Sirt1 and NF-κB p65. CONCLUSIONS: Scopoletin effectively reverses the adverse behavioral and biochemical effects induced by early-life maternal separation in male mice, suggesting its potential as a therapeutic agent for treating anxiety-like and depression-like behaviors. Modulation of neuroinflammatory pathways and the Sirt1/NF-κB signaling axis is one possible mechanism.

Cross-species analysis uncovers the mitochondrial stress response in the hippocampus as a shared mechanism in mouse early life stress and human depression.

Depression, or major depressive disorder, poses a significant burden for both individuals and society, affecting approximately 10.8% of the general population. This psychiatric disorder leads to approximately 800,000 deaths per year. A combination of genetic and environmental factors such as early life stress (ELS) increase the risk for development of depression in humans, and a clear role for the hippocampus in the pathophysiology of depression has been shown. Nevertheless, the underlying mechanisms of depression remain poorly understood, resulting in a lack of effective treatments. To better understand the core mechanisms underlying the development of depression, we used a cross-species design to investigate shared hippocampal pathophysiological mechanisms in mouse ELS and human depression. Mice were subjected to ELS by a maternal separation paradigm, followed by RNA sequencing analysis of the adult hippocampal tissue. This identified persistent transcriptional changes linked to mitochondrial stress response pathways, with oxidative phosphorylation and protein folding emerging as the main mechanisms affected by maternal separation. Remarkably, there was a significant overlap between the pathways involved in mitochondrial stress response we observed and publicly available RNAseq data from hippocampal tissue of depressive patients. This cross-species conservation of changes in gene expression of mitochondria-related genes suggests that mitochondrial stress may play a pivotal role in the development of depression. Our findings highlight the potential significance of the hippocampal mitochondrial stress response as a core mechanism underlying the development of depression. Further experimental investigations are required to expand our understanding of these mechanisms.

Protective effects of rosmarinic acid against autistic-like behaviors in a mouse model of maternal separation stress: behavioral and molecular amendments.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with worldwide increasing incidence. Maternal separation (MS) stress at the beginning of life with its own neuroendocrine changes can provide the basis for development of ASD. Rosmarinic acid (RA) is a phenolic compound with a protective effect in neurodegenerative diseases. The aim of this study was to determine the effect of RA on autistic-like behaviors in maternally separated mice focusing on its possible effects on neuroimmune response and nitrite levels in the hippocampus. In this study, 40 mice were randomly divided into five groups of control (received normal saline (1 ml/kg)) and MS that were treated with normal saline (1 ml/kg) or doses of 1, 2, and 4 mg/kg RA, respectively, for 14 days. Three-chamber sociability, shuttle box, and marble burying tests were used to investigate autistic-like behaviors. Nitrite level and gene expression of inflammatory cytokines including TNF-α, IL-1ß, TLR4, and iNOS were assessed in the hippocampus. The results showed that RA significantly increased the social preference and social novelty indexes, as well as attenuated impaired passive avoidance memory and the occurrence of repetitive and obsessive behaviors in the MS mice. RA reduced the nitrite level and gene expression of inflammatory cytokines in the hippocampus. RA, probably via attenuation of the nitrite level as well as of the neuroimmune response in the hippocampus, mitigated autistic-like behaviors in maternally separated mice.

Maternal Substance Use and Early-Life Adversity: Inducing Drug Dependence in Offspring, Interactions, Mechanisms, and Treatments.

The likelihood of substance dependency in offspring is increased in cases when there is a family history of drug or alcohol use. Mothering is limited by maternal addiction because of the separation. Maternal separation (MS) leads to the development of behavioural and neuropsychiatric issues in the future. Despite the importance of this issue, empirical investigations of the influences of maternal substance use and separation on substance use problems in offspring are limited, and studies that consider both effects are rare. This study aims to review a few studies on the mechanisms, treatments, genetics, epigenetics, molecular and psychological alterations, and neuroanatomical regions involved in the dependence of offspring who underwent maternal addiction and separation. The PubMed database was used. A total of 95 articles were found, including the most related ones in the review. The brain's lateral paragigantocellularis (LPGi), nucleus accumbens (NAc), caudate-putamen (CPu), prefrontal cortex (PFC), and hippocampus, can be affected by MS. Dopamine receptor subtype genes, alcohol biomarker minor allele, and preproenkephalin mRNA may be affected by alcohol or substance use disorders. After early-life adversity, histone acetylation in the hippocampus may be linked to brain-derived neurotrophic factor (BDNF) gene epigenetics and glucocorticoid receptors (GRs). The adverse early-life experiences differ in offspring>s genders and rewire the brain>s dopamine and endocannabinoid circuits, making offspring more susceptible to dependence. Related psychological factors rooted in early-life stress (ELS) and parental substance use disorder (SUD). Treatments include antidepressants, histone deacetylase inhibitors, lamotrigine, ketamine, choline, modafinil, methadone, dopamine, cannabinoid 1 receptor agonists/antagonists, vitamins, oxytocin, tetrahydrocannabinol, SR141716A, and dronabinol. Finally, the study emphasizes the need for multifaceted strategies to prevent these outcomes.

Gut-brain barrier dysfunction bridge autistic-like behavior in mouse model of maternal separation stress: A behavioral, histopathological, and molecular study.

Autism spectrum disorder (ASD) is a fast-growing neurodevelopmental disorder throughout the world. Experiencing early life stresses (ELS) like maternal separation (MS) is associated with autistic-like behaviors. It has been proposed that disturbance in the gut-brain axis-mediated psychiatric disorders following MS. The role of disruption in the integrity of gut-brain barrier in ASD remains unclear. Addressing this knowledge gap, in this study we aimed to investigate role of the gut-brain barrier integrity in mediating autistic-like behaviors in mouse models of MS stress. To do this, mice neonates are separated daily from their mothers from postnatal day (PND) 2 to PND 14 for 3 hours. During PND58-60, behavioral tests related to autistic-like behaviors including three-chamber sociability, shuttle box, and resident-intruder tests were performed. Then, prefrontal cortex (PFC), hippocampus, and colon samples were dissected out for histopathological and molecular evaluations. Results showed that MS is associated with impaired sociability and social preference indexes, aggressive behaviors, and impaired passive avoidance memory. The gene expression of CLDN1 decreased in the colon, and the gene expression of CLDN5, CLDN12, and MMP9 increased in the PFC of the MS mice. MS is associated with decrease in the diameter of CA1 and CA3 areas of the hippocampus. In addition, MS led to histopathological changes in the colon. We concluded that, probably, disturbance in the gut-brain barrier integrities mediated the autistic-like behavior in MS stress in mice.