Serotonergic modulation of the circuits and cell-types of the lateral habenula

Project Summary Serotonin (5-HT)-releasing neurons in the mammalian mid/hindbrain are critical for fundamental behaviors and cognitive processes, including emotional control, arousal, and motor control. Selective serotonin reuptake inhibitors (SSRIs) increase brain 5-HT levels and are the most commonly prescribed treatment for major- depression in humans. However, our understanding of the mechanisms by which 5-HT influences synapses, cells, and circuits is limited, prohibiting improvement of depression therapeutics. A major target of 5-HT neurons is the lateral habenula (LHb), a subcortical structure principally implicated in evaluating the outcome (positive or negative) of an action. The LHb is the only brain region that shows consistent hyperactivity several rodent models of chronic stress and additional studies have recently refined this observation indicating “burst- firing” in LHb is causally related several behavioral phenotypes (including anhedonia) following chronic stress. Recently, using single-cell transcriptome wide sequencing, we genetically defined the neuronal subclasses within the LHb for the first time revealing cell-type specific expression of both 5-HT receptors and genes related to burst-firing. Our central hypothesis is that 5-HT release dynamically modulates the habenula circuit though neuron-type specific expression of 5-HT receptors and that burst-firing in specific, genetically defined LHb neuron-types is required for anhedonia following chronic stress. This proposal seeks to 1) identify the neuron-type(s) in the LHb that exhibit burst-firing in vitro and in vivo, 2) determine how 5-HT modulates neuron-types and local connectivity within the LHb and 3) define the neuron-types in the LHb required for chronic stress induced anhedonia. By revealing how 5-HT modulates habenular circuits, the proposed work will provide a comprehensive understanding of the cellular and circuit targets of this important neuromodulator. These findings will form the foundation for understanding the principal mechanisms by which SSRIs impact synapses and circuits of the LHb, uncovering new avenues for therapeutic intervention in major depressive disorder and other neurological disorders treated by these drugs.