Early life stress disrupts social behavior and prefrontal cortex parvalbumin interneurons at an earlier time-point in females than in males

Abstract

Early life stress exposure (ELS) yields risk for psychiatric disorders that might occur though a population-specific mechanism that impacts prefrontal cortical development. Sex differences in ELS effects are largely unknown and are also essential to understand social and cognitive development. ELS can cause dysfunction within parvalbumin (PVB)-containing inhibitory interneurons in the prefrontal cortex and in several prefrontal cortex-mediated behaviors including social interaction. Social behavior deficits are often the earliest observed changes in psychiatric disorders, therefore the time-course and causation of social interaction deficits after ELS are important to determine. PVB interneuron dysfunction can disrupt social behavior, and has been correlated in males with elevated markers of oxidative stress and inflammation, such as cyclooxygenase-2 after ELS. Here, we measured the effects of maternal separation ELS on social interaction behaviors in males and females. Prefrontal cortex PVB and cyclooxygenase-2 were also measured in juveniles and adolescents using Western blots. ELS led to social interaction alterations earlier in females than males. Sexually dimorphic behavioral changes were consistent with prefrontal cortex PVB loss after ELS. PVB levels were decreased in ELS-exposed juvenile females, while males exposed to ELS do not display parvalbumin decreases until adolescence. Early behavioral and PVB changes in females did not appear to be mediated through cyclooxygenase-2, since levels were not affected in ELS females. Therefore, these data suggest that ELS affects males and females differently and with distinct developmental profiles.

Social Origins of Developmental Risk for Mental and Physical Illness

“…For example, sex differences in anxiety emerge from adolescence, with females more susceptible especially if they have experienced ELS (for review, see Bale and Epperson, 2015). Likewise, we found that ELS in mice predisposes to internalizing or externalizing behaviors in a sex-dependent manner, which may reflect differentially wired inhibitory circuitry in their prefrontal cortex (Z.Y., H.S.K., C.J., and T. K.H., unpublished observations;Holland et al, 2014).…”

“…To address this, an alternative limited-bedding paradigm was initially developed in rats (Gilles et al, 1996), obviating the requirement for overt separation of pups and dams typically used in rodent ELS models . This paradigm induces inconsistent and fragmented maternal care (Heun-Johnson and Levitt, 2016), which has since been validated and adopted for use with mice by multiple laboratories Wang et al, 2011Wang et al, , 2013Gunn et al, 2013;Malter Cohen et al, 2013;Liao et al, 2014;Kohl et al, 2015;Naninck et al, 2015;Yang et al, 2015;Arp et al, 2016;Bath et al, 2016Bath et al, , 2017Liu et al, 2016;McIlwrick et al, 2016McIlwrick et al, , 2017Yam et al, 2017). The paradigm provides an ethologically relevant framework for addressing heritability of risk-, sex-, and developmentally dependent influences that determine outcomes following ELS.…”

“…Except for two studies, which report altered astrocyte glutamate transporter function in the hypothalamus (Gunn et al, 2013) and a premature increase in myelin basic protein in the hippocampus (Bath et al, 2016), the involvement of non-neuronal cells has not been studied. Based on their central roles in regulating neuronal development and function, including synaptogenesis (Hong and Stevens, 2016), disruption of non-neuronal cells likely contributes to the long-term effects of ELS on neuronal function and behavioral outcomes.…”

“…Recent studies indicate that, even in the absence of placental effects, the early postnatal period represents a distinct developmental window for sex-dependent responses to early life stressors (Kawakami et al, 2007;Coutellier and Würbel, 2009;Kikusui and Mori, 2009;Gross et al, 2012;Kawakami et al, 2013;Naninck et al, 2015;Arp et al, 2016;Fuentes et al, 2016;Lerch et al, 2016;Bath et al, 2017;de Azeredo et al, 2017;Yam et al, 2017). For the most part, the mechanisms underlying sex-dependent outcomes in response to exposure to stressors during this later period are poorly understood.…”

“…Indeed, selective downregulation was found there for tbr1 (de Campo et al, 2017), a transcription factor directing neuroblasts to differentiate into glutamatergic neurons (Hodge et al, 2012). Thus, maternal separation has differential effects on amygdala gene expression reflecting specific trajectories of brain maturation, reinforcing the concept that a circuit's developmental stage contributes essentially to its response to ELS.…”