Spinally projecting serotonergic neurons in motor network modulation

Spinally projecting serotonergic (5-HTsp) neurons represent a heterogeneous population of brainstem neurons whose relevance to the control of movement has largely been inferred. Numerous studies across multiple species have suggested that 5-HTsp neurons exert a widespread influence on spinal sensorimotor networks, operating at multiple levels (primary afferents, interneurons, and motoneurons) through various serotonin receptor subtypes. However, despite the anatomical and neurochemical complexity of the 5-HTsp system, supporting evidence has been mostly derived from indirect approaches [e.g., exogenous application of serotonin (5-HT) and agonists/antagonists of 5-HT receptors]. Direct demonstrations of specific anatomical and functional connectivity have been limited, occasionally yielding discrepant results. Consequently, as the primary provider of serotonin to the spinal cord, the exact contributions of 5-HTsp neurons remain to be fully elucidated. For this mini-review, we sifted through the literature of the last six decades, starting after the characterization of brainstem raphe nuclei and monoaminergic systems, to provide a clearer picture of the anatomy and influences of different 5-HTsp neuron populations on sensorimotor circuits and motor behaviors. We focused on studies reporting direct manipulation of brainstem 5-HTsp neurons, excluding those targeting 5-HT neurotransmission by exogenous application of 5-HT. This emphasis aims to highlight the urgency of resolving how 5-HTsp neuron subpopulations differentiate anatomically and functionally so they can be integrated as dedicated components in current models of supraspinal control of movement and motor diseases such as Parkinson's and amyotrophic lateral sclerosis. Along the way, we point out gaps in knowledge that may be filled using newly available research tools.