Postnatal Maternal Separation Research Articles

Effect of a multi-strain probiotic mixture consumption on anxiety and depression symptoms induced in adult mice by postnatal maternal separation

BackgroundIntestinal microbial composition not only affects the health of the gut but also influences centrally mediated systems involved in mood, through the “gut-brain” axis, a bidirectional communication between gut microbiota and the brain.In this context, the modulation of intestinal microbiota and its metabolites through the administration of probiotics seems to represent a very promising approach in the treatment of the central nervous system alterations.Early postnatal life is a critical period during which the brain undergoes profound and essential modulations in terms of maturation and plasticity. Maternal separation (MS), i.e., the disruption of the mother–pup interaction, represents a pivotal paradigm in the study of stress-related mood disorders, by inducing persistent changes in the immune system, inflammatory processes, and emotional behavior in adult mammals.ResultsWe conducted experiments to investigate whether sustained consumption of a multi-strain probiotic formulation by adult male mice could mitigate the effects of maternal separation. Our data demonstrated that the treatment with probiotics was able to totally reverse the anxiety- and depressive-like behavior; normalize the neuro-inflammatory state, by restoring the resting state of microglia; and finally induce a proneurogenic effect. Mice subjected to maternal separation showed changes in microbiota composition compared to the control group that resulted in permissive colonization by the administered multi-strain probiotic product. As a consequence, the probiotic treatment also significantly affected the production of SCFA and in particular the level of butyrate.ConclusionGut microbiota and its metabolites mediate the therapeutic action of the probiotic mix on MS-induced brain dysfunctions. Our findings extend the knowledge on the use of probiotics as a therapeutic tool in the presence of alterations of the emotional sphere that significantly impact on gut microbiota composition.AdianNxLDM2uLY8oFPQcaDVideo

Long-term impacts of prenatal maternal immune activation and postnatal maternal separation on maternal behavior in adult female rats: Relevance to postpartum mental disorders

Early life adversities are known to exert long-term negative impacts on psychological and brain functions in adulthood. The present work examined how a prenatal brain insult and a postnatal stressor independently or interactively influence the quality of maternal care of postpartum female rats and their cognitive and emotional functions, as a way to identify the behavioral dysfunctions underlying childhood trauma-induced postpartum mental disorders (as indexed by impaired maternal care). Sprague-Dawley female offspring born from mother rats exposed to polyinosinic:polycytidylic acid (PolyI:C, 4.0–6.0 mg/kg) intended to cause gestational maternal immune activation (MIA) or saline were subjected to a repeated maternal separation stress (RMS, 3 h/day) or no separation for 9 days in the first two weeks of life (a 2 × 2 design). When these offspring became mothers, their attentional filtering ability (as measured in the prepulse inhibition of acoustic startle reflex test), positive hedonic response (as measured in the sucrose preference test), and negative emotional response (as measured in the startle reflex and fear-potentiated startle test) were examined, along with their home-cage maternal behavior. Virgin littermates served as controls in all the behavioral tests except in maternal behavior. Results showed that mother rats who experienced RMS displayed impaired nest building and crouching/nursing activities. RMS also interacted with MIA to alter pup retrieval latency and startle reactivity, such that MIA-RMS dams demonstrated significantly slower pup retrieval latency and higher startle magnitude compared to either RMS-only and MIA-only mothers. MIA also disrupted attentional filtering ability, with significantly lower prepulse inhibition. However, neither prenatal MIA nor postnatal RMS impaired sucrose preference or the acquisition of fear-potentiated startle. These results indicate that prenatal stress and postnatal adversity could impair maternal behavior individually, and interact with each other, causing impairments in attention, emotion and maternal motivation.

Epigenetic Impacts of Early Life Stress in Fetal Alcohol Spectrum Disorders Shape the Neurodevelopmental Continuum.

Neurodevelopment in humans is a long, elaborate, and highly coordinated process involving three trimesters of prenatal development followed by decades of postnatal development and maturation. Throughout this period, the brain is highly sensitive and responsive to the external environment, which may provide a range of inputs leading to positive or negative outcomes. Fetal alcohol spectrum disorders (FASD) result from prenatal alcohol exposure (PAE). Although the molecular mechanisms of FASD are not fully characterized, they involve alterations to the regulation of gene expression via epigenetic marks. As in the prenatal stages, the postnatal period of neurodevelopment is also sensitive to environmental inputs. Often this sensitivity is reflected in children facing adverse conditions, such as maternal separation. This exposure to early life stress (ELS) is implicated in the manifestation of various behavioral abnormalities. Most FASD research has focused exclusively on the effect of prenatal ethanol exposure in isolation. Here, we review the research into the effect of prenatal ethanol exposure and ELS, with a focus on the continuum of epigenomic and transcriptomic alterations. Interestingly, a select few experiments have assessed the cumulative effect of prenatal alcohol and postnatal maternal separation stress. Regulatory regions of different sets of genes are affected by both treatments independently, and a unique set of genes are affected by the combination of treatments. Notably, epigenetic and gene expression changes converge at the clustered protocadherin locus and oxidative stress pathway. Functional studies using epigenetic editing may elucidate individual contributions of regulatory regions for hub genes and further profiling efforts may lead to the development of non-invasive methods to identify children at risk. Taken together, the results favor the potential to improve neurodevelopmental outcomes by epigenetic management of children born with FASD using favorable postnatal conditions with or without therapeutic interventions.

Effects of postnatal ethanol exposure and maternal separation on mood, cognition and hippocampal arborization in adolescent rats

Ethanol exposure and early life stress during brain development are associated with an increased risk of developing psychiatric disorders. We used a third-trimester equivalent model of fetal alcohol spectrum disorders combined with a maternal separation (MS) protocol to evaluate whether these stressors cause sexually dimorphic behavioral and hippocampal dendritic arborization responses in adolescent rats. Wistar rat pups were divided into four experimental groups: 1) Control; 2) MS (MS, for 3 h/day from postnatal (PND) 2 to PND14); 3) EtOH (EtOH, 5 g/kg/day, i.p., PND2, 4, 6, 8, and 10); 4) EtOH + MS. All animals were divided into two cohorts and subjected to a battery of behavioral tests when they reached adolescence (PND37−44). Animals from cohort 1 were submitted to: 1) the open field test; 2) self-cleaning behavior (PND38); and 3) the motivation test (PND39−41). Animals from cohort 2 were submitted to: 1) the novel object recognition (PND37−39); 2) social investigation test (PND40); and 3) Morris water maze test (PND41−44). At PND45, the animals were euthanized, and the brains were collected for subsequent dendritic analysis. Postnatal ethanol exposure (PEE) caused anxiety-like behavior in females and reduced motivation, and increased hippocampal dendritic arborization in both sexes. MS reduced body weight, increased locomotor activity in females, and increased motivation, and hippocampal dendritic arborization in both sexes. We found that males from the EtOH + MS groups are more socially engaged than females, who were more interested in sweets than males. Altogether, these data suggest that early life adverse conditions may alter behavior in a sex-dependent manner in adolescent rats.

Long-Term Treatment with Fluvoxamine Decreases Nonmotor Symptoms and Dopamine Depletion in a Postnatal Stress Rat Model of Parkinson's Disease.

Nonmotor symptoms (NMS) such as anxiety, depression, and cognitive deficits are frequently observed in Parkinson's disease (PD) and precede the onset of motor symptoms by years. We have recently explored the short-term effects of Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) on dopaminergic neurons in a parkinsonian rat model. Here, we report the long-term effects of Fluvoxamine, on early-life stress-induced changes in the brain and behavior. We specifically evaluated the effects of Fluvoxamine on brain mechanisms that contribute to NMS associated with PD in a unilateral 6-hydroxydopamine-lesioned rat model. A 14-day early postnatal maternal separation protocol was applied to model early-life stress followed by unilateral intracerebral infusion of 6-hydroxydopamine (6-OHDA) to model aspects of parkinsonism in rats. The anxiolytic, antidepressant, and cognitive effects of Fluvoxamine were confirmed using the elevated plus-maze (EPM) test, sucrose preference test (SPT), and Morris water maze (MWM) test. Further to that, our results showed that animals exposed to early-life stress displayed increased plasma corticosterone and malondialdehyde (MDA) levels which were attenuated by Fluvoxamine treatment. A 6-OHDA lesion effect was evidenced by impairment in the limb-use asymmetry test as well as decreased dopamine (DA) and serotonin levels in the striatum, prefrontal cortex, and hippocampus. These effects were surprisingly attenuated by Fluvoxamine treatment in all treated rats. This study is the first to suggest that early and long-term treatment of neuropsychological diseases with Fluvoxamine may decrease the vulnerability of dopaminergic neurons that degenerate in the course of PD.

Prenatal immobilization stress and postnatal maternal separation cause differential neuroendocrine responses to fasting stress in adult male rats.

Prenatal immobilization stress (PNS) and postnatal maternal separation (MS180) are two widely used rodent models of early-life stress (ELS) that affect the hypothalamus-pituitary-adrenal (HPA) axis, cause behavioral alterations, and affect glucose tolerance in adults. We compared anxiety-like behavior, coping strategies, and HPA axis activity in PNS and MS180 adult (4-month-old) male rats and assessed their glucose tolerance and HPA axis response after mild fasting stress. Both PNS and MS180 induced a passive coping strategy in the forced swimming test, without affecting anxiety-like behavior in the elevated plus-maze. Moreover, both PNS and MS180 increased the hypothalamic corticotropin-releasing hormone expression; however, only MS180 increased the circulating corticosterone levels. Both early life stressors increased fasting glucose levels and this effect was significantly higher in PNS rats. MS180 rats showed impaired glucose tolerance 120min after intravenous glucose administration, whereas PNS rats displayed an efficient homeostatic response. Moreover, MS180 rats showed higher circulating corticosteroid levels in response to fasting stress (overnight fasting, 12hr), which were restored after glucose administration. In conclusion, early exposure to postnatal MS180, unlike PNS, increases the HPA axis response to moderate fasting stress, indicating a differential perception of fasting as a stressor in these two ELS models.

Evidence that neuropsychological deficits following early life adversity may underlie vulnerability to depression

Early life adversity (ELA) is a risk factor for major depressive disorder (MDD), however the underlying mechanisms are not well understood. Clinical studies suggest that negative affective biases (the process, whereby cognitive processes such as learning and memory and decision-making are modified by emotional state) represent a vulnerability factor for MDD. In this study we investigate the impact of ELA on affective biases and reward-associated behaviours in rats. Sprague Dawley rat pups underwent 14 days of postnatal maternal separation (180 min/day from postnatal day 1: MS180) whilst control pups remained unhandled. In adulthood, affective biases associated with reward learning and decision-making were assessed using the affective bias test (ABT), or judgement bias task (JBT) respectively. Changes in motivation and reward sensitivity were tested in a progressive ratio (PR) schedule of operant responding and the sucrose preference test (SPT) respectively. We observed that MS180 animals expressed enhanced negative biases in response to acute corticosterone treatment but without effects on antidepressant-induced positive biases. ELA animals were impaired in their ability to develop appropriate biases in response to changes in reward value in a modified ABT but in the absence of any changes in reward sensitivity or motivation. No effects on decision-making were observed in the JBT but MS180 animals failed to develop the same more optimistic behavioural profile as controls in response to an increase in reward value. These findings suggest that ELA in rats increases vulnerability to negative affective biases and impairs animals’ ability to appropriately learn reward value, independent of a reward sensitivity or changes in motivation. These data provide important evidence linking ELA with relevant neuropsychological impairments that may explain increased risk of developing MDD.

Evidence that neuropsychological deficits following early life adversity may underlie vulnerability to depression.

Early life adversity (ELA) is a risk factor for major depressive disorder (MDD), however the underlying mechanisms are not well understood. Clinical studies suggest that negative affective biases (the process, whereby cognitive processes such as learning and memory and decision-making are modified by emotional state) represent a vulnerability factor for MDD. In this study we investigate the impact of ELA on affective biases and reward-associated behaviours in rats. Sprague Dawley rat pups underwent 14 days of postnatal maternal separation (180 min/day from postnatal day 1: MS180) whilst control pups remained unhandled. In adulthood, affective biases associated with reward learning and decision-making were assessed using the affective bias test (ABT), or judgement bias task (JBT) respectively. Changes in motivation and reward sensitivity were tested in a progressive ratio (PR) schedule of operant responding and the sucrose preference test (SPT) respectively. We observed that MS180 animals expressed enhanced negative biases in response to acute corticosterone treatment but without effects on antidepressant-induced positive biases. ELA animals were impaired in their ability to develop appropriate biases in response to changes in reward value in a modified ABT but in the absence of any changes in reward sensitivity or motivation. No effects on decision-making were observed in the JBT but MS180 animals failed to develop the same more optimistic behavioural profile as controls in response to an increase in reward value. These findings suggest that ELA in rats increases vulnerability to negative affective biases and impairs animals' ability to appropriately learn reward value, independent of a reward sensitivity or changes in motivation. These data provide important evidence linking ELA with relevant neuropsychological impairments that may explain increased risk of developing MDD.

The combination of postnatal maternal separation and social stress in young adulthood does not lead to enhanced inflammatory pain sensitivity and depression-related behavior in rats.

The cumulative and match/mismatch hypotheses of stress are still under discussion regarding the effects of early life stress (ELS) on the vulnerability or resilience to psychopathology. In this context, an additional stress in later life (second hit) often leads to stress-related disorders that frequently include comorbid pain states. We previously observed that maternal separation (MS), a model of ELS, reduces vulnerability to neuropathic and inflammatory pain in rats. In the present study, we investigated the effects of an additional later stressor on the vulnerability to inflammatory pain. Sprague Dawley pups were divided into 4 groups: controls (CON, no stress), MS, social stress (SS) and MS+SS. At young adult age (from 7 to 15 weeks), stress- as well as pain-related parameters were evaluated prior and during 21 days following the induction of paw inflammation with complete Freund’s adjuvant (CFA). Finally spinal glutamatergic transmission, immunocompetent cells, pro-inflammatory cytokines and growth factors were examined using qPCR. None of the stress conditions had a significant impact on corticosterone levels and anhedonia. In the forced swim test, MS and SS displayed increased passive coping whereas the combination of both stressors revoked this effect. The different stress conditions had no influence on basal mechanical thresholds and heat sensitivity. At 4 days post-inflammation all stress groups displayed lower mechanical thresholds than CON but the respective values were comparable at 7, 10, and 14 days. Only on day 21, MS rats were more sensitive to mechanical stimulation compared to the other groups. Regarding noxious heat sensitivity, MS+SS animals were significantly less sensitive than CON at 10 and 21 days after CFA-injection. qPCR results were mitigated. Despite the finding that stress conditions differentially affected different players of glutamatergic transmission, astrocyte activity and NGF expression, our biochemical results could not readily be related to the behavioral observations, precluding a congruent conclusion. The present results do neither confirm the cumulative nor corroborate or disprove the match/mismatch hypothesis.

Postnatal separation prevents the development of prenatal stress‐induced anxiety in association with changes in oestrogen receptor and oxytocin immunoreactivity in female mandarin vole (Microtus mandarinus) offspring

Oestrogen has both anxiogenic and anxiolytic effects because of variation in opposing action on alpha (ERα) and beta (ERβ) estrogen receptors in the medial preoptic area (mPOA), bed nucleus of the stria terminalis (BNST) and medial amygdala (MeA). Oxytocin (OT) reverses some of the anxiogenic effects of oestrogen in the hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON). Because anxiety disorders are twice as common in women as in men, and oestrogen and OT are more important in females, we examined interactions between prenatal restraint stress (GS) and postnatal early short-term maternal separation (MS) and female mandarin vole behaviour, estrogen receptors and OT. The results show that adult female offspring from GS/noMS mothers showed increased anxiety in open-field and elevated plus-maze tests and had lower serum 17-beta-oestradiol (E2 ) levels than female offspring from GS/MS, noGS/MS and noGS/noMS mothers. GS/noMS females had more immunoreactive neurons for ERα in several brain regions and less ERβ- and OT-immunoreactive neurons in brain areas compared to GS/MS, noGS/MS and noGS/noMS offspring. Interestingly, noGS/MS and GS/MS offspring were similar to noGS/noMS offspring in that they did not develop anxiety as adults. We propose that MS alters the serum concentration of E2 and that the ERβ/ERα ratio and OT level in the brain may be responsible for the decrease in anxiety-like behaviour in adult female offspring initially exposed to anxiety-inducing conditions via an adverse foetal environment.

Low doses of prenatal ethanol exposure and maternal separation alter HPA axis function and ethanol consumption in adult male rats

Adverse maternal behaviors during pregnancy and unfavorable postnatal experiences during development are associated with an increased risk of developing psychiatric disorders, as well as, a vulnerability to alcohol addiction in adulthood. Here, we examined the effects of combined ethanol exposure during late pregnancy and postnatal maternal separation (MS) on HPA responsiveness, anxiety behavior and preference for alcohol consumption in adult male rats. Animals exposed to both conditions revealed a decrease in blood levels of allopregnanolone accompanied by increased anxiety behavior. In addition, basal blood levels of corticosterone were markedly decreased in all experimental groups while increases in the foot-shock-induced corticosterone levels were more pronounced in MS animals. Finally, evaluating EtOH drinking behavior, MS animals exhibited a remarkable EtOH preference even at low doses (0.1–1%). Altogether, these data suggest that adverse conditions, alone or in combination, may alter anxiety–like states as well as modify behavior towards alcohol consumption.

Maternal separation induces hippocampal changes in cadherin-1 (CDH-1) mRNA and recognition memory impairment in adolescent mice

In rodents, disruption of mother-infant attachment induced by maternal separation (MS) is associated with recognition memory impairment and long-term neurobiological consequences. Particularly stress-induced modifications have been associated to disruption of cadherin (CDH) adhesion function, which plays an important role in remodeling of neuronal connection and synaptic plasticity. This study investigated the sex-dependent effect of MS on recognition memory and mRNA levels of classical type I and type II CDH and the related β -catenin (β -Cat) in the hippocampus and prefrontal cortex of late adolescent mice. We provided evidence that the BALB/c mice exposed to MS present deficit in recognition memory, especially females. Postnatal MS induced higher hippocampal CDH-2 and CDH-8 mRNA levels, as well as an upregulation of CDH-1 in the prefrontal cortex in both males and females. MS-reared female mice presented lower CDH-1 mRNA levels in the hippocampus. In addition, hippocampal CDH-1 mRNA levels were positively correlated with recognition memory performance in females. MS-reared male mice exhibited higher β -Cat mRNA levels in the hippocampus. Considering sex-specific effects on CDH mRNA levels, it has been demonstrated mRNA changes in CDH-1, β -Cat, and CDH-6 in the hippocampus, as well as CDH-1, CDH-8 and CDH-11 in the prefrontal cortex. Overall, these findings suggest a complex interplay among MS, CDH mRNA expression, and sex differences in the PFC and hippocampus of adolescent mice.

Early life stress increases stress vulnerability through BDNF gene epigenetic changes in the rat hippocampus

Early life stress (ELS) exerts long-lasting epigenetic influences on the brain and makes an individual susceptible to later depression. It is poorly understood whether ELS and subsequent adult chronic stress modulate epigenetic mechanisms. We examined the epigenetic mechanisms of the BDNF gene in the hippocampus, which may underlie stress vulnerability to postnatal maternal separation (MS) and adult restraint stress (RS). Rat pups were separated from their dams (3 h/day from P1–P21). When the pups reached adulthood (8 weeks old), we introduced RS (2 h/day for 3 weeks) followed by escitalopram treatment. We showed that both the MS and RS groups expressed reduced levels of total and exon IV BDNF mRNA. Furthermore, RS potentiated MS-induced decreases in these expression levels. Similarly, both the MS and RS groups showed decreased levels of acetylated histone H3 and H4 at BDNF promoter IV, and RS exacerbated MS-induced decreases of H3 and H4 acetylation. Both the MS and RS groups had increased MeCP2 levels at BDNF promoter IV, as well as increased HDAC5 mRNA, and the combination of MS and RS exerted a greater effect on these parameters than did RS alone. In the forced swimming test, the immobility time of the MS + RS group was significantly higher than that of the RS group. Additionally, chronic escitalopram treatment recovered these alterations. Our results suggest that postnatal MS and subsequent adult RS modulate epigenetic changes in the BDNF gene, and that these changes may be related to behavioral phenotype. These epigenetic mechanisms are involved in escitalopram action.

Artificially reared mice exhibit anxiety-like behavior in adulthood.

It is important to establish experimental animal techniques that are applicable to the newborn and infant phases for nutrition and pharmacological studies. Breeding technology using the artificial suckling method without breast milk is very effective for the study of newborn nutrition. Using this method, we separated newborn mice from dams within 48 h of birth and provided them with artificial milk. We evaluated mouse anxiety levels after early postnatal maternal separation. Artificially reared mice were subjected to elevated plus-maze tests to assess emotional behavior at 9 weeks of age. Artificially reared mice showed a significantly lower frequency of entries and dipping into the open arms of the maze compared with dam-reared mice. This result indicates that the anxiety level of artificially reared mice was higher than that of dam-reared mice. Moreover, the concentration of monoamines in the brain was determined after the behavioral experiment. The hippocampal norepinephrine, serotonin, and 5-hydroxyindoleacetic acid levels in the artificially reared mice were significantly higher than those of the dam-reared mice. These results suggest that maternal-offspring interactions are extremely important for the emotional development of newborn infants during the lactation period. In future studies, it is necessary to consider the environmental factors and conditions that minimize the influence of artificial rearing on emotional behavior.

Maternal separation produces alterations of forebrain brain-derived neurotrophic factor expression in differently aged rats.

Early life adversity, such as postnatal maternal separation (MS), play a central role in the development of psychopathologies during individual ontogeny. In this study, we investigated the effects of repeated MS (4 h per day from postnatal day (PND) 1–21) on the brain-derived neurotrophic factor (BDNF) expression in the medial prefrontal cortex (mPFC), the nucleus accumbens (NAc) and the hippocampus of male and female juvenile (PND 21), adolescent (PND 35) and young adult (PND 56) Wistar rats. The results indicated that MS increased BDNF in the CA1 and the dentate gyrus (DG) of adolescent rats as well as in the DG of young adult rats. However, the expression of BDNF in the mPFC in the young adult rats was decreased by MS. Additionally, in the hippocampus, there was decreased BDNF expression with age in both the MS and non separated rats. However, in the mPFC, the BDNF expression was increased with age in the non separated rats; nevertheless, the BDNF expression was significantly decreased in the MS young adult rats. In the NAc, the BDNF expression was increased with age in the male non-maternal separation (NMS) rats, and the young adult female MS rats had less BDNF expression than the adolescent female MS rats. The present study shows unique age-differently changes on a molecular level induced by MS and advances the use of MS as a valid animal model to detect the underlying neurobiological mechanisms of mental disorders.

Perinatal stress effects on later anxiety and hormone secretion in male mandarin voles.

The estradiol (E2), estrogen receptor-α (ERα), testosterone (T), and androgen receptor (AR) can contribute to anxiety, but whether they are associated with the reversion of prenatal adverse outcomes remains unclear. Here, we tested the interactive effects of prenatal maternal restraint stress and early postnatal short-term maternal separation on adult male mandarin vole (Microtus mandarinus) behavior and changes in E2, T, and their receptors. The results showed that PS adult males (PS/NH) exhibited an increase in anxiety-like behavior in open-field and elevated plus-maze tests than the other 3 groups, including adult male offspring controls (PC/NH), adult male offspring controls with short-term maternal separation (PC/H), and PS adult males with short-term maternal separation (PS/H). The increase in anxiety-like behavior was associated with significantly lower E2 and T serum levels, had significantly more ERα immunoreactive neurons (ERα-IRs) in some brain regions, as well as significantly fewer AR immunoreactive neurons (AR-IRs) in some brain regions than the other 3 groups. We found it interesting that the PC/H and PS/H were similar to the PC/NH in that they did not produce anxiety-like behavior. However, early postnatal short-term maternal separation reversed prenatally induced changes in E2 and T serum levels and altered ERα-IRs and AR-IRs in the brain. These data suggest that changes in anxious adults may be governed by early environmental factors and their interactions because changes in E2 and T serum levels and the distribution of ERα and AR in the brain result in behavioral changes related to less anxiety into adulthood.

The different effects of maternal separation on spatial learning and reversal learning in rats

Early postnatal maternal separation (MS) can play an important role in the development of psychopathologies during ontogeny. In the present study, we investigated the effects of repeated MS (4h per day from postnatal day (PND) 1 to 21) on locomotor activity and anxiety behavior in open field, spatial learning and reversal learning in Morris water maze of male and female juvenile (PND 21), adolescent (PND 35) and early adult (PND 56) Wistar rats. The results indicated that MS increased locomotor activity of rats across all ages and reduced anxiety behavior of adolescent rats in open field test. MS also increased swim distance in spatial learning and decreased escape latency in reversal learning in adolescent and early adult rats. Additionally, for socially reared rats, there was increased spontaneous locomotion with age, decreased reversal learning ability with age. The present study provides novel insights into the consequences of MS and demonstrates unique age-dependent changes at the behavioral levels.

1H NMR-based urinary metabolic profiling reveals changes in nicotinamide pathway intermediates due to postnatal stress model in rat.

The maternal separation protocol in rodents is a widely recognized model of early life stress allowing acute and chronic physiological consequences to be studied. An (1)H NMR-based metabolomic approach was applied to urines to evaluate the systemic metabolic consequences of maternal separation stress in female rats after the beginning of weaning and 4 weeks later when the rats were reaching adulthood. Furthermore, because maternal separation is considered as a model mimicking the inflammatory bowel syndrome, the lactulose/mannitol test was used to evaluate the influence of postnatal maternal separation on gut permeability and mucosal barrier function by (1)H NMR spectroscopy analysis of urine. The results showed no statistical differences in gut permeability due to maternal separation. The application of ANOVA simultaneous component analysis allowed the contributions of physiological adaptations to the animal's development to be separated from the metabolic consequences due to postnatal stress. Systemic metabolic differences in the maternally separated pups were mainly due to the tryptophan/NAD pathway intermediate levels and to the methyladenosine level. Urinary NMR-based metabolic profiling allowed us to disentangle the metabolic adaptive response of the rats to postnatal stress during the animal's growth, highlighting the metabolic changes induced by weaning, gut closure, and maturity.

Epigenetic Upregulation of Corticotrophin-Releasing Hormone Mediates Postnatal Maternal Separation-Induced Memory Deficiency

Accumulating evidences demonstrated that early postnatal maternal separation induced remarkable social and memory defects in the adult rodents. Early-life stress induced long-lasting functional adaptation of neuroendocrine hypothalamic-pituitary-adrenal axis, including neuropeptide corticotrophin-releasing hormone (CRH) in the brain. In the present study, a significantly increased hippocampal CRH was observed in the adult rats with postnatal maternal separation, and blockade of CRHR1 signaling significantly attenuated the hippocampal synaptic dysfunction and memory defects in the modeled rats. Postnatal maternal separation enduringly increased histone H3 acetylation and decreased cytosine methylation in Crh promoter region, resulting from the functional adaptation of several transcriptional factors, in the hippocampal CA1 of the modeled rats. Enriched environment reversed the epigenetic upregulation of CRH, and ameliorated the hippocampal synaptic dysfunction and memory defects in the adult rats with postnatal maternal separation. This study provided novel insights into the epigenetic mechanism underlying postnatal maternal separation-induced memory deficiency, and suggested environment enrichment as a potential approach for the treatment of this disorder.

Postnatal maternal separation enhances tonic GABA current of cortical layer 5 pyramidal neurons in juvenile rats and promotes genesis of GABAergic neurons in neocortical molecular layer and subventricular zone in adult rats

Postnatal maternal separation (PMS) has been shown to be associated with an increased vulnerability to psychiatric illnesses in adulthood. However, the underlying neurological mechanisms are not well understood. Here we evaluated its effects on neurogenesis and tonic GABA currents of cortical layer 5 (L5) pyramidal neurons. PMS not only increased cell proliferation in the subventricular zone, cortical layer 1 and hippocampal dentate gyrus in the adult brain, but also promoted the newly generated cells to differentiate into GABAergic neurons, and PMS adult brain maintained higher ratios of GABAergic neurons in the survival of newly generated cells within 5 days immediately post PMS. Additionally, PMS increased the tonic currents at P7–10 and P30–35 in cortical L5 pyramidal cells. Our results suggest that the newly generated GABAergic neurons and the low GABA concentration-activated tonic currents may be involved in the development of psychiatric disorders after PMS.