Maternal Deprivation Rats Research Articles

Targeting histone deacetylation for recovery of maternal deprivation-induced changes in BDNF and AKAP150 expression in the VTA

Severe early life stressors increase the probability of developing psychiatric disorders later in life through modifications in neuronal circuits controlling brain monoaminergic signaling. Our previous work demonstrated that 24 h maternal deprivation (MD) in male Sprague Dawley rats modifies dopamine (DA) signaling from the ventral tegmental area (VTA) through changes at GABAergic synapses that were reversible by in vitro histone deacetylase (HDAC) inhibition which led to restoration of the scaffold A-kinase anchoring protein (AKAP150) signaling and subsequently recovered GABAergic plasticity (Authement et al., 2015). Using a combination of in situ hybridization, Western blots and immunohistochemistry, we confirmed that MD-induced epigenetic modifications at the level of histone acetylation were associated with an upregulation of HDAC2. MD also increased Akap5 mRNA levels in the VTA. Western blot analysis of AKAP150 protein expression showed an increase in synaptic levels of AKAP150 protein in the VTA with an accompanying decrease in synaptic levels of protein kinase A (PKA). Moreover, the abundance of mature brain-derived neurotrophic factor (BDNF) protein of VTA tissues from MD rats was significantly lower than in control groups. In vivo systemic injection with a selective class I HDAC inhibitor (CI-994) was sufficient to reverse MD-induced histone hypoacetylation in the VTA for 24 h after the injection. Furthermore, HDAC inhibition normalized the levels of mBDNF and AKAP150 proteins at 24 h. Our data suggest that HDAC-mediated targeting of BDNF and AKAP-dependent local signaling within VTA could provide novel therapeutics for prevention of later-life psychopathology.

Combined early life stressors: Prenatal nicotine and maternal deprivation interact to influence affective and drug seeking behavioral phenotypes in rats

Early life stress (ELS) increases the risk for later cognitive and emotional dysfunction, and has been implicated in the etiology of multiple psychiatric disorders. We hypothesize that combined insults during gestation and infancy, critical periods of neural development, could exacerbate neuropsychiatric outcomes in later life. Thus, we investigated the effects of maternal deprivation (MD) stress alone or combined with prenatal nicotine exposure (PNE) on negative affective states, ethanol drinking, and development of mesolimbic loci that regulate depression and drug dependence. On the elevated plus maze (EPM), MD rats exhibited ∼50% increase in risk-taking behavior/decreased anxiety when compared to control, but the combined MD + PNE did not affect this specific behavior. In the open field test, however, both MD and MD + PNE groups showed 2-fold greater locomotor activity. Furthermore, whereas MD showed greater latency to fall at 40 RPM on the rotarod compared to control, the MD + PNE animals’ latency to fall was significantly greater at all RPMs tested, with an approximate 15% enhancement in motor coordination overall compared to control and MD. Analyses of depressive symptomatology with the forced swim test (FST) yielded 2- and 3-fold higher immobility times in MD and MD + PNE respectively. When tested in an operant drinking paradigm to quantify the effect of treatment on 10%v/v ethanol drinking, the MD and MD + PNE groups showed heightened ethanol consumption by ∼3- and 2-fold respectively. However, the experience of PNE reduced ethanol consumption in adults relative to MD alone. To test the stressors’ impact on neurons in the amygdala and ventral tegmental area (VTA), mesolimbic anatomical regions associated with mood and reward, unbiased stereological measurements were performed and revealed ∼15% increase in number and density of neurons in the amygdala for both MD and MD + PNE, and ∼13% reduction in dopaminergic-like neurons in the VTA compared to control. We report here that multiple early stressors including prenatal nicotine and MD can modulate the neuroanatomy of the amygdala and VTA. These early life stressors can interact to influence the development of depressive-like and addictive behaviors.

Sensitization of P2X3 receptors in insular cortex contributes to visceral pain of adult rats with neonatal maternal deprivation.

AimsInsular cortex is a brain region critical for processing of the sensation. Purinergic receptors are involved in the formation of chronic pain. The aim of the present study was to explore the role and mechanism of P2X3 receptors (P2X3Rs) in insular cortex in chronic visceral pain.MethodsChronic visceral pain in adult rats was induced by neonatal maternal deprivation and measured by detecting the threshold of colorectal distension. Western blotting, immunofluorescence, and real-time quantitative polymerase chain reaction techniques were used to detect the expression and distribution of P2X3Rs. Synaptic transmission in insular cortex was recorded in brain slices by patch clamp techniques.ResultsExpression of P2X3Rs both at mRNA and protein levels in right hemisphere of insular cortex was significantly increased in neonatal maternal deprivation rats. In addition, P2X3Rs were expressed with NeuN or synaptophysin but not with glial fibrillary acidic protein and CD11b. The co-localization of P2X3Rs with NeuN or synaptophysin was greatly enhanced in right hemisphere of insular cortex in neonatal maternal deprivation rats. Furthermore, neonatal maternal deprivation markedly increased both the frequency and amplitude of miniature excitatory postsynaptic current in right hemisphere of insular cortex. Incubation of A347091 significantly decreased the frequency of spontaneous excitatory postsynaptic current and miniature excitatory postsynaptic current of insular cortex neurons of neonatal maternal deprivation rats. Incubation of P2X3Rs agonists α,β-mATP remarkably increased the frequency of spontaneous excitatory postsynaptic current and miniature excitatory postsynaptic current of the right hemisphere of insular cortex neurons of healthy control rats. Importantly, injection of A317491 significantly enhanced the colorectal distension threshold of neonatal maternal deprivation rats, while injection of α,β-mATP into right but not left insular cortex markedly decreased the colorectal distension threshold in healthy control rats.ConclusionsOverall, our data provide integrated pharmacological, biochemical, and functional evidence demonstrating that P2X3Rs are physically and functionally interconnected at the presynaptic level to control synaptic activities in the right insular cortex, thus contributing to visceral pain of neonatal maternal deprivation rats.

Green tea protects against memory deficits related to maternal deprivation

Maternal deprivation (MD) in early life affects the development of the brain, causing cognitive losses in adulthood. Oxidative imbalance may be one of the factors that trigger these deficits. Therapies with antioxidant components, like green tea from Camellia sinensis (GT) has been used to treat or prevent memory deficits in a variety of conditions related to oxidative stress. Here we demonstrate that memory deficits caused by MD can be prevented by GT antioxidant activity in hippocampus. Pregnant female rats were used. Her puppies were submitted to MD and intake of GT. Recognition and aversive memory were evaluated, as well as hippocampal oxidative status. Data showed that MD prejudice short and long-term recognition and aversive memory and that GT protected memory. Hippocampal reactive oxygen species levels were increased in MD rats; this increase was avoided by GT supplementation. GSH was decreased on hippocampus MD rats. GT did not avoid GSH decrease, but promote the increase of total antioxidant capacity in MD rats' hippocampus. In conclusion, GT protects against memory deficits related to MD, and one of the implicated mechanism seems to be the antioxidant effects of GT.

Divergent anomaly in mesocorticolimbic dopaminergic circuits might be associated with different depressive behaviors, an animal study.

BackgroundThe mesocorticolimbic dopamine system, which originates from the ventral tegmental area (VTA) and projects primarily to the prefrontal cortex (PFC), olfactory tubercle (OT), nucleus accumbens (NAc), dorsal striatum (ST), and the amygdala (AMy), plays a pivotal role in determining individual motivation and sensitivity to rewards, namely, anhedonia. Not all depressive individuals exhibited anhedonia, thus, it is natural to speculate that the heterogenous manifestations of depression might be related to the mesocorticolimbic dopamine system. Maternal deprivation (MD) and chronic unpredictable stress (CUPS) are two well‐established depressogenic stressors, and they were proven to induce different depressive phenotypes.MethodsThe depressive and anxiety‐like behaviors of MD and CUPS‐treated rats were measured by classical behavioral tests including open field, forced swimming, and sucrose preference test. The expression of D1‐5 dopamine receptors and DAT mRNA and protein in the mesocorticolimbic dopamine system of rats exposed to MD and CUPS were measured by real‐time PCR and Western blot, respectively.ResultsSevere anhedonia was observed in MD but not CUPS rats. Divergent expression of D1 and D2 receptors and DAT mRNA and protein in the mesocorticolimbic dopamine system were found between MD and CUPS rats. Significant correlations between different depressive behaviors and D1‐/D2‐like receptors and DAT protein levels in the mesocorticolimbic dopamine system were observed.ConclusionDifferent depressive behaviors of rats such as anhedonia, passive coping behavior, and declined exploratory interest might be related to divergent dopaminergic pathways. Anhedonia is associated with the dysfunction of VTA‐NAc and VTA‐OT dopaminergic pathways, the passive coping behavior is related to the dysregulation of VTA‐PFC and VTA‐AMy pathways, and individual exploratory interest is associated with abnormal activity of VTA‐PFC and VTA‐ST pathways.

Transient Prepubertal Mifepristone Treatment Normalizes Deficits in Contextual Memory and Neuronal Activity of Adult Male Rats Exposed to Maternal Deprivation

Early life adversity is a well-known risk factor for behavioral dysfunction later in life, including the formation of contextual memory; it is also (transiently) accompanied by hyperactivity of the stress system. We tested whether mifepristone (MIF) treatment, which among other things blocks glucocorticoid receptors (GRs), during the prepubertal period [postnatal days (PND)26-PND28] normalizes memory deficits in adult male rats exposed to 24-h maternal deprivation (MD) at PND3. MD reduced body weight gain and increased basal corticosterone (CORT) levels during the PND26, but not in adulthood. In adulthood, contextual memory formation of MD compared to noMD (i.e., control) male rats was significantly impaired. This impairment was fully prevented by MIF treatment at PND26-PND28, whereas MIF by itself did not affect behavior. A second behavioral test, a rodent version of the Iowa Gambling Task (rIGT), revealed that flexible spatial learning rather than reward-based aspects of performance was impaired by MD; the deficit was prevented by MIF. Neuronal activity as tested by c-Fos staining in the latter task revealed changes in the right hippocampal-dorsomedial striatal pathway, but not in prefrontal areas involved in reward learning. Follow-up electrophysiological recordings measuring spontaneous glutamate transmission showed reduced frequency of miniature postsynaptic excitatory currents in adult CA1 dorsal hippocampal and enhanced frequency in dorsomedial striatal neurons from MD versus noMD rats, which was not seen in MIF-treated rats. We conclude that transient prepubertal MIF treatment normalizes hippocampus-striatal-dependent contextual memory/spatial learning deficits in male rats exposed to early life adversity, possibly by normalizing glutamatergic transmission.

Optimized animal model to mimic the reality of stress-induced depression in the clinic

BackgroundAnimal models are useful tools for verifying the relationship between stress and depression; however, an operational criterion for excluding the resilient animals from the analysis has not been established yet, which hinders the model’s ability to more accurately mimic the scenario in humans.MethodsTo induce depression-like symptoms, rats received maternal deprivation (MD) during PND1–14, and/or chronic unpredictable stress (CUS) exposure. The latent profile analysis (LPA) was used to determine latent subgroups in treatment naive adult rats. The percentile method was used to distinguish sensitive and non-sensitive behaviors in rats.ResultsThe sucrose preference rate of treatment naive adult rats was fit using a Beta distribution, while immobility time was fit using a Gamma distribution. Indexes of behavioral tests revealed the 4-class model as the best fit for treatment naive adult rats. The incidence of stress-resilience in MD rats was significantly higher than that in CUS rats and MD + CUS rats. There was a significantly higher incidence of stress-resilience in CUS rats compared with MD + CUS rats. Recovery rate of anhedonia-like and sub anhedonia-like behaviors in CUS rats was significantly higher than that in MD and MD + CUS rats. There was a significantly higher recovery rate of anhedonia-like behaviors in MD rats compared to MD + CUS rats.ConclusionsThe percentile method is suitable for setting up an operational cutoff to classify depression-like, sub depression-like, and resilient behaviors in rats exposed to MD and CUS.

Long-Term Effects of Maternal Deprivation on Redox Regulation in Rat Brain: Involvement of NADPH Oxidase.

Maternal deprivation (MD) causes perinatal stress, with subsequent behavioral changes which resemble the symptoms of schizophrenia. The NADPH oxidase is one of the major generators of reactive oxygen species, known to play a role in stress response in different tissues. The aim of this study was to elucidate the long-term effects of MD on the expression of NADPH oxidase subunits (gp91phox, p22phox, p67phox, p47phox, and p40phox). Activities of cytochrome C oxidase and respiratory chain Complex I, as well as the oxidative stress parameters using appropriate spectrophotometric techniques were analyzed. Nine-day-old Wistar rats were exposed to a 24 h maternal deprivation and sacrificed at young adult age. The structures affected by perinatal stress, cortex, hippocampus, thalamus, and caudate nuclei were investigated. The most prominent findings were increased expressions of gp91phox in the cortex and hippocampus, increased expression of p22phox and p40phox, and decreased expression of gp91phox, p22phox, and p47phox in the caudate nuclei. Complex I activity was increased in all structures except cortex. Content of reduced glutathione was decreased in all sections while region-specific changes of other oxidative stress parameters were found. Our results indicate the presence of long-term redox alterations in MD rats.

The difference among the depression-like behaviours induced by three widely-used stress models in rats

Objective In order to study the difference of depression-like behaviours among three widely-used stress models in rats. Methods The new-born Spragne-Dawley rats were randomly divided into maternal deprivation(MD) group(n=27), chronic mild stress(CMS) group (n=29), dual stress(DS) group (n=31) and control(C) group (n=30) on postnatal day 1.MD rats only received maternal deprivation.CMS rats only received chronic mild stress when 10 weeks old.DS rats received both maternal deprivation and chronic mild stress.Control rats received no experimental handling.Behavior tests including forced swimming test and sucrose consumption which were carried out to evaluate rats' depression-like behaviors in the thirteenth weeks.The extend time of floating and sucrose preference ratio should be recorded in the forced swimming test and sucrose consumption test respectively to reflect the behavior of helplessness and anhedonia of rats. Results In the forced swimming test, the extend floating time of MD group(119.30±65.56)s, CMS group(145.00±80.24)s and DS group(170.03±61.75)s were longer than the control group(81.14±52.40)s(F=11.53, P 0.05). Conclusion The results suggest that MD, CMS and DS may induce some kind of depression-like behaviors in rodents such as anhedonia or the behavior of helplessness and the depression-like behaviors induced by different stresses are similar in male and female individuals. Key words: Stress; Depression-like behavior; Forced swimming test; Sucrose consumption test; Sexual difference

Effect of maternal deprivation on learning and memory ability and hippocampal nerve regeneration in rats with hypoxic-ischemic brain damage

Objective To observe the effect of maternal deprivation(MD) on learning and memory ability and hippocampal pathology and nestin expression in rats with hypoxic-ischemic brain damage (HIBD). Methods The models of HIBD SD male rats were established by the method of Rice, and were randomly divided into 2 groups: MD group and control group.In addition, the sham-operation group(sham group) models were established.The MD group rats were separated from their mother 3 hours per day from the second day after modeling to the 21st postnatal day.After 28 postnatal days, Morris water maze was used to evaluate the learning and memory ability of the rat models.HE staining was employed to observe the hippocampal pathological change in the rats.Then, the expression of nestin in the hippocampus was measured by the method of immunohistochemistry. Results Their body mass changes showed that quality of sham group was higher than that of the control and the MD groups, and quality was improved in the control group, compared with the MD group, and the differences were statistically significant(q=9.860 8, 3.880 7, 5.980 1, all P<0.05). The water maze scores of the MD group in place navigation test and spatial probe test were much lower than that of the control group and the sham group, and the scores of the sham group were higher than that of the control group, the differences were statistically significant(all P<0.05). The findings of HE stain showed that the pathology in the right-sided hippocampus of the sham group was normal and neurons were well-arranged, and that of control group was minimally abnormal, and the neurons were almost arranged orderly and remained normal.While, the pathomorphology of the MD group was obviously abnormal, the neurons were arranged disorderly, many of the neurons lost.According to the immunohistochemical findings, the number of nestin-positive cells in right-sided hippocampus of the MD group was significantly less than that of the control group, and the number of nestin-positive cells of the sham group was less than that of the MD group, which showed significant differences among the groups(all P<0.05). Conclusions MD aggravated injury to learning and memory ability of neonatal rats with HIBD, and decrease the number of nestin-positive cells of MD markedly, which is not good for the recovery of brain injury. Key words: Hypoxic-ischemic; Maternal deprivation; Learning and memory; Pathology; Nestin

Interaction between neonatal maternal deprivation and serum leptin levels on metabolism, pubertal development, and sexual behavior in male and female rats.

BackgroundMaternal deprivation (MD) during neonatal life can have long-term effects on metabolism and behavior, with males and females responding differently. We previously reported that MD during 24 h at postnatal day (PND) 9 blocks the physiological neonatal leptin surge in both sexes. It is known that modifications in neonatal leptin levels can affect metabolism in adulthood. Thus, we hypothesized that at least some of the long-term metabolic changes that occur in response to MD are due to the decline in serum leptin during this critical period of development. Hence, we predicted that treatment with leptin during MD would normalize these metabolic changes, with this response also differing between the sexes.MethodsMD was carried-out in Wistar rats for 24 h on PND9. Control and MD rats of both sexes were treated from PND 9 to 13 with leptin (3 mg/kg/day sc) or vehicle. Weight gain, food intake, glucose tolerance, and pubertal onset were monitored. Sexual behavior was analyzed in males. Rats were killed at PND90, and serum hormones and hypothalamic neuropeptides involved in metabolic control and reproduction were measured. Results were analyzed by three-way analysis of covariance using sex, MD, and leptin treatment as factors and litter as the covariate and employing repeated measures where appropriate.ResultsIn males, MD advanced the external signs of puberty and increased serum insulin and triglyceride levels and hypothalamic proopiomelanocortin mRNA levels at PND90. Neonatal leptin treatment normalized these effects. In contrast, MD decreased circulating triglycerides, as well as estradiol levels, in females at PND90 and these changes were also normalized by neonatal leptin treatment. Neonatal leptin treatment also had long-term effects in control rats as it advanced the external signs of puberty in control males, but delayed them in females. Neonatal leptin treatment increased serum insulin and hypothalamic mRNA levels of the leptin receptor and cocaine- and amphetamine-regulated transcript in control males and increased orexin mRNA levels in controls of both sexes. Although pubertal onset in males was advanced by either MD or neonatal leptin treatment in males and delayed by leptin treatment in females, the mRNA levels of hypothalamic neuropeptides and receptors related to reproduction were not affected by MD or neonatal leptin treatment in either sex at PND90.ConclusionsThese findings indicate that some of the long-term changes in metabolic and reproductive parameters induced by MD, such as advanced pubertal onset and increased hypothalamic proopiomelanocortin (POMC) expression, hyperinsulinemia, and hypertriglyceridemia in adult males and decreased serum triglyceride and estradiol levels in females, are most likely due to the decrease in leptin levels during the period of MD.

Physical exercise prevents short and long-term deficits on aversive and recognition memory and attenuates brain oxidative damage induced by maternal deprivation

It is known from previous research that physical exercise prevents long-term memory deficits induced by maternal deprivation in rats. But we could not assume similar effects of physical exercise on short-term memory, as short- and long-term memories are known to result from some different memory consolidation processes. Here we demonstrated that, in addition to long-term memory deficit, the short-term memory deficit resultant from maternal deprivation in object recognition and aversive memory tasks is also prevented by physical exercise. Additionally, one of the mechanisms by which the physical exercise influences the memory processes involves its effects attenuating the oxidative damage in the maternal deprived rats' hippocampus and prefrontal cortex.

Long Term Hippocampal and Cortical Changes Induced by Maternal Deprivation and Neonatal Leptin Treatment in Male and Female Rats.

Maternal deprivation (MD) during neonatal life has diverse long-term behavioral effects and alters the development of the hippocampus and frontal cortex, with several of these effects being sexually dimorphic. MD animals show a marked reduction in their circulating leptin levels, not only during the MD period, but also several days later (PND 13). A neonatal leptin surge occurs in rodents (beginning around PND 5 and peaking between PND 9 and 10) that has an important neurotrophic role. We hypothesized that the deficient neonatal leptin signaling of MD rats could be involved in the altered development of their hippocampus and frontal cortex. Accordingly, a neonatal leptin treatment in MD rats would at least in part counteract their neurobehavioural alterations. MD was carried out in Wistar rats for 24 h on PND 9. Male and female MD and control rats were treated from PND 9 to 13 with rat leptin (3 mg/kg/day sc) or vehicle. In adulthood, the animals were submitted to the open field, novel object memory test and the elevated plus maze test of anxiety. Neuronal and glial population markers, components of the glutamatergic and cannabinoid systems and diverse synaptic plasticity markers were evaluated by PCR and/or western blotting. Main results include: 1) In some of the parameters analyzed, neonatal leptin treatment reversed the effects of MD (eg., mRNA expression of hippocampal IGF1 and protein expression of GFAP and vimentin) partially confirming our hypothesis; 2) The neonatal leptin treatment, per se, exerted a number of behavioral (increased anxiety) and neural effects (eg., expression of the following proteins: NG2, NeuN, PSD95, NCAM, synaptophysin). Most of these effects were sex dependent. An adequate neonatal leptin level (avoiding excess and deficiency) appears to be necessary for its correct neuro-programing effect.

Sodium Butyrate, a Histone Deacetylase Inhibitor, Reverses Behavioral and Mitochondrial Alterations in Animal Models of Depression Induced by Early- or Late-life Stress.

The aim of the present study was to evaluate the effects of sodium butyrate on depressive-like behavior and mitochondrial alteration parameters in animal models of depression induced by maternal deprivation or chronic mild stress in Wistar rats. maternal deprivation was established by separating pups from their mothers for 3 h daily from postnatal day 1 to day 10. Chronic mild stress was established by water deprivation, food deprivation, restraint stress, isolation and flashing lights. Sodium butyrate or saline was administered twice a day for 7 days before the behavioral tests. Depressive behavior was evaluated using the forced swim test. The activity of tricarboxylic acid cycle enzymes (succinate dehydrogenase and malate dehydrogenase) and of mitochondrial chain complexes (I, II, II-III and IV) was measured in the striatum of rats. From these analyses it can be observed that sodium butyrate reversed the depressive-like behavior observed in both animal models of depression. Additionally, maternal deprivation and chronic mild stress inhibited mitochondrial respiratory chain complexes and increased the activity of tricarboxylic acid cycle enzymes. Sodium butyrate treatment reversed -maternal deprivation and chronic mild stress- induced dysfunction in the striatum of rats. In conclusion, sodium butyrate showed antidepressant effects in maternal deprivation and chronic mild stress-treated rats, and this effect can be attributed to its action on the neurochemical pathways related to depression.

Maternal deprivation of rat pups reduces body weight and alters behavior in adulthood in a gender-specific manner

The early postnatal environment is critical for its capacity to influence adult behavior, and is associated with traits of altered physiological and neurobiological function and long-term predisposition to depression. Here we describe the delayed effects of maternal deprivation (MD) in male and female Wistar pups on their physical development and behavior in adulthood in tasks designed to explore depressive-like (forced swimming test, FST), and anxiety-like behaviors (elevated plus maze, EPM). We observed that MD led to reduced body weight in adulthood, anxiety-like traits in the EPM test and increased activity in the phases of the FST. Particularly, a consistent sexual dimorphism was observed in the responses to MD. A lower increase in body weight during maturation of MD rats was more pronounced in males than in females. MD anxiogenic effects were more pronounced in females, while in FST only MD males showed a marked increase in swimming activity followed by decreased immobility.

Vasopressin deficiency diminishes acute and long-term consequences of maternal deprivation in male rat pups

Early life events have special importance in the development as postnatal environmental alterations may permanently affect the lifetime vulnerability to diseases. For the interpretation of the long-term consequences it is important to understand the immediate effects. As the role of vasopressin in hypothalamic-pituitary-adrenal axis regulation as well as in affective disorders seem to be important we addressed the question whether the congenital lack of vasopressin will modify the stress reactivity of the pups and will influence the later consequences of single 24h maternal deprivation (MD) on both stress-reactivity and stress-related behavioral changes.Vasopressin-producing (di/+) and deficient (di/di) Brattleboro rat were used. In 10-day-old pups MD induced a remarkable corticosterone rise in both genotypes without adrenocorticotropin (ACTH) increase in di/di rats. Studying the later consequences at around weaning (25–35-day-old rats) we found somatic and hormonal alterations (body weight reduction, dysregulation of the stress axis) which were not that obvious in di/di rats. The more anxious state of MD rats was not detectable in di/di rats both at weaning and in adulthood (7–12-week-old).The lack of vasopressin abolished all chronic stress and anxiety-like tendencies both at weaning and in adulthood probably as a consequence of reduced ACTH rise immediately after MD in pups. This finding suggests that postnatal stress-induced ACTH rise may have long-term developmental consequences.

Sodium butyrate functions as an antidepressant and improves cognition with enhanced neurotrophic expression in models of maternal deprivation and chronic mild stress.

It is known that cognitive processes, such as learning and memory, are affected in depression. Several authors have described histone deacetylase (HDAC) inhibitors as a class of drugs that improves long-term memory formation. The current study examined the effects of maternal deprivation (MD) and chronic mild stress (CMS), which have been shown as animal models of depression, and the effects of sodium butyrate (SB), a HDAC inhibitor, on recognition memory. Considering that neurotrophic factors has been pointed as a key event involved with cognition and depressive disorder, levels of neurotrophic factors (BDNF, NGF and GDNF) were also investigated. MD and CMS induced depressive-like behavior in the forced swimming test (FST) and memory impairment in the object recognition (OR) test, without altering locomotor activity of rats. In addition, SB was able to reverse the stress-induced neurotrophic factors decrease and reversed memory impairment. The results indicate that the stress both at early and later stage of life may induce cognitive impairment in animals and neurotrofic factors (BDNF, NGF and GDNF) levels decrease. SB treatment improved the recognition memory and reversed the neurotrophins levels decreased in the hippocampus of rats submitted to the MD and CMS models. Together, our results reinforce the notion that SB displays a specific antidepressant profile and improve cognition in MD and CMS rats that may be, at least in part, due to its upregulation of neurotrophic factors.

Anhedonia was associated with the dysregulation of hippocampal HTR4 and microRNA Let-7a in rats

ObjectiveDepression is a serious mental illness. However, the molecular mechanisms responsible for the development of depression remain unknown. MethodsIn this study, animal models of depression were established using maternal deprivation (MD) and chronic unpredictable stress (CUPS). Behavioral performance of rats was monitored by open field test, forced swim test, and sucrose consumption test. The expression of serotonin receptor-4 (Htr4) mRNA and Let-7a microRNA was detected by real-time PCR, while Htr4 protein level was measured by Western blot. ResultsIn the open field test, rats subjected to MD and CUPS exhibited significant decreases in vertical activity. CUPS rats spent less time in the central area and excreted more fecal pellets than MD and control rats. In the forced swim and sucrose consumption tests, CUPS and MD rats exhibited significantly longer floating time and consumed less sucrose than control rats. MD rats exhibited significantly shorter floating time and consumed less sucrose than CUPS rats. MD rats showed significantly lower Htr4 mRNA and protein expression and significantly higher Let-7a level in the hippocampus than control rats. Htr4 mRNA and protein expression negatively correlated with Let-7a expression. Htr4 mRNA expression positively correlated with sucrose preference rate, while Let-7a expression negatively correlated with the sucrose preference rate. ConclusionAnhedonia, not despair or a decline in exploratory interest, may be associated with upregulation of Let-7a and downregulation of Htr4 expression in the hippocampus. The hippocampal Htr4 level may be regulated by Let-7a in rats.

Changes in Intestinal Glucocorticoid Sensitivity in Early Life Shape the Risk of Epithelial Barrier Defect in Maternal-Deprived Rats

Glucocorticoids (GC) contribute to human intestine ontogeny and accelerate gut barrier development in preparation to birth. Rat gut is immature at birth, and high intestinal GC sensitivity during the first two weeks of life resembles that of premature infants. This makes suckling rats a model to investigate postpartum impact of maternal separation (MS)-associated GC release in preterm babies, and whether GC sensitivity may shape MS effects in immature gut. A 4 hours-MS applied once at postnatal day (PND)10 enhanced plasma corticosterone in male and female pups, increased by two times the total in vivo intestinal permeability (IP) to oral FITC-Dextran 4 kDa (FD4) immediately after the end of MS, and induced bacterial translocation (BT) to liver and spleen. Ussing chamber experiments demonstrated a 2-fold increase of permeability to FD4 in the colon immediately after the end of MS, but not in the ileum. Colonic permeability was not only increased for FD4 but also to intact horseradish peroxidase 44 kDa in MS pups. In vivo, the glucocorticoid receptor (GR) antagonist RU486 or ML7 blockade of myosin light chain kinase controlling epithelial cytoskeleton contraction prevented MS-induced IP increase to oral FD4 and BT. In addition, the GR agonist dexamethasone dose-dependently mimicked MS-increase of IP to oral FD4. In contrast, MS effects on IP to oral FD4 and BT were absent at PND20, a model for full-term infant, characterized by a marked drop of IP to FD4 in response to dexamethasone, and decreased GR expression in the colon only compared to PND10 pups. These results show that high intestinal GC responsiveness in a rat model of prematurity defines a vulnerable window for a post-delivery MS, evoking immediate disruption of epithelial integrity in the large intestine, and increasing susceptibility to macromolecule passage and bacteremia.

Long-Term Effects of Maternal Deprivation on the Neuronal Soma Area in the Rat Neocortex

Early separation of rat pups from their mothers (separatio a matrem) is considered and accepted as an animal model of perinatal stress. Adult rats, separated early postnatally from their mothers, are developing long-lasting changes in the brain and neuroendocrine system, corresponding to the findings observed in schizophrenia and affective disorders. With the aim to investigate the morphological changes in this animal model we exposed 9-day-old (P9) Wistar rats to a 24 h maternal deprivation (MD). At young adult age rats were sacrificed for morphometric analysis and their brains were compared with the control group bred under the same conditions, but without MD. Rats exposed to MD had a 28% smaller cell soma area in the prefrontal cortex (PFCX), 30% in retrosplenial cortex (RSCX), and 15% in motor cortex (MCX) compared to the controls. No difference was observed in the expression of glial fibrillary acidic protein in the neocortex of MD rats compared to the control group. The results of this study demonstrate that stress in early life has a long-term effect on neuronal soma size in cingulate and retrosplenial cortex and is potentially interesting as these structures play an important role in cognition.