LAUSR

Understanding the molecular and neuroanatomical underpinnings of mood disorders such as depression and anxiety may help to develop diagnostic tools or to identify alternative targets for drug discovery. Mood disorders share comorbidities with pain syndromes. Clinically, a principal mood disturbance can enhance pain perception, whereas primary pain pathologies can aggravate mood disorders. Such comorbidities can be studied in animal models, thereby offering alternative tools to investigate molecular mechanisms inducing depression and to support the development of tailored treatments for depressive patients. In this issue of Biological Psychiatry, Barthas et al. (1) show that chronic pain–induced depressive-like behavior in mice is accompanied by the overexpression of mitogen-activatedprotein kinase phosphatase-1 (MKP-1) in the anterior cingulate cortex (ACC). MKP-1 is an upstream negative regulator of the extracellular signal-regulated kinase (ERK) signaling pathway, which has been recently shown to be activated in the circuits involved in pain-associated mood disorders (2). From an evolutionary point of view, linking mood modulation and pain perception might have important functional effects—e.g., on synaptic changes that regulate the expression of appropriate behavioral responses to specific external/internal stimuli that may represent a danger for body integrity. Among several cortical areas, the ACC is a critical region for mood disorders and pain perception. Anatomical and functional studies have shown that the ACC receives sensory inputs from the thalamus and other subcortical structures and projects to sensory brain areas, such as the motor cortex, amygdala, midbrain areas, brainstem, and spinal cord. Human brain imaging studies additionally revealed that ACC neurons react in pain conditions with a strong associated emotional component, such as sadness due to the loss of loved ones. Moreover, animal studies have proven that inhibition of ACC activity is analgesic in different animal models of acute pain as well as of chronic pain (3). However, although the ACC is highly interconnected with brain regions that integrate stimuli with either emotional or pain valence, lesion experiments in this area unequivocally demonstrated that its functional inhibition selectively prevented pain-induced depressive-like behavior but not sensory mechanical sensitivity. This strongly confirms the relevance of the ACC specifically for the pathophysiology of depression and for identifying its underlying molecular aspects. In their work, Barthas et al. revealed a time-dependent progressive increase in MKP-1 expression in the ACC after pain-induced depressive-like behavior, suggesting the slow development of adaptive responses and the hypothesis that a