Wiring transmission in the serotonergic system

Serotonergic neurons are part of one of the most widely distributed systems of the mammalian brain. Indeed, serotonin is involved in a wide range of physiological processes, including the control of appetite, sleep, memory, mood, stress and sexual behavior. The raphe nuclei (B1-9) of the brain stem are the origin of serotonergic projections to the whole central nervous system. In the last years, several studies have unraveled the heterogeneity of serotonergic neurons, in terms of developmental programs, molecular and electrophysiological properties. Recently, a map of the complex topographical organization of the serotonergic fibers has been drawn using intersectional fate mapping strategy, as well as retrograde or anterograde tracing (Bang et al, 2012; Fernandez et al. 2015; Muzerelle et al, 2014). Serotonergic neurons have un-myelinated fiber varicosities, where the transmitter is synthesized, stored and released in a “volume transmission” (VT) mode (Agnati et al, 1995). To a lesser extent, serotonergic fibers also present synapse-like specializations where synaptic contacts are established by 5-HT terminals with specific neuronal targets acting in a conventional “wiring transmission” (WT) mode. However, experimental strategies used to map serotonergic projections so far where not selective for VT versus WT, and the organization of WT is still the object of investigation. Taking advantage of the properties of the rabies virus, whose envelope can drive the infection of neurons exclusively through their presynaptic terminals, we have selectively mapped the serotonergic WT system originating in the raphe nuclei. We injected recombinant G-deleted rabies virus in several brain regions of Tph2::GFP knock-in mice, in which serotonergic neurons were clearly labeled by the expression of GFP (Migliarini et al, 2013). We also used monosynaptic tracing, coupling pseudotyped recombinant rabies virus with a helper adeno-associated virus (Wall et al, 2010). This experimental approach revealed that each brain district hereby investigated receives WT from a relatively small and region-specific number of serotonergic neurons, thus making it possible to establish a correlation map between specific serotonergic neurons in the raphe nuclei and distinct brain areas. Altogether, this study sheds new light on communication properties of serotonergic system, and may help understand the selective role of serotonergic WT in health and disease