Concerted modulation of spontaneous behavior and time-integrated whole-brain neuronal activity by serotonin receptors

Serotonin neurons from the raphe nuclei project across the entire brain and modulate diverse physiology and behavior by acting on 14 distinct receptors. Here, we take a step dissecting this complex process by examining the effects of agonists and antagonists of four widely expressed serotonin receptors (2A, 2C, 1A, and 1B) on spontaneous mouse behavior. We also analyzed time-integrated whole-brain neuronal activity of these same mice based on intensity of Fos, product of an immediate-early gene. Low-dimensional representations of behavioral and Fos map data shed light on the dominant factors of variation in each domain, captured predictable differences across drug groups, and enabled predictions of behavioral changes following perturbations in Fos maps and vice versa. Our study provides rich resources on the effects of manipulating serotonin receptors on animal behavior and whole-brain integrated neuronal activity. It also establishes an experimental and analysis paradigm for interrogating the relationship between behavior and neuronal activity across different time scales.