Stress has pronounced effects on the brain, and thus behavioral outputs. This is particularly true when the stress occurs during vulnerable points in development. A review of the clinical literature regarding the moderating effects of sex on psychopathology in individuals exposed to childhood maltreatment (CM) is complicated by a host of variables that are difficult to quantify and control in clinical settings. As a result, the precise role of sex in moderating the consequences of CM remains elusive. In this review, we explore the rationale for studying this important question and their implications for treatment. We examine this issue using the threat/deprivation conceptual framework and highlight a growing body of work demonstrating important sex differences in human studies and in animal models of early life stress (ELS). The challenges and obstacles for effectively studying this question are reviewed and are followed by recommendations on how to move forward at the clinical and preclinical settings. We hope that this review will help inspire additional studies on this important topic.

Here, we present a mechanistically grounded theory detailing a novel function of the behavioral immune system (BIS), the psychological system that prompts pathogen avoidance behaviors. We propose that BIS activity allows the body to downregulate basal inflammation, preventing resultant oxidative damage to DNA and promoting longevity. Study 1 investigated the relationship between a trait measure of pathogen avoidance motivation and in vitro and in vivo proinflammatory cytokine production. Study 2 examined the relationship between this same predictor and DNA damage often associated with prolonged inflammation. Results revealed that greater trait pathogen avoidance motivation predicts a) lower levels of spontaneous (but not stimulated) proinflammatory cytokine release by peripheral blood mononuclear cells (PBMCs), b) lower plasma levels of the proinflammatory cytokine interleukin-6 (IL-6), and c) lower levels of oxidative DNA damage. Thus, the BIS may promote health by protecting the body from the deleterious effects of inflammation and oxidative stress.

It is currently unclear whether early life stress (ELS) affects males and females differently. However, a growing body of work has shown that sex moderates responses to stress and injury, with important insights into sex-specific mechanisms provided by work in rodents. Unfortunately, most of the ELS studies in rodents were conducted only in males, a bias that is particularly notable in translational work that has used human imaging. Here we examine the effects of unpredictable postnatal stress (UPS), a mouse model of complex ELS, using high resolution diffusion magnetic resonance imaging. We show that UPS induces several neuroanatomical alterations that were seen in both sexes and resemble those reported in humans. In contrast, exposure to UPS induced fronto-limbic hyper-connectivity in males, but either no change or hypoconnectivity in females. Moderated-mediation analysis found that these sex-specific changes are likely to alter contextual freezing behavior in males but not in females.

Here, we propose a novel theoretical model linking present-focused decision-making to the activities of the immune system. We tested our model by examining the relationship between inflammatory activity – in vivo and in vitro – and decision-making characterized by impulsivity, present focus, and an inability to delay gratification. Results support our model, revealing that inflammation predicts these outcomes even after controlling for factors that may contribute to a spurious linkage between them. Moreover, subsequent analyses revealed that our model was a better fit for the data than alternative models using present-focused decision-making and its health-harming behavioural sequelae (e.g., smoking, risky sexual behaviour) to predict inflammation, lending support for the proposed directionality of this relationship. Together, these results suggest that inflammation may contribute to decision-making patterns that can result in undesirable personal and societal outcomes.

Most large pharmaceutical companies have downscaled or closed their clinical neuroscience research programs in response to the low clinical success rate for drugs that showed tremendous promise in animal experiments intended to model psychiatric pathophysiology. These failures have raised serious concerns about the role of preclinical research in the identification and evaluation of new pharmacotherapies for psychiatry. In the absence of a comprehensive understanding of the neurobiology of psychiatric disorders, the task of developing “animal models” seems elusive. The purpose of this review is to highlight emerging strategies to enhance the utility of preclinical research in the drug development process. We address this issue by reviewing how advances in neuroscience, coupled with new conceptual approaches, have recently revolutionized the way we can diagnose and treat common psychiatric conditions. We discuss the implications of these new tools for modeling psychiatric conditions in animals and advocate for the use of systematic reviews of preclinical work as a prerequisite for conducting psychiatric clinical trials. We believe that work in animals is essential for elucidating human psychopathology and that improving the predictive validity of animal models is necessary for developing more effective interventions for mental illness.