Resilience and vulnerability to stress-related psychiatric disorders induced by stress during neurodevelopment: the role of neuroinflammation.

Abstract

Exposure to stress during development alters brain maturation, leading to different behavioural phenotypes. Although adversities in childhood and adolescence increase the risk for stress-related psychiatric disorders (SRPD) such as anxiety, panic, depression and posttraumatic stress disorder (PTSD), there is significant individual variability in the outcomes, indicating the existence of stress resilience and vulnerability factors. Resilience is defined as the ability to adaptively recover from adversity, returning to, or even improving above, the basal state, without permanent impairments to physical and mental health. Vulnerability can be defined as the inability to cope with stress, resulting in maladaptive responses and impairing recovery. Both conditions are dynamic processes, dependent on environmental, biological and behavioural factors. The search for resilience biomarkers can help finding new and more effective therapeutic targets and to establish biological parameters of resilience that may be extrapolated to humans, it is essential to create translational animal models that present individual variability, include both sexes and reproduce comorbidities seen in SRPD. Profs. Suchecki's (UNIFESP) and Zangrossi's (FMUSP-USP) groups have been developing these animal models, using relevant stressors for different developmental life phases. Increased pro-inflammatory cytokines in plasma, have been associated with SRPD in humans, indicating that (neuro)inflammation may be an important mediator of the relationship between stress and psychiatric disorders. These cytokines augment the activity of indoleamine-2,3-dyoxigenase (IDO), an enzyme that uses tryptophan as a substrate in the kynurenine pathway resulting in quinolinic acid (NMDA agonist) or kynurenic acid (NMDA antagonist). Increased IDO activity reduces tryptophan availability to produce serotonin, which has a negative impact on BDNF levels and on neurogenesis and neuronal survival. This proposal will test a novel hypothesis that resilience and vulnerability are related to IDO activity and imbalance in the production of quinolic and kynurenic acids and/or altered production of annexin-1 (AnxA1), an anti-inflammatory protein. To do so, we will assess individual variability in behaviours relevant to the study SRPD, using a novel combination of tests designed to reveal comorbidities, in both male and female rodents exposed to stressors in the pre- and neonatal periods and seek to establish relationships with neurobiological parameters, including plasma levels of corticosterone and ACTH, pro- and anti-inflammatory cytokines and AnxA1; molecular and morpho-functional markers of neuronal plasticity (single-cell chromatin accessibility and transcriptomic profiles); brain levels of serotonin, IDO and its products, and BDNF; morphology of microglia and astrocytes, and neurogenesis. Using this strategy, we seek to 1) Understand how different stressors during development impact the behavioural profile that typify vulnerability or resilience to SRPD; 2) examine the immediate and long-term effects of these stressors on behaviours and neurobiological systems mentioned above; 3) determine whether and which neuroinflammatory/neurobiological markers could serve as signatures of stress vulnerability and resilience and whether there is sexual dimorphism in these biomarkers; 4) understand how perinatal adversities induce epigenetic and transcriptomic changes in neurons and glial cells implicated on adult SRPD-related behaviours; 5) assess the therapeutic efficacy of environmental and pharmacological manipulations on maladaptive changes induced by these models. Using translational animal models will be helpful to understand the neurobiology of individual differences in stress responses to test new molecular targets for the treatment of these burdensome disorders. (AU)