Sex Differences in Affective Dysfunction and Alterations in Parvalbumin in Rodent Models of Early Life Adversity.

Seneca N Ellis,Jennifer A Honeycutt

doi:10.3389/fnbeh.2021.741454

Abstract

The early life environment markedly influences brain and behavioral development, with adverse experiences associated with increased risk of anxiety and depressive phenotypes, particularly in females. Indeed, early life adversity (ELA) in humans (i.e., caregiver deprivation, maltreatment) and rodents (i.e., maternal separation, resource scarcity) is associated with sex-specific emergence of anxious and depressive behaviors. Although these disorders show clear sex differences in humans, little attention has been paid toward evaluating sex as a biological variable in models of affective dysfunction; however, recent rodent work suggests sex-specific effects. Two widely used rodent models of ELA approximate caregiver deprivation (i.e., maternal separation) and resource scarcity (i.e., limited bedding). While these approaches model aspects of ELA experienced in humans, they span different portions of the pre-weaning developmental period and may therefore differentially contribute to underlying mechanistic risk. This is borne out in the literature, where evidence suggests differences in trajectories of behavior depending on the type of ELA and/or sex; however, the neural underpinning of these differences is not well understood. Because anxiety and depression are thought to involve dysregulation in the balance of excitatory and inhibitory signaling in ELA-vulnerable brain regions (e.g., prefrontal cortex, amygdala, hippocampus), outcomes are likely driven by alterations in local and/or circuit-specific inhibitory activity. The most abundant GABAergic subtypes in the brain, accounting for approximately 40% of inhibitory neurons, contain the calcium-binding protein Parvalbumin (PV). As PV-expressing neurons have perisomatic and proximal dendritic targets on pyramidal neurons, they are well-positioned to regulate excitatory/inhibitory balance. Recent evidence suggests that PV outcomes following ELA are sex, age, and region-specific and may be influenced by the type and timing of ELA. Here, we suggest the possibility of a combined role of PV and sex hormones driving differences in behavioral outcomes associated with affective dysfunction following ELA. This review evaluates the literature across models of ELA to characterize neural (PV) and behavioral (anxiety- and depressive-like) outcomes as a function of sex and age. Additionally, we detail a putative mechanistic role of PV on ELA-related outcomes and discuss evidence suggesting hormone influences on PV expression/function which may help to explain sex differences in ELA outcomes.

Highlights

Adversity in early life is widespread (Finkelhor et al, 2013) and places individuals at an increased risk for developing later-life psychiatric disorders, such as anxiety and depression (Gatt et al, 2009; Nugent et al, 2011; Heim and Binder, 2012)
Experiencing adverse environmental stressors during early development and/or childhood has been linked to impaired cognitive function and maladaptive behavioral outcomes (Chapman et al, 2004; Krugers et al, 2017; Vaiserman and Koliada, 2017), with onset often occurring in a protracted manner, years after the adverse experience (Spertus et al, 2003; Hagan et al, 2015; Russell et al, 2018)
Early-life adversity (ELA) is a prevalent issue globally, and its contribution to individual risk of developing later-life psychiatric disorders places an undue burden on society at large

Summary

Introduction

Adversity in early life is widespread (Finkelhor et al, 2013) and places individuals at an increased risk for developing later-life psychiatric disorders, such as anxiety and depression (Gatt et al, 2009; Nugent et al, 2011; Heim and Binder, 2012). Experiencing adverse environmental stressors during early development and/or childhood has been linked to impaired cognitive function and maladaptive behavioral outcomes (Chapman et al, 2004; Krugers et al, 2017; Vaiserman and Koliada, 2017), with onset often occurring in a protracted manner, years after the adverse experience (Spertus et al, 2003; Hagan et al, 2015; Russell et al, 2018). Early-life adversity (ELA) manifests in a variety of instances and includes both physical and sexual abuse, emotional/psychological abuse, adverse family circumstances, neglect, poverty, and other environmental factors (Felitti et al, 1998; Kuhlman et al, 2020). Life experiences play a significant role in shaping shortand long-term outcomes regarding both cognitive-behavioral and neural development (Kundakovic and Champagne, 2015; Chen and Baram, 2016). It is critical that we leverage findings from preclinical models to identify putative neurobiological drivers of sex-specific risk following ELA to reveal windows of opportunity for individualized intervention and/or treatment

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Conclusion