The Long-Term Effects of Early Postnatal Stress on Cognitive Abilities and Expression of Genes of the Glutamatergic System in Mice

Reshetnikov, Vasiliy V.; Lepeshko, Arina A.; Ryabushkina, Yu. A.; Studenikina, A. A.; Merkulova, T. I.; Bondar, Natalia P.

doi:10.1134/s1819712418020095

Cited by 10 publications

(7 citation statements)

References 52 publications

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“…Additionally, exploratory and locomotor activities were evaluated using this test. All conditions and apparatuses were described elsewhere . The test was performed in a square arena (white plastic box, 40 × 40 × 25 cm) during three consecutive days.…”

Section: Methodsmentioning

confidence: 99%

“…The protocol of dam-offspring separation was described previously. 16,42 Briefly, we applied two types of early-life stress from postnatal day 2 (PND 2) to PND 14 (the day of birth was PND 0): prolonged separation of pups from their mothers (maternal separation for 3 hours once a day, MS) and brief separation (handling for 15 minutes once a day, HD). Nonhandled control mice were not separated from dams (normal conditions, NC).…”

Section: Experimental Designmentioning

confidence: 99%

“…All conditions and apparatuses were described elsewhere. 42 The test was performed in a square arena (white plastic box, 40 × 40 × 25 cm) during three consecutive days. On test day 1, each mouse was placed in the empty arena for habituation ( Figure 3A, day 1); on day 2, two completely novel identical objects (blue blocks, 5.5 × 5.5 × 5.5 cm) were placed 13 cm apart and 8 cm away from each wall on the no-mouse side of the chamber, and the mouse was allowed to investigate the new objects ( Figure 3A, day 2).…”

Section: The Nor Testmentioning

confidence: 99%

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Stress early in life leads to cognitive impairments, reduced numbers of CA3 neurons and altered maternal behavior in adult female mice

Reshetnikov

Ковнер

Lepeshko

et al. 2018

Genes Brain and Behavior

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The hippocampus is a crucial part of the limbic system involved both in cognitive processing and in the regulation of responses to stress. Adverse experiences early in life can disrupt hippocampal development and lead to impairment of the hypothalamic‐pituitary‐adrenal axis response to subsequent stressors. In our study, two types of early‐life stress were used: prolonged separation of pups from their mothers (for 3 hours/day, maternal separation, MS) and brief separation (for 15 minutes/day, handling, HD). In the first part of our study, we found that adult female mice (F0) who had experienced MS showed reduced locomotor activity and impairment of long‐term spatial and recognition memory. Analysis of various hippocampal regions showed that MS reduced the number of mature neurons in CA3 of females, which is perhaps a crucial hippocampal region for learning and memory; however, neurogenesis remained unchanged. In the second part, we measured maternal care in female mice with a history of early‐life stress (F0) as well as the behavior of their adult offspring (F1). Our results indicated that MS reduced the level of maternal care in adult females (F0) toward their own progeny and caused sex‐specific changes in the social behavior of adult offspring (F1). In contrast to MS, HD had no influence on female behavior or hippocampal plasticity. Overall, our results suggest that prolonged MS early in life affects the adult behavior of F0 female mice and hippocampal neuronal plasticity, whereas the mothers' previous experience has effects on the behavior of their F1 offspring through disturbances of mother‐infant interactions.

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Section: Methodsmentioning

confidence: 99%

Section: Experimental Designmentioning

confidence: 99%

Section: The Nor Testmentioning

confidence: 99%

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Stress early in life leads to cognitive impairments, reduced numbers of CA3 neurons and altered maternal behavior in adult female mice

Reshetnikov

Ковнер

Lepeshko

et al. 2018

Genes Brain and Behavior

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“…Different models of maternal separation may cause differences in the expression of NMDARs and receptor signaling because the 24-h maternal deprivation on PND 9 reduced the mRNA levels of Grin2A and Grin2B subunits in the hippocampus and prefrontal cortex of adult rats [ 84 ]. In another study, no alterations in the mRNA levels of Grin2A and Grin2B were detected in the prefrontal cortex and hippocampus of adult mice subjected to 15-min or 3-h maternal separation for the first two weeks [ 85 ] suggesting that the impact of maternal separation on proteomic profiling of brain tissue may be mediated at the level of protein synthesis, folding, processing and degradation.…”

Section: Resultsmentioning

confidence: 99%

Proteome profiling of different rat brain regions reveals the modulatory effect of prolonged maternal separation on proteins involved in cell death-related processes

et al. 2021

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Background Early-life stress in the form of maternal separation can be associated with alterations in offspring neurodevelopment and brain functioning. Here, we aimed to investigate the potential impact of prolonged maternal separation on proteomic profiling of prefrontal cortex, hippocampus and cerebellum of juvenile and young adult rats. A special attention was devoted to proteins involved in the process of cell death and redox state maintenance. Methods Long-Evans pups were separated from their mothers for 3 h daily over the first 3 weeks of life (during days 2–21 of age). Brain tissue samples collected from juvenile (22-day-old) and young adult (90-day-old) rats were used for label-free quantitative (LFQ) proteomic analysis. In parallel, selected oxidative stress markers and apoptosis-related proteins were assessed biochemically and by Western blot, respectively. Results In total, 5526 proteins were detected in our proteomic analysis of rat brain tissue. Approximately one tenth of them (586 proteins) represented those involved in cell death processes or regulation of oxidative stress balance. Prolonged maternal separation caused changes in less than half of these proteins (271). The observed alterations in protein expression levels were age-, sex- and brain region-dependent. Interestingly, the proteins detected by mass spectrometry that are known to be involved in the maintenance of redox state were not markedly altered. Accordingly, we did not observe any significant differences between selected oxidative stress markers, such as the levels of hydrogen peroxide, reduced glutathione, protein carbonylation and lipid peroxidation in brain samples from rats that underwent maternal separation and from the corresponding controls. On the other hand, a number of changes were found in cell death-associated proteins, mainly in those involved in the apoptotic and autophagic pathways. However, there were no detectable alterations in the levels of cleaved products of caspases or Bcl-2 family members. Taken together, these data indicate that the apoptotic and autophagic cell death pathways were not activated by maternal separation either in adolescent or young adult rats. Conclusion Prolonged maternal separation can distinctly modulate expression profiles of proteins associated with cell death pathways in prefrontal cortex, hippocampus and cerebellum of juvenile rats and the consequences of early-life stress may last into adulthood and likely participate in variations in stress reactivity.

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“…Thus, more marked cognitive deficits result from neonatal dexamethasone administration than from the stress caused by maternal separation, because the former affects both learning and the reproduction of newly learned information. A comparison of available data on other aspects of cognitive functions shows that impairments in novel object recognition that are due to both early-life stress (Reshetnikov et al, 2018a) and neonatal dexamethasone treatment (Li et al, 2014a) are similar.…”

Section: Discussionmentioning

confidence: 99%

Effect of neonatal dexamethasone treatment on cognitive abilities of adult male mice and gene expression in the hypothalamus

et al. 2019

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The early postnatal period is critical for the development of the nervous system. Stress during this period causes negative long-term effects, which are manifested at both behavioral and molecular levels. To simulate the elevated glucocorticoid levels characteristic of early-life stress, in our study we used the administration of dexamethasone, an agonist of glucocorticoid receptors, at decreasing doses at the first three days of life (0.5, 0.3, 0.1 mg/kg, s.c.). In adult male mice with neonatal dexamethasone treatment, an increase in the relative weight of the adrenal glands and a decrease in body weight were observed, while the basal level of corticosterone remained unchanged. Dexamethasone treatment in early life had a negative impact on the learning and spatial memory of adult mice in the Morris water maze. We analyzed the effect of elevated glucocorticoid levels in early life on the expression of the Crh, Avp, Gr, and Mr genes involved in the regulation of the HPA axis in the hypothalami of adult mice. The expression level of the mineralocorticoid receptor gene (Mr) was significantly downregulated, and the glucocorticoid receptor gene (Gr) showed a tendency towards decreased expression (p = 0.058) in male mice neonatally treated with dexamethasone, as compared with saline administration. The expression level of the Crh gene encoding corticotropin-releasing hormone was unchanged, while the expression of the vasopressin gene (Avp) was increased in response to neonatal administration of dexamethasone. The obtained results demonstrate a disruption of negative feedback regulation of the HPA axis, which involves glucocorticoid and mineralocorticoid receptors, at the level of the hypothalamus. Malfunction of the HPA axis as a result of activation of the glucocorticoid system in early life may cause the development of cognitive impairment in the adult mice.

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The Long-Term Effects of Early Postnatal Stress on Cognitive Abilities and Expression of Genes of the Glutamatergic System in Mice

Cited by 10 publications

References 52 publications

Stress early in life leads to cognitive impairments, reduced numbers of CA3 neurons and altered maternal behavior in adult female mice

Stress early in life leads to cognitive impairments, reduced numbers of CA3 neurons and altered maternal behavior in adult female mice

Proteome profiling of different rat brain regions reveals the modulatory effect of prolonged maternal separation on proteins involved in cell death-related processes

Effect of neonatal dexamethasone treatment on cognitive abilities of adult male mice and gene expression in the hypothalamus

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