Early life chronic stress-disrupted activity of the dorsal raphe nucleus selectively drives behavioral impairments

Stress elicits variable systemic and neural changes in vertebrates, with outcomes ranging from adaptive to pathological. Several studies have implicated the dorsal raphe nucleus (DRN), a brainstem nucleus containing a heterogeneous population of serotonergic (5-HT) neurons, in the adaptive stress response and the pathological changes resulting from chronic stress. However, it is not known whether early life chronic stress affects the developing DRN activity, or whether the stress-induced changes affect 5-HT DRN neurons in a subregion- or phenotype-specific manner. To answer these questions, we used in vivo 2-photon calcium imaging of 5-HT DRN neurons in larval zebrafish exposed to chronic unpredictable stress during early life. We found that early life chronic stress prevented the normal habituation of the serotonergic system to a repeated acute stressor by altering the balance of excitatory/inhibitory responses within the DRN. Interestingly, these changes were most pronounced in a subset of stress-vulnerable serotonergic cells co-expressing GABAergic markers. Further, using chemogenetic ablation of 5-HT DRN neurons, we showed that stress-induced plasticity of the DRN contributed to changes in startle response habituation and in locomotive activity, but not in anxiety-like behaviors. Collectively, our results emphasize the role of stress-induced plasticity of DRN neurons in the selective regulation of maladaptive behavioral outcomes.