Toward an understanding of the habenula's various roles in human depression

The habenula is an evolutionarily conserved structure in the vertebrate brain. Lesion and electrophysiological studies in animals have suggested that it is involved in the regulation of monoaminergic activity through projection to the brain stem nuclei. Since studies in animal models of depression and human functional imaging have indicated that increased activity of the habenula is associated with depressive phenotypes, this structure has attracted a surge of interest in neuroscience research. According to pathway- and cell-type-specific dissection of habenular function in animals, we have begun to understand how the heterogeneity of the habenula accounts for alteration of diverse physiological functions in depression. Indeed, recent studies have revealed that the subnuclei embedded in the habenula show a wide variety of molecular profiles not only in neurons but also in glial cells implementing the multifaceted regulatory mechanism for output from the habenula. In this review, we overview the known facts on mediolateral subdivision in the habenular structure, then discuss heterogeneity of the habenular structure from the anatomical and functional viewpoint to understand its emerging role in diverse neural functions relevant to depressive phenotypes. Despite the prevalent use of antidepressants acting on monoamine metabolisms, ~30% of patients with major depression are reported to be treatment-resistant. Thus, cellular mechanisms deciphering such diversity in depressive symptoms would be a promising candidate for the development of new antidepressants.