Forming effective responses to threatening stimuli requires the adequate and coordinated
emergence of stress-related internal states. Such ability depends on early-life experiences
and, in connection, the adequate formation of neuromodulatory systems, particularly
serotonergic signaling. Here, we assess the serotonergic background of experience-dependent
behavioral responsiveness using male and female zebrafish (Danio rerio). For the first
time, we have characterized a period during behavioral metamorphosis in which zebrafish
are highly reactive to their environment. Absence of social stimuli during this phase
established by isolated rearing fundamentally altered the behavioral phenotype of
postmetamorphic zebrafish in a challenge-specific manner, partially due to reduced
responsiveness and an inability to develop stress-associated arousal state. In line
with this, isolation differentially affected whole-brain serotonergic signaling in
resting and stress-induced conditions, an effect that was localized in the dorsal
pallium and was negatively associated with responsiveness. Administration of the serotonin
receptor 1A partial agonist buspirone prevented the isolation-induced serotonin response
to novelty in the level of the whole brain and the forebrain as well, without affecting
catecholamine levels, and rescued stress-induced arousal along with challenge-induced
behaviors, which together indicates functional connection between these changes. In
summary, there is a consistent negative association between behavioral responsiveness
and serotonergic signaling in zebrafish, which is well recognizable through the modifying
effects of developmental perturbation and pharmacological manipulations as well. Our
results imply a conserved serotonergic mechanism that context-dependently modulates
environmental reactivity and is highly sensitive to experiences acquired during a
specific early-life time window, a phenomenon that was previously only suggested in
mammals.
