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The correction notice in the journal "Frontiers in Pharmacology" addresses errors in Figures 1D, 2E, 4E, 4F, 5D, and 5E of the article on glia-neuron interactions in mice with visceral hyperalgesia following maternal separation. The corrected figures show the impact of EphrinB2/EphB2 signaling on spinal cord responses to colorectal distension, highlighting the role of MAP kinases and other key proteins. The authors acknowledge the errors but affirm that they do not affect the scientific conclusions of the study. [Extracted from the article]

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-1β, 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. [ABSTRACT FROM AUTHOR]

Visceral hypersensitivity, a hallmark of disorders of the gut‐brain axis, is associated with exposure to early‐life stress (ELS). Activation of neuronal β3‐adrenoceptors (AR) has been shown to alter central and peripheral levels of tryptophan and reduce visceral hypersensitivity. In this study, we aimed to determine the potential of a β3‐AR agonist in reducing ELS‐induced visceral hypersensitivity and possible underlying mechanisms. Here, ELS was induced using the maternal separation (MS) model, where Sprague Dawley rat pups were separated from their mother in early life (postnatal day 2–12). Visceral hypersensitivity was confirmed in adult offspring using colorectal distension (CRD). CL‐316243, a β3‐AR agonist, was administered to determine anti‐nociceptive effects against CRD. Distension‐induced enteric neuronal activation as well as colonic secretomotor function were assessed. Tryptophan metabolism was determined both centrally and peripherally. For the first time, we showed that CL‐316243 significantly ameliorated MS‐induced visceral hypersensitivity. Furthermore, MS altered plasma tryptophan metabolism and colonic adrenergic tone, while CL‐316243 reduced both central and peripheral levels of tryptophan and affected secretomotor activity in the presence of tetrodotoxin. This study supports the beneficial role of CL‐316243 in reducing ELS‐induced visceral hypersensitivity, and suggests that targeting the β3‐AR can significantly influence gut‐brain axis activity through modulation of enteric neuronal activation, tryptophan metabolism, and colonic secretomotor activity which may synergistically contribute to offsetting the effects of ELS. [ABSTRACT FROM AUTHOR]

• Aberrant LHb hyperactivity drives susceptibility to depressive-like behaviors induced by maternal separation. • LHb IL-10 levels suppress neuronal activation and exert an anti-depressant effect. • IL-10 regulates the trafficking of LHb GABA A receptors and functions through PI3K/pAKT/gephyrin cascades. 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 GABA A receptor proteins while reducing abnormally elevated GSK3β 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 GABA A 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 GABA A receptor function. [ABSTRACT FROM AUTHOR]

Recent research has highlighted cerebellar involvement in cognition and several psychiatric conditions such as mood and anxiety disorders and schizophrenia. Attention‐deficit/hyperactivity disorder and autism spectrum disorder have been linked to reduced cerebellar volume as well. Cerebellar alterations are frequently present after early adversity in humans and animals, but a systematic integration of results is lacking. To this end, a systematic literature search was conducted in PubMed, Web of Science, and EBSCO databases using the keywords "early adversity OR early life stress" AND "cerebellum OR cerebellar." A total of 45 publications met the inclusion criteria: 25 studies investigated human subjects and 20 reported results from animal models. Findings in healthy subjects show bilateral volume reduction and decreased functional connectivity within the cerebellum and between the cerebellum and frontal regions after adversity throughout life, especially when adversity was assessed with the Childhood Trauma Questionnaire. In clinical populations, adults demonstrate increased cerebellar volume and functional connectivity after adversity, whereas pediatric patients show reduced cerebellar volume. Animal findings reveal cerebellar alterations without necessarily co‐occurring pathological behavior, highlighting alterations in stress hormone receptor levels, cell density, and neuroinflammation markers. Cerebellar alterations after early adversity are robust findings across human and animal studies and occur independent of clinical symptoms. [ABSTRACT FROM AUTHOR]

The article discusses a correction made to a study on the activation of EphrinB2/EphB2 signaling in the spinal cord and its impact on glia-neuron interactions in mice with visceral hyperalgesia following maternal separation. The correction addresses errors in figures and does not affect the scientific conclusions of the original article. The study explores the role of EphrinB2/EphB2 signaling in altering glia-neuron interactions and the effects of inhibiting this signaling pathway on mitigating the impact of maternal separation-induced hyperalgesia. [Extracted from the article]

Background: Sress early in life has been linked to visceral hyperalgesia and associated functional gastrointestinal disorders. In a mouse model of visceral hyperalgesia, we investigated whether the EphB2 receptor and its EphrinB2 ligand in spinal cord contribute to dysregulation of glia-neuron interactions. Methods: An established mouse model of stress due to maternal separation (MS). Pups were separated from their mothers for 14 days during early development, then analyzed several weeks later in terms of visceral sensitivity based on the abdominal withdrawal reflex score and in terms of expression of c-fos, EphrinB2, EphB2, and phosphorylated MAP kinases (ERK, p38, JNK). Results: Visceral hyperalgesia due to MS upregulated EphB2, EphrinB2 and c-fos in the spinal cord, and c-fos levels positively correlated with those of EphB2 and EphrinB2. Spinal astrocytes, microglia, and neurons showed upregulation of EphB2, EphrinB2 and phosphorylated MAP kinases. Blocking EphrinB2/EphB2 signaling in MS mice reduced visceral sensitivity, activation of neurons and glia, and phosphorylation of NMDA receptor. Activating EphrinB2/EphB2 signaling in unstressed mice induced visceral hyperalgesia, upregulation of c-fos, and activation of NMDA receptor similar to maternal separation. Conclusion: The stress of MS during early development may lead to visceral hyperalgesia by upregulating EphrinB2/EphB2 in the spinal cord and thereby altering neuron-glia interactions. [ABSTRACT FROM AUTHOR]

Objective To explore the effect and mechanism of Shenqi Jieyu Formula ( SQJYF) on depression and anxiety-like behavior in adult ofispring rats after maternal separation ( MS). This was done by observing the levels of metabolites in the hippocampus and prefrontal cortex of the Papez circuit through magnetic resonance spectroscopy ( MRS). Methods Twenty-four Sprague-Dawley rats at 16 days of pregnancy were divided into the normal, model, SQJYF, and fluoxetine groups using the random number table method, with six rats per group. MS was performed 4 h a day from the first to the 21st day after birth. Starting from the 15th day, the corresponding medications ( SQJYF group: 12. 5 g/kg, fluxetine group: 2. 33 mg/kg) were administered to mother rats once a day for 7 consecutive days. Normal breastfeeding was performed during the gavage. The offspring rats were weaned on the 22nd day. According to the experimental grouping of mother rats, one male and one female offspring rat of each mother rat were randomly selected using the random number table method, with six rats per group. They were divided into normal, model, SQJYF, and fluoxetine female and male rat groups, respectively. After 8 weeks of feeding, the offspring rats in each group were subjected to forced swimming test ( FST), the sucrose water consumption test, and open field tests ( OFT), and the elevated plus maze ( EPM) test was conducted. The relative values of N-acetyl-aspartate ( NAA), choline ( Cho), glutamic acid ( Glu), myo-inositol (ml), and creatine (Cr) in the hippocampus and prefrontal cortex were detected using MRS. Results Compared with that of the normal female and male rat groups, the weight of the rats in the model group was decreased as well as sucrose water consumption and the horizontal and vertical scores of OFT, whereas the immobility time of FST increased. Compared with the normal female and male rat group, the NAA/Cr and Glu/Cr values in the bilateral hippocampus and prefrontal cortex of the female and male rats in the model group decreased ( all P<0. 01). The proportion of rats entering the open arm and open arm residence time of the model female rat group in the EPM test decreased, whereas the Cho/ Cr value of the right hippocampus of the female rats in the model group increased ( P<0. 05). Compared with the model female and male rat group, the weight of the rats in the SQJYF and fluoxetine groups increased, the immobility time of FST decreased, but the sucrose water consumption and the horizontal and vertical OFT scores increased ( P<0. 01). The proportion of rats entering the open arm and open arm residence time in the EPM increased in the SQJYF and fluoxetine female rat groups compared to those of the model female rat group ( P<0.01). Compared with the model female rat group, the NAA/Cr and Glu/ Cr values in the bilateral hippocampus and prefrontal cortex of female rats in the SQJYF and fluoxetine groups increased. The NAA/Cr and Glu/Cr values in the right hippocampus and prefrontal cortex of male rats in the SQJYF and fluoxetine groups were higher than those in the model group ( P< 0. 05), whereas the Cho/Cr value in the right hippocampus of female and male rats in the SQJYF and fluoxetine groups decreased ( P < 0. 05). Conclusion MS in early life can lead to depression and anxiety-like behavior in adult offspring. However, SQJYF may exert antidepressant and anti-anxiety effects by regulating the metabolite levels in related brain regions of the Papez circuit. [ABSTRACT FROM AUTHOR]

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-1β, 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. [ABSTRACT FROM AUTHOR]

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 themost 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 inflammationassociated 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 unpredictablemild 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. HIGHLIGHTS: Sexual dimorphism exists in the effects of late maternal separation (LMS) LMS provides resilience to stress-induced anxiety and depression in male mice LMS upregulates NPY and NPVF system in the hypothalamus of male mice No effect of LMS on stress-induced corticosterone levels [ABSTRACT FROM AUTHOR]

Objective To observe the effect of Lactobacillus casei(L.casei) on the depression-like behaviors of offspring rats induced by maternal separation (MS), and explore the potential action mechanism of probiotics to improve central nervous inflammation in depression-like behaviors. Methods MS stress was used to establish a depressed animal model in offspring.Female SD rats were randomly divided into control group (CON), MS group, and MS+L.casei group, with 8 animals in each group.The female rats and their offspring in the control group did not undergo MS intervention after delivery, while those in the MS group were separated 3 h each day, for 14 consecutive days after normal delivery.The offspring of the MS+L.casei group was given intervention of 8×108 CFU/(kg·d)L.casei gavage for 4 weeks.Source preference test (SPT) and forced swimming test (FST) were used to evaluate the changes in depressive behaviors of the offspring rats.ELISA was employed to determine the levels of TNF-α, IL-6, IL-1 β and IL-10 in serum and hippocampus tissue.Real-time fluorescence quantitative PCR was applied to detect the mRNA expression levels of indoleamine 2, 3-dioxygenase-1(IDO1) and 5-HT mRNA in hippocampus. Results Compared with the CON group, the offspring in the MS group had significantly reduced percentage of source preference (P < 0.05), prolonged immobility time during forced swimming (P < 0.05), and decreased number of grid crossings in spontaneous activity test (though no statistical difference), indicating that the offspring rats had obvious depression-like behaviors after MS.L.casei treatment improved the behavioral changes of offspring rats caused by MS stress, with significantly increased percentage of source preference (P < 0.05) and shortened immobility time of forced swimming (P < 0.05).Compared with the conditions in the MS group, L.casei reduced the levels of IL-6, IL-1 β and TNF-α(P < 0.01) and increased that of IL-10(P < 0.05) in the hippocampus and peripheral blood, and decreased mRNA level of IDO1 and enhanced 5-HT mRNA level in hippocampus (P < 0.01) in the offspring rats of the MS+L.casei group. Conclusion MS stress induces depression-like behavior in offspring rats.L.casei inhibits the hippocampal expression of IDO1 and enhances that of 5-HT by regulating inflammatory factors in hippocampus and peripheral blood, and thus, improves depression-like behavior.

Autism spectrum disorder (ASD) is a neurodegenerative disease with increasing incidence in the world. The maternal separation (MS) stress at early life with its own neuroendocrine and neurostructural changes can provide the basis for development of ASD. Previously it has been reported neuroprotective characteristics for anethole. The PI3K/AKT/mTOR signaling pathway has pivotal role in the function of central nervous system (CNS). This study aimed to evaluate the possible effects of anethole on the autistic-like behaviors in the maternally separated (MS) mice focusing on the potential role of the PI3K/AKT/mTOR pathway. Forty male Naval Medical Research Institute (NMRI) mice were assigned to five groups (n = 8) comprising a control group (treated with normal saline) and four groups subjected to MS and treated with normal saline and or anethole at doses of 31.25, 62.5 and 125 mg/kg, respectively. All gents were administrated via intraperitoneal (i.p.) route for 14 constant days. Behavioral tests were conducted, including the three-chamber test, shuttle box and resident-intruder test. The gene expression of the PI3K, AKT and mTOR assessed in the hippocampus by qRT-PCR. Findings indicated that MS is associated with autistic-like behaviors. Anethole increased the sociability and social preference indexes in the three-chamber test, increased duration of secondary latency in the shuttle box test and decreased aggressive behaviors in the resident-intruder test. Also, anethole increased the gene expression of PI3K, AKT and mTOR in the hippocampus of MS mice. We concluded that anethole through increase in the gene expression of PI3K/ AKT/mTOR mitigated autistic-like behaviors induced by MS in mice.

• Maternal separation increased sensitivity to frustration in adult males but not females. • Maternal separation did not affect frustration during adolescence. • Dorsal hippocampus NMDA receptor composition was altered in the susceptible animals. • This molecular shift possibly signals a stronger memory of the devaluation experience. • Strong emotional memories might hinder the ability to cope with frustration. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Early-life stress affects brain development, eventually resulting in adverse behavioral and physical health consequences in adulthood. The present study assessed the hypothesis that short-term early-life stress during infancy before weaning, a period for the maturation of mastication and sleep, poses long-lasting adverse effects on masticatory function and intraoral sensations later in life. Rat pups were exposed to either maternal separation (MS) or intermittent hypoxia (IH-Infancy) for 6 h/day in the light/sleep phase from postnatal day (P)17 to P20 to generate "neglect" and "pediatric obstructive sleep apnea" models, respectively. The remaining rats were exposed to IH during P45–P48 (IH-Adult). Masticatory ability was evaluated based on the rats' ability to chew pellets and bite pasta throughout the growth period (P21–P70). Intraoral chemical and mechanical sensitivities were assessed using two-bottle preference drinking tests, and hind paw pain thresholds were measured in adulthood (after P60). No differences were found in body weight, grip force, and hind paw sensitivity in MS, IH-Infancy, and IH-Adult rats compared with naïve rats. Masticatory ability was lower in MS and IH-Infancy rats from P28 to P70 than in naïve rats. MS and IH-Infancy rats exhibited intraoral hypersensitivity to capsaicin and mechanical stimulations in adulthood. The IH-Adult rats did not display inferior masticatory ability or intraoral hypersensitivity. In conclusion, short-term early-life stress during the suckling–mastication transition period potentially causes a persistent decrease in masticatory ability and intraoral hypersensitivity in adulthood. The period is a "critical window" for the maturation of oral motor and sensory functions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: Two-step weaning using an intermediate separation step of nose-flaps or a fenceline aims to decrease the impact of abrupt weaning for both cows and calves, but the previous evaluations of such weaning methods have been conducted over the first step of weaning (4–7 days post-weaning). Additionally, behavioural measurements were collected using interval visual observations. However, the use of sensor technology allows for continuous and objective behavioural measurements. Here, the impact of abrupt and fenceline weaning methods on cattle stress response, live weight gain, and behaviour (using sensor and visual observations) was determined over 14 days. Although both groups were stressed in response to weaning, abruptly weaned animals were more stressed. In general, the impact of stress for fenceline-weaned animals occurred after 3 days of separation by a fenceline. Together, our results suggest that calves be fenceline-weaned for three days followed by total separation. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Neonatal maternal separation is used to evaluate the effects of early life stress on various systems. The current study evaluated the impact of early life stress exposure on the morphometry and ultrastructure of adult male albino rat testis and clarified its intimate relation with hypothalamic-pituitarythyroid/Adrenal and gonadal axes. Thirty pregnant rats (dams) were divided into groups (i), (ii) and (iii). Neonates(pups) were also divided into; control (I), and neonatal maternal separation II (NMS II): pups were segregated from their dams for 2 hours /day. Group (NMSIII): pups were segregated from their dams for 4 hours/day from postnatal day 0 to postnatal day 14. Histological results revealed distortion affecting the testicular parenchyma in groups (II) and (III). Sections from both groups revealed markedly disrupted seminiferous tubules; decreased height of germinal epithelium; and decreased tubular diameter with widened interstitium. Immunohistochemical results revealed that the number of proliferating cells (ki67 positive cells) and inducible nitric oxide synthetase (iNOS positive cells) were significantly attenuated in both groups II, III. No substantial change was observed in the quantity of apoptotic cells. Degenerative signs were observed by transmission electron microscopy in both groups II and III; but much more extensive in group III. Sertoli cells, spermatogonia and primary spermatocytes showed irregular nuclear membrane, degenerated mitochondria with distorted crista, dilated endoplasmic reticulum and rarified cytoplasm. Extensive drop in sperm density in epididymal tissue was clearly observed in group III. Biochemical analysis revealed increased serum levels of oxidative stress markers and significant attenuation of different hormones of the Hypothalamic-Pituitary axis in groups II and III. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder is prevalent across different societies, affecting individuals from various cultural and socioeconomic backgrounds. Dysregulation of the nitric oxide (NO) pathway and increased oxidative stress have been implicated as contributing factors. Purpose: This study aimed to explore the antidepressant potential of β-caryophyllene in a mouse model subjected to maternal separation stress, with a focus on its effects on oxidative stress and nitrite levels. Study Design: The research involved 40 male mice, which were divided into five groups. Methods: The control group received 1 ml/kg of normal saline, while the maternal separation (MS) groups were administered normal saline in conjunction with β-caryophyllene at doses of 10, 20, and 50 mg/kg. Various behavioral tests, including the open field test (OFT), forced swimming test (FST), and splash test, were employed to assess the impact of β-caryophyllene. Additionally, measurements of total antioxidant capacity (TAC), malondialdehyde (MDA), and nitrite levels in the hippocampus were conducted. Results: The findings demonstrated that maternal separation stress induced depressive-like behaviors in mice, as evidenced by increased immobility time in the FST and decreased grooming behavior in the splash test. Furthermore, MS was associated with elevated MDA and nitrite levels and reduced TAC in the hippocampus. However, administration of β-caryophyllene increased grooming activity in the splash test and decreased immobility time in the FST. Additionally, β-caryophyllene exhibited antioxidant properties, lowering MDA and nitrite levels while enhancing TAC in the hippocampus. Conclusion: These results suggest that β-caryophyllene may possess antidepressant-like effects in mice subjected to maternal separation, likely due to its antioxidant actions in the hippocampus.

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”.

The olfactory system is a niche of continuous structural plasticity, holding postnatal proliferative neurogenesis in the olfactory bulbs and a population of immature neurons in the piriform cortex. These neurons in the piriform cortex are generated during embryonic development, retain the expression of immaturity markers such as doublecortin, and slowly mature and integrate into the olfactory circuit as the animal ages. To study how early life experiences affect this population of cortical immature neurons, we submitted mice of the C57/Bl6J strain to a protocol of maternal separation for 3 h per day from postnatal day 3 to postnatal day 21. Control mice were continuously with their mothers. After weaning, mice were undisturbed until 6 weeks of age, when they were weighted and tested in the elevated plus-maze, a standard test for anxiety-like behavior, to check for phenotypical effects. Mice were then perfused, and their brains processed for the immunofluorescent detection of doublecortin and the endogenous proliferation marker Ki67. We found that maternal separation induced a significant increase in the body weight of males, but not females. Further, maternally separated mice displayed increased exploratory-like behavior (i.e., head dipping, velocity and total distance traveled in the elevated plus maze), but no significant differences in anxiety-like behavior or corticosterone levels after behavioral testing. Finally, we observed a significant increase in the number of complex doublecortin neurons in the piriform cortex, but not in the olfactory bulbs, of mice submitted to maternal separation. Interestingly, most doublecortin neurons in the piriform cortex, but not the olfactory bulb, express the epigenetic reader MeCP2. In summary, mild early life stress results, during adolescence, in a male-specific increase in body weight, alteration of the exploratory behaviors, and an increase in doublecortin neurons in the piriform cortex, suggesting an alteration in their maturation process.

Abstract The occurrence of major depressive disorder is widespread and can be observed in individuals belonging to all societies. It has been suggested that changes in the NO pathway and heightened oxidative stress may play a role in developing this condition. Anethole is a diterpene aromatic compound found in the Umbelliferae, Apiaceae, and Schisandraceae families. It has potential pharmacological effects like antioxidant, anxiolytic, analgesic, anti-inflammatory, antidiabetic, gastroprotective, anticancer, estrogenic, and antimicrobial activities. This study aimed to investigate the potential antidepressant properties of Anethole in a mouse model experiencing maternal separation stress while also examining its impact on oxidative stress and nitrite levels. The research involved the participation of 40 male NMRI mice, separated into five distinct groups to conduct the study. The control group was administered 1 ml/kg of normal saline, while the MS groups were given normal saline and Anethole at 10, 50, and 100 mg/kg doses. The study comprised various behavioural tests, including the open field test (OFT), forced swimming test (FST), and splash test, to assess the effects of Anethole on the mice. In addition to the behavioural tests, measurements were taken to evaluate the total antioxidant capacity (TAC), malondialdehyde (MDA), and nitrite levels in the hippocampus of the mice. According to the findings, maternal separation stress (MS) led to depressive-like conduct in mice, including a rise in immobility duration during the FST and a reduction in the duration of grooming behaviour in the splash test. Additionally, the results indicated that MS correlated with an increase in the levels of MDA and nitrite and a reduction in the TAC in the hippocampus. However, the administration of Anethole resulted in an increase in grooming activity time during the splash test and a decrease in immobility time during the FST. Anethole also exhibited antioxidant characteristics, as demonstrated by its ability to lower MDA and nitrite levels while increasing the TAC in the hippocampus. The results suggest that Anethole may have an antidepressant-like impact on mice separated from their mothers, likely partly due to its antioxidant properties in the hippocampus.

Introduction: Depression is a human mental disorder that can also be inferred in non-human animals. This study explored whether time spent inactive but awake ("IBA") in the home-cage in mice was further triggered by risk factors similar to those increasing vulnerability to depression in humans (early life stress, genetic predispositions, adulthood stress). Methods: Eighteen DBA/2 J and 18 C57BL/6 J females were tested, of which half underwent as pups a daily maternal separation on post-natal days 2-14 (early-life stress "ELS") (other half left undisturbed). To assess the effect of the procedure, the time the dams from which the 18 subjects were born spent active in the nest (proxy for maternal behavior) was recorded on post-natal days 2, 6, 10 and 14 for 1 h before separation and following reunion (matched times for controls), using live instantaneous scan sampling (total: 96 scans/dam). For each ELS condition, about half of the pups were housed post-weaning (i.e., from 27 days old on average) in either barren (triggering IBA and depression-like symptoms) or larger, highly enriched cages (n = 4-5 per group). Time mice spent IBA post-weaning was observed blind to ELS treatment using live instantaneous scan sampling in two daily 90-min blocks, two days/week, for 6 weeks (total: 192 scans/mouse). Data were analyzed in R using generalized linear mixed models. Results: The dams were significantly more active in the nest over time (p = 0.016), however with no significant difference between strains (p = 0.18), ELS conditions (p = 0.20) and before/after separation (p = 0.83). As predicted, postweaning barren cages triggered significantly more time spent IBA in mice than enriched cages (p < 0.0001). However, neither ELS (p = 0.4) nor strain (p = 0.84) significantly influenced time mice spent IBA, with no significant interaction with environmental condition (ELS × environment: p = 0.2861; strain × environment: p = 0.5713). Discussion: Our results therefore only partly support the hypothesis that greater time spent IBA in mice is triggered by risk factors for human depression. We discuss possible explanations for this and further research directions. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is the fastest‐growing neurodevelopmental disease throughout the world. Neuro‐immune responses from prenatal to adulthood stages of life induce developmental defects in synaptic signaling, neurotransmitter imbalance, and even structural changes in the brain. In this study, we aimed to focus on the possible role of neuroinflammatory response in the hippocampus in development of the autistic‐like behaviors following maternal separation (MS) stress in mice. To do this, mice neonates daily separated from their mothers from postnatal day (PND) 2 to PND 14 for 3 h. During PND45–60, behavioral tests related to autistic‐like behaviors including three‐chamber sociability, Morris water maze (MWM), shuttle box, resident‐intruder, and marble burying tests were performed. Then, hippocampi were dissected out, and the gene expression of inflammatory mediators including TNF‐α, IL‐1β, TLR4, HMGB1, and NLRP3 was assessed in the hippocampus using RT‐PCR. Results showed that MS mice exerted impaired sociability preference, repetitive behaviors, impaired passive avoidance, and spatial memories. The gene expression of inflammatory mediators significantly increased in the hippocampi of MS mice. We concluded that MS stress probably via activating of the HMGB1/TLR4 signaling cascade in the hippocampus induced autistic‐like behaviors in mice. Maternal separation (MS), in part at least, through activation of the HMGB1/TLR4 signaling cascade in the hippocampus provokes autistic‐like behaviors in mice as impaired sociability preference, repetitive behaviors as well as impaired passive avoidance and spatial memories. [ABSTRACT FROM AUTHOR]

Maternal care during the early postnatal period of altricial mammals is a key factor in the survival and adaptation of offspring to environmental conditions. Natural variations in maternal care and experimental manipulations with maternal–child relationships modeling early‐life adversity (ELA) in laboratory rats and mice have a strong long‐term influence on the physiology and behavior of offspring in rats and mice. This literature review is devoted to the latest research on the role of epigenetic mechanisms in these effects of ELA and mother–infant relationship, with a focus on the regulation of hypothalamic–pituitary–adrenal axis and brain‐derived neurotrophic factor. An important part of this review is dedicated to pharmacological interventions and epigenetic editing as tools for studying the causal role of epigenetic mechanisms in the development of physiological and behavioral profiles. A special section of the manuscript will discuss the translational potential of the discussed research. [ABSTRACT FROM AUTHOR]

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.

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.

Abstract Background Mother-infant separation, which is occurring with an increasing incidence, is a barrier to direct breastfeeding. Owing to the importance of breast milk to hospitalized infants, mothers are actively encouraged to express milk during their infants’ neonatal intensive care unit (NICU) stay. However, mothers are often faced with a number of challenges in this process. There is a need to understand such mothers’ real-life experiences of breast milk expression to develop supportive strategies to reduce the burden on mothers and increase breastfeeding rates. Methods A comprehensive search of 12 databases was conducted for relevant studies published from database construction to December 2022. All qualitative and mixed-method studies published in English and Chinese that reported on mothers’ experiences of human milk expression during separation from their hospitalized infants were included. Two reviewers independently conducted screening, data extraction, and quality appraisal, with disagreements resolved by a third reviewer. The process of searching followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. The JBI Qualitative Assessment and Review Instrument was used to assess study quality and the credibility of study findings. Meta-aggregation was performed to integrate the results. Results This systematic review aggregated mothers’ experiences of milk expression during separation from their hospitalized infants. Database search yielded 600 records, of which 19 full-text documents were screened. Finally, 13 studies of good quality were included with data from 332 mothers across seven countries. A total of 61 primary findings with illustrations were extracted from the 13 eligible studies, the findings were generalized into 16 categories, and further were concluded as four synthesized findings: purpose and motivation, physical and emotional experiences, barrier factors, and coping styles. Conclusion Mothers were driven by extrinsic motivation in their decision to express breast milk. They experienced physical exhaustion and many negative emotional feelings while expressing. This process was affected by numerous barriers. Social support was essential to the initiation and maintenance of milk expression. Medical staff and families should pay more attention to the mental health of mothers with infants in the NICU. Future research should incorporate strategies to cope with emotional responses and offer practical strategies for managing milk expression. Systematic review registration [ www.crd.york.ac.uk ], identifier [PROSPERO 2022 CRD42022383080].

Early-life stress is associated with a high prevalence of mental illnesses such as post-traumatic stress disorders, attention-deficit/hyperactivity disorder, schizophrenia, and anxiety or depressive behavior, which constitute major public health problems. In the early stages of brain development after birth, events such as synaptogenesis, neuron maturation, and glial differentiation occur in a highly orchestrated manner, and external stress can cause adverse long-term effects throughout life. Our body utilizes multifaceted mechanisms, including neuroendocrine and neurotransmitter signaling pathways, to appropriately process external stress. Newborn individuals first exposed to early-life stress deploy neurogenesis as a stress-defense mechanism; however, in adulthood, early-life stress induces apoptosis of mature neurons, activation of immune responses, and reduction of neurotrophic factors, leading to anxiety, depression, and cognitive and memory dysfunction. This process involves the hypothalamus-pituitary-adrenal axis and neurotransmitters secreted by the central nervous system, including norepinephrine, dopamine, and serotonin. The rodent early-life stress model is generally used to experimentally assess the effects of stress during neurodevelopment. This paper reviews the use of the early-life stress model and stress response mechanisms of the body and discusses the experimental results regarding how early-life stress mediates stress-related pathways at a high vulnerability of psychiatric disorder in adulthood.

This document is an editorial published in Frontiers in Neuroscience titled "Brain abnormalities due to genetic alterations or developmental exposure to environmental factors, volume II." The editorial discusses a research topic that focuses on the influences of genetic and environmental factors on brain development. The articles included in the research topic cover various topics such as neurodevelopmental disorders, genetic alterations, and the effects of environmental factors on brain development. The editorial highlights the different approaches used in the studies and hopes to provide insights and suggestions for further research in the field of neurodevelopment. [Extracted from the article]

Background: Mother-infant separation, which is occurring with an increasing incidence, is a barrier to direct breastfeeding. Owing to the importance of breast milk to hospitalized infants, mothers are actively encouraged to express milk during their infants' neonatal intensive care unit (NICU) stay. However, mothers are often faced with a number of challenges in this process. There is a need to understand such mothers' real-life experiences of breast milk expression to develop supportive strategies to reduce the burden on mothers and increase breastfeeding rates. Methods: A comprehensive search of 12 databases was conducted for relevant studies published from database construction to December 2022. All qualitative and mixed-method studies published in English and Chinese that reported on mothers' experiences of human milk expression during separation from their hospitalized infants were included. Two reviewers independently conducted screening, data extraction, and quality appraisal, with disagreements resolved by a third reviewer. The process of searching followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. The JBI Qualitative Assessment and Review Instrument was used to assess study quality and the credibility of study findings. Meta-aggregation was performed to integrate the results. Results: This systematic review aggregated mothers' experiences of milk expression during separation from their hospitalized infants. Database search yielded 600 records, of which 19 full-text documents were screened. Finally, 13 studies of good quality were included with data from 332 mothers across seven countries. A total of 61 primary findings with illustrations were extracted from the 13 eligible studies, the findings were generalized into 16 categories, and further were concluded as four synthesized findings: purpose and motivation, physical and emotional experiences, barrier factors, and coping styles. Conclusion: Mothers were driven by extrinsic motivation in their decision to express breast milk. They experienced physical exhaustion and many negative emotional feelings while expressing. This process was affected by numerous barriers. Social support was essential to the initiation and maintenance of milk expression. Medical staff and families should pay more attention to the mental health of mothers with infants in the NICU. Future research should incorporate strategies to cope with emotional responses and offer practical strategies for managing milk expression. Systematic review registration: [www.crd.york.ac.uk], identifier [PROSPERO 2022 CRD42022383080]. [ABSTRACT FROM AUTHOR]

Adversity during early life, a critical period for brain development, increases vulnerability and can have a lasting impact on the brain and behaviour of a child. However, the long-term effects of cumulative early-life stressors on brain and behaviour are not well known. We studied a 2-hit rat model of early-life adversity using maternal separation (MS) and immune activation (lipopolysaccharide (LPS)). Rat pups underwent MS for 15 (control) or 180 (MS) minutes per day from postnatal day (P)2–14 and were administered saline or LPS (intraperitoneal) on P3. Open-field (OFT) and object-place recognition tests were performed on rat offspring at P33–35 and P42–50, respectively. The pre-frontal cortex (PFC) and hippocampus were removed at the experimental endpoint (P52–55) for mRNA expression. MS induced anxiety-like behaviour in OFT in male and reduced locomotor activity in both male and female offspring. LPS induced a subtle decline in memory in the object-place recognition test in male offspring. MS increased glial fibrillary acidic protein (GFAP) and brain-derived neurotrophic factor expression in PFC and ionised calcium-binding adapter molecule-1 expression in male hippocampus. MS and LPS resulted in distinct behavioural phenotypes in a sex-specific manner. The combination of MS and LPS had a synergistic effect on the anxiety-like behaviour, locomotor activity, and GFAP mRNA expression outcomes. [ABSTRACT FROM AUTHOR]

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 earlylife 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. [ABSTRACT FROM AUTHOR]

Early life stress (ELS) affects neurogenesis and spatial learning, and increases neuroinflammation after a pediatric mild traumatic brain injury (mTBI). Previous studies have shown that ELS has minimal effects in juveniles but shows age-dependent effects in adults. Hence, we aimed to evaluate the effects of ELS in adult male rats after an mTBI. Maternal separation for 180 min per day (MS180) during the first 21 post-natal (P) days was used as the ELS model. At P110, the rats were subjected to a mild controlled cortical impact injury (2.6 mm) or sham surgery. Spatial learning was evaluated in the Morris water maze (MWM) 14 days after surgery and both microglial activation and neurogenesis were quantified. The results indicate that MS180 + mTBI, but not control (CONT) + mTBI, rats show deficiencies in the acquisition of spatial learning. mTBI led to comparable increases in microglial activation in both the hilus and cortical regions for both groups. However, MS180 + mTBI rats exhibited a greater increase in microglial activation in the ipsilateral CA1 hippocampus subfield compared with CONT + mTBI. Interestingly, for the contralateral CA1 region, this effect was observed exclusively in MS180 + mTBI. ELS and mTBI independently caused a decrease in hippocampal neurogenesis and this effect was not increased further in MS180 + mTBI rats. The findings demonstrate that ELS and mTBI synergistically affect cognitive performance and neuroinflammation, thus supporting the hypothesis that increased inflammation resulting from the combination of ELS and mTBI could underlie the observed effects on learning. [ABSTRACT FROM AUTHOR]

Early child maltreatment, such as child abuse and neglect, is well known to affect the development of social skills. However, the mechanisms by which such an adverse environment interrupts the development of social skills remain unelucidated. Identifying the period and brain regions that are susceptible to adverse environments can lead to appropriate developmental care later in life. We recently reported an excitatory/inhibitory imbalance and low activity during social behavior in the medial prefrontal cortex (mPFC) of the maternal separation (MS) animal model of early life neglect after maturation. Based on these results, in the present study, we investigated how MS disturbs factors related to excitatory and inhibitory neurons in the mPFC until the critical period of mPFC development. Additionally, we evaluated whether the effects of MS could be recovered in an enriched environment after MS exposure. Rat pups were separated from their dams on postnatal days (PDs) 2-20 (twice daily, 3 h each) and compared with the mother-reared control (MRC) group. Gene expression analysis revealed that various factors related to excitatory and inhibitory neurons were transiently disturbed in the mPFC during MS. A similar tendency was found in the sensory cortex; however, decreased parvalbumin (PV) expression persisted until PD 35 only in the mPFC. Moreover, the number of PV+ interneurons decreased in the ventromedial prefrontal cortex (vmPFC) on PD 35 in the MS group. Additionally, perineural net formation surrounding PV+ interneurons, which is an indicator of maturity and critical period closure, was unchanged, indicating that the decreased PV+ interneurons were not simply attributable to developmental delay. This reduction of PV+ interneurons improved to the level observed in the MRC group by the enriched environment from PD 21 after the MS period. These results suggest that an early adverse environment disturbs the development of the mPFC but that these abnormalities allow room for recovery depending on the subsequent environment. Considering that PV+ interneurons in the mPFC play an important role in social skills such as empathy, an early rearing environment is likely a very important factor in the subsequent acquisition of social skills. [ABSTRACT FROM AUTHOR]

• Maternal separation increased adult motivated responding to a sucrose reward. • Sustained increases in motivation induced by maternal separation were sex dependent. • Maternal separation increased c-Fos expression in the dorsal and ventral striatum. • Correlations between c-Fos and motivation were early adversity-dependent. In both people and animals, exposure to adverse experiences early in life can alter neurodevelopment and lead to long-term behavioral effects, including effects on reward processing. In the current study, we use a well-validated rodent model of maternal neglect, maternal separation (MS), to investigate the impact of early life adversity on reward learning and motivation and identify associated modifications in cellular activation in reward-relevant areas. Litters of Long-Evans rats were separated from the dam for either 15 min (brief) or 180 min (prolonged)/day from postnatal day (PND)2 to PND14. As adults, offspring were trained to lever press for a sucrose pellet using fixed ratio (FR) schedules and motivation was tested using a progressive ratio (PR) schedule over 10 daily sessions to assess sustained effects on effort-based responding. Immunohistochemical staining for c-Fos was conducted in a subset of animals that underwent an additional PR session. While there were no effects on reward learning, both MS180 males and females demonstrated increased effort-based responding on the first day of PR testing, while only MS180 males demonstrated a sustained increase in effort across all 10 days. MS180-induced changes in c-Fos expression in the dorsal and ventral striatum were observed, with subregion-specific effects along the rostrocaudal axis. Moreover, regression analyses suggest that motivated responding for a sucrose food reward in MS180-exposed, but not MS15-exposed animals, was associated with increased c-Fos expression in the rostral nucleus accumbens core. These findings implicate specific striatal regions in sex-specific modulation of sustained effort-based reward behavior following early life adversity. [ABSTRACT FROM AUTHOR]

The principal motive of this study is to explore the influence maternal separation (MS) exhibits on the mRNA expression of major drug metabolizing-cyp450s in parallel with the assessment of pathological changes that can be induced by MS in the livers of experimental mice. Eighteen Balb/c mouse pups, comprising of both males and females, were separated from their mothers after birth. Following a six-week period during when the pups became adults, the mice were sacrificed and their livers were isolated for analysis of weight, pathohistological alterations, and the mRNA expression of drug metabolizing cyp450 genes: cyp1a1, cyp3a11, cyp2d9, and cyp2c29. The study demonstrated that MS markedly downregulated (p<0.05) the mRNA expression of all tested drug-metabolizing cyp450s in livers of female and male mice. Furthermore, the mRNA levels of major drug-metabolizing cyp450s were notably lower (p<0.05) in livers of female MS mice as compared with male MS mice. It was found that values of the total body weight and liver weight of MS mice did not vary significantly (p>0.05) from those of the control groups. Additionally, histological examination revealed that the hepatic tissue of MS mice was normal, similar to that of the control mice. In summary, MS downregulates the gene expression of major hepatic drug-metabolizing cyp450s without inducing pathological alterations in the livers of mice. These findings provide an explanation for the heterogeneity in pharmacokinetics and drug response of patients with early life stress. [ABSTRACT FROM AUTHOR]

Epidemiological studies have indicated that child maltreatment, such as neglect, is a risk factor of escalated aggression, potentially leading to delinquency and violent crime in the future. However, little is known about the mechanisms by which an early adverse environment may later cause violent behavior. In this study, we aimed to thoroughly examine the association between aggression against conspecific animals and the activity of amygdala subnuclei using the maternal separation (MS) model, which is a common model of early life stress. In the MS group, pups of Sprague–Dawley rats were separated from their dam during postnatal days 2–20 (twice a day, 3 h each). We only included 9‐week‐old male offspring for each analysis and compared the MS group with the mother‐reared control group; both groups were raised by the same dam during postnatal days 2–20. The results revealed that the MS group exhibited higher aggression and excessive activity of only the central amygdala (CeA) among the amygdala subnuclei during the aggressive behavior test. Moreover, a significant positive correlation was observed between higher aggression and CeA activation. While CeA activity is known to be involved in hunting behavior for prey, some previous studies have also indicated a relationship between CeA and intraspecific aggression. It remains unclear, however, whether excessive CeA activity directly induces intraspecific aggression. Therefore, we stimulated the CeA using optogenetics with 8‐week‐old rats to clarify the relationship between intraspecific aggression and CeA activity. Notably, CeA activation resulted in higher aggression, even when the opponent was a conspecific animal. In particular, bilateral CeA activation resulted in more severe displays of aggressive behavior than necessary, such as biting a surrendered opponent. These findings suggest that an adverse environment during early development intensifies aggression through excessive CeA activation, which can increase the risk of escalating to violent behavior in the future. [ABSTRACT FROM AUTHOR]

Widely used rodent anxiety assays like the elevated plus maze (EPM) and the open field test (OFT) are conflated with rodents' natural preference for dark over light environments or protected over open spaces. The EPM and OFT have been used for decades but are often criticized by behavioral scientists. Years ago, two revised anxiety assays were designed to improve upon the "classic" tests by excluding the possibility to avoid or escape aversion. The 3‐D radial arm maze (3DR) and the 3‐D open field test (3Doft) utilize continual motivational conflict to better model anxiety; each consist of an open space connected to ambiguous paths toward uncertain escape. Despite their utility, the revised assays have not caught on. This could be because no study yet has directly compared classic and revised assays in the same animals. To remedy this, we contrasted behavior from a battery of assays (EPM, OFT, 3DR, 3Doft and a sociability test) in mice defined genetically by isogenic strain, or environmentally by postnatal experience. One major motivation for this work is to inform future studies by offering a transparent look at individual outcomes on these assays, as there is no one‐size‐fits‐all test to assess rodent anxiety‐like behavior. Findings suggest that classic assays may sufficiently characterize differences across genetically defined groups, but the revised 3DR may be advantageous for investigating more nuanced behavioral differences such as those stemming from environmental factors. Finally, exposure to multiple assays significantly affected sociability, highlighting concerns for designing and interpreting batteries of rodent behavioral tests. [ABSTRACT FROM AUTHOR]

IntroductionDepression is a human mental disorder that can also be inferred in non-human animals. This study explored whether time spent inactive but awake (“IBA”) in the home-cage in mice was further triggered by risk factors similar to those increasing vulnerability to depression in humans (early life stress, genetic predispositions, adulthood stress).MethodsEighteen DBA/2 J and 18 C57BL/6 J females were tested, of which half underwent as pups a daily maternal separation on post-natal days 2–14 (early-life stress “ELS”) (other half left undisturbed). To assess the effect of the procedure, the time the dams from which the 18 subjects were born spent active in the nest (proxy for maternal behavior) was recorded on post-natal days 2, 6, 10 and 14 for 1 h before separation and following reunion (matched times for controls), using live instantaneous scan sampling (total: 96 scans/dam). For each ELS condition, about half of the pups were housed post-weaning (i.e., from 27 days old on average) in either barren (triggering IBA and depression-like symptoms) or larger, highly enriched cages (n = 4–5 per group). Time mice spent IBA post-weaning was observed blind to ELS treatment using live instantaneous scan sampling in two daily 90-min blocks, two days/week, for 6 weeks (total: 192 scans/mouse). Data were analyzed in R using generalized linear mixed models.ResultsThe dams were significantly more active in the nest over time (p = 0.016), however with no significant difference between strains (p = 0.18), ELS conditions (p = 0.20) and before/after separation (p = 0.83). As predicted, post-weaning barren cages triggered significantly more time spent IBA in mice than enriched cages (p

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.

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.

Abstract Neonatal mice emit ultrasonic vocalizations (USVs) when separated from their mothers. Since the USVs attract their mothers' attention and trigger maternal retrieval, they are considered to serve as social signals for communication. We have modeled paternal aging effects on the vocal communication of offspring in mice. However, little is known about the neural basis underlying neonatal USV production. To identify responsible brain regions driving the vocal behavior, we comprehensively mapped the neuronal activity associated with USV production in the entire brain of mice at postnatal day 6 (P6). Using an expression of immediate‐early gene c‐Fos as a neuronal activity marker, correlations between the numbers of USVs and c‐Fos positive neurons were analyzed. We identified 23 candidate brain regions associated with USV production in the mice at P6. Our study would be a first step toward comprehensively understanding the neuronal mechanisms that regulate and develop vocal behaviors in neonatal mice.

Background We have previously reported that male mice exposed to maternal separation and early weaning (MSEW), a model of early life stress, show sympathetic activation and increased blood pressure in response to a chronic high‐fat diet. The goal of this study was to investigate the contribution of the renin–angiotensin–aldosterone system to the mechanism by which MSEW increases blood pressure and vasomotor sympathetic tone in obese male mice. Methods and Results Mice were exposed to MSEW during postnatal life. Undisturbed litters served as controls. At weaning, both control and MSEW offspring were placed on a low‐fat diet or a high‐fat diet for 20 weeks. Angiotensin peptides in serum were similar in control and MSEW mice regardless of the diet. However, a high‐fat diet induced a similar increase in angiotensinogen levels in serum, renal cortex, liver, and fat in both control and MSEW mice. No evidence of renin–angiotensin system activation was found in adipose tissue and renal cortex. After chronic treatment with enalapril (2.5 mg/kg per day, drinking water, 7 days), an angiotensin‐converting enzyme inhibitor that does not cross the blood–brain barrier, induced a similar reduction in blood pressure in both groups, while the vasomotor sympathetic tone remained increased in obese MSEW mice. In addition, acute boluses of angiotensin II (1, 10, 50 μg/kg s.c.) exerted a similar pressor response in MSEW and control mice before and after enalapril treatment. Conclusions Overall, elevated blood pressure and vasomotor sympathetic tone remained exacerbated in MSEW mice compared with controls after the peripheral inhibition of angiotensin‐converting enzyme, suggesting a mechanism independent of angiotensin II.