Neuromodulatory Control of Spinal Function in Health and Disease

Neuromodulators profoundly affect the function of individual neurons and consequently, the operation of neural circuits and behavior. This is achieved by altering cellular excitability, synaptic transmission (release probability, postsynaptic receptor responsiveness, thus altering synaptic strength and efficacy), and network properties. They provide flexibility of the nervous system to adapt neural output according to the functional requirements and/or demands of the individual and achieve the desired behavioral state in a changing environment. The “classical” transmitters glutamate and glycine/GABA (gamma-amino butyric acid) are those which cause a primary excitation and inhibition of the “anatomical network”, be it simple reflexes as the monosynaptic stretch reflex (and its reciprocal inhibition of antagonists), the sensory pathways, or spinal networks underlying more complex motor behavior like locomotion. These “simple” functions can be profoundly altered by neuromodulation acting both at pre- and post-synaptic levels but at times it appears that the “neuromodulators” have a more primary function in activating and controlling complex networks than the term “modulator” would tend to imply.
Transmitters acting as neuromodulators affect G-protein coupled receptors and include monoamines (serotonin, noradrenaline and dopamine), acetylcholine, but also glutamate and GABA (referred to above as those mediating the primary excitation and inhibition). In addition, neuropeptides (e.g., substance P, neuropeptide Y, vasopressin, oxytocin, etc.) and purines (adenosine and/or ATP release affecting P2X/Y receptors) act as neuromodulators. Other chemical mediators such as nitric oxide and growth factors (e.g., NGF, BDNF or NT3) may also have similar actions. Neuromodulatory transmitter systems are found throughout the central nervous system including the spinal cord where they affect many functions related to locomotion, respiration (via phrenic and other respiratory motoneurons), posture, balance, fine movements, autonomic functions (including control of bowel, bladder, blood pressure and heart rate), reflexes and sensory information processing (nociception, etc.). The aim of this Research Topic is to highlight recent advances in our understanding of neuromodulatory systems affecting spinal function and to emphasize how these advances strengthen, modify or challenge existing conceptual models of sensorimotor and autonomic control. In addition to work addressing neuromodulatory control in normal animals, we particularly encourage experimental work that examines the consequences of spinal cord injury and/or disease involving neuromodulatory control. Since many neuromodulatory transmitter systems (e.g., such as those releasing monoamines) originate from neurons outside of the spinal cord, injuries to the spinal cord will necessarily damage their descending projections in addition to other non-neuromodulatory pathways controlling the anatomical network. Such injuries will therefore effect not only the initiation and control of spinal networks, but also the ability to adjust their output according to ongoing functional demands. What are the physiological consequences (adaptations) to such injuries and how can one reestablish modulatory control of spinal neurons? In this issue we encourage submissions of basic and/or clinical studies utilizing new and innovative experimental paradigms in addition to new applications of established paradigms. We also encourage the submission of review papers that summarize current knowledge and point out important deficiencies in our current understanding of these important systems.