A multispecies approach for understanding neuroimmune mechanisms of stress

Abstract

The relationship between stress challenges and adverse health outcomes, particularly for the development of affective disorders, is now well established. The highly conserved neuroimmune mechanisms through which responses to stressors are transcribed into effects on males and females have recently garnered much attention from researchers and clinicians alike. The use of animal models, from mice to guinea pigs to primates, has greatly increased our understanding of these mechanisms on the molecular, cellular, and behavioral levels, and research in humans has identified particular brain regions and connections of interest, as well as associations between stress-induced inflammation and psychiatric disorders. This review brings together findings from multiple species in order to better understand how the mechanisms of the neuroimmune response to stress contribute to stress-related psychopathologies, such as major depressive disorder, schizophrenia, and bipolar disorder.

Keywords: depression; guinea pig; inflammatory mediator; microglia; neuroimmune response; nonhuman primate; sickness; stress reactivity.

Figure 1.. A multispecies approach toward understanding neuroimmune mechanisms of stress and their relation to human affective disorders. The neuroimmune consequences of stress are highly conserved across mammalian species, yet vary within species as a function of sex, age, and past history of stress. Mouse and rat models are commonly used to examine basic molecular and cellular components of the stress response. The use of guinea pigs is advantageous as they are born highly precocious and form a strong attachment to their mother, thereby creating a highly tractable model of maternal separation during early life. Findings from guinea pigs can be applied to generate hypotheses to test on nonhuman primates, such as rhesus macaques, which will then inform basic research and clinical applications in humans that can guide therapeutic approaches. Rat photo courtesy of Dr Lisa M. Savage; guinea pig photo was contributed by Dr Michael B. Hennessy; photo showing troop of rhesus macaques was courtesy of the California National Primate Research Center; human photo courtesy of Anastacia Kudinova.

Figure 2. Stress-related neuroinflammation mediates the post-stress recuperative period. Acute stress induces activation of the sympathetic nervous system and HPA axis, leading to release of inflammatory factors, such as cytokines (eg, IL-1), chemokines (eg, CCL2/MCP1), and prostaglandins (eg, PGE2). These factors regulate various features of the post-stress recuperative period, in which the subject displays reduced food and water intake, impaired social behavior, and often sickness-like responses. This constellation of behavioral changes probably represents a recuperative motivational state that promotes recovery after intensely stressful experiences. CCL2/MCP1, chemokine (C-C motif) ligand 2, also referred to as monocyte chemoattractant protein 1; HPA, hypothalamic-pituitary-adrenal; IL, interleukin; PGE2, prostaglandin; SNS, sympathetic nervous system

Figure 3. Signaling molecules involved in regulating stress-related neuroinflammation. Neuroimmune signaling molecules that control inflammatory response can be categorized into three types, as follows: (i) host-derived danger, damage, and disease signals—including cytokines, chemokines, and damage-associated molecular patterns (DAMPS)—that acutely activate inflammatory signaling pathways; (ii) rapid neural signals, such as norepinephrine and glutamate, that rapidly drive the stress response and cytokine production throughout the body; and (iii) neuroendocrine signals, particularly corticosteroids and progesterone, which may serve to constrain the inflammatory process and dampen production of inflammatory factors. AP-1 , activator protein 1 ; ATP, adenosine triphosphate; AR, adrenergic receptor; cAMP, cyclic adenosine monophosphate; CRE, cAMP-response element; CREB, cAMP-response-element binding protein; DAMPs, damage-associated molecular patterns; ERK, extracellular-signal-regulated kinase; GR, glucocorticoid receptor; HMGB1, high-mobility group box 1 ; HSPs, heat shock proteins; ICE, interleukin-1 -converting enzyme; IL, interleukin; MAPK, mitogen-activated protein kinase; MyD88, myeloid differentiation primary response gene 88; NFkB, nuclear factor kB; nGRE, negative glucocorticoid response element; NMDAR, N-methyl-d-aspartate receptor; PKA, protein kinase A; PKC, protein kinase C; TNF, tumor necrosis factor; TLR, Toll-like receptor; TRAF6, TNF receptor-associated factor 6