Serotonergic Modulation of Locomotor Activity From Basal Vertebrates to Mammals

Abstract

During the last 50 years, the serotonergic (5-HT) system was reported to exert a complex modulation of locomotor activity. Here, we focus on two key factors that likely contribute to such complexity. First, locomotion is modulated directly and indirectly by 5-HT neurons. The locomotor circuitry is directly innervated by 5-HT neurons in the caudal brainstem and spinal cord. Also, indirect control of locomotor activity results from ascending projections of 5-HT cells in the rostral brainstem that innervate multiple brain centers involved in motor action planning. Second, each approach used to manipulate the 5-HT system likely engages different 5-HT-dependent mechanisms. This includes the recruitment of different 5-HT receptors, which can have excitatory or inhibitory effects on cell activity. These receptors can be located far or close to the 5-HT release sites, making their activation dependent on the level of 5-HT released. Here we review the activity of different 5-HT nuclei during locomotor activity, and the locomotor effects of 5-HT precursors, exogenous 5-HT, selective 5-HT reuptake inhibitors (SSRI), electrical or chemical stimulation of 5-HT neurons, genetic deletions, optogenetic and chemogenetic manipulations. We highlight both the coherent and controversial aspects of 5-HT modulation of locomotor activity from basal vertebrates to mammals. This mini review may hopefully inspire future studies aiming at dissecting the complex effects of 5-HT on locomotor function.

Keywords: brainstem; locomotion; raphe nuclei; serotonin; spinal cord.

Figure 1

The locomotor circuitry and the serotonergic (5-HT) neurons. (A) Schematic representation of the elements constituting the locomotor circuitry, their location in the nervous system, and their connectivity illustrated with black arrows (for review Grillner and El Manira, 2020). (B) Schematic representation of the rostral group of 5-HT nuclei (for review Hornung, 2010). These include, in the midbrain, the caudal linear raphe nucleus, the dorsal raphe nucleus, the median raphe nucleus, and in the rostral pons, the pontine and supralemniscal nuclei. The rostral group mostly send ascending projections to the forebrain (thick lines), but also a limited amount of descending projections to the spinal cord (thin lines), and local projections in the brainstem. (C) Schematic representation of the caudal group of brainstem 5-HT nuclei and the spinal 5-HT neurons (for review Hornung, 2010). These include the nucleus raphe magnus at the border of the pons and medulla oblongata, and in the medulla oblongata, the nucleus raphe obscurus, nucleus raphe pallidus, and 5-HT neurons of the lateral medullary reticular formation (lateral paragigantocellular nucleus, LPGi). The caudal 5-HT nuclei mainly send descending projections to the spinal cord, but also a limited amount of ascending projections to the forebrain, and local projections to many regions of the brainstem, as well as to the cerebellum. Finally, the spinal 5-HT neurons send local projections rostrally, caudally, and laterally in the spinal cord. Cb, cerebellum, CPG, Central Pattern Generator, DA, dopaminergic neurons, MLR, Mesencephalic Locomotor Region, RS, reticulospinal neurons, TH, thalamus.