Abstract
Serotonin (5-HT)-synthetizing neurons, which are confined in the raphe nuclei of the rhombencephalon, provide a pervasive innervation of the central nervous system (CNS) and are involved in the modulation of a plethora of functions in both developing and adult brain. Classical studies have described the post-natal development of serotonergic axons as a linear process of terminal field innervation. However, technical limitations have hampered a fine morphological characterization. With the advent of genetic mouse models, the possibility to label specific neuronal populations allowed the rigorous measurement of their axonal morphological features as well as their developmental dynamics. Here, we used the Tph2GFP knock-in mouse line, in which GFP expression allows punctual identification of serotonergic neurons and axons, for confocal microscope imaging and we performed 3-dimensional reconstruction in order to morphologically characterize the development of serotonergic fibers in specified brain targets from birth to adulthood. Our analysis highlighted region-specific developmental patterns of serotonergic fiber density ranging from a linear and progressive colonization of the target (Caudate/Putamen, Basolateral Amygdala, Geniculate Nucleus and Substantia Nigra) to a transient increase in fiber density (medial Prefrontal Cortex, Globus Pallidus, Somatosensory Cortex and Hippocampus) occurring with a region-specific timing. Despite a common pattern of early post-natal morphological maturation in which a progressive rearrangement from a dot-shaped to a regular and smooth fiber morphology was observed, starting from post-natal day 28 serotonergic fibers acquire the region specific morphological features present in the adult. In conclusion, we provided novel, target-specific insights on the morphology and temporal dynamics of the developing serotonergic fibers.
Highlights
The whole central nervous system (CNS) of vertebrates is reached and profusely innervated by serotonin (5-hydroxytryptamine; 5-HT) releasing fibers
Examples of the first scenario were observed in CPu, Basolateral Amygdala (BLA), Dorsal Lateral Geniculate Nucleus (DLG) and Substantia Nigra (SN), where the total length of serotonergic fibers increased starting from PND 7 (BLA and SN) or PND 14 (CPu and DLG), peaked at PND 28 and remained unchanged up to adulthood
Given the well-established role of 5-HT signaling in brain development (Teissier et al, 2017), and given that the density of serotonergic fibers could be directly linked to 5-HT levels, the presence of two distinct and region-specific patterns of serotonergic fiber development may account for different developmental roles of 5-HT
Summary
The whole central nervous system (CNS) of vertebrates is reached and profusely innervated by serotonin (5-hydroxytryptamine; 5-HT) releasing fibers. Such a diffuse distribution of serotonergic axons arises entirely from a relatively small number of somata (approximately 28,000 in the mouse; Ishimura et al, 1988) that are confined in the brainstem and clustered in B1 to B9 raphe nuclei. Starting from E13.5, serotonergic fibers are driven along the main brain trajectories, reaching their targets by the end of gestation (Lidov and Molliver, 1982; Gaspar et al, 2003). The subsequent post-natal terminal field development has been described as a gradual colonization of the target with a region-specific timing (Lidov and Molliver, 1982). D-fibers appear thin with fusiform homogeneous varicosities and are more abundant than M-fibers, which show larger and oval varicosities along thin axons (Kosofsky and Molliver, 1987; Mamounas and Molliver, 1988; Wilson et al, 1989; Törk, 1990; Bang et al, 2012)
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