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

Abstract

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. Many of the better known experimentally induced models are then reviewed in terms of the pathways they involve and the reorganization and recovery that have been shown to follow. The better understood neuronal mechanisms mediating such post-injury plasticity, including dendritic spine growth and axonal sprouting, are then examined.

Figure 1

(A, D) Terminal distributions for the different primary afferent subpopulations terminating in the dorsal horn (left side), and the major ascending (color), and descending (gray scale) tracts involved in the transmission of sensorimotor information within the cord (right side). (A–C) Monkey neuroanatomy and (D–F) the equivalent for the rat. (B, E) Major sensorimotor ascending and descending pathways of the cervical spinal cord. (C, F) Some of the organizational features of the primary somatosensory cortex, and in the case of the rat (F), there is only a single body map. In the macaque (C), there are four different somatosensory regions, each with a separate hand (and body) representation. Some other major species differences are evident in, for example, the location of the major corticospinal tract (medial and ventral to the dorsal columns in the rat, and dorsolateral in the macaque and human). (Adapted from Darian-Smith 2008 with permission from Elsevier.)

Figure 1

(A, D) Terminal distributions for the different primary afferent subpopulations terminating in the dorsal horn (left side), and the major ascending (color), and descending (gray scale) tracts involved in the transmission of sensorimotor information within the cord (right side). (A–C) Monkey neuroanatomy and (D–F) the equivalent for the rat. (B, E) Major sensorimotor ascending and descending pathways of the cervical spinal cord. (C, F) Some of the organizational features of the primary somatosensory cortex, and in the case of the rat (F), there is only a single body map. In the macaque (C), there are four different somatosensory regions, each with a separate hand (and body) representation. Some other major species differences are evident in, for example, the location of the major corticospinal tract (medial and ventral to the dorsal columns in the rat, and dorsolateral in the macaque and human). (Adapted from Darian-Smith 2008 with permission from Elsevier.)

Figure 2

(A–C) Data from a monkey (M3) that received a dorsal rhizotomy that removed input initially from the thumb, index, and middle fingers. (A) Monkey’s cortical receptive field map 22 weeks following the rhizotomy. The photograph and cortical map illustrates the sites of microelectrode penetrations caudal to the central sulcus (CS) in the somatosensory cortex. The cortical field of each digit representation is outlined and color coded and a silent cortical zone resulting from the deafferentation of the digits is identified by the unfilled circles. Note the partial reemergence of input from the index and middle fingers and the corresponding partial recovery of the use of these digits in C. Scale bar = 2 mm. (B) Success rates (y axis) for target retrievals over the postinjury weeks (x axis). This monkey did not successfully retrieve the target for the first 7 weeks but then began to regain function in its first three digits. Although the distal pads of the thumb and index finger were not used again to contact and retrieve the object, this monkey recovered a remarkable amount of function in the thumb, index, and middle digits, after an initial delay. (C) Four frame sequences showing the predominant manual stratagems used after lesion in the same monkey. Column 1 shows the normal prelesion precision grip stratagem executed by opposing the distal pads of the thumb and index finger. Column 2 shows the impaired hand at one week following the lesion; there was a complete loss of the ability to sense and respond to the clamp or target. The hand was held “paddle” style, and all attempts to remove the object failed. Columns 3 and 4 show successful but abnormal and alternate stratagems (opposition of the thumb and middle finger) adopted by the 11th week (shown here in the 13th week) and used and improved over the remaining assessment period. (From Darian-Smith and Ciferri 2005 with permission.)

Figure 3

Somatotopic maps of the representation of the hand in the cuneate nucleus in a monkey that received rhizotomies similar to the animal in Figure 2, which blocked input from digits D1–D3. Receptive fields (RFs) were significantly reorganized within the nucleus on the side of the lesion at 29 weeks following the dorsal root lesion, and input from the thumb was virtually absent (only 1 RF in track 8). A core unresponsive region was also consistently found on the side of the lesion in a region corresponding to D1–D3 representation on the normal side. This matched behavioral recovery over the postinjury period in which thumb use was limited, and cortical maps in which thumb representation was also greatly reduced. Scale bar = 1 mm. (From Darian-Smith and Ciferri 2006 with permission.)

Figure 4

(A) A series of sections taken through the cervical spinal dorsal horn of a macaque monkey showing the distributions of terminals of primary afferents labeled with cholera toxin subunit B conjugated to horseradish peroxidase injected bilaterally into the thumb and index finger in a monkey with a postoperative survival period of 16 weeks. The rostrocaudal extent of the lesion is shown by the oblique black bar on the left of a series of transverse sections of the cervical spinal cord. The six enlarged cross-sections illustrate the distributions of labeled terminals within the dorsal horn in C6 and C7. Labeling in the dorsal horn now occurred throughout the lesion zone in the left hemicord, defined by the distribution of label in the right normal hemicord. Inset shows a distribution map superimposed on an adjacent section (Luxol Fast Blue). Note the myelin sparse degeneration zone within the dorsal column and the presence of terminal labeling within superficial and deep laminae of the spinal dorsal horn. Gray shading through the section stack outlines the rostrocaudal extent of labeling within the dorsal horn on each side of the cord. Roman numerals show the approximate location of the different laminae within the dorsal horn. Scale bar = 2.5 mm. (B) Distribution territory histograms of terminal labeling within the spinal dorsal horn in each of the monkeys used in the analysis. Each bar gives the volume estimate for any one section. Gray indicates distribution territory histograms on the control side; black indicates distributions on the side of the lesion. Dashed pale gray lines indicate lesion positioning and rostrocaudal extent. All short-term comparisons were statistically significant and long-term insignificant. P.O., postoperative. (From Darian-Smith 2004 with permission.)

Figure 5

(A) Count profiles of two synaptic elements through the superficial laminae of the dorsal horn in two monkeys. Counts shown are mean values for all sections through segments C5-7, normalized so that numbers are presented per 100 μm². Data on the side of the lesion (blue diamond) are directly compared with data on the nonlesioned side (filled squares), and paired sample t-tests used to determine the statistical differences of elemental profiles on the two sides of the cord. P values and distribution profiles are given for each data set and indicate a similar profile distribution pattern across the two monkeys. These data show that primary afferent terminals decrease dramatically (C type) whereas inhibitory profiles increase significantly (F-GABA-ir) on the side of the lesion during the early months following a cervical dorsal root lesion. (B) Electron micrograph of GABAergic terminals (colloidal gold immunolabeling) within the deprived (left) and “normal” (right) dorsal horn in a monkey that received a cervical dorsal rhizotomy four months earlier. In the left image, inhibitory terminals synapse with dendrites, D, and the synapse shown in the right image is axosomatic.

Figure 6

(A) Examples of cells within the dorsal horn in the lesion zone of a monkey that had received a cervical dorsal rhizotomy five weeks previously, colabeled with the cell division marker 5-bromo-2-deoxyuridine (BrdU) and either the neuronal markers, neuron-specific nuclear protein (NeuN), or GABA. The location of these colabeled neurons is shown top right. Orthogonal images and a spectral intensity profile show mark colabeling. (B) A histogram showing total numbers of 5-bromo-2-deoxyuridine/neuron-specific nuclear protein (BrdU/NeuN)–colabeled cells through cervical segments C5-8 in the monkey, estimated using the fractionator method (West and others 1991) for each half (R, rostral; C, caudal) cervical segment. Counts were significantly higher in the dorsal horn on the side of the lesion compared with the contralateral “control” side. (C) Examples of cells immunopositive for neuronal markers and BrdU in a rat that also received a dorsal root lesion. (From Vessal and others 2007 with permission.)