Understanding the pathophysiology of depression requires knowledge of the anatomical pathways that malfunction in this disorder. The anatomy of depression involves limbic and hypothalamic activation mediating stress and anxiety. These interact with cortical areas, primarily the medial prefrontal cortex (mPFC), which appears to mediate the cognitive aspects of depression. The mPFC in turn innervates the thalamus and lateral habenula (l. habenula). The anatomy of melancholia has recently been advanced through an understanding of the role of the l. habenula and incorporation of this structure between the cortical and limbic inputs and the monoaminergic nuclei. The l. habenula controls the midbrain monoaminergic nuclei, whose output pathways interact with each other, as well as providing strong modulatory control of limbic and cortical areas. Recently understanding of how the dopamine system is regulated by the l. habenula in normal (Matsumoto and Hikosaka, 2009) and affectively disturbed states (Li et al, 2011) has been investigated. Over activity in the l. habenula is seen in both the learned helplessness model (Li et al, 2011) and in patients who express depressive symptoms following tryptophan depletion (Roiser et al, 2009). This over activity causes decreased dopaminergic stimuation, suppressing reward signals (Matsumoto and Hikosaka, 2009). It also depresses 5HT signals (Wang and Aghajanian, 1997), which feed back further increasing l. habenular activity. The l. habenula receives strong inputs from both the limbic system, through the basal nucleus of the stria terminalis, which carries information from the amygdala related to anxiety and from the mPFC, which may be related to the cognitive aspects of depression (Li et al, 2011) and sends its output to the midbrain aminergic nuclei.

Glutaminergic over activity in the mPFC drives the over activation of the l. habenula (Li et al, 2011) in the chronically helpless line of animals, allowing the development of a depressive state mediated, in part, by altered monoaminergic function. Excess cortical glutamate in the mPFC, resulting from stress, leads to decreases in cortical synapses, a well-documented effect that can be reversed by ketamine. Chronically helpless animals show a 40% loss of synapses, suggesting enhanced stress sensitivity. The excess glutamate appears to be sustained through decreased astrocytic glutamate transporter in these learned helpless animals (Zink et al, 2010), suggesting that astrocytic dysfunction may be a fundamental step in the pathophysiology of depression.

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