Neuroimmune mechanisms of stress: sex differences, developmental plasticity, and implications for pharmacotherapy of stress-related disease

Abstract

The last decade has witnessed profound growth in studies examining the role of fundamental neuroimmune processes as key mechanisms that might form a natural bridge between normal physiology and pathological outcomes. Rooted in core concepts from psychoneuroimmunology, this review utilizes a succinct, exemplar-driven approach of several model systems that contribute significantly to our knowledge of the mechanisms by which neuroimmune processes interact with stress physiology. Specifically, we review recent evidence showing that (i) stress challenges produce time-dependent and stressor-specific patterns of cytokine/chemokine expression in the CNS; (ii) inflammation-related genes exhibit unique expression profiles in males and females depending upon individual, cooperative, or antagonistic interactions between steroid hormone receptors (Estrogen and Glucocorticoid receptors); (iii) adverse social experiences incurred through repeated social defeat engage a dynamic process of immune cell migration from the bone marrow to brain and prime neuroimmune function; and (iv) early developmental exposure to an inflammatory stimulus (carageenin injection into the hindpaw) has a lasting influence on stress reactivity across the lifespan. As such, the present review provides a theoretical framework for understanding the role that neuroimmune mechanisms might play in stress plasticity and pathological outcomes, while at the same time pointing toward features of the individual (sex, developmental experience, stress history) that might ultimately be used for the development of personalized strategies for therapeutic intervention in stress-related pathologies.

A cross-sectional comparison of ethanol-related cytokine expression in the hippocampus of young and aged Fischer 344 rats

“…Indeed, sex differences in HPA axis responses are well precedented (for reviews, see Kudielka & Kirschbaum, 2005; Weinberg, Sliwowska, Lan, & Hellemans, 2008) and, based on the present findings, do not appear to be predictive of neuroimmune gene alterations produced by acute ethanol exposure. With that said, CORT and PROG responses to acute ethanol challenge provide an important physiological context to the cytokine alterations, as previous studies have demonstrated a key role for neuroendocrine hormones in the regulation of cytokines (see Deak et al, 2015 for review).…”

Sustained alterations in neuroimmune gene expression after daily, but not intermittent, alcohol exposure

“…Not only is corticosterone a useful marker of sensitivity to ethanol (Glavas et al, 2007), but it also exerts a profound influence on neuroimmune gene expression in a variety of contexts (see Deak et al, 2015 for a recent review). In the current studies, ethanol-induced elevations in corticosterone were present after acute exposure, but have been shown to habituate with chronic (2 g/kg i.p.…”

(Putative) sex differences in neuroimmune modulation of memory

“…Immune proteins are required for normal synaptic plasticity (O'Connor and Coogan, 1999; del Rey et al, 2013) and stress may influence memory via interactions with immune signaling (Deak et al, 2015; Vecchiarelli et al, 2015). Furthermore, activation of the peripheral immune system during illness or injury, and the resulting neuroimmune response (Figure 1), dramatically alters memory processes.…”

“…There is growing evidence for a central role of immune cells and signaling in memory formation and its modulation (Donzis and Tronson, 2014;Haydon and Nedergaard, 2015;Wu et al, 2015). Immune proteins are required for normal synaptic plasticity (O'Connor and Coogan, 1999;del Rey et al, 2013), and stress may influence memory via interactions with immune signaling (Deak et al, 2015;Vecchiarelli et al, 2015). Furthermore, activation of the peripheral immune system during illness or injury, and the resulting neuroimmune response (Fig.…”