Projection Neuron Axon Collaterals in the Dorsal Horn: Placing a New Player in Spinal Cord Pain Processing

The pain experience depends on the relay of nociceptive signals from the spinal cord dorsal horn to higher brain centers. This function is ultimately achieved by the output of a small population of highly specialized neurons called projection neurons (PNs). Like output neurons in other central nervous system (CNS) regions, PNs are invested with a substantial axon collateral system that ramifies extensively within local circuits. These axon collaterals are widely distributed within and between spinal cord segments. Anatomical data on PN axon collaterals have existed since the time of Cajal, however, their function in spinal pain signaling remains unclear and is absent from current models of spinal pain processing. Despite these omissions, some insight on the potential role of PN axon collaterals can be drawn from axon collateral systems of principal or output neurons in other CNS regions, such as the hippocampus, amygdala, olfactory cortex, and ventral horn of the spinal cord. The connectivity and actions of axon collaterals in these systems have been well-defined and used to confirm crucial roles in memory, fear, olfaction, and movement control, respectively. We review this information here and propose a framework for characterizing PN axon collateral function in the dorsal horn. We highlight that experimental approaches traditionally used to delineate axon collateral function in other CNS regions are not easily applied to PNs because of their scarcity relative to spinal interneurons (INs), and the lack of cellular organization in the dorsal horn. Finally, we emphasize how the rapid development of techniques such as viral expression of optogenetic or chemogenetic probes can overcome these challenges and allow characterization of PN axon collateral function. Obtaining detailed information of this type is a necessary first step for incorporation of PN collateral system function into models of spinal sensory processing.

Corticospinal neurons encode complex motor signals that are broadcast to dichotomous striatal circuits

SummarySensorimotor cortex controls movement in part through direct projections to the spinal cord. Here we show that these corticospinal neurons (CSNs) possess axon collaterals that innervate many supraspinal brain regions critical for motor control, most prominently the main input to the basal ganglia, the striatum. Corticospinal neurons that innervate the striatum form more synapses on D1-than D2-striatal projection neurons (SPNs). This biased innervation strategy corresponds to functionally distinct patterns of termination in spinal cord. CSNs are strongly driven during a striatum-dependent sequential forelimb behavior, and often represent high level movement features that are not linearly related to kinematic output. Copies of these activity patterns are relayed in a balanced fashion to both D1 and D2 projection pathways. These results reveal a circuit logic by which motor cortex corticospinal neurons relay both kinematic-related and unrelated signals to distinct striatal and spinal cord pathways, where postsynaptic connectivity ultimately dictates motor specificity.HighlightsCorticospinal neurons send axon collaterals most abundantly to the striatumBiases in striatal innervation correspond to biases in spinal innervationCSNs represent complex movement sequence informationCorollary motor sequence signals are relayed to both striatal projection pathwayseTOC BlurbNelson, A. et al. detail the organization of corticospinal neurons and their coordinated cell type-specific targets in the dorsolateral striatum and spinal cord. Corticospinal neurons encode both kinematic-related and unrelated signals during motor sequences, and relay this information in a balanced fashion to dichotomous striatal pathways.

Evidence for genetically distinct direct and indirect spinocerebellar pathways mediating proprioception

Proprioception, the sense of limb and body position, generates a map of the body that is essential for proper motor control, yet we know little about precisely how neurons in proprioceptive pathways develop and are wired. Proprioceptive and cutaneous information from the periphery is sent to secondary neurons in the spinal cord that integrate and relay this information to the cerebellum either directly or indirectly through the medulla. Defining the anatomy of these direct and indirect pathways is fundamental to understanding how proprioceptive circuits function. Here, we use genetic tools in mice to define the developmental origins and unique anatomical trajectories of these pathways. Developmentally, we find that Clarke’s column (CC) neurons, a major contributor to the direct spinocerebellar pathway, derive from the Neurog1 progenitor domain. By contrast, we find that two of the indirect pathways, the spino-lateral reticular nucleus (spino-LRt) and spino-olivary pathways, are derived from the Atoh1 progenitor domain, despite previous evidence that Atoh1-lineage neurons form the direct pathway. Anatomically, we also find that the mossy fiber terminals of CC neurons diversify extensively with some axons terminating bilaterally in the cerebellar cortex. Intriguingly, we find that CC axons do not send axon collaterals to the medulla or cerebellar nuclei like other mossy fiber sources. Altogether, we conclude that the direct and indirect spinocerebellar pathways derive from distinct progenitor domains in the developing spinal cord and that the proprioceptive information from CC neurons is processed only at the level of granule cells in the cerebellum.Significance StatementWe find that a majority of direct spinocerebellar neurons in mice originate from Clarke’s column (CC), which derives from the Neurog1-lineage, while few originate from Atoh1-lineage neurons as previously thought. Instead, we find that spinal cord Atoh1-lineage neurons form mainly the indirect spino-lateral reticular nucleus and spino-olivary tracts. Moreover, we observe that mossy fiber axon terminals of CC neurons diversify proprioceptive information across granule cells in multiple lobules on both ipsilateral and contralateral sides without sending axon collaterals to the medulla or cerebellar nuclei. Altogether, we define the development and the anatomical projections of direct and indirect pathways to the cerebellum from the spinal cord.

Central and peripheral innervation patterns of defined axial motor units in larval zebrafish

Spinal motor neurons and the peripheral muscle fibers they innervate form discrete motor units that execute movements of varying force and speed. Subsets of spinal motor neurons also exhibit axon collaterals that influence motor output centrally. Here, we have used in vivo imaging to anatomically characterize the central and peripheral innervation patterns of axial motor units in larval zebrafish. Using early born ‘primary’ motor neurons and their division of epaxial and hypaxial muscle into four distinct quadrants as a reference, we define three distinct types of later born ‘secondary’ motor units. The largest are ‘m-type’ units, which innervate deeper fast-twitch muscle fibers via medial nerves. Next in size are ‘ms-type’ secondaries, which innervate superficial fast-twitch and slow fibers via medial and septal nerves, followed by ‘s-type’ units, which exclusively innervate superficial slow muscle fibers via septal nerves. All types of secondaries innervate up to four axial quadrants. Central axon collaterals are found in subsets of primaries based on soma position and predominantly in secondary fast-twitch units (m, ms) with increasing likelihood based on number of quadrants innervated. Collaterals are labeled by synaptophysin-tagged fluorescent proteins, but not PSD95, consistent with their output function. Also, PSD95 dendrite labeling reveals that larger motor units receive more excitatory synaptic input. Collaterals are largely restricted to the neuropil, however perisomatic connections are observed between motor units. These observations suggest that recurrent interactions are dominated by motor neurons recruited during stronger movements and set the stage for functional investigations of recurrent motor circuitry in larval zebrafish.

Axonal plasticity associated with perceptual learning in adult macaque primary visual cortex

Perceptual learning is associated with changes in the functional properties of neurons even in primary sensory areas. In macaque monkeys trained to perform a contour detection task, we have observed changes in contour-related facilitation of neuronal responses in primary visual cortex that track their improvement in performance on a contour detection task. We have previously explored the anatomical substrate of experience-dependent changes in the visual cortex based on a retinal lesion model, where we find sprouting and pruning of the axon collaterals in the cortical lesion projection zone. Here, we attempted to determine whether similar changes occur under normal visual experience, such as that associated with perceptual learning. We labeled the long-range horizontal connections in visual cortex by virally mediated transfer of genes expressing fluorescent probes, which enabled us to do longitudinal two-photon imaging of axonal arbors over the period during which animals improve in contour detection performance. We found that there are substantial changes in the axonal arbors of neurons in cortical regions representing the trained part of the visual field, with sprouting of new axon collaterals and pruning of preexisting axon collaterals. Our findings indicate that changes in the structure of axonal arbors are part of the circuit-level mechanism of perceptual learning, and further support the idea that the learned information is encoded at least in part in primary visual cortex.