Depression: a repair response to stress-induced neuronal microdamage that can grade into a chronic neuroinflammatory condition?

Abstract

Depression is a major contributor to the global burden of disease and disability, yet it is poorly understood. Here we review data supporting a novel theoretical model for the biology of depression. In this model, a stressful life event leads to microdamage in the brain. This damage triggers an injury repair response consisting of a neuroinflammatory phase to clear cellular debris and a spontaneous tissue regeneration phase involving neurotrophins and neurogenesis. During healing, released inflammatory mediators trigger sickness behavior and psychological pain via mechanisms similar to those that produce physical pain during wound healing. The depression remits if the neuronal injury repair process resolves successfully. Importantly, however, the acute psychological pain and neuroinflammation often transition to chronicity and develop into pathological depressive states. This hypothesis for depression explains substantially more data than alternative models, including why emerging data show that analgesic, anti-inflammatory, pro-neurogenic and pro-neurotrophic treatments have antidepressant effects. Thus, an acute depressive episode can be conceptualized as a normally self-limiting but highly error-prone process of recuperation from stress-triggered neuronal microdamage.

Figure 1

Theoretical model for depression. In this model, a major adverse stressful life event (reviewed in section 2) leads to neuronal microdamage such as reduction of dendritic length, spines and branching in the hippocampus and prefrontal cortex (section 3). Such microdamage elicits a neuroinflammatory response (section 4), which inhibits neurogenesis and neurotrophin activity (section 3). The activated neuroinflammatory system releases inflammatory mediators which elicit sickness symptoms (section 5). In addition, these neuroinflammatory mediators hypersensitize psychological pain circuits by a similar mechanism to that by which they are known to hypersensitize physical pain circuits in the context of bodily injury (section 9.2). If the neuroinflammatory response fails to resolve, the depressive episode becomes chronic (section 10). On the other hand, a healthy inflammatory response will spontaneously resolve and transition to the proliferative phase of injury repair (section 9.1). In this transition, the decreased neuroinflammatory activity releases inhibition of neurotrophin activity and neurogenesis, and these trophic processes increase. As the injury repair nears completion, the release of proinflammatory mediators decrease, allowing depressive symptoms to remit. Because antidepressant treatments have anti-neuroinflammatory effects and lead to an increase in neurogenesis and neurotrophin expression (section 7), these treatments promote resolution of the injury repair response.