PsyHab · Investigting the effects of psychedelics on Lateral Habenula-Dorsal Raphe Nuclei circuitry in a Chronic Unpredictable Stress model of depression

The lateral habenula (LHb) and dorsal raphe nuclei (DRN) are key structures in the brain involved in mood regulation, reward processing, and aversive signaling. The LHb is a small, yet critical brain region that acts as a major negative regulator of midbrain dopamine systems. It plays a significant role in processing aversive stimuli and encoding negative reward prediction errors, which are crucial for adaptive behaviors and decision-making processes. The DRN, on the other hand, is the primary source of serotonergic projections to various brain regions and is a key structure involved in mood regulation and the pathophysiology of depression. Understanding the precise anatomical and functional connections between the LHb and DRN is essential, as disruptions in the LHb-DRN circuitry are believed to contribute to various neuropsychiatric disorders, including depression and anxiety. Psychedelics have garnered significant interest in both clinical and neuropharmacological research due to their profound effects on perception, cognition, and mood. Their influence on the activity of the LHb is not yet fully understood, but we hypothesize that it could potentially reduce the hyperactivity of the LHb by altering its neural inputs or by modulating the overall excitability of the neurons within the LHb. The proposed research is aimed at examining how psychedelics affect LHb-DRN circuitry in the chronic mild stress model of depression. We will combine viral tracing, in situ sequencing, fiber photometry, chemogenetics, and unsupervised learning in order to evaluate the effects that psychedelics exert on projections from DRN to LHb, and how those translate into changes in animal behavior. The proposed research will contribute to a better understanding of the antidepressant potential of psychedelics and help to improve pharmacotherapy of affective disorders. The applicant will acquire new skills, and the experience to launch and lead his own research group in the future.