Spontaneous rhythmic activity in early chick spinal cord influences distinct motor axon pathfinding decisions

Abstract

During embryonic development chick and mouse spinal cords are activated by highly rhythmic episodes of spontaneous bursting activity at very early stages, while motoneurons are still migrating and beginning to extend their axons to the base of the limb. While such spontaneous activity has been shown to be important in refining neural projections once axons have reached their targets, early pathfinding events have been thought to be activity independent. However, in-ovo pharmacological manipulation of the transmitter systems that drive such early activity has shown that early motor axon pathfinding events are highly dependent on the normal pattern of bursting activity. A modest decrease in episode frequency resulted in dorsal-ventral pathfinding errors by lumbar motoneurons, and in the downregulation of several molecules required to successfully execute this guidance decision. In contrast, increasing the episode frequency was without effect on dorsal-ventral pathfinding. However, it prevented the subsequent motoneuron pool specific fasciculation of axons and their targeting to appropriate muscles, resulting in marked segmental pathfinding errors. These observations emphasize the need to better evaluate how such early spontaneous electrical activity may influence the molecular and transcription factor pathways that have been shown to regulate the differentiation of motor and interneuron phenotypes and the formation of spinal cord circuits. The intracellular signaling pathways by which episode frequency affects motor axon pathfinding must now be elucidated and it will be important to more precisely characterize the patterns with which specific subsets of motor and inter-neurons are activated normally and under conditions that alter spinal circuit formation.

Versican V0 and V1 Direct the Growth of Peripheral Axons in the Developing Chick Hindlimb

“…Although the axons following these basic pathways intermingle initially in the spinal nerves, they subsequently segregate within the plexus region into separate pools, which already bear the capacity to later respond differentially to region-specific cues within the developing limbs. Rhythmic electrical bursts originating from the early spinal cord appear to sustain this axonal pooling and, hence, further influence subsequent pathfinding decisions (Hanson et al, 2008). Controlled by this second-level and more sophisticated guidance mechanism, axon bundles enter the hindlimb and stereotypically bifurcate into ventral and dorsal nerve trunks.…”

“…This early phase of motor and sensory innervation is at least partly accompanied by the selective deposition and turnover of inhibitory extracellular matrices (ECMs). Once pioneering axons have begun to invade permissive mesenchymal tissues and successive nerve fibers have followed by fasciculation, a refined system of diffusible and stationary attractants and repellents in combination with specific receptor sets on the advancing growth cones controls numerous branch point decisions and directs segregating axons toward their individual targets (Landmesser, 2001;Hanson et al, 2008).…”

Development of human locomotion

“…Thus, the episodes of spontaneous activity are presumably triggered by motoneurons, but the periodicity of activity is set by recurrent excitatory interactions in the network [21]. Bursting activity occurs while motoneurons are still migrating and prolonging their axons toward the base of the limbs, so that correct motor axon path-finding is contingent on normal bursting activity [22]. In addition, spontaneous motor activity at an early developmental stage may facilitate the self-organization of neural circuits at both spinal and supra-spinal levels [21].…”

“…Thus, motor activity modulates the spinal circuits of central pattern generators (CPG) and those of nociceptive withdrawal reflexes [23], and it also modulates cortical somatosensory maps in a somatotopic manner [24]. Once established, spinal CPGs underlie fetal movements [22], but developing supra-spinal structures (such as the transient cortical subplate) presumably also play a role in more complex sequences of general movements, as demonstrated by the abnormality of general movements in human fetuses with brain disorders [10].…”

The Development of Developmental Neuroscience

“…Waves of activity are prominent in the prenatal retina (Torborg and Feller, 2005), indicating that intrinsic activity plays a role at earlier stages of development, even if sensory activity does not emanate from external environment (Hanson et al, 2008). A debate ensued thereafter on whether activity is the sole influence on afferent-specific innervation or whether molecular cues also participate (Katz and Shatz, 1996).…”