Recent research has linked early life exposure to selective serotonin reuptake inhibitor medications (SSRIs) to modifications of social behaviors in children. Serotonin is a key regulator of neurodevelopment, social behaviors and mental health, and with the growing use of SSRIs to treat maternal affective disorders during the perinatal period, questions have been raised about the benefits and risks of perinatal SSRI exposure on the developing child. This review will highlight how perinatal SSRIs affect maternal care and neurodevelopmental outcomes related to social affiliative behaviors in offspring; such as play behaviors, social interactions, reproductive behaviors, and maternal care of the next generation. We will also review how early life exposure to SSRIs can alter related neurobiology, and the epigenome. Both clinical research and findings from animal models will be discussed. Understanding the impact of perinatal SSRIs on neurobehavioral outcomes will improve the health and well-being of subsequent generations.
Siblings share similar genetics and environments, however, their behavior can be quite different. To determine if within-litter variance in neonatal-maternal interactions predict adult sibling behavioral variance, we observed mother-pup interactions during postnatal days 1-8 in four Sprague-Dawley rat litters and measured adult offspring behavioral responses to social and physical novelty. Our results indicate that pup and maternal behavior varied by at least twofold within each litter, and that specific pup behaviors within each litter (perioral contact) were associated with increased maternal licking. Furthermore, siblings that received more licks and made more perioral contact during postnatal days 1-8 had longer latencies to approach novel objects in adulthood than siblings that received less licking and made less perioral contact. This within-litter variance in postnatal mother and pup behavior and offspring adult behavior indicates that early social dynamics within families are an important area to examine to understand the development of sibling variance.
In female mammals, the postpartum period involves dramatic shifts in many socioemotional behaviors. This includes a suppression of anxiety-related behaviors that requires recent physical contact with offspring. Factors contributing to differences among females in their susceptibility to the anxiety-modulating effect of offspring contact are unknown, but could include their innate anxiety and brain monoaminergic activity. Anxiety behavior was assessed in a large group of nulliparous female rats and the least-anxious and most-anxious tertiles were mated. Anxiety was assessed again postpartum after females were permitted or prevented from contacting their offspring 4 h before testing. Levels of dopamine β-hydroxylase (DBH, norepinephrine synthesizing enzyme) and tryptophan hydroxylase- 2 (TPH2, serotonin synthesizing enzyme) were measured in the brainstem and dorsal raphe, respectively. It was found that anxiety-related behavior in the two groups did not differ when dams were permitted contact with offspring before testing. Removal of the offspring before testing, however, differentially affected anxiety based on dams’ innate anxiety. Specifically, dams reverted back to their pre-mating levels of anxiety such that offspring removal slightly increased anxiety in the most-anxious females but greatly lowered anxiety in the least-anxious females. This reduction in anxiety in the least-anxious females after litter removal was associated with lower brainstem DBH. There was no relationship between females’ anxiety and dorsal raphe TPH2. Thus, a primary effect of recent contact with offspring on anxiety-related behavior in postpartum rats is to shift females away from their innate anxiety to a more moderate level of responding. This effect is particularly true for females with the lowest anxiety, may be mediated by central noradrenergic systems, and has implications for their ability to attend to their offspring.
The need to obtain data from individual laboratory animals has forced many researchers to singlyhouse rodents and small animals. Isolation is an abnormal condition for many species, and adverse effects of single-housing on physiology and behavior threaten the validity of experimental results and generalization to humans, who are also social. This study assessed the practical use of a housing device -dubbed "Buddy Barrier" (BB) -that allows rats social stimulation in a paired-housing situation while at the same time permitting the collection of individual measures that traditionally require individual-housing. To assess stress responses to the BB, adult male rats were single or pairhousing for several days with and without a BB in the cage and fecal corticosterone metabolites (fCORT), food intake and body weight were monitored. Plasma corticosterone and adrenal catecholamine levels were also assessed at the end of the housing manipulation. Stress hormone measures did not differ in paired vs. singly-housed rats and paired rats quickly habituated to the BB taken in and out of the cage. Barring a trend for paired rats to eat more in the first 4hrs of the dark, there was no difference in 24hr intakes or body weight gain between singly and paired-housed rats. While the BB attenuated 24hr intakes in both groups, intakes normalized to non-BB conditions by the third BB reintroduction. A device such as the BB can enhance the welfare of animals by providing social enrichment without compromising the integrity of experimental manipulations in protocols that traditionally have required single-housing.
Several personality/temperament traits have been linked to health outcomes in humans and animals but underlying physiological mechanisms for these differential outcomes are minimally understood. In this paper, we compared the strength of a behavioral trait (behavioral inhibition) and an associated physiological trait (glucocorticoid production) in predicting life span. In addition, we examined the relative stability of both the behavioral and physiological trait within individuals over a significant portion of adulthood, and tested the hypothesis that a stable behavioral trait is linked with a stable physiological bias. In a sample of 60 Sprague-Dawley male rats, we found that stable inhibition/ neophobia was a stronger predictor of life span than stably elevated glucocorticoid production. In addition, these predictors appeared to have an additive influence on life span in that males with both risk factors (stable inhibition and consistently high glucocorticoid production) had the shortest life spans of all, suggesting both traits are important predictors of life span. Across a 4-month period in young adulthood, inhibition and glucocorticoid reactivity were relatively stable traits, however these two traits were not highly correlated with one another. Interestingly, baseline glucocorticoid production was a better predictor of life span than reactivity levels. The results indicate that glucocorticoid production in young adulthood is an important predictor of life span, although not as strong a predictor as inhibition, and that other physiological processes may further explain the shortened life span in behaviorally-inhibited individuals.
This article is part of a Special Issue "Parental Care". The effects of differential maternal care received on offspring phenotype in rodents has been extensively studied between litters, but the consequences of differential mothering within litters on offspring neurobehavioral development have been rarely examined. We here investigated how variability in maternal care received among female rat siblings (measured four times daily on postnatal days 4, 6, 8, and 10) relates to the siblings' later emotional and maternal behaviors. As previously reported, we found that some female pups received up to three times more maternal licking bouts compared to their sisters; this difference was positively correlated with the pups' body weights. The number of maternal licking bouts that females received was negatively correlated with their later neophobic behaviors in an open field during periadolescence, but positively correlated with their anxiety-related behavior in an elevated plus maze during adulthood. Licking received was also positively correlated with females' later likelihood to retrieve pups in a maternal sensitization paradigm. In addition, females' neophobia during adolescence and anxiety-related behavior during adulthood predicted some aspects of both postpartum and sensitized maternal responsiveness. Medial prefrontal cortex expression of tryptophan hydroxylase-2 (TPH2; enzyme necessary for serotonin synthesis) was negatively associated with early maternal licking received. Interestingly, cortical TPH2 was positively associated with the maternal responsiveness of sensitized virgins but negatively associated with it in postpartum females. These results indicate that within-litter differences in maternal care received is an often neglected, but important, contributor to individual differences in offspring socioemotional behaviors as well as to the cortical serotonin neurochemistry that may influence these behaviors.
We investigated the possible involvement of OTX2, a homeobox gene crucial for forebrain development, in the pathogenesis of schizophrenia and bipolar disorder. The disruption of this gene results in cortical malformations and causes serotonergic and dopaminergic cells in the midbrain to be expressed in aberrant locations. Resequencing of DNA from OTX2 exons and surrounding introns from 60 individuals (15 schizophrenia, 15 bipolar disorder, 15 depression, and 15 control) revealed two intronic polymorphisms, rs2277499 (C/T) and rs28757218 (G/T), but no other variations. The minor allele of rs2277499 (T) did not associate with clinical diagnosis. However, using a Taqman genotyping assay, we found the rs28757218 minor allele (T) in 30 out of 720 (4.2%) individuals with bipolar disorder but only in 6 out of 526 (1.1%) control individuals (odds ratio 3.5, 95% confidence interval 1.4-10.4, P = 0.003). On the other hand, the rs28757218 minor allele was only found in 6 out of 458 (1.3%) individuals with schizophrenia. All individuals with the rs28757218 polymorphism were heterozygous for the allele. Based on this positive case-control association finding, we conclude that variations in OTX2 might confer risk for the development of bipolar disorder.
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