Neurobiology of resilience in depression: immune and vascular insights from human and animal studies

Abstract

Major depressive disorder (MDD) is a chronic and recurrent psychiatric condition characterized by depressed mood, social isolation and anhedonia. It will affect 20% of individuals with considerable economic impacts. Unfortunately, 30-50% of depressed individuals are resistant to current antidepressant treatments. MDD is twice as prevalent in women and associated symptoms are different. Depression's main environmental risk factor is chronic stress, and women report higher levels of stress in daily life. However, not every stressed individual becomes depressed, highlighting the need to identify biological determinants of stress vulnerability but also resilience. Based on a reverse translational approach, rodent models of depression were developed to study the mechanisms underlying susceptibility vs resilience. Indeed, a subpopulation of animals can display coping mechanisms and a set of biological alterations leading to stress resilience. The aetiology of MDD is multifactorial and involves several physiological systems. Exacerbation of endocrine and immune responses from both innate and adaptive systems are observed in depressed individuals and mice exhibiting depression-like behaviours. Increasing attention has been given to neurovascular health since higher prevalence of cardiovascular diseases is found in MDD patients and inflammatory conditions are associated with depression, treatment resistance and relapse. Here, we provide an overview of endocrine, immune and vascular changes associated with stress vulnerability vs. resilience in rodents and when available, in humans. Lack of treatment efficacy suggests that neuron-centric treatments do not address important causal biological factors and better understanding of stress-induced adaptations, including sex differences, could contribute to develop novel therapeutic strategies including personalized medicine approaches.

Keywords: blood-brain barrier; cytokines; depression; immune; sex differences; stress; vascular.

Figure 1

HPA axis‐driven mechanisms promoting stress susceptibility vs resilience. The HPA axis is one of the primary endocrine systems rapidly recruited in order to promote and establish the maintenance of body homeostasis after a challenge or stressor. When exposed to physical and/or psychological stress, neurons from the paraventricular nucleus of the hypothalamus release the CRH. CRH enters blood circulation and reaches the anterior pituitary where it can interact with specific receptors leading to the release of ACTH, which in turn acts in the cortex of the adrenal glands to promote GC release (a). The peripherally released GCs can enter the CNS through P‐gp transporters (purple) present in the endothelial cells that line the BBB. Once into the CNS, GCs can interact with steroid receptors highly expressed in brain cells such as astrocytes (orange), microglia (red) and neurons (brown). The excess of GCs or prolonged binding to these cells can generate an inflammatory status that might contribute to the development of depression (b). In the body periphery, GCs are primarily involved in energy mobilization and use. They also present an anti‐inflammatory effect and can induce macrophage cell apoptosis (green) in order to counteract the inflammatory processes, mechanisms that might be involved in stress susceptibility and MDD (c). On the other hand, during health and resilience, increased number of GC receptors (green) in brain cells (d) and decreased levels of circulating GCs (e) indicate a proper HPA function and cessation. Abbreviations: HPA: hypothalamus–pituitary–adrenal; CRH: corticotropin‐releasing hormone; ACTH: adrenocorticotropic hormone; GC: glucocorticoid; CNS: central nervous system; P‐gp: P‐glycoprotein transporters; BBB: blood–brain barrier; MDD: major depressive disorder

Figure 2

Immune mechanisms affecting blood–brain barrier permeability in stress vulnerability and resilience. Chronic stress may be sufficient to mobilize deleterious activation of the innate immune system driving increased proliferation and release of inflammatory Ly6C^high monocytes (a, e) and neutrophils. Resilient phenotype is characterized by lack of exacerbated immune responses following acute or chronic stressors. Moreover, depressive‐like behaviour has been shown to be reversed due to the decrease in circulating pro‐inflammatory cytokines levels by the antidepressant treatment, humanized antibodies or IL‐6^−/− bone marrow transplants (b). In comparison, susceptible animals and MDD patients display increase in circulating levels of pro‐inflammatory cytokines (IL‐1β and IL‐6) in blood leading to astrocyte activation and a deleterious cascade of pro‐inflammatory cytokine production (f). Animal studies have shown that T‐cell‐dependent immunization to CNS‐related antigens prior to the exposure to chronic mild stress ameliorated subsequent depression‐like behaviours (c). Minocycline, a microglial activation inhibitor, abolishes stress‐induced hyper‐ramification and reverses depression‐like behaviours (d). This would suggest that lowering microglia reactivity as well as NLRP3 inflammasome activation, highly abundant in microglia, could contribute to resilient phenotype. On the other hand, chronic stress induces pro‐ramifying effect on microglia. For instance, TLR4‐induced activation of NLRP3 inflammasome leads to production and secretion of pro‐inflammatory cytokine IL‐1β (g). Microglia‐derived cytokine, CCL2, attracts patrolling immature Ly6C^high monocytes, which can cross the BBB and penetrate into the brain parenchyma (h). In stress‐related brain regions, these monocytes could differentiate into phagocytic macrophages positive for microglia marker Iba1. Abbreviations: BBB: blood–brain barrier, CCL2: chemokine ligand 2, CNS: central nervous system, Iba1: ionized calcium binding adaptor molecule 1, IL‐1β: interleukin‐1β, IL‐6: interleukin‐6, Ly6C^highmonocytes: lymphocyte Ag 6C high monocytes, MDD: major depressive disorder, NLRP3 inflammasome: nucleotide‐binding domain and leucine‐rich repeat protein‐3 (NLRP3) inflammasome, TLR4: toll‐like receptor 4

Figure 3

Differences in human immune system which could underlie sex differences in MDD pathogenesis. (a) In the central nervous system (CNS), the ratio of primed over ramified microglia is increased in MDD patients compared to healthy controls, with possibly exacerbated priming in MDD women. GFAP‐immunoreactive astrocyte levels and astrocyte packing density are found to be decreased in both male and female MDD subjects. (b) In the body periphery, healthy women have higher numbers of Th cells, B cells and neutrophils compared to healthy men. Both MDD men and women have increased neutrophils counts; however, this effect is more pronounced in women. Moreover, while healthy men have higher NK cell numbers, MDD men and women have similar numbers of circulating NK cells. Healthy individuals have low numbers of circulating eosinophils. However, stress results in increased eosinophil numbers in males, but decreased numbers in females. Regulation of T helper cells in MDD has been a matter of debate. Abbreviations: MDD: major depressive disorder; Th: T helper cell (CD4⁺); NK: natural killer cell