Characterization of habenular neurocircuitry. A potential novel target for treating depression

Sammanfattning: In the last decade, there has been an explosion of interest within the psychiatric research community in a small diencephalic brain region called the habenula. It has been uncovered as a key regulator of monoaminergic transmission, playing a fundamental role in decision making, behavioral flexibility, inhibitory control, sleep, pain and analgesia. Perturbation of the habenular neurocircutry in animals produce effects that mimic rewards and punishments, animals actively seek habenula inactivation while avoiding activation. From a psychiatric viewpoint, the habenula is a promising target for diseases like depression, drug dependence and ADHD. Given that the morphology and connectivity of the habenula is highly conserved throughout the vertebrate subphylum, animal research is both valid and necessary to map the circuitry and neuronal populations that constitute the habenular complex. Due to the small size and position of the habenula, techniques for modulating this brain area in humans are both invasive, difficult and risky. To overcome this issue, we have characterized an orphan G protein-coupled receptor (Gpr151) that may serve as a future non-invasive target for habenula modulation. We demonstrate that it is highly enriched in the habenular circuitry, with a pattern that is evolutionary conserved. Using monosynaptic pseudorabies and adenoassociated viral tracing techniques we have dissected the connectivity of the habenular neurons expressing the orphan G-protein coupled receptor Gpr151. We have also performed initial screening experiments with the aim of identifying ligands to the receptor. Our results indicate that Gpr151 can possibly modulate a brain network providing a link between the basal forebrain and neuromodulatory brain stem targets, a circuitry with a involved in a multitude of functions with importance for psychiatric disease. Moreover, we continued the characterization of the inhibitory interneurons in the habenula, a neuronal population which has received very little attention previously. The existence of various types of intrinsic neurons within the habenular nucleus adds to the already very complex picture of this intriguing structure. Psychiatry is in dire need of new effective treatments, and the habenula and Gpr151 might provide possible novel targets for psychopharmacological research and future drug development.