Carine Parent

The programming of individual differences in defensive responses and reproductive strategies in the rat through variations in maternal care

There are profound maternal effects on individual differences in defensive responses and reproductive strategies in species ranging literally from plants to insects to birds. Maternal effects commonly reflect the quality of the environment and are most likely mediated by the quality of the maternal provision (egg, propagule, etc.), which in turn determines growth rates and adult phenotype. In this paper, we review data from the rat that suggest comparable forms of maternal effects on both defensive responses to threat and reproductive behavior and which are mediated by variations in maternal behavior. Ultimately, we will need to contend with the reality that neural development, function and health are defined by social and economic influences.

The influence of natural variations in maternal care on play fighting in the rat.

Naturally occurring variations in maternal care in the rat influence the sensitivity of offspring to stress in adulthood. The offspring of mothers that show lower levels of pup licking/grooming (i.e., low-LG mothers) demonstrate enhanced responses to stress and increased anxiety compared to those of high-LG mothers. Low-LG offspring are also more sensitive to the influence of environmental enrichment than high-LG offspring. This study examined play fighting in the juvenile offspring of high-LG and low-LG dams in a multiple-play partners housing environment. Male offspring from low-LG dams demonstrated a significantly higher frequency of pouncing, pinning and aggressive social grooming than did high-LG males and high-LG and low-LG females. Consistent with earlier reports, male pups engaged in more play fighting than did females and maternal care was associated with differences in play fighting but only in males. Lower levels of stimulation in the form of LG from the dam during perinatal development may thus increase sensitivity for the stimulating effects of play behavior in periadolescence, in part explaining the increased solicitation of play fighting through increased pouncing in the male offspring of the low-LG mothers. These findings identify a possible influence of variations in maternal care on play fighting and suggest that maternal care in the perinatal period influence social interactions during periadolescence.

Maternal Programming of Individual Differences in Defensive Responses in the Rat

Abstract: This paper describes the results of a series of studies showing that variations in mother‐pup interactions program the development of individual differences in behavioral and endocrine stress responses in the rat. These effects are associated with altered expression of genes in brain regions, such as the amygdala, hippocampus, and hypothalamus, that regulate the expression of stress responses. Studies from evolutionary biology suggest that such “maternal effects” are common and often associated with variations in the quality of the maternal environment. Together these findings suggest an epigenetic process whereby the experience of the mother alters the nature of the parent‐offspring interactions and thus the phenotype of the offspring.

Maternal Care and Individual Differences in Defensive Responses

Familial transmission of mental illness is common. Recent studies in behavioral neuroscience and biological psychiatry reveal the importance of epigenetic mechanisms of transmission that center on the developmental consequences of variations in parental care. Studies with rats suggest that environmental adversity results in patterns of parent–offspring interactions that increase stress reactivity through sustained effects on gene expression in brain regions known to regulate behavioral, endocrine, and autonomic responses to stress. While such effects might be adaptive, the associated cost involves an increased risk for stress-related illness.

Maternal care associates with play dominance rank among adult female rats

Variations in maternal care influence important life history traits that determine reproductive fitness. The adult female offspring of mothers that show reduced levels of pup licking/grooming (LG; i.e., low-LG mothers) show increased defensive responses to stress, accelerated pubertal development, and greater sexual receptivity than the female offspring of high-LG mothers. Amongst several species an accelerated pattern of reproductive development is associated with increased dominance-related behaviors and higher social rank. We hypothesize that rats from low-LG dams may thus also secure higher social rank as a means to compete for limited resources with conspecifics. In this study, social interactions were observed in triads of adult female rats aged p90 that received low, mid, and high levels of pup LG over the first week of life. Low- and mid-LG females had the highest pinning scores and high-LG rats the lowest, showing that low- and mid-LG adult females engage in greater play dominance-related behavior. Likewise, low- and mid-LG rats spent significantly more time drinking following 24 hr of water deprivation in a water competition test thus allowing them to secure a limited resource more easily than high-LG rats. Interestingly, pinning by play dominant females was increased when subordinates were sexually receptive (proestrus/estrus), suggestive of a process of reproductive suppression. Some evidence suggests that low-LG and mid-LG rats also show greater fecundity than high-LG rats. Variations in maternal care may thus have a long-term influence on the development of play dominance and possibly social rank in the female rat, which might contribute to reproductive success within a competitive environment.

Cumulative prenatal exposure to adversity reveals associations with a broad range of neurodevelopmental outcomes that are moderated by a novel, biologically informed polygenetic score based on the serotonin transporter solute carrier family C6, member 4 (SLC6A4) gene expression

While many studies focus on the association between early life adversity and the later risk for psychopathology, few simultaneously explore diverse forms of environmental adversity. Moreover, those studies that examined the cumulative impact of early life adversity focus uniquely on postnatal influences. The objective of this study was to focus on the fetal period of development to construct and validate a cumulative prenatal adversity score in relation to a wide range of neurodevelopmental outcomes. We also examined the interaction of this adversity score with a biologically informed genetic score based on the serotonin transporter gene. Prenatal adversities were computed in two community birth cohorts using information on health during pregnancy, birth weight, gestational age, income, domestic violence/sexual abuse, marital strain, as well as maternal smoking, anxiety, and depression. A genetic score based on genes coexpressed with the serotonin transporter in the amygdala, hippocampus, and prefrontal cortex during prenatal life was constructed with an emphasis on functionally relevant single nucleotide polymorphisms, that is, expression quantitative trait loci. Prenatal adversities predicted a wide range of developmental and behavioral alterations in children as young as 2 years of age in both cohorts. There were interactions between the genetic score and adversities for several domains of the Child Behavior Checklist (CBCL), with pervasive developmental problems remaining significant adjustment for multiple comparisons. Scores combining different prenatal adverse exposures predict childhood behavior and interact with the genetic background to influence the risk for psychopathology.

Maternal care associates with differences in morphological complexity in the medial preoptic area

Abstract The medial preoptic area (MPOA) is implicated in the expression of maternal behavior including the frequency of pup licking/grooming (LG) in the rat. Cyclic adenosine monophosphate (cAMP) responsive element‐binding protein (CREB) is a transcription factor that regulates the expression of many genes. We found that lactating rats that are more maternal towards their pups showing increased licking/grooming (i.e. high‐LG mothers) had increased levels of phosphorylated CREB (pCREB) in the MPOA following a nursing bout and they displayed a reduced population of greater dendritic complexity index (DCI) neurons compared to less maternal rats showing decreased licking/grooming (i.e. low‐LG mothers). CREB overexpression in MPOA neuronal cultures associated with a decrease in dendritic complexity and an increase in the expression of Rem2 and brain‐derived neurotrophic factor (BDNF), genes implicated in dendritic pruning. While there were no differences in Rem2 expression in virgin high and low‐LG female rats, Rem2 was significantly increased in the MPOA of high‐LG compared to low‐LG lactating rats. CREB activity in the MPOA associates with maternal behavior and reduced dendritic complexity possibly by increasing Rem2 expression.

Generalization of Conditioned Auditory Fear is Regulated by Maternal Effects on Ventral Hippocampal Synaptic Plasticity

Maternal care shapes individual differences in fear-associated neural circuitry. In rats, maternal licking and grooming (LG) in early life regulates ventral hippocampal (VH) function and plasticity in adulthood, but its consequent effect on the regulation of fear memories remains unknown. We report an effect of maternal care on generalization of learned fear, such that offspring of high LG mothers express generalized fear responses when confronted with neutral stimuli following auditory fear conditioning. These animals simultaneously display a reduction in the magnitude of VH long-term potentiation (LTP) expressed and reduced input–output transformation in Schaffer collateral synapses. Inhibition of VH-LTP during learning specifically increases fear generalization in offspring of low LG mothers during recall, suggesting a role for VH synaptic plasticity in the specification of fear memories. These findings suggest that rearing by low LG dams enhances the efficacy of fear-related neural systems to support accurate encoding of fear memories through effects on the VH.

Birth weight and catch up growth are associated with childhood impulsivity in two independent cohorts

Individuals born after intrauterine growth restriction (IUGR) are more impulsive towards palatable foods, but it is not clear 1) if IUGR-related impulsivity is specific for foods and solely based on response inhibition and 2) if the development of impulsivity is due to being born IUGR per se or to growing up fast in the first few years of life (catch up growth). Children were classified in the IUGR group if the birth weight ratio was below 0.85. Delta z score for BMI was used as a measure of catch up growth. In MAVAN (N = 274), impulsivity was measured by the Information Sampling Task from the Cambridge Neuropsychological Test Automated Battery (IST - CANTAB), and in GUSTO using the Sticker Delay Task (N = 327). There is a significant effect of interaction between being born IUGR and the magnitude of catch up growth on the reflection impulsivity from IST-CANTAB at 60 months, in which greater catch up growth associates with greater impulsivity in the IST fixed condition in IUGR children. The finding was reproduced in children from the GUSTO cohort using the Sticker Delay Task. We confirmed that catch up growth interacts with IUGR, having a major role in the development of impulsivity in the first years of life and influencing inhibitory control and decision making processes.

Community study found that cutaneous allergies in childhood were associated with conduct problems in girls

Several studies have shown that children with eczema, which is the most common form of cutaneous allergy, have an increased prevalence of psychological and behavioural problems or mental health disorders (1). Higher rates of anxiety and depression have been found in females than males with eczema (2) in adult studies, but the role that sex plays in influencing the association between eczema and the risk for mental health problems has not been extensively studied in young children. Our goal was to determine whether cutaneous allergies during childhood were associated with socioemotional outcomes in young girls and boys. Our community-based sample consisted of 630 mother–child dyads who were recruited in Montr eal and Hamilton, Canada, at 13– 20 weeks of gestation from antenatal care clinics during routine ultrasound visits or through advertisements displayed at local hospitals. The demographic information is in Table S1. The participants were part of the Maternal Adversity, Vulnerability, and Neurodevelopment study, which examined the development of individual differences in phenotypes associated with multiple forms of psychopathology. The study was conducted between 2003 and 2016. Mothers were first assessed during their pregnancy, between 24 and 36 weeks, and then followed at multiple time points, which included home visits and laboratory sessions. Written informed consent was obtained from all the participants. Ethics approval was obtained from the Douglas Mental Health University Institute at McGill University, Montreal, and St. Joseph’s Healthcare Hamilton at McMaster University, Hamilton. Mothers were asked to report on the state of their child’s health at different time points by answering questions on the Child’s Health Questions questionnaire (CHQ). The CHQ questionnaire was designed by Louise S eguin, MD, based on questions used for the Longitudinal Study of Child Development study in Quebec from1998 to 2002 and theNational Longitudinal Survey of Children and Youth study, (NLSCY 1994-present) which started in 1994 and is still continuing. This questionnaire was administered to themothers when their study child was 3, 6, 12 and 18 months and in the months they turned three, four, five and six years of age. The mothers were asked if their child had been diagnosedwith an allergy in the last six months at each time point, and the answers were dichotomised into yes or no. We also identified the presence or absence of cutaneous allergies, with eczema being the most common form. Therefore, a cutaneous allergy was used as a proxy for eczema. Socio-emotional development was assessed using the mother-reported Child Behavior Checklist (CBCL) at four and five years and the Strengths and Difficulties Questionnaire (SDQ) at five and six years. From the original 630 mother–child pairs recruited into the study, we were able to collect mother reports of child socio-emotional outcomes from 369 children at four years (41% attrition), 325 children at five years (48% attrition) and 260 children at six years (59% attrition). A generalised estimating equations analysis was used to account for repeated measurements of cutaneous allergies and socio-emotional outcome assessments at different times in boys and girls separately. An a priori split of the data on the boys and girls was conducted as previous findings showed differences in the risk for eczema, severity of eczema symptoms and impairments in quality of life between males and females with eczema (3). The presence of a childhood cutaneous allergy was the independent variable, and the dependent variables were the various socioemotional outcomes reported by the mother using the SDQ scores at five and six years and the CBCL scores at four and five years. Adjustments for maternal depression, gathered using the scores from the Center for Epidemiologic Studies Depression Scale Revised questionnaire, and family socio-economic status were added to the models. The data were analysed using the R statistical package (R Core Team, Vienna, Austria) and the Statistical Package for the Social Sciences version 20.0 (IBM Corp, Armonk, NY, USA). The Bonferroni–Holm correction was applied to adjust for multiple comparisons. The data are presented as beta values. Beta is an estimated regression coefficient representing the effect of the presence of a cutaneous allergy on a behavioural or psychological outcome. A p value of less than 0.05 was regarded as statistically significant. In addition to the demographic information on the mother–child dyads (Table S1), our data show that girls with a cutaneous allergy had higher emotional reactivity (Table S2) and higher emotional symptoms scores and higher conduct problems (Table 1) than girls without