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

Abstract

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.

Maternal Separation Early in Life Alters the Expression of Genes Npas4 and Nr1d1 in Adult Female Mice: Correlation with Social Behavior

“…The specific aim of the present study was to characterize the expression of immediate early genes in the prefrontal cortex of adult female mice as a marker of modified neuroplasticity elicited both by stress early in life and by previous social interaction. In addition, we analyzed the expression of these genes in the dorsal hippocampus, as a region affected by stress early in life, as demonstrated by us previously [15]. In that study [15], by means of the same model of stress in females, we showed that prolonged maternal separation reduces the number of mature neurons in the CA3 area of the dorsal hippocampus and impairs long-term spatial and recognition memory.…”

“…In addition, we analyzed the expression of these genes in the dorsal hippocampus, as a region affected by stress early in life, as demonstrated by us previously [15]. In that study [15], by means of the same model of stress in females, we showed that prolonged maternal separation reduces the number of mature neurons in the CA3 area of the dorsal hippocampus and impairs long-term spatial and recognition memory. Thus, in the present study, we wanted to estimate how these observed behavioral changes in emotional states are related to the neuroplasticity of the dorsal hippocampus.…”

“…Early-life experience can shape the developing brain and encode subsequent behavior of the individuals. Our previous studies have revealed that early-life experience leads to enhanced social behavior of females with a history of brief or prolonged maternal separation [14], and these alterations may affect the next generation too: the level of social behavior was also high (at least among males), and the social coping strategy was different in the descendants that were brought up by the mothers with a history of prolonged maternal separation [15,71]. We can theorize that the upregulation of Npas4 and Nr1d1 in females with a history of early-life stress and the corresponding enhancement of social behavior may be considered an adaptation mechanism reversing the possible aberrations caused by early-life stress.…”

“…We found that both types of stress result in enhanced social behavior in female mice. On the other hand, there are reports of greater anxiety [14] and worsening of cognitive functions [15] in females with a history of prolonged maternal separation. Thus, similar enhancements of social behavior develop during different molecular changes in the brain, possibly indicating different mechanisms underlying the changes in social behavior after exposure to one of these two types of stress.…”

Sex differences in mechanisms of disease

“…Two papers in this issue examine factors that can disrupt a behavior that is (at least in most laboratory rodents) uniquely female—maternal care—which can have long‐lasting effects on offspring development and mental health. Reshetnikov et al find that prolonged separation from their pups during the first 2 weeks of life causes a robust decrease in pup licking, an effect accompanied by cell loss in the hippocampus and spatial memory deficits. Poor maternal care was also observed in mice with a double knockout (dKO) of two diacylglycerol kinase genes (eta and iota) .…”