Structural and metabolic activity differences in serotonergic cell groups in a rat model of individual differences of emotionality and stress reactivity

Abstract

Serotonin regulates a diverse set of functions, including emotional behavior, cognition, sociability, appetite, and sleep. Serotonin is also a key trophic factor that shapes neurodevelopmental processes. Genetic and environmental factors that drive individual differences in the serotonergic system have the capacity to impact brain structure and behavior, and likely contribute to pathophysiological processes involved in neuropsychiatric disorders. Using adult rats selectively bred for low novelty exploration (Low Responders, LR), we previously demonstrated pronounced increases in the levels of their anxiety- and depression- relevant behaviors as compared to the selectively bred High Novelty Responder (HR) rats. These behavioral differences were accompanied by alterations in the expression of genes that regulate serotonin synthesis in the brainstem, and its signaling in the forebrain. The present study extends these observations with a focus on the organization and the metabolism of brainstem serotonin cell groups that provide serotonergic innervation of the hippocampus and other limbic regions of male HR/LR rats. Using design-based stereology, we found the median raphe (MnR) in adult male LR rats contains increased number of serotonergic neurons as compared to the HRs. This is preceded by an increase in the metabolic activity of the caudal dorsal raphe (DRC) and the intrafascicular DR (DRI) during early postnatal development. These findings suggest that structural and functional differences in the raphe-limbic projections shape behavioral inhibition throughout the lifespan.

Keywords: 5-hydroxytryptamine (5-HT); Anxiety; Depression; Dorsal raphe; Tryptophan hydroxylase 2 (Tph2).