Chronic Adaptations in the Dorsal Horn Following a Cervical Spinal Cord Injury in Primates.

Spinal cord injury (SCI) is devastating, with limited treatment options and variable outcomes. Most in vivo SCI research has focused on the acute and early post-injury periods, and the promotion of axonal growth, so little is understood about the clinically stable chronic state, axonal growth over time, and what plasticity endures. Here, we followed animals into the chronic phase following SCI, to address this gap.

Small sensory spinal lesions that affect hand function in monkeys greatly alter primary afferent and motor neuron connections in the cord.

Small sensory spinal injuries induce plasticity across the neuraxis, but little is understood about their effect on segmental connections or motor neuron (MN) function. Here, we begin to address this at two levels. First, we compared afferent input distributions from the skin and muscles of the digits with corresponding MN pools to determine their spatial relationship, in both the normal state and 4-6 months after a unilateral dorsal root/dorsal column lesion (DRL/DCL), affecting digits 1-3.

Reorganization of the Primate Dorsal Horn in Response to a Deafferentation Lesion Affecting Hand Function.

The loss of sensory input following a spinal deafferentation injury can be debilitating, and this is especially true in primates when the hand is involved. Although significant recovery of function occurs, little is currently understood about the reorganization of the neuronal circuitry, particularly within the dorsal horn. This region receives primary afferent input from the periphery, and cortical input via the somatosensory subcomponent of the corticospinal tract (S1 CST), and is critically important in modulating sensory transmission, both in normal and lesioned states.

Somatosensory corticospinal tract axons sprout within the cervical cord following a dorsal root/dorsal column spinal injury in the rat.

The corticospinal tract (CST) is the major descending pathway controlling voluntary hand function in primates, and though less dominant, it mediates voluntary paw movements in rats. As with primates, the CST in rats originates from multiple (albeit fewer) cortical sites, and functionally different motor and somatosensory subcomponents terminate in different regions of the spinal gray matter. We recently reported in monkeys that following a combined cervical dorsal root/dorsal column lesion (DRL/DCL), both motor and S1 CSTs sprout well beyond their normal terminal range.

Spinal cord injury transiently alters Meissner's corpuscle density in the digit pads of macaque monkeys.

Meissner's corpuscles (MCs) are cutaneous mechanoreceptors found in glabrous skin and are exquisitely sensitive to light touch. Along with other receptors, they provide continuous sensory feedback that informs the execution of fine manual behaviors. Following cervical spinal deafferentation injuries, hand use can be initially severely impaired, but substantial recovery occurs over many weeks, even when ~95% of the original input is permanently lost.

Extensive somatosensory and motor corticospinal sprouting occurs following a central dorsal column lesion in monkeys.

The corticospinal tract (CST) forms the major descending pathway mediating voluntary hand movements in primates, and originates from ∼nine cortical subdivisions in the macaque. While the terminals of spared motor CST axons are known to sprout locally within the cord in response to spinal injury, little is known about the response of the other CST subcomponents. We previously reported that following a cervical dorsal root lesion (DRL), the primary somatosensory (S1) CST terminal projection retracts to 60% of its original terminal domain, while the primary motor (M1) projection remains robust (Darian-Smith et al.

Corticospinal sprouting differs according to spinal injury location and cortical origin in macaque monkeys.

The primate corticospinal tract (CST), the major descending pathway mediating voluntary hand movements, comprises nine or more functional subdivisions. The role of subcomponents other than that from primary motor cortex, however, is not well understood. We have previously shown that following a cervical dorsal rhizotomy (Darian-Smith et al.

Corticospinal sprouting occurs selectively following dorsal rhizotomy in the macaque monkey.

The corticospinal tract in the macaque and human forms the major descending pathway involved in volitional hand movements. Following a unilateral cervical dorsal root lesion, by which sensory input to the first three digits (D1-D3) is removed, monkeys are initially unable to perform a grasp retrieval task requiring sensory feedback. Over several months, however, they recover much of this capability.

Adult neurogenesis occurs in primate sensorimotor cortex following cervical dorsal rhizotomy.

Adult neurogenesis remains controversial in the cerebral cortex. We have previously shown in monkeys and rats that reactive neurogenesis occurs in the spinal dorsal horn 6-8 weeks after a cervical dorsal rhizotomy. Here, in three monkeys with the same lesion, we asked whether it also occurs coincidentally in the corresponding primary somatosensory and motor cortex, where significant topographic and neuronal reorganization is known to occur.

Changes in synaptic populations in the spinal dorsal horn following a dorsal rhizotomy in the monkey.

Studies in monkeys have shown substantial neuronal reorganization and behavioral recovery during the months following a cervical dorsal root lesion (DRL; Darian-Smith [2004] J. Comp. Neurol.

Synaptic plasticity, neurogenesis, and functional recovery after spinal cord injury.

Spinal cord injury research has greatly expanded in recent years, but our understanding of the mechanisms that underlie the functional recovery that can occur over the weeks and months following the initial injury, is far from complete. To grasp the scope of the problem, it is important to begin by defining the sensorimotor pathways that might be involved by a spinal injury. This is done in the rodent and nonhuman primate, which are two of the most commonly used animal models in basic and translational spinal injury research.

Adult neurogenesis in primate and rodent spinal cord: comparing a cervical dorsal rhizotomy with a dorsal column transection.

Neurogenesis has not been shown in the primate spinal cord and the conditions for its induction following spinal injury are not known. In the first part of this study, we report neurogenesis in the cervical spinal dorsal horn in adult monkeys 6-8 weeks after receiving a well-defined cervical dorsal rhizotomy (DRL). 5-bromo-2-deoxyuridine (BrdU) was administered 2-4 weeks following the lesion.

Monkey models of recovery of voluntary hand movement after spinal cord and dorsal root injury.

The hand is unique to the primate and manual dexterity is at its finest in the human (Napier 1980), so it is not surprising that cervical spinal injuries that even partially block sensorimotor innervation of the hand are frequently debilitating (Anderson 2004). Despite the clinical need to understand the neuronal bases of hand function recovery after spinal and/or nerve injuries, relatively few groups have systematically related subtle changes in voluntary hand use following injury to neuronal mechanisms in the monkey. Human and macaque hand anatomy and function are strikingly similar, which makes the macaque the favored nonhuman primate model for the study of postinjury dexterity.

Synaptic protein dynamics in hibernation.

Neurons in hibernating mammals exhibit a dramatic form of plasticity during torpor, with dendritic arbors retracting as body temperature cools and then regrowing rapidly as body temperature rises. In this study, we used immunohistochemical imaging and Western blotting of several presynaptic and postsynaptic proteins to determine the synaptic changes that accompany torpor and to investigate the mechanisms behind these changes. We show torpor-related alterations in synaptic protein localization that occur rapidly and uniformly across several brain regions in a temperature-dependent manner.

Ubiquitous and temperature-dependent neural plasticity in hibernators.

Hibernating mammals are remarkable for surviving near-freezing brain temperatures and near cessation of neural activity for a week or more at a time. This extreme physiological state is associated with dendritic and synaptic changes in hippocampal neurons. Here, we investigate whether these changes are a ubiquitous phenomenon throughout the brain that is driven by temperature.

Cuneate nucleus reorganization following cervical dorsal rhizotomy in the macaque monkey: its role in the recovery of manual dexterity.

Immediately following a dorsal rhizotomy that removes input from the thumb, index, and middle fingers, the macaque is unable to execute movements that require controlled apposition of these digits. We have previously shown that within the early weeks and months following one of these lesions, there is 1) a re-emergence of part or all of the cortical hand map; 2) central axonal sprouting of spared primary afferents into the dorsal horn and cuneate nucleus; and 3) substantial although incomplete recovery of hand function (Darian-Smith [204] J. Comp.

Loss and recovery of voluntary hand movements in the macaque following a cervical dorsal rhizotomy.

The recovery of manual dexterity was analyzed in the macaque following a cervical dorsal root section that abolished cutaneous feedback from selected digits of one hand. Monkeys were trained to retrieve a target object from a clamp using thumb and index finger opposition. Dorsal rootlets containing electrophysiologically identified axons projecting from the thumb and index finger were then cut in two monkeys (Group 1).

Primary afferent terminal sprouting after a cervical dorsal rootlet section in the macaque monkey.

We examined the role of primary afferent neurons in the somatosensory cortical "reactivation" that occurs after a localized cervical dorsal root lesion (Darian-Smith and Brown [2000] Nat. Neurosci. 3:476-481).