Late-Onset Cognitive Impairments after Early-Life Stress Are Shaped by Inherited Differences in Stress Reactivity.

Silja Mcilwrick,Chadi Touma,Tobias Pohl,Alon Chen

doi:10.3389/fncel.2017.00009

Abstract

Early-life stress (ELS) has been associated with lasting cognitive impairments and with an increased risk for affective disorders. A dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis, the body’s main stress response system, is critically involved in mediating these long-term consequences of adverse early-life experience. It remains unclear to what extent an inherited predisposition for HPA axis sensitivity or resilience influences the relationship between ELS and cognitive impairments, and which neuroendocrine and molecular mechanisms may be involved. To investigate this, we exposed animals of the stress reactivity mouse model, consisting of three independent lines selectively bred for high (HR), intermediate (IR), or low (LR) HPA axis reactivity to a stressor, to ELS and assessed their cognitive performance, neuroendocrine function and hippocampal gene expression in early and in late adulthood. Our results show that HR animals that were exposed to ELS exhibited an HPA axis hyper-reactivity in early and late adulthood, associated with cognitive impairments in hippocampus-dependent tasks, as well as molecular changes in transcript levels involved in the regulation of HPA axis activity (Crh) and in neurotrophic action (Bdnf). In contrast, LR animals showed intact cognitive function across adulthood, with no change in stress reactivity. Intriguingly, LR animals that were exposed to ELS even showed significant signs of enhanced cognitive performance in late adulthood, which may be related to late-onset changes observed in the expression of Crh and Crhr1 in the dorsal hippocampus of these animals. Collectively, our findings demonstrate that the lasting consequences of ELS at the level of cognition differ as a function of inherited predispositions and suggest that an innate tendency for low stress reactivity may be protective against late-onset cognitive impairments after ELS.

Highlights

Many affective disorders have their roots in the perinatal phase of development, when important networks in the central nervous system (CNS) are being shaped (Heim and Nemeroff, 2002; Provencal and Binder, 2015)
Before the start of the early-life stress (ELS) paradigm, on P2, there were no significant differences in bodyweight between pups of the three mouse lines, or between pups assigned to the ELS or STD condition (Figure 1B)
We present evidence showing that the lasting effects of ELS on cognitive function can differ greatly between individuals and that one key determinant of the long-term outcome is the individual’s inherited predisposition for high or low stress reactivity

Summary

Introduction

Many affective disorders have their roots in the perinatal phase of development, when important networks in the central nervous system (CNS) are being shaped (Heim and Nemeroff, 2002; Provencal and Binder, 2015). Early-life programming may be adaptive in some cases [e.g., the attenuation of the enzyme 11β-HSD 2 can be beneficial to regulate sodium retention in nutrient poor environments (Yehuda and Seckl, 2011)] Studies in both humans and animal models have shown that programming in response to early-life stress (ELS) exposure can precipitate a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in later life (Heim et al, 2000; Shea et al, 2005; Korosi and Baram, 2010; McIlwrick et al, 2016). Dysregulation of the HPA axis can have detrimental consequences for future health and coping (Meaney, 2001; Pryce and Feldon, 2003), as it significantly increases the risk for affective disorders, including major depressive disorders (MDD) and anxiety disorders (Holsboer, 1999, 2000; Sanchez et al, 2001; Yehuda and Seckl, 2011; Heim and Binder, 2012)

Objectives

Methods

Results

Discussion

Conclusion