From Threat to State Switches: Circuit and Brain-Wide Mechanisms of Serotonergic Control

Project Overview

Animals constantly face a basic problem: should they keep going after something valuable, or stop and protect themselves when the world becomes threatening? This project asks how the brain makes that switch. We focus on serotonin, a chemical messenger that is widely involved in mood, motivation, and flexible behavior. Although serotonin is important in many brain disorders and is targeted by common antidepressants, we still do not fully understand what signals serotonin neurons carry or how they help guide behavior.
Our idea is that serotonin helps the brain decide whether to stay engaged with a current course of action or to shift into a different behavioral mode when danger rises. We will study a brain pathway linking the habenula, which helps detect negative or threatening events, to serotonin-producing cells in the dorsal raphe. Our work suggests that this pathway works in a surprising nonlinear way: small amounts of threat may support continued action, while stronger threat can sharply suppress serotonin signals. This circuit motif may act like a tipping-point detector and push behavior toward withdrawal or disengagement.
To test this, we will combine experiments in mice and larval zebrafish. In mice, we will examine how threat changes learned reward-seeking behavior in a foraging task while measuring and manipulating the habenula-serotonin pathway. In zebrafish, we will use advanced imaging methods to watch activity across the brain during stress and safety, and test how specific habenula activity patterns influence serotonin systems.
By comparing these two models, we aim to uncover general rules for how the brain turns gradual changes in the environment into clear behavioral choices. This could improve our understanding of conditions such as depression, anxiety, and addiction, in which behavior can become too rigid, unstable, or poorly matched to the situation.

Partners and Donors

Brain Canada, Weizmann Canada, and the Weizmann Institute of Science