Circuit-based frameworks of depressive behaviors: The role of reward circuitry and beyond

Major depressive disorder (MDD) is a common but serious neuropsychiatric affliction that comprises a diverse set of symptoms such as the inability to feel pleasure, lack of motivation, changes in appetite, and cognitive difficulties. Given the patient to patient symptomatic variability in MDD and differing severities of individual symptoms, it is likely that maladaptive changes in distinct brain areas may mediate discrete symptoms in MDD. The advent and recent surge of studies using viral-genetic approaches have allowed for circuit-specific dissection of networks underlying motivational behavior. In particular, areas such as the ventral tegmental area (VTA), nucleus accumbens (NAc), and ventral pallidum (VP) are thought to generally promote reward, with the medial prefrontal cortex (mPFC) providing top-down control of reward seeking. On the contrary, the lateral habenula (LHb) is considered to be the aversive center of the brain as it has been shown to encode negative valence. The behavioral symptoms of MDD may arise from a disruption in the reward circuitry, hyperactivity of aversive centers, or a combination of the two. Thus, gaining access to specific circuits within the brain and how separate motivational-relevant regions transmit and encode information between each other in the context of separate depression-related symptoms can provide critical knowledge towards symptom-specific treatment of MDD. Here, we review published literature emphasizing circuit- and cell type-specific dissection of depressive-like behaviors in animal models of depression with a particular focus on the chronic social defeat stress model of MDD.