Increased vulnerability to psychosocial stress in heterozygous serotonin transporter knockout mice

Abstract

Epidemiological evidence links exposure to stressful life events with increased risk for mental illness. However, there is significant individual variability in vulnerability to environmental risk factors, and genetic variation is thought to play a major role in determining who will become ill. Several studies have shown, for example, that individuals carrying the S (short) allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) have an increased risk for major depression following exposure to stress in adulthood. Identifying the molecular mechanisms underlying this gene-by-environment risk factor could help our understanding of the individual differences in resilience to stress. Here, we present a mouse model of the 5-HTT-by-stress risk factor. Wild-type and heterozygous 5-HTT knockout male mice were subjected to three weeks of chronic psychosocial stress. The 5-HTT genotype did not affect the physiological consequences of stress as measured by changes in body temperature, body weight gain and plasma corticosterone. However, when compared with wild-type littermates, heterozygous 5-HTT knockout mice experiencing high levels of stressful life events showed significantly depressed locomotor activity and increased social avoidance toward an unfamiliar male in a novel environment. Heterozygous 5-HTT knockout mice exposed to high stress also showed significantly lower levels of serotonin turnover than wild-type littermates, selectively in the frontal cortex, which is a structure that is known to control fear and avoidance responses, and that is implicated in susceptibility to depression. These data may serve as a useful animal model for better understanding the increased vulnerability to stress reported in individuals carrying the 5-HTTLPR S allele, and suggest that social avoidance represents a behavioral endophenotype of the interaction between 5-HTT and stress

Social stress shortens lifespan in mice

“…Operationally, for the purpose of this study, a 4‐week long CPS phase , characterized by daily aggressive interaction and sensory (sight, sound, and smell) cohousing, was followed by an aging phase , characterized by lifelong sensory housing in the absence of overt aggressive interactions (Figure 1a). C57BL/6J male mice were randomly paired to resident males of either the CD1 or the Sv129Ev strain to attain exposure to a gradient of territorial aggression, reportedly higher in CD1 (Bartolomucci et al., 2010; Dadomo et al., 2011; Zou, Storm & Xia, 2013). High‐fat diet (HFD) was previously reported to exacerbate stress‐induced metabolic syndrome‐like (Sanghez et al., 2013) and to shorten lifespan (Baur et al., 2006), prompting us to test the hypothesis that there could be an interaction between stress and hypercaloric diet on survival.…”

“…Thus, we reanalyzed our dataset based on the more restrictive standard definition of achieved dominant and subordinate social status (see methods; Figure 2a) previously shown to explain individual vulnerability to cardiovascular (Costoli et al., 2004), metabolic (Sanghez et al., 2013), and psychiatric (Bartolomucci et al., 2010) disorders.…”

“…Briefly each C57BL/6J ( N  = 172) male mouse, representing the experimental subject, was randomized using a simple randomization procedure of flipping a coin (Suresh, 2011) to be transferred as intruder to the home cage of either a CD1 ( N  = 86) or Sv129Ev ( N  = 86) resident mouse. The CD1 strain manifests high territorial aggression, while the Sv129Ev manifests a much lower level of territorial aggression and can thus be considered a weaker dominant (Bartolomucci et al., 2010; Dadomo et al., 2011; Zou et al., 2013). Resident and intruder mice were allowed to freely interact for a maximum of 10 min.…”

“…Furthermore, social status was determined as previously established. Specifically, subordinate social status was defined by the display of upright posture, flight behavior, and squeaking vocalization (Bartolomucci et al., 2010; Dadomo et al., 2011). After 1 week, half the dyads were randomized to a STD or a HFD using a simple randomization procedure of flipping a coin.…”

“…Furthermore, we used a design intended to expand upon past research which had examined the association with spontaneously achieved social status (dominant vs. subordinate) on healthspan (e.g., Bartolomucci et al., 2010; Sanghez et al., 2013) to examine the contribution of social status to longevity. The design employed a randomized experimental manipulation (described above) to increase the variability in achieved status thereby increasing the plausible variance in outcomes explained by the achieved status and, consequently, increasing statistical power and reducing the proportion of any relation between achieved status and subsequent outcomes due to potential confounding variables.…”