A multi-level investigation into the effects of chronic stress on lateral habenula circuitry

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Depression is a debilitating disease that can dramatically affect a person's health and life. People suffering from depression experience extended periods of sadness, despair, reduced motivation and hopelessness, and they are often unable to enjoy activities once found pleasurable. At present, effective treatments for depression and other dysfunctional emotional states remain elusive. Traditional treatment perspectives have conceptualized depression as a dysfunction of specific monoaminergic neurotransmitter systems. Recently, more nuanced conceptual frameworks have arisen as a result of efforts to correlate disease symptoms with dysfunction of specific brain networks mediating mood and reward responses. The lateral habenula (LHb), a part of the reward circuit that provides ‘negative value’ to midbrain dopamine neurons in the ventral tegmental area (VTA), has emerged as a key brain region for the pathophysiology of depression. LHb neurons projecting to the VTA are hyperactive in an animal model of depression, and reducing synaptic transmission onto LHb neurons through deep brain stimulation can ameliorate depression-related behaviors. However, the identities of afferent pathways that drive hyperactivity of these neurons are largely unknown. Here, we propose an innovative experimental strategy that employs a combination of state-of-the-art methods, including novel molecular and genetic tools, electrophysiology, optogenetics and behavioral paradigms to investigate how chronic stress, an important cause for depression in humans, alters synaptic transmission in specific LHb afferent pathways. Our goals are to (1) identify precisely which LHb pathways are altered following chronic stress exposure, (2) describe the underlying synaptic mechanisms and (3) develop circuit-specific strategies to reverse chronic stress-induced behavioral changes. Linking chronic stress-induced synaptic adaptations to relevant LHb pathways will provide important insights into how the brain processes chronic stress in order to generate maladaptive behavioral responses, which may inspire novel treatment strategies that involve reprogramming of specific brain circuits for treating depression.