Study of the role of serotonin in emotional regulation

Adaptation to environmental insults is an evolutionary mechanism essential for survival. The hippocampus participates in controlling adaptive responses to stress and emotional state through the modulation of neuroplasticity events, which are dysregulated in stress-related neuropsychiatric disorders. The involvement of 5-HT in emotional regulation is well established. The levels of 5-HT, the cellular mechanism for its reuptake/degradation and the activity of serotonergic neurons are reported to be dysregulated in animal models of neuropsychiatric disorders. Importantly, several hippocampal physiological processes disrupted in these pathological conditions are normalized upon serotonergic drug treatment. However, the direct role of 5-HT signaling in the modulation of emotional behavior and of the brain regions involved mood regulation remains largely unclear. In the present PhD project, I have investigated primarily the impact of 5-HT deficiency on hippocampal activity combining RNA-seq, in vivo neuroimaging, neuroanatomical, biochemical and behavioral experiments. Tph2 -/- mice, depleted of brain 5-HT, showed mania-like behaviors and increased functional activity in the hippocampus that exhibited transcriptional alterations strikingly similar to those observed in hippocampal neurons derived from bipolar disorder patients. Interestingly, exposure to environmental stress triggered in Tph2 -/- mice a mania-into-depression behavioral switch. As assessed by biochemical and transcriptomic analyses, such a transition was likely induced by a failure in the establishment of an adaptive response to stress in the hippocampus, suggesting a critical role for an appropriate physiological response to stress in bipolar disorder pathology. Concurrent with hippocampal alterations, Tph2 -/- mice showed impaired circadian transcriptional oscillation in dopamine signaling-controlling genes that likely contributed to their mania-like symptoms. Altogether, these findings pinpoint a previously unreported buffering role of 5-HT in instructing hippocampal activity and circadian oscillation of dopaminergic signaling, affecting two important modules that alter emotional processing and adaptation to the environment.