Maternal Separation Rats Research Articles

Influence of environmental enrichment on the volume of brain regions sensitive to early life stress by maternal separation in rats

Exposure to maternal separation (MS) in rodents may have long-lasting consequences for the structure and function of several brain regions, eventually associated with alterations in cognition and emotion later in life. Post-weaning environmental enrichment (EE) has been reported to ameliorate the detrimental effects of exposure to early life stress mainly in the hippocampus. In vivo magnetic resonance imaging (MRI) was applied to evaluate possible volumetric changes in the dorsal and ventral hippocampus, the medial prefrontal cortex and the dorsal striatum of 90-day-old male rats after daily MS for 240 min from postnatal days 2-21. No significant volume changes were found in the selected brain regions in MS animals as compared with an age-matched control group. However, additional groups of control and MS animals with EE from days 21-60 showed significant volume increases in the medial prefrontal cortex and the ventral hippocampus as compared to the groups without EE. In addition, general hemispheric asymmetry was found in the volume of the brain regions measured. Our results demonstrate that EE could have differential effects depending on previous exposure to MS and on the development of brain lateralization.

Effects of early life stress on cocaine conditioning and AMPA receptor composition are sex-specific and driven by TNF

Exposure to early life adversity can predispose adolescents to the formation of substance abuse disorders. In rodents, early stressors such as repeated maternal separation (MS) impact AMPAR activity in the prefrontal cortex (PFC) and nucleus accumbens (NAc), regions involved in drug-cue association after cocaine-induced conditioned place preference (CPP). Notably, previous reports suggest that the pro-inflammatory cytokine tumor necrosis factor (TNF) regulates AMPAR subunit composition; increased TNF levels are reported to reduce GluA2-positive AMPARs. Since MS can elevate adolescent TNF levels, the stressor may therefore alter AMPAR subunit composition via neuroimmune signaling, thereby affecting cocaine-induced CPP. We tested the specific role of soluble TNF in MS-induced GluA2 loss and cocaine-induced CPP with biologic disruption of TNF signaling. TNF gene and protein expression were elevated in both PFC and NAc of MS males, but not females. GluA2 expression was reduced in both regions in only male MS rats, and systemic treatment with either ibudilast – a phosphodiesterase inhibitor, or XPro1595 – a blood-brain barrier-permeable blocker of soluble TNF – reversed such loss. MS males also formed greater preference for a cocaine-paired environment, the expression of which returned to control levels after XPro1595 administration. These data suggest a sex-specific mechanistic link between TNF signaling and changes in GluA2 expression and drug-cue conditioning, thereby providing further evidence for a role of MS and neuro-immune activity in cortical and striatal AMPAR changes. Moreover, manipulation of the TNF signaling pathway represents a novel approach for influencing response to reinforcing effects of drug use.

SA11 - THE EXPRESSION OF KAINATE RECEPTORS IN THE HIPPOCAMPUS OF MATERNAL SEPARATION RAT PUPS

Background Adverse experiences during early life such as social isolation, child abuse and parental loss is a significant risk factor for neuropsychiatric diseases such as cognitive deficits, anxiety disorders, and depression. Maternal Separation (MS) in rats during the early postnatal period, which is a well-established animal model of early life stress, is served as a model of psychopathology for anxiety disorders and depression. Methods To determine the molecular mechanism on the development of psychiatric problems following ELS, we assessed the alteration of molecules in the hippocampus of MS rats (during postnatal day 14–21) using microarray method. Results MS decreased the 59 genes and increased 23 genes more than two-fold. Interestingly, among them, we observed that the expressions of kainate receptor 1 (KA1) and 2 (KA2) genes were up-regulated in MS pups. This result was also confirmed by RT-PCR. Additionally, the immunoreactivities of KA1 and KA2 in the hippocampus were increased in the MS group compared to the control group. Discussion Our studies showed that MS-induced ELS induced the increased expressions of the hippocampal KA1 and KA2 receptors. These findings suggest that the alteration of glutamate system induced by ELS may be involved in the pathology of the psychiatric diseases such as depression and anxiety disorders.

Effect of enriched environment during adolescence on spatial learning and memory, and voluntary consumption of morphine in maternally separated rats in adulthood.

This study was designed to examine the effect of environmental enrichment (EE) during adolescence on spatial learning and memory and voluntary morphine consumption in maternally separated (MS) male and female rats in adulthood. Male Wistar rats were allowed to mate with female virgin Wistar rats. Pups were separated from the dams daily for 180min during postnatal days 2-14. All pups were weaned on day 21. The pups of both sexes were reared in a standard (SE) or enriched (EE) environment during postnatal days 21-50. Then, adulthood rats were tested for spatial learning and memory (Morris Water Maze), and voluntary consumption of morphine using a two-bottle choice paradigm (TBC). We found that the MS/SE rats showed longer escape latencies to find the platform on the third (the male) and fourth (the female) days of training than No MS/SE rats. Also, exposure to EE shortened the latency to escape in the male and female MS rats as training progressed than MS/SE rats. Moreover, the No MS/EE and MS/EE male rats spent significantly more time in the target zone compared with the SE control groups in the probe test. We also found that voluntary morphine consumption was higher in the male and female MS/SE than No MS/SE rats, while it was lower in the male and female MS/EE rats. The present results have shown that EE treatment may have potential therapeutic application for the prevention of the development of drug addiction and recovery from cognitive deficits following neonatal MS during adulthood.

The impact of early-life stress on corticosteroid carrier protein levels and 11β-hydroxysteroid dehydrogenase 1 expression in adolescent rats.

Corticosteroid-binding globulin (CBG), albumin and 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes play crucial roles in the bioavailability of glucocorticoids. Downstream of the adrenal glands, these proteins affect glucocorticoid levels in target tissues. Early-life stress (ELS) is known to program glucocorticoid action at many levels. The effects of ELS on the concentrations and synthesis of CBG and albumin and on the expression of 11β-HSD remain unclear. The maternal separation (MS) procedure in rats on postnatal days 1-14 was used as a model of ELS. On postnatal day 35 (adolescence), the serum corticosterone, CBG and albumin concentrations of male rats were measured by ELISA, while the mRNA and protein levels of CBG, albumin and 11β-HSD1 in the liver and brain were examined by RT-qPCR and Western blot, respectively. Under basal conditions, MS rats displayed lower levels of serum CBG and albumin. However, MS did not affect CBG or albumin synthesis in the liver, suggesting that the half-life and/or secretion of these proteins were influenced by MS. Additionally, MS rats showed increased protein expression of 11β-HSD1, specifically in the medial prefrontal cortex. These results indicate that ELS may potentially program glucocorticoid action through its effects on glucocorticoid bioavailability in tissues.

Evidence for intact 5-HT1A receptor-mediated feedback inhibition following sustained antidepressant treatment in a rat model of depression

Serotonin (5-HT) neurons are strongly implicated in mood disorders such as depression and are importantly regulated by feedback inhibition mediated by 5-HT1A receptors. These receptors may play a role, albeit a poorly understood one, in the generation of mood disorders, treatment response to antidepressants and delayed therapeutic efficacy. Here we sought to gain insight into the role of 5-HT1A receptor-mediated feedback inhibition in these processes by studying Fos protein expression within serotonin neurons in a rat model of stress-related mood disorder, early life maternal separation (MS), combined with two-week treatment with the antidepressant fluoxetine (FLX) in adulthood. We gauged 5-HT1A receptor-mediated feedback inhibition by the ability of the antagonist, WAY-100635 (WAY), to disinhibit Fos expression in 5-HT neurons. We found that two-week FLX treatment dramatically inhibited Fos expression in serotonin neurons and that this effect was reversed by blocking 5-HT1A receptors with WAY. Together these observations reveal that after prolonged exposure to SSRIs, endogenous 5-HT1A receptors continue to exert feedback inhibition of serotonin neurons. Furthermore we found unique effects of pharmacological treatments after MS in that the WAY effect was greatest in MS rats treated with FLX, a phenomenon selective to the rostral 2/3 of the dorsal raphe nucleus (B7). These results indicate that the balance between activation and feedback inhibition of serotonin neurons in B7 is altered and uniquely sensitive to FLX after early-life stress.

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.

Effect of probiotic Bifidobacterium bifidum G9-1 on the relationship between gut microbiota profile and stress sensitivity in maternally separated rats

Although gut microbiota and early life events are likely involved in the development of irritable bowel syndrome (IBS), it remains unclear how these factors interact in the pathophysiology of IBS. In the present study, using rats subjected to maternal separation (MS) as a model of IBS, we investigated interrelationships among gut microbiota, stress susceptibility and intestinal permeability, and examined the effect of the probiotic Bifidobacterium bifidum G9-1 (BBG9-1) on those interrelationships. When compared with the controls at postnatal day 20, MS rats showed hypercorticosteronemia, enhanced intestinal permeability and changes in gut microbiota structure. All of these changes in MS rats were prevented by treatment with BBG9-1. Although the gut microbiota profile and basal serum corticosterone level did not differ between MS and control rats at postnatal day 56, MS rats showed hypersensitivity to restraint stress in terms of serum corticosterone level and fecal frequency. However, such hypersensitivity was not observed in MS rats treated with BBG9-1. These findings suggest that MS initiates the link between gut microbiota alteration and hypersensitivity to stress and that the triggering of this process can be prevented by the treatment with the probiotic BBG9-1.

Nesfatin-1 in the dorsal raphe nucleus influences visceral sensitivity via 5-HT neurons in male maternally separated rats

Nesfatin-1, a satiety molecule processed from nucleobindin2 (NUCB2), is implicated in visceral hypersensitivity in rats and colocalized with 5-hydroxytryptamine (5-HT) in the dorsal raphe nucleus (DRN). Maternal separation (MS) in rats contributes to visceral hypersensitivity via elevated expression of 5-HT in the DRN. Intracerebroventricular injection of nesfatin-1 activates DRN 5-HT neurons. In this study, A model of visceral hypersensitivity was developed by subjecting rats to MS. Colorectal distension was used to detect visceral sensitivity, which was evaluated by abdominal withdrawal reflex (AWR) scores and electromyogram (EMG) magnitude. MS rats exhibited higher AWR scores and EMG magnitude compared with controls. The numbers of nesfatin-1- and tryptophan hydroxylase (TPH, the rate-limiting enzyme for 5-HT synthesis)-positive cells in the DRN were significantly elevated accordingly. Visceral hypersensitivity was significantly alleviated in MS rats treated with intra-DRN administration of anti-nesfatin-1/NUCB2, accompanied by decreased expression of 5-HT and TPH in the DRN, compared with the vehicle-treated group. In contrast, intra-DRN administration of nesfatin-1 into normal adult rats induced visceral hypersensitivity, which correlated with elevated expression of 5-HT and TPH in the DRN. In conclusion, Nesfatin-1 has critical effects on visceral hypersensitivity; the underlying mechanisms might be related to the activation of DRN 5-HT neurons.

Previous Early-life Stress Modifies Acute Corticosterone-induced Synaptic Plasticity in the Medial Prefrontal Cortex of Adolescent Rats

Stress can either strengthen coping strategies or enhance the risk of depression and anxiety. Synaptic plasticity is one of the key brain functions that can be affected by stress. We have previously shown that early-life stress in the form of maternal separation (MS) impairs functional synaptic plasticity in the medial prefrontal cortex (mPFC), i.e., long-term potentiation (LTP), in adolescent rats. It has been postulated that a previous experience of prolonged stress can modify the response to a subsequent acute stress challenge and influence coping strategies. Therefore, in the present study, we examined how previous MS experience influenced acute stress-induced changes in the LTP and expression of genes and proteins engaged in synaptic plasticity in the mPFC of adolescent rats. To mimic acute stress, we applied acute injections of corticosterone (CORT) and its vehicle (VEH). In control rats, acute CORT injection enhanced LTP in the mPFC. In contrast, MS rats generally exhibited an impairment of LTP that was not further affected by CORT. Moreover, for many studied parameters, such as induction of cFos and Arc mRNA and protein and activation of BDNF, GDNF and NCAM mRNA, MS rats showed diminished, vague or absent responses to acute VEH/CORT compared with those of control rats. These results suggest that previous early-life stress experiences may induce adaptive plasticity within the mPFC, which influences the response to acute stress challenge and coping strategies in adolescents. Depending on the specific environmental context, this phenomenon may lead to either future vulnerability or future resilience to stress-related psychopathologies.

Beneficial effects of environmental enrichment on behavior, stress reactivity and synaptophysin/BDNF expression in hippocampus following early life stress

Exposure to environmental enrichment can beneficially influence the behavior and enhance synaptic plasticity. The aim of the present study was to investigate the mediated effects of environmental enrichment on postnatal stress-associated impact with regard to behavior, stress reactivity as well as synaptic plasticity changes in the dorsal hippocampus. Wistar rat pups were submitted to a 3 h maternal separation (MS) protocol during postnatal days 1–21, while another group was left undisturbed. On postnatal day 23, a subgroup from each rearing condition (maternal separation, no-maternal separation) was housed in enriched environmental conditions until postnatal day 65 (6 weeks duration). At approximately three months of age, adult rats underwent behavioral testing to evaluate anxiety (Elevated Plus Maze), locomotion (Open Field Test), spatial learning and memory (Morris Water Maze) as well as non-spatial recognition memory (Novel Object Recognition Test). After completion of behavioral testing, blood samples were taken for evaluation of stress-induced plasma corticosterone using an enzyme-linked immunosorbent assay (ELISA), while immunofluorescence was applied to evaluate hippocampal BDNF and synaptophysin expression in dorsal hippocampus. We found that environmental enrichment protected against the effects of maternal separation as indicated by the lower anxiety levels and the reversal of spatial memory deficits compared to animals housed in standard conditions. These changes were associated with increased BDNF and synaptophysin expression in the hippocampus. Regarding the neuroendocrine response to stress, while exposure to an acute stressor potentiated corticosterone increases in maternally-separated rats, environmental enrichment of these rats prevented this effect. The current study aimed at investigating the compensatory role of enriched environment against the negative outcomes of adverse experiences early in life concurrently on emotional and cognitive behaviors, HPA function and neuroplasticity markers.

Anhedonic behavior and γ-amino butyric acid during a sensitive period in female rats exposed to early adversity

Early life adversity increases depressive behavior that emerges during adolescence. Sensitive periods have been associated with fewer GABAergic interneurons, especially parvalbumin (PV), brain derived growth factor, and its receptor, TrkB. Here, maternal separation (MS) and social isolation (ISO) were used to establish a sensitive period for anhedonic depression using the learned helplessness (LH) paradigm. Female Sprague-Dawley rat pups underwent MS for 4-h/day or received typical care (CON) between postnatal days 2–20; for the ISO condition, separate cohorts were individually housed between days 20–40 or served as controls (CON2). Anhedonia was defined by dichotomizing subjects into two groups based on one standard deviation of the mean number of escapes for the CON group (<14). This approach categorized 22% of CON subjects and 44% of MS subjects as anhedonic (p < 0.05), similar to the prevalence in maltreated human populations. Only 12.5% of ISO rats met criterion versus 28.5% in CON2 rats. Levels of PV and TrkB were reduced in the amygdala and prelimbic prefrontal cortex (PFC) in MS rats with <14 escapes, but elevated in behaviorally resilient MS rats (>13 escapes). The number of escapes in MS subjects significantly correlated with PV and TrkB levels (PFC: r = 0.93 and 0.91 and amygdala: r = 0.63 and 0.81, respectively; n = 9), but not in CON/ISO/CON2 subjects. Calretinin, but not calbindin, was elevated in the amygdala of MS subjects. These data suggest that low levels of PV and TrkB double the risk for anhedonia in females with an MS history compared to normal adolescent females.

Reversal of visceral hypersensitivity in rat by Menthacarin® , a proprietary combination of essential oils from peppermint and caraway, coincides with mycobiome modulation.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder associated with altered gastrointestinal microflora and increased nociception to colonic distension. This visceral hypersensitivity can be reversed in our rat maternal separation model by fungicides. Menthacarin® is a proprietary combination of essential oils from Mentha x piperita L. and Carum carvi. Because these oils exhibit antifungal and antibacterial properties, we investigated whether Menthacarin® can reverse existing visceral hypersensitivity in maternally separated rats. In non-handled and maternally separated rats, we used the visceromotor responses to colorectal distension as measure for visceral sensitivity. We evaluated this response before and 24hours after water-avoidance stress and after 7days treatment with Menthacarin® or control. The pre- and post-treatment mycobiome and microbiome were characterized by sequencing of fungal internal transcribed spacer 1 (ITS-1) and bacterial 16s rDNA regions. In vitro antifungal and antimicrobial properties of Menthacarin® were studied with radial diffusion assay. Menthacarin® inhibited in vitro growth of yeast and bacteria. Water-avoidance caused visceral hypersensitivity in maternally separated rats, and this was reversed by treatment. Multivariate analyses of ITS-1 and 16S high throughput data showed that maternal separation, induced changes in the myco- and microbiome. Menthacarin® treatment of non-handled and maternally separated rats shifted the mycobiomes to more similar compositions. The development of visceral hypersensitivity in maternally separated rats and the Menthacarin® -mediated reversal of hypersensitivity is associated with changes in the mycobiome. Therefore, Menthacarin® may be a safe and effective treatment option that should be tested for IBS.

Persistent attenuation of brain oxidative stress through aging in perinatal maternal separated rat pups supplemented with choline and docosahexaenoic acid or Clitoria ternatea aqueous root extract.

Perinatal maternal separation stress (PMSS) induces brain lipid peroxidation and reduction in endogenous antioxidants. The present study was designed to assess the brain oxidative stress (MDA) and protein thiol levels through various stages of aging in PMSS rat pups supplemented with choline with docosahexaenoic acid (DHA) or Clitoria ternatea (Linn) aqueous root extract (CTR). Study groups, control, PMSS, PMSS + choline with DHA, PMSS + CTR (n = 6/group) were included in the study. Pups of PMSS groups were separated from their mothers for aperiod of 6 h/day for 30 days. PMSS + supplemented groups were treated as appropriate during the same period. Rats were sacrificed on day 30, 60, 90, 210 and 360. Brains were processed for MDA and protein thiol levels. Brain MDA levels were significantly increased in PMSS rats at day 30, 60 (p < 0.001), 90 (p < 0.01) and attenuated in PMSS pups supplemented with choline with DHA and CTR at day 30, 60 (p < 0.01), 90 (p < 0.01, p < 0.05) and 360 (p < 0.001) when compared to the same in age-matched controls and PMSS rats, respectively. Alternatively, brain protein thiol levels in PMSS rats were reduced in all age groups when compared to the same in age-matched controls. Asignificant increase in brain thiol levels was observed in supplemented groups at day 60 (p < 0.01) and 210 (p < 0.01, p < 0.05) when compared to the same in age-matched PMSS rats. PMSS causes enhanced brain lipid peroxidation (MDA levels) and reduces endogenous antioxidants. Supplementation of choline and DHA or CTR during PMSS in rats persistently attenuates brain oxidative stress through aging.

Maternal separation stress leads to resilience against neuropathic pain in adulthood

Early life stress (ELS) leads to a permanent reprogramming of biochemical stress response cascades that may also be relevant for the processing of chronic pain states such as neuropathy. Despite clinical evidence, little is known about ELS-related vulnerability for neuropathic pain and the possibly underlying etiology.In the framework of experimental studies aimed at investigating the respective relationships we used the established ELS model of maternal separation (MS). Rat dams and neonates were separated for 3 h/day from post-natal day 2–12. At adulthood, noxious mechanical and thermal thresholds were assessed before and during induction of neuropathic pain by chronic constriction injury (CCI). The potential involvement of spinal glutamatergic transmission, glial cells, pro-inflammatory cytokines and growth factors was studied by using qPCR.MS per se did not modify pain thresholds. But, when exposed to neuropathic pain, MS rats exhibited a marked reduction of thermal sensitivity and a delayed development of mechanical allodynia/hyperalgesia when compared to control animals. Also, MS did not alter glucocorticoid receptor mRNA levels, but prevented the CCI-induced down-regulation of NR1 and NR2 sub-units of the NMDA receptor and of the glutamate transporter EAAT3 as observed at 21 days post-surgery. Additionally, CCI-provoked up-regulation of glial cell markers was either prevented (GFAP for astrocytes) or dampened (Iba1 for microglia) by MS. Pro-inflammatory cytokine mRNA expression was either not affected (IL-6) or reduced (IL-1β) by MS shortly after CCI. The growth factors GDNF and NGF were only slightly downregulated 4 days after CCI in the MS-treated animals. The changes in glutamatergic signaling, astroglial and cytokine activation as well as neurotrophin expression could, to some extent, explain these changes in pain behavior. Taken together, the results obtained in the described experimental conditions support the mismatch theory of chronic stress where an early life stress, rather than predisposing individuals to certain pathologies, renders them resilient.

Oxytocin inhibited stress induced visceral hypersensitivity, enteric glial cells activation, and release of proinflammatory cytokines in maternal separated rats

Visceral hypersensitivity (VH) is a significant contributor to irritable bowel syndrome (IBS). Oxytocin (OT) possesses analgesic effects on the central nervous system (CNS) and attenuates microglial activation, however, little is known about its peripheral effects and involvement in VH of IBS. Reactive enteric glial cells (EGCs) contributes to abnormal motility in gastrointestinal (GI) diseases. The aim of this study was to evaluate the peripheral use of OT to maintain VH and activation of EGCs through involvement of the Toll-like receptor (TLR) 4/MyD88/NF-κB signaling. After assessing a baseline visceromotor response (VMR) to colorectal distension (CRD), rats were exposed to a 1h water avoidance stress (WAS) session. Before each WAS session, intraperitoneal injection of OT (1mg/kg body weight, in phosphate-buffered saline (PBS)) atosiban (0.5mg/kg body weight, in PBS) or PBS (as a vehicle control, 1ml/kg body weight) was administered. Animas are killed 24h after the last WAS session. EGCs activity, relative OT receptor expression, glial fibrillary acidic protein (GFAP) expression and TLR4/MyD88/NF-κB signaling were evaluated. Neonatal maternal separation (MS) significantly increased the OT receptor expression and enhanced VMR to CRD. WAS improved VMR to CRD only during neonatal MS. OT treatment prevented WAS-induced higher VMRs to CRD, which was reversed by an OT receptor antagonist administration. Compared to the vehicle, OT pre-treated rats reduced EGCs activation, GFAP expression and TLR4/MyD88/NF-κB signaling. We conclude that neonatal MS induces VH and visceral pain in rats. Furthermore, exogenous OT attenuated stress-induced VH and EGCs activation, which was mediated by TLR4/MyD88/NF-κB signaling.

Maternal high-fat diet and early life stress differentially modulate spine density and dendritic morphology in the medial prefrontal cortex of juvenile and adult rats.

The medial prefrontal cortex (mPFC) is a key area for the regulation of numerous brain functions including stress response and cognitive processes. This brain area is also particularly affected by adversity during early life. Using an animal model in rats, we recently demonstrated that maternal exposure to a high-fat diet (HFD) prevents maternal separation (MS)-induced gene expression alterations in the developing PFC and attenuates several long-term deleterious behavioral effects of MS. In the present study, we ask whether maternal HFD could protect mPFC neurons of pups exposed to early life stress by examining dendritic morphology and spine density in juvenile [postnatal day (PND) 21] and adult rats submitted to MS. Dams were fed either a control or an HFD throughout gestation and lactation, and pups were submitted to MS from PND2 to PND14. We report that maternal HFD prevents MS-induced spine loss at PND21 and dendritic atrophy at adulthood. Furthermore, we show in adult MS rats that PFC-dependent memory extinction deficits are prevented by maternal HFD. Finally, perinatal HFD exposure reverses gut leakiness following stress in pups and seems to exert an anti-stress effect in dams. Overall, our work demonstrates that maternal HFD affects the developing brain and suggests that nutrition, possibly through gut-brain interactions, could modulate mPFC sensitivity to early stress.

Maternal Separation Induced Visceral Hypersensitivity from Childhood to Adulthood.

Background/AimsEarly adverse life events (EALs) are relevant to irritable bowel syndrome in adulthood. Maternal separation (MS), as one of the EALs, has proved to induce visceral hypersensitivity in adult rats. However, the effect of MS on visceral hypersensitvity from the post-weaning period to adulthood remains unknown.MethodsOne hundred and ten neonatal Sprague-Dawley rats were randomly divided into 2 groups: rats in the MS group were exposed to 3 hours daily MS on postnatal day (PND) 2–14; the normal control (NC) group remained undisturbed. Visceral sensitivity was determined by measuring the visceromotor response to colorectal distention on PND21, 35, and 56. Anxiety-like behaviors were measured by the open field test.ResultsCompared with NC rats, MS rats showed significant visceral hypersensitivity from the post-weaning period to adult. The proportion of visceral hypersensitive rats decreased with age from 87.5% to 70.0% in the female MS group and from 90.0% to 66.7% in the male MS group. The relative VMR ratio of MS and NC on PND21 was higher than PND35 and PND56. MS rats showed decreased ability of movement and exploration to the novel environment in the post-weaning period, obesity in the prepubertal period, and more anxiety-like behaviors in adulthood.ConclusionsMS can significantly affect visceral sensitivity and behaviors of rats in different age stages, especially in the post-weaning period. Visceral hypersensitivity of MS rats is more pronounced in the post-weaning period and slightly restored in adults. Thus, visceral hypersensitivity in the post-weaning period might play a more meaningful pathophysiologic role in the formation of adult irritable bowel syndrome.

Tu1611 - Changes of Microbiota in Rat Maternal Separation Stress Model

Tu1611 - Changes of Microbiota in Rat Maternal Separation Stress Model

Effects of early life stress and adolescent ethanol exposure on adult cognitive performance in the 5-choice serial reaction time task in Wistar male rats.

Early life stress combined with heavy adolescent alcohol use predicts impaired neuropsychological functioning in adulthood. We investigated whether adolescent intermittent ethanol (AIE) exposure combined with neonatal maternal separation in rats altered attentional processes and impulsivity in adulthood. Male Wistar rat pups were exposed to maternal separation (postnatal days (PNDs) 1-14) and moderate AIE exposure (PNDs 28-57). Adult rats were tested in the five-choice serial reaction time task, which provides separate measures of attention, motor impulsivity, and compulsivity. Rats were tested under baseline conditions and in response to task manipulations that increased attentional load and impulsive behaviors, and after acute ethanol administration. Short stimulus and short intertrial interval (ITI) durations disrupted attention while long ITI durations impaired impulsivity in all rats. Moderate- and high-dose ethanol challenges impaired attention in all rats. Rats exposed to maternal separation and/or AIE exposure had significantly decreased omissions than non-handled water-exposed rats at baseline and tended to retain this effect in response to task challenges (i.e., the shorter stimulus and ITI durations, longer test session) and ethanol challenges, indicating moderate improvement of attentional performance. Maternal separation significantly increased perseverative responses at baseline and in response to decreased stimulus duration challenge, suggesting increased compulsivity. Separate or combined exposure to early life stress and AIE exposure moderately disrupts some aspects of adult executive control functions (e.g., increased compulsivity) but improves others (e.g., increased attention). The relative intensity of either manipulation during neonatal and adolescent periods may influence the direction in which cognitive behaviors are affected in adulthood.