Depression is a common disease that causes significant morbidity and mortality in humans. There is currently no clarity regarding the underlying molecular, cellular or circuit mechanisms. Presently, therapeutic intervention is not well understood mechanistically and often unsuccessful. It is important to derive a mechanistic understand of depressive disorders so that effective treatment can be developed. Abnormalities in parts of the brain that participate in the reward system are thought to play important roles. The lateral habenula (LHb) is an important part of the reward circuit by providing `reward prediction error' signals: when an animal receives a reward that is less than expected (i.e. is disappointed) or anticipates punishment (i.e. expects something bad), the LHb is active, and this information is thought normally to be used to shape future behavior to maximize reward and avoid unpleasant events. An individual with overly active LHb would be expected to be easily or continually disappointed and generally expect bad outcomes. It is therefore not a surprise that a number of studies in humans and rodents indicate that excessive activity in the LHb contributes to major depression. This grant proposes to examine how information in the LHb is processed in normal rodents, and modified by manipulations related to depression.
Neurons in the lateral habenula provide `disappointment' signals in the brain. We have found overactive excitation by synapses onto these neurons in rodent models of depression. Thus, reducing activity of these synapses may alleviate some forms of major depressive disorders.
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