[Roles of altered striatal function in major depression]

Major depression, a psychiatric disorder characterized by depressive mood and loss of interest and pleasure, is a leading cause of disability and suicide in developed countries. However, the mechanisms that underlie major depression remain to be elucidated. Clinical studies on patients with major depression have shown abnormalities in multiple brain areas, each of which can account for a distinct symptom or endophenotype. Notably, the striatum in healthy control subjects responds to positive emotional stimuli and to positive feedback signals during cognitive tasks, but these striatal responses are greatly reduced in depressive patients. Given the role of the striatum in behavioral learning with positive reinforcers, abnormalities as such suggest that impairment in reward processing and/or reinforcement learning in major depression is the basis of anhedonia and reduced psychomotor activity. In animal studies, stress -a risk factor for major depression- is frequently used to induce behavioral depression. Repeated social defeat stress increases the excitability of dopamine neurons and subsequent CREB-mediated transcription in the nucleus accumbens shell, leading to behavioral depression. Surprisingly, this pathway seems not to be involved in behavioral depression caused by prolonged social isolation, suggesting distinct mechanisms underlying the two stressful contexts. In contrast, ΔFosB-mediated gene expression in the nucleus accumbens shell confers resilience to stress. Repeated social defeat stress induces accumbal ΔFosB expression in a stress-resilient subset of individuals, whereas prolonged social isolation decreases this expression, leading to stress susceptibility. In addition to emotional changes, chronic stress also alters the mode of instrumental behavior from goal-directed to habitual responding, with consistent morphological changes in striatal subregions responsible for the corresponding behavioral modes. Therefore, these clinical and preclinical findings suggest that striatal abnormalities play a role in emotional and cognitive changes associated with major depression.