The negative effects of stress on behavior are familiar to many of us. A recent study in Neuron (71, 498–511) discloses a possible molecular mechanism to account for them.

Experimenting on mice, Michael Bruchas et al. focused on the serotonergic neurons of the dorsal raphe nuclei—a brain region crucial for mood-related behaviors. The team selectively knocked out the α isoform of p38 mitogen-activated protein kinase (MAPK)—which regulates stress-dependent responses—from raphe neurons and found that the mutant mice were more resilient to stress. So, whereas wild-type mice showed depression and increased drug seeking in response to stress, the mice lacking p38α kept their cool in the face of adversity.

Mechanistically, stress induced p38α activation, which caused serotonin transporters to translocate to the membrane and speed up the clearance of serotonin from the synapse. In mutant mice, serotonin uptake was reduced, leading to a behavioral effect that shares some similarities to the effects of the very popular antidepressants known as selective serotonin uptake inhibitors.