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Maria-paz Viveros - One of the best experts on this subject based on the ideXlab platform.

  • Long Term Hippocampal and Cortical Changes Induced by Maternal Deprivation and Neonatal Leptin Treatment in Male and Female Rats
    PloS one, 2015
    Co-Authors: Virginia Mela, Francisca Díaz, Erika Borcel, Jesús Argente, Julie A. Chowen, Maria-paz Viveros
    Abstract:

    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.

  • Maternal Deprivation effects on brain plasticity and recognition memory in adolescent male and female rats
    Neuropharmacology, 2013
    Co-Authors: Eva M. Marco, Erika Borcel, Barbara Aisa, Maria J Ramirez, Manuel Valero, Oscar De La Serna, Maria-paz Viveros
    Abstract:

    Abstract Data from both human and animal studies suggest that exposure to stressful life events at neonatal stages may increase the risk of psychopathology at adulthood. In particular, early Maternal Deprivation, 24 h at postnatal day (pnd) 9, has been associated with persistent neurobehavioural changes similar to those present in developmental psychopathologies such as depression and schizophrenic-related disorders. Most neuropsychiatric disorders first appear during adolescence, however, the effects of MD on adolescent animals' brain and behaviour have been scarcely explored. In the present study, we aimed to investigate the emotional and cognitive consequences of MD in adolescent male and female rats, as well as possible underlying neurobiological mechanisms within frontal cortex and hippocampus. Animals were exposed to a battery of behavioural tasks, from pnd 35 to 42, to evaluate cognitive [spontaneous alternation task (SAT) and novel object test (NOT)] and anxiety-related responses [elevated plus maze (EPM)] during adolescence. Changes in neuronal and glial cells, alterations in synaptic plasticity as well as modifications in cannabinoid receptor expression were investigated in a parallel group of control and adolescent (pnd 40) male and female animals. Notably, MD induced a significant impairment in recognition memory exclusively among females. A generalized decrease in NeuN expression was found in MD animals, together with an increase in hippocampal glial fibrillar acidic protein (GFAP) expression exclusively among MD adolescent males. In addition, MD induced in the frontal cortex and hippocampus of male and female adolescent rats a significant reduction in brain derived neurotrophic factor (BDNF) and postsynaptic density (PSD95) levels, together with a decrease in synaptophysin in frontal cortex and neural cell adhesion molecule (NCAM) in hippocampus. MD induced, in animals of both sexes, a significant reduction in CB1R expression, but an increase in CB2R that was statistically significant only for the frontal cortex. Taken together, these results indicate that adolescent females are more vulnerable than males to the cognitive deficits derived from MD despite the changes in neural cells, cannabinoid receptors, as well as the reduction in neural plasticity seem to be similar in both sexes. Further investigation is needed to understand the neurobiological mechanisms underlying the sexual dimorphisms associated to the MD effects, and thus, for a better understanding of the specific sex-dependent vulnerabilities to early life stress. This article is part of the Special Issue entitled ‘Neurodevelopmental Disorders’.

  • Maternal Deprivation exacerbates the response to a high fat diet in a sexually dimorphic manner
    PLOS ONE, 2012
    Co-Authors: Virginia Mela, Francisca Díaz, Jesús Argente, Maria-paz Viveros, Alvaro Llorenteberzal, Julie A. Chowen
    Abstract:

    Maternal Deprivation (MD) during neonatal life has diverse long-term effects, including affectation of metabolism. Indeed, MD for 24 hours during the neonatal period reduces body weight throughout life when the animals are maintained on a normal diet. However, little information is available regarding how this early stress affects the response to increased metabolic challenges during postnatal life. We hypothesized that MD modifies the response to a high fat diet (HFD) and that this response differs between males and females. To address this question, both male and female Wistar rats were Maternally deprived for 24 hours starting on the morning of postnatal day (PND) 9. Upon weaning on PND22 half of each group received a control diet (CD) and the other half HFD. MD rats of both sexes had significantly reduced accumulated food intake and weight gain compared to controls when raised on the CD. In contrast, when maintained on a HFD energy intake and weight gain did not differ between control and MD rats of either sex. However, high fat intake induced hyperleptinemia in MD rats as early as PND35, but not until PND85 in control males and control females did not become hyperleptinemic on the HFD even at PND102. High fat intake stimulated hypothalamic inflammatory markers in both male and female rats that had been exposed to MD, but not in controls. Reduced insulin sensitivity was observed only in MD males on the HFD. These results indicate that MD modifies the metabolic response to HFD intake, with this response being different between males and females. Thus, the development of obesity and secondary complications in response to high fat intake depends on numerous factors.

  • Maternal Deprivation and adolescent cannabinoid exposure impact hippocampal astrocytes cb1 receptors and brain derived neurotrophic factor in a sexually dimorphic fashion
    Neuroscience, 2012
    Co-Authors: Meritxell Lopezgallardo, Alvaro Llorenteberzal, Antonio Armario, Roser Nadal, Ana Belen Lopezrodriguez, David Rotllant, Ken Mackie, Maria-paz Viveros
    Abstract:

    We have recently reported that early Maternal Deprivation (MD) for 24 h [postnatal day (PND) 9–10] and/or an adolescent chronic treatment with the cannabinoid agonist CP-55,940 (CP) [0.4 mg/kg, PND 28–42] in Wistar rats induced, in adulthood, diverse sex-dependent long-term behavioral and physiological modifications. Here we show the results obtained from investigating the immunohistochemical analysis of CB1 cannabinoid receptors, glial fibrillary acidic protein (GFAP) positive (+) cells and brain-derived neurotrophic factor (BDNF) expression in the hippocampus of the same animals. MD induced, in males, a significant increase in the number of GFAP+ cells in CA1 and CA3 areas and in the polymorphic layer of the dentate gyrus (DG), an effect that was attenuated by CP in the two latter regions. Adolescent cannabinoid exposure induced, in control non-deprived males, a significant increase in the number of GFAP+ cells in the polymorphic layer of the DG. MD induced a decrease in CB1 expression in both sexes, and this effect was reversed in males by the cannabinoid treatment. In turn, the drug “per se” induced, in males, a general decrease in CB1 immunoreactivity, and the opposite effect was observed in females. Cannabinoid exposure tended to reduce BDNF expression in CA1 and CA3 of females, whereas MD counteracted this trend and induced an increase of BDNF in females. As a whole, the present results show sex-dependent long-term effects of both MD and juvenile cannabinoid exposure as well as functional interactions between the two treatments.

  • sex dependent effects of Maternal Deprivation and adolescent cannabinoid treatment on adult rat behaviour
    Addiction Biology, 2011
    Co-Authors: Alvaro Llorenteberzal, Maria-paz Viveros, Meritxell Lopezgallardo, Silvia Fuentes, Humberto Gagliano, Antonio Armario, Roser Nadal
    Abstract:

    Early life experiences such as Maternal Deprivation (MD) exert long-lasting changes in adult behaviour and reactivity to stressors. Adolescent exposure to cannabinoids is a predisposing factor in developing certain psychiatric disorders. Therefore, the combination of the two factors could exacerbate the negative consequences of each factor when evaluated at adulthood. The objective of this study was to investigate the long-term effects of early MD [24 hours at postnatal day (PND) 9] and/or an adolescent chronic treatment with the cannabinoid agonist CP-55,940 (0.4 mg/kg, PND 28-42) on diverse behavioural and physiological responses of adult male and female Wistar rats. We tested them in the prepulse inhibition (PPI) of the startle response and analysed their exploratory activity (holeboard) and anxiety (elevated plus maze, EPM). In addition, we evaluated their adrenocortical reactivity in response to stress and plasma leptin levels. Maternal behaviour was measured before and after Deprivation. MD induced a transient increase of Maternal behaviour on reuniting. In adulthood, Maternally deprived males showed anxiolytic-like behaviour (or increased risk-taking behaviour) in the EPM. Adolescent exposure to the cannabinoid agonist induced an impairment of the PPI in females and increased adrenocortical responsiveness to the PPI test in males. Both, MD and adolescent cannabinoid exposure also induced sex-dependent changes in plasma leptin levels and body weights. The present results indicate that early MD and adolescent cannabinoid exposure exerted distinct sex-dependent long-term behavioural and physiological modifications that could predispose to the development of certain neuropsychiatric disorders, though no synergistic effects were found.

Seymour Levine - One of the best experts on this subject based on the ideXlab platform.

  • brain corticotropin releasing hormone crh circuits in the developing rat effect of Maternal Deprivation
    Brain Research, 2006
    Co-Authors: Delia M Vázquez, Juan F López, Charles E Bailey, Gersham Dent, Darren Okimoto, Amy E Steffek, Seymour Levine
    Abstract:

    Early in life, there is a delicate and critical balance aimed to maintain low hormone responses derived from the stress responsive hypothalamic–pituitary–adrenal axis (HPA). However, in the infant rat hypothalamic corticotrophin-releasing hormone (CRH) stress responses to environmental events are clearly seen even though other elements of the HPA axis may have limited responses. In view of the role of CRH in mediating behavior associated with stress and anxiety, we considered the ontogeny and the effects of prolonged Maternal Deprivation (DEP) in brain areas that express CRH-related molecules outside the hypothalamus. We hypothesized that DEP would alter the ontogeny of CRH, CRH binding protein and CRH receptor 1 in prefrontal cortex, amygdala, septum and hippocampus, areas that are part of the CRH extra hypothalamic system, and that a differential modulation would be observed in response to restraint. We compared non-deprived animals to animals subjected to 24 h of DEP at 6, 12 and 18 days of life. We found (1) developmental patterns, which were idiosyncratic to the anatomical area examined, and (2) a temporal response of mRNA levels which was also site specific. The genomic changes are not always related to Maternal Deprivation status, in fact DEP enhanced, suppressed or had no consequence on the underlying ontogenic progression and restraint response of these CRH-related molecules. We conclude that the extra hypothalamic CRH system is a dynamic system responding to developmental and environmental demands challenging the basic assumption of stress hypo responsiveness in the infant rat. This modulation may have important repercussions on morphological organization and events leading to neuroprotection.

  • The dynamics of the hypothalamic-pituitary-adrenal axis during Maternal Deprivation.
    Journal of neuroendocrinology, 2004
    Co-Authors: Mathias V Schmidt, Seymour Levine, Leo Enthoven, J H G Van Woezik, E.r. De Kloet, Melly S Oitzl
    Abstract:

    A close contact between the dam and the litter is essential for the normal development of the hypothalamic-pituitary-adrenal (HPA) axis in rats and mice. Maternal signals, as licking and feeding, have been shown to sustain the HPA axis of the pups in a hypo-responsive state. Disruption of this mother-pup interaction by 24 h of Maternal Deprivation activates the otherwise quiescent stress system of the neonates, resulting in an enhanced adrenal sensitivity to adrenocorticotropic hormone (ACTH) and a decreased expression of central HPA markers, such as corticotropin-releasing hormone (CRH). However, the dynamics of these central and peripheral changes over the 24h period are largely unknown. In this study, we examined the time course of some of the central and peripheral indices of HPA activity during 24 h of Maternal Deprivation. We measured corticosterone and ACTH in the blood as well as CRH, mineralocorticoid and glucocorticoid receptor expression in the brain. Our results demonstrate that each of the components of the HPA axis responds to Maternal Deprivation at different time points following removal of the mother and with a very specific time course. The main activation of the HPA axis occurred between 4 h and 8 h of Maternal absence. By contrast, during the second half of the Deprivation period, negativefeedback mechanisms restrained the further increase in ACTH and corticosterone release. We conclude that Maternal Deprivation triggers a cascade of sequential changes at the various levels of the stress system, and that measuring only one aspect of the system at one time point does not accurately reflect the dynamic alterations of the HPA axis.

  • the hpa system during the postnatal development of cd1 mice and the effects of Maternal Deprivation
    Developmental Brain Research, 2002
    Co-Authors: Mathias V Schmidt, Melly S Oitzl, Seymour Levine, Ronald E De Kloet
    Abstract:

    Abstract In this study we describe in 9- and 18-day-old CD1 mice (i) the basal and stress-induced activity of markers of the HPA system in blood, brain and pituitary, (ii) the effects of a 24-h Maternal Deprivation and (iii) the influence of anogenital stimulation (stroking) in deprived pups on these markers. We found low basal concentrations of ACTH and corticosterone at postnatal day (pnd) 9 and no or little response to a mild stressor at this age, confirming the existence of a SHRP in mice. At pnd 18 the mice displayed an adult-like ACTH and corticosterone response following a mild stressor. Maternal Deprivation resulted in enhanced basal and stress levels of corticosterone at both ages. Interestingly, basal ACTH levels were elevated following Maternal Deprivation at pnd 9. At pnd 18 Maternal Deprivation resulted in a blunted ACTH response. Maternal Deprivation resulted in a down-regulation of GR, MR, CRH and POMC transcript in the brain. However, Maternally deprived 18-day-old pups displayed increased levels of CRH and POMC transcript, while GR and MR mRNA was also down-regulated. Anogenital stroking could reverse Maternal Deprivation effects on ACTH and MR mRNA, but not CRH mRNA. We conclude that (i) at the two measured time points the HPA axis develops similar in mice as in rats, (ii) Maternal Deprivation has pronounced effects in mice, which are similar to that found in the rat and (iii) there are a number of significant differences, which mainly concern the central CRH–ACTH components of the axis.

  • Maternal Deprivation increases cell death in the infant rat brain
    Brain research. Developmental brain research, 2002
    Co-Authors: Li-xin Zhang, Seymour Levine, Gersham W. Dent, Yutian Zhan, Guoqiang Xing, Darren K. Okimoto, M. Kathleen Gordon, Robert M. Post, Mark A Smith
    Abstract:

    Prolonged separation from the mother can interfere with normal growth and development and is a significant risk factor for adult psychopathology. In rodents, separation of a pup from its mother increases the behavioral and endocrine responses to stress for the lifetime of the animal. Here we investigated whether Maternal Deprivation could affect brain development of infant rats via changes in the rate of cell death as measured by labeling the 3' end of DNA fragments using terminal transferase (ApopTag). At postnatal day 12 (P12), the number of cells undergoing cell death approximately doubled in the cerebral cortex, cerebellar cortex and in several white matter tracts following 24 h of Maternal Deprivation. Deprivation strongly increased the number of ApopTag-labeled cells at P6 but not at P20. Stroking the infant rats only partially reversed the effects of Maternal Deprivation. Increased cell death in white matter tracts correlated with an induction of nerve growth factor which has been previously associated with oligodendrocyte cell death. Cell birth was either unchanged or decreased in response to Deprivation. These results indicate that Maternal Deprivation can alter normal brain development by increasing cell death of neurons and glia, and provides a potential mechanism by which early environmental stressors may influence subsequent behavior.

  • Maternal Deprivation regulates serotonin 1A and 2A receptors in the infant rat.
    Brain research, 2000
    Co-Authors: Delia M Vázquez, Juan F López, Helga Van Hoers, Stanley J. Watson, Seymour Levine
    Abstract:

    Abstract Several studies have demonstrated that 5-HT1A and 5-HT2A receptors are altered in rat brain following chronic stress. While this is true in the adult animal, this may be different in the developing animal, which has a limited corticosterone response to acute challenges between days 3 and 14 of life. Methods: We investigated the effect of Maternal Deprivation on 5-HT2A and 5-HT1A receptor mRNA levels in the developing brain. In situ hybridization was used to quantify gene expression in rat pups at three ages: 6, 9, and 12 days old. In each age group, half were Maternally deprived for 24 h and half were kept with their mothers. Maternally deprived animals showed elevated ACTH and corticosterone plasma levels when compared to NDEP animals, significantly elevated 5-HT1A mRNA levels in the CA1 hippocampal region and, significantly elevated 5-HT2A mRNA levels in the parietal cortex. No changes were observed in 5-HT1A or 5-HT-transporter mRNA levels in the dorsal raphe. Our results indicate that post-synaptic 5-HT receptors in the developing hippocampus and cortex are sensitive to Maternal Deprivation. Because hippocampal 5-HT1A gene expressions are known to decrease in the adult animal after chronic glucocorticoid elevation, this data also suggests that other mechanisms, perhaps central, predominate during development.

E.r. De Kloet - One of the best experts on this subject based on the ideXlab platform.

  • Effects of Maternal Deprivation of CD1 mice on performance in the water maze and swim stress.
    Behavioural brain research, 2007
    Co-Authors: Leo Enthoven, E.r. De Kloet, Melly S Oitzl
    Abstract:

    Rat pups subjected to a single 24h Maternal Deprivation show altered stress responsiveness and cognitive performance in the water maze in adulthood. Here we show in 6-month-old male CD1 mice (deprived 24h at postnatal day 8) an initial impairment in reversal learning: relocating the platform revealed perseverance in search for the former location. Spatial learning, long-term memory and swim-induced corticosterone responses were not affected. We conclude that reduced flexibility is a subtle long-lasting behavioural change induced by Maternal Deprivation.

  • The dynamics of the hypothalamic-pituitary-adrenal axis during Maternal Deprivation.
    Journal of neuroendocrinology, 2004
    Co-Authors: Mathias V Schmidt, Seymour Levine, Leo Enthoven, J H G Van Woezik, E.r. De Kloet, Melly S Oitzl
    Abstract:

    A close contact between the dam and the litter is essential for the normal development of the hypothalamic-pituitary-adrenal (HPA) axis in rats and mice. Maternal signals, as licking and feeding, have been shown to sustain the HPA axis of the pups in a hypo-responsive state. Disruption of this mother-pup interaction by 24 h of Maternal Deprivation activates the otherwise quiescent stress system of the neonates, resulting in an enhanced adrenal sensitivity to adrenocorticotropic hormone (ACTH) and a decreased expression of central HPA markers, such as corticotropin-releasing hormone (CRH). However, the dynamics of these central and peripheral changes over the 24h period are largely unknown. In this study, we examined the time course of some of the central and peripheral indices of HPA activity during 24 h of Maternal Deprivation. We measured corticosterone and ACTH in the blood as well as CRH, mineralocorticoid and glucocorticoid receptor expression in the brain. Our results demonstrate that each of the components of the HPA axis responds to Maternal Deprivation at different time points following removal of the mother and with a very specific time course. The main activation of the HPA axis occurred between 4 h and 8 h of Maternal absence. By contrast, during the second half of the Deprivation period, negativefeedback mechanisms restrained the further increase in ACTH and corticosterone release. We conclude that Maternal Deprivation triggers a cascade of sequential changes at the various levels of the stress system, and that measuring only one aspect of the system at one time point does not accurately reflect the dynamic alterations of the HPA axis.

  • differential and age dependent effects of Maternal Deprivation on the hypothalamic pituitary adrenal axis of brown norway rats from youth to senescence
    Journal of Neuroendocrinology, 2001
    Co-Authors: Judith O. Workel, Melly S Oitzl, Marc Fluttert, Heidi M B Lesscher, Adriaan M Karssen, E.r. De Kloet
    Abstract:

    In this study, the hypothesis was tested that infants deprived from Maternal care show persistent changes in hypothalamic-pituitary-adrenal activity. For this purpose, we studied the effect of Maternal Deprivation in one cohort of the healthy ageing Brown Norway rat strain showing still more than 80% survival rate at 32 months of age. Three-day-old male Brown Norway rats were either Maternally deprived for 24 h or remained with the dam. In 3, 12 and 30-32 months (young, adult, senescent) deprived rats and their nondeprived littermates (controls), we determined basal resting and stress-induced plasma adrenocorticotropic hormone (ACTH) and corticosterone as well as corticotropin releasing hormone (CRH) mRNA expression in the paraventricular nucleus (PVN) of the hypothalamus. Mineralocorticoid (MR) and glucocorticoid receptors (GR) in hippocampus and PVN were also assessed using in vitro cytosol binding and in situ hybridization. The effect of ageing per se showed that in the control nondeprived Brown Norway rats, basal corticosterone and ACTH concentrations did not change during life. However, with age, the corticosterone response to novelty stress became progressively attenuated, but prolonged, while there was an age-related increase in the ACTH response. CRH mRNA expression in PVN decreased with age. Hippocampal MR binding and MR mRNA expression in the dentate gyrus were reduced at senescence, as were the GR binding capacities in hippocampus and hypothalamus. Maternal Deprivation did not affect survival rate, body weight, nor adrenal weight of the ageing Brown Norway rats. Basal corticosterone and ACTH levels were not affected by Deprivation, except for a rise in basal corticosterone concentrations at 3 months. At this age, the corticosterone output in response to novelty was attenuated in the deprived rats. In contrast, a striking surge in novelty stress-induced corticosterone output occurred at midlife while, at senescence, the corticosterone and ACTH responses were attenuated again in the deprived animals, particularly after the more severe restraint stressor. CRH mRNA expression was reduced only during adulthood in the deprived animals. After Maternal Deprivation, the MR mRNA in dentate gyrus showed a transient midlife rise. GR binding in hypothalamus and hippocampus GR binding was reduced in young rats while, in the senescent deprived animals, a reduced GRmRNA expression was observed in PVN and hippocampal CA1. In conclusion, in the Brown Norway rat, ageing causes a progressive decline in corticosterone output after stress, which is paralleled at senescence by decreased MR and GR mRNA expression in hippocampus and hypothalamus. The long-term effects of Maternal Deprivation become manifest differently at different ages and depend on test conditions. The Deprivation effect culminates in a midlife corticosterone surge and results at senescence in a strongly reduced corticosterone output.

  • Maternal Deprivation affects behaviour from youth to senescence: amplification of individual differences in spatial learning and memory in senescent Brown Norway rats
    The European journal of neuroscience, 2000
    Co-Authors: Melly S Oitzl, E.r. De Kloet, Judith O. Workel, Marc Fluttert, Fawzia Frösch
    Abstract:

    Previous studies have shown that Deprivation of the infant rat from Maternal care has pronounced effects on the stress system during ontogeny. Here we test the hypothesis that 24 h of Maternal Deprivation at postnatal day 3 will cause persistent changes in behaviour. Spatial learning and memory of male Brown Norway rats deprived as infants were observed in the Morris water maze at 3, 12, 24 and 30-32 months of age (young, adult, aged, senescent). Their nondeprived mother-reared littermates served as controls. (i) With increasing age, water maze performance declined in deprived and nondeprived groups. However, once the task was learned the animals maintained their good performance during retest at later ages. (ii) Maternal Deprivation delayed acquisition until adulthood and caused at every age a higher degree of persistent behaviour as judged from the performance of deprived rats' free swim trials and reversal trials. (iii) At senescence the mean performance in the water maze did not differ between the groups. Instead, the individual performance was strikingly different within each group. Senescent deprived rats were either nonimpaired or impaired with only a few animals showing an intermediate performance. Thus, a large group of animals ( approximately 40%) ages successfully as they are resistant to the effect of Maternal Deprivation. In contrast, the majority of the control animals displayed intermediate performance. Taken together, Maternal Deprivation has life-long consequences for behaviour and culminates at senescence in amplification of individual differences in learning ability rather than in a generalized deterioration of cognitive functions.

Melly S Oitzl - One of the best experts on this subject based on the ideXlab platform.

  • Effects of Maternal Deprivation of CD1 mice on performance in the water maze and swim stress.
    Behavioural brain research, 2007
    Co-Authors: Leo Enthoven, E.r. De Kloet, Melly S Oitzl
    Abstract:

    Rat pups subjected to a single 24h Maternal Deprivation show altered stress responsiveness and cognitive performance in the water maze in adulthood. Here we show in 6-month-old male CD1 mice (deprived 24h at postnatal day 8) an initial impairment in reversal learning: relocating the platform revealed perseverance in search for the former location. Spatial learning, long-term memory and swim-induced corticosterone responses were not affected. We conclude that reduced flexibility is a subtle long-lasting behavioural change induced by Maternal Deprivation.

  • The dynamics of the hypothalamic-pituitary-adrenal axis during Maternal Deprivation.
    Journal of neuroendocrinology, 2004
    Co-Authors: Mathias V Schmidt, Seymour Levine, Leo Enthoven, J H G Van Woezik, E.r. De Kloet, Melly S Oitzl
    Abstract:

    A close contact between the dam and the litter is essential for the normal development of the hypothalamic-pituitary-adrenal (HPA) axis in rats and mice. Maternal signals, as licking and feeding, have been shown to sustain the HPA axis of the pups in a hypo-responsive state. Disruption of this mother-pup interaction by 24 h of Maternal Deprivation activates the otherwise quiescent stress system of the neonates, resulting in an enhanced adrenal sensitivity to adrenocorticotropic hormone (ACTH) and a decreased expression of central HPA markers, such as corticotropin-releasing hormone (CRH). However, the dynamics of these central and peripheral changes over the 24h period are largely unknown. In this study, we examined the time course of some of the central and peripheral indices of HPA activity during 24 h of Maternal Deprivation. We measured corticosterone and ACTH in the blood as well as CRH, mineralocorticoid and glucocorticoid receptor expression in the brain. Our results demonstrate that each of the components of the HPA axis responds to Maternal Deprivation at different time points following removal of the mother and with a very specific time course. The main activation of the HPA axis occurred between 4 h and 8 h of Maternal absence. By contrast, during the second half of the Deprivation period, negativefeedback mechanisms restrained the further increase in ACTH and corticosterone release. We conclude that Maternal Deprivation triggers a cascade of sequential changes at the various levels of the stress system, and that measuring only one aspect of the system at one time point does not accurately reflect the dynamic alterations of the HPA axis.

  • the hpa system during the postnatal development of cd1 mice and the effects of Maternal Deprivation
    Developmental Brain Research, 2002
    Co-Authors: Mathias V Schmidt, Melly S Oitzl, Seymour Levine, Ronald E De Kloet
    Abstract:

    Abstract In this study we describe in 9- and 18-day-old CD1 mice (i) the basal and stress-induced activity of markers of the HPA system in blood, brain and pituitary, (ii) the effects of a 24-h Maternal Deprivation and (iii) the influence of anogenital stimulation (stroking) in deprived pups on these markers. We found low basal concentrations of ACTH and corticosterone at postnatal day (pnd) 9 and no or little response to a mild stressor at this age, confirming the existence of a SHRP in mice. At pnd 18 the mice displayed an adult-like ACTH and corticosterone response following a mild stressor. Maternal Deprivation resulted in enhanced basal and stress levels of corticosterone at both ages. Interestingly, basal ACTH levels were elevated following Maternal Deprivation at pnd 9. At pnd 18 Maternal Deprivation resulted in a blunted ACTH response. Maternal Deprivation resulted in a down-regulation of GR, MR, CRH and POMC transcript in the brain. However, Maternally deprived 18-day-old pups displayed increased levels of CRH and POMC transcript, while GR and MR mRNA was also down-regulated. Anogenital stroking could reverse Maternal Deprivation effects on ACTH and MR mRNA, but not CRH mRNA. We conclude that (i) at the two measured time points the HPA axis develops similar in mice as in rats, (ii) Maternal Deprivation has pronounced effects in mice, which are similar to that found in the rat and (iii) there are a number of significant differences, which mainly concern the central CRH–ACTH components of the axis.

  • differential and age dependent effects of Maternal Deprivation on the hypothalamic pituitary adrenal axis of brown norway rats from youth to senescence
    Journal of Neuroendocrinology, 2001
    Co-Authors: Judith O. Workel, Melly S Oitzl, Marc Fluttert, Heidi M B Lesscher, Adriaan M Karssen, E.r. De Kloet
    Abstract:

    In this study, the hypothesis was tested that infants deprived from Maternal care show persistent changes in hypothalamic-pituitary-adrenal activity. For this purpose, we studied the effect of Maternal Deprivation in one cohort of the healthy ageing Brown Norway rat strain showing still more than 80% survival rate at 32 months of age. Three-day-old male Brown Norway rats were either Maternally deprived for 24 h or remained with the dam. In 3, 12 and 30-32 months (young, adult, senescent) deprived rats and their nondeprived littermates (controls), we determined basal resting and stress-induced plasma adrenocorticotropic hormone (ACTH) and corticosterone as well as corticotropin releasing hormone (CRH) mRNA expression in the paraventricular nucleus (PVN) of the hypothalamus. Mineralocorticoid (MR) and glucocorticoid receptors (GR) in hippocampus and PVN were also assessed using in vitro cytosol binding and in situ hybridization. The effect of ageing per se showed that in the control nondeprived Brown Norway rats, basal corticosterone and ACTH concentrations did not change during life. However, with age, the corticosterone response to novelty stress became progressively attenuated, but prolonged, while there was an age-related increase in the ACTH response. CRH mRNA expression in PVN decreased with age. Hippocampal MR binding and MR mRNA expression in the dentate gyrus were reduced at senescence, as were the GR binding capacities in hippocampus and hypothalamus. Maternal Deprivation did not affect survival rate, body weight, nor adrenal weight of the ageing Brown Norway rats. Basal corticosterone and ACTH levels were not affected by Deprivation, except for a rise in basal corticosterone concentrations at 3 months. At this age, the corticosterone output in response to novelty was attenuated in the deprived rats. In contrast, a striking surge in novelty stress-induced corticosterone output occurred at midlife while, at senescence, the corticosterone and ACTH responses were attenuated again in the deprived animals, particularly after the more severe restraint stressor. CRH mRNA expression was reduced only during adulthood in the deprived animals. After Maternal Deprivation, the MR mRNA in dentate gyrus showed a transient midlife rise. GR binding in hypothalamus and hippocampus GR binding was reduced in young rats while, in the senescent deprived animals, a reduced GRmRNA expression was observed in PVN and hippocampal CA1. In conclusion, in the Brown Norway rat, ageing causes a progressive decline in corticosterone output after stress, which is paralleled at senescence by decreased MR and GR mRNA expression in hippocampus and hypothalamus. The long-term effects of Maternal Deprivation become manifest differently at different ages and depend on test conditions. The Deprivation effect culminates in a midlife corticosterone surge and results at senescence in a strongly reduced corticosterone output.

  • Maternal Deprivation affects behaviour from youth to senescence: amplification of individual differences in spatial learning and memory in senescent Brown Norway rats
    The European journal of neuroscience, 2000
    Co-Authors: Melly S Oitzl, E.r. De Kloet, Judith O. Workel, Marc Fluttert, Fawzia Frösch
    Abstract:

    Previous studies have shown that Deprivation of the infant rat from Maternal care has pronounced effects on the stress system during ontogeny. Here we test the hypothesis that 24 h of Maternal Deprivation at postnatal day 3 will cause persistent changes in behaviour. Spatial learning and memory of male Brown Norway rats deprived as infants were observed in the Morris water maze at 3, 12, 24 and 30-32 months of age (young, adult, aged, senescent). Their nondeprived mother-reared littermates served as controls. (i) With increasing age, water maze performance declined in deprived and nondeprived groups. However, once the task was learned the animals maintained their good performance during retest at later ages. (ii) Maternal Deprivation delayed acquisition until adulthood and caused at every age a higher degree of persistent behaviour as judged from the performance of deprived rats' free swim trials and reversal trials. (iii) At senescence the mean performance in the water maze did not differ between the groups. Instead, the individual performance was strikingly different within each group. Senescent deprived rats were either nonimpaired or impaired with only a few animals showing an intermediate performance. Thus, a large group of animals ( approximately 40%) ages successfully as they are resistant to the effect of Maternal Deprivation. In contrast, the majority of the control animals displayed intermediate performance. Taken together, Maternal Deprivation has life-long consequences for behaviour and culminates at senescence in amplification of individual differences in learning ability rather than in a generalized deterioration of cognitive functions.

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  • early Maternal Deprivation immunologically primes hippocampal synapses by redistributing interleukin 1 receptor type i in a sex dependent manner
    Brain Behavior and Immunity, 2014
    Co-Authors: Barbara Viviani, Ricardo Llorente, Eva M. Marco, Mariaserena Boraso, Manuel Valero, Fabrizio Gardoni, Emanuela Corsini, C L Galli, Monica Di Luca
    Abstract:

    Challenges experienced in early life cause an enduring phenotypical shift of immune cells towards a sensitised state that may lead to an exacerbated reaction later in life and contribute to increased vulnerability to neurological diseases. Peripheral and central inflammation may affect neuronal function through cytokines such as IL-1. The extent to which an early life challenge induces long-term alteration of immune receptors organization in neurons has not been shown. We investigated whether a single episode of Maternal Deprivation (MD) on post-natal day (PND) 9 affects: (i) the synapse distribution of IL-1RI together with subunits of NMDA and AMPA receptors; and (ii) the interactions between IL-1RI and the GluN2B subunit of the NMDAR in the long-term, at PND 45. MD increased IL-1RI levels and IL-1RI interactions with GluN2B at the synapse of male hippocampal neurons, without affecting the total number of IL-1RI or NMDAR subunits. Although GluN2B and GluN2A were slightly but not significantly changed at the synapse, their ratio was significantly decreased in the hippocampus of the male rats who had experienced MD; the levels of the GluA1 and GluA2 subunits of the AMPAR were also decreased. These changes were not observed immediately after the MD episode. None of the observed alterations occurred in the hippocampus of the females or in the prefrontal cortex of either sex. These data reveal a long-term, sex-dependent modification in receptor organisation at the hippocampal post-synapses following MD. We suggest that this effect might contribute to priming hippocampal synapses to the action of IL-1β.

  • long term sex dependent psychoneuroendocrine effects of Maternal Deprivation and juvenile unpredictable stress in rats
    Journal of Neuroendocrinology, 2011
    Co-Authors: Ricardo Llorente, Erika Borcel, C Miguelblanco, Barbara Aisa, Servane Lachize, Onno C Meijer, Maria J Ramirez, E R De Kloet, Maria-paz Viveros
    Abstract:

    We have analysed the long-term psychoneuroendocrine effects of Maternal Deprivation (MD) [24 h at postnatal day (PND) 9] and/or exposure to chronic unpredictable stress (CUS) during the periadolescent period (PND 28 to PND 43) in male and female Wistar rats. Animals were tested in the elevated plus maze (EPM, anxiety) at PND 44 and in two memory tests, spontaneous alternation and novel object recognition (NOT) in adulthood. The expression of hippocampal glucocorticoid (GR) and mineralocorticoid (MR) receptors, as well as of synaptophysin, neural cell adhesion molecule and brain-derived neurotrophic factor, was analysed by in situ hybridisation in selected hippocampal regions. Endocrine determinations of leptin, testosterone and oestradiol plasma levels were carried out by radioimmunoassay. Young CUS animals showed decreased anxiety behaviour in the EPM (increased percentage of time and entries in the open arms) irrespective of neonatal treatment. Memory impairments were induced by the two stressful treatments as was revealed by the NOT, with males being most clearly affected. Although each stressful procedure, when considered separately, induced different (always decrements) effects on the three synaptic molecules analysed and affected males and females differently, the combination of MD and CUS induced an unique disruptive effect on the three synaptic plasticity players. MD induced a long-term significant decrease in hippocampal GR only in males, whereas CUS tended to increase MR in males and decrease MR in females. Both neonatal MD and periadolescent CUS induced marked reductions in testosterone and oestradiol in males, whereas MD male animals also showed significantly decreased leptin levels. By contrast, in females, none of the hormones analysed was altered by any of the stressful procedures. Taking our data together in support of the 'two-hit' hypothesis, MD during neonatal life and/or exposure to CUS during the periadolescent period induced a permanent deficit in memory, which was accompanied by a decrement in markers for hippocampal plasticity. The long-term effects on body weight and hormone levels, particularly among males, might reflect sex-dependent lasting metabolic alterations as well as an impaired reproductive function.

  • Maternal Deprivation has sexually dimorphic long term effects on hypothalamic cell turnover body weight and circulating hormone levels
    Hormones and Behavior, 2010
    Co-Authors: Maria-paz Viveros, Francisca Díaz, Jesús Argente, Ricardo Llorente, Francisco Javier Bermudezsilva, Silvana Y Romerozerbo, Fernando Rodriguez De Fonseca, Julie A. Chowen
    Abstract:

    Maternal Deprivation (MD) has numerous outcomes, including modulation of neuroendocrine functions. We previously reported that circulating leptin levels are reduced and hypothalamic cell-turnover is affected during MD, with some of these effects being sexually dimorphic. As leptin modulates the development of hypothalamic circuits involved in metabolic control, we asked whether MD has long-term consequences on body weight, leptin levels and the expression of neuropeptides involved in metabolism. Rats were separated from their mother for 24 h starting on postnatal day (PND) 9 and sacrificed at PNDs 13, 35 and 75. In both sexes MD reduced body weight, but only until puberty, while leptin levels were unchanged at PND 35 and significantly reduced at PND 75. Adiponectin levels were also reduced at PND 75 in females, while testosterone levels were reduced in males. At PND 13, MD modulated cell-turnover markers in the hypothalamus of males, but not females and increased nestin, a marker of immature neurons, in both sexes, with males having higher levels than females and a significantly greater rise in response to MD. There was no effect of MD on hypothalamic mRNA levels of the leptin receptor or metabolic neuropeptides or the mRNA levels of leptin and adiponectin in adipose tissue. Thus, MD has long-term effects on the levels of circulating hormones that are not correlated with changes in body weight. Furthermore, these endocrine outcomes are different between males and females, which could be due to the fact that MD may have sexually dimorphic effects on hypothalamic development.

  • early Maternal Deprivation induces changes on the expression of 2 ag biosynthesis and degradation enzymes in neonatal rat hippocampus
    Brain Research, 2010
    Co-Authors: Juan Suarez, Ricardo Llorente, Francisco Javier Bermudezsilva, Silvana Y Romerozerbo, Fernando Rodriguez De Fonseca, Patricia Rivera, Maria-paz Viveros
    Abstract:

    Abstract Early Maternal Deprivation (MD) in rats (24 h, PND 9–10) is a model for neurodevelopmental stress. Our previous data showed that MD altered the hippocampal levels of the endocannabinoid 2-AG and the expression of hippocampal cannabinoid receptors in 13-day-old rats, with males being more markedly affected. The aim of this study was to analyze the impact of MD on the enzymes involved in 2-AG biosynthesis (DAGLα and DAGLβ) and degradation (MAGL) in relevant areas (DG, CA1, CA3) of the hippocampus in 13-day-old neonatal rats. The expression of the enzymes was evaluated by quantitative RT–PCR, immunohistochemistry, and densitometry. MD induced a significant increase in DAGLα immunoreactivity in both males and females, which was mainly associated with fibers in the polymorphic cell layer of the dentate gyrus and in the stratum pyramidale of CA3. In contrast, the molecular layer of the dentate gyrus showed a significant decrease in DAGLα immunoreactivity in MD males and females. No changes were observed in DAGLβ immunoreactivity. MD induced a significant decrease in MAGL immunoreactivity in hippocampal CA3 and CA1 areas, more marked in males than in females, and that was mainly associated with fibers in all strata of CA3 and CA1. The results also showed a significant decrease of MAGL mRNA levels in MD males. These data support a clear association between neurodevelopmental stress and dysregulation of the endocannabinoid system. This association may be relevant for schizophrenia and other neurodevelopmental psychiatric disorders.

  • sex dependent Maternal Deprivation effects on brain monoamine content in adolescent rats
    Neuroscience Letters, 2010
    Co-Authors: Ricardo Llorente, Esther Oshea, Dolores M Gutierrezlopez, Alvaro Llorenteberzal, M I Colado, Maria-paz Viveros
    Abstract:

    Rats subjected to a single prolonged episode of Maternal Deprivation (MD) [24h, postnatal days 9-10] show, later in life, behavioural alterations that resemble specific signs of schizophrenia and other neuropsychiatric signs including increased levels of impulsivity and an apparent difficulty to cope with stressful situations. Some of these behavioural modifications are observable in the periadolescent period. However there is no previous information regarding the possible underlying neurochemical correlates at this critical developmental period. In this study we have addressed the effects of MD on the levels of serotonin (5-HT), dopamine (DA) and their respective metabolites in prefrontal cortex, hippocampus, striatum, midbrain and cerebellum of male and female periadolescent Wistar rats. MD rats showed significantly increased levels of 5-HT in all regions studied with the exception of cerebellum. In addition, MD animals showed increased levels of DA in PFC as well as increased levels of DA and a decrease of DOPAC/DA and HVA/DA ratios in striatum. The effect of MD on the monoaminergic systems was in several cases sex-dependent.