Rescuing transient corticospinal terminations and promoting growth with corticospinal stimulation in kittens - PubMed (original) (raw)

Rescuing transient corticospinal terminations and promoting growth with corticospinal stimulation in kittens

Iran Salimi et al. J Neurosci. 2004.

Abstract

Development of corticospinal (CS) terminations is activity dependent. In the cat, activity-dependent refinement of termination topography occurs between weeks 3 and 6. Initially, sparse terminals are present in the gray matter bilaterally, including the motor nuclei. By week 6, virtually all motor nuclear terminations are eliminated, as are most ipsilateral terminations. In this study, we determined whether electrical stimulation of CS axons could be used to rescue transient terminations and promote their growth. We implanted microwires in the pyramid or spinal white matter to stimulate CS axons (2 hr/d, 330 Hz, 45 msec burst, 2 sec intervals) for 2-3 weeks during the refinement period. CS terminations were traced using wheat germ agglutinin conjugated to horseradish peroxidase. Animals were killed after week 6. Stimulation produced dense terminations bilaterally, including within the motor nuclei. Termination density was least in lamina 1 and ventral lamina 9. Reticular formation stimulation produced a control (i.e., nonstimulated) termination pattern. To determine whether CS stimulation affected development of the nonstimulated CS system, we traced terminations from the contralateral cortex using biotinylated dextran amine. Compared with controls or after reticular formation stimulation, there was a shift in the distribution of terminations of the nonstimulated side to more dorsal laminas, which is where the stimulated CS system had fewer terminals. This distribution shift is consistent with competition for termination space between the CS systems on both sides. Our findings indicate that activity can be harnessed to bias CS axon terminal development. This has important implications for using activity to modify motor system organization after perinatal CNS trauma.

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Figures

Figure 2.

Figure 2.

Effect of PT stimulation on CS axon terminal topography (experiment 2). A, Transverse section through the cervical enlargement (montage of 5 polarized dark-field micrographs). B, Nissl-stained section through the ventral portion of the medulla showing the pyramids. The solid line marks the electrode tract. The circle and arrow show the location of the marking lesion in the medial pyramid. C, Horizontal section through the dorsal horn (see inset for level) of the C6-C7 segments. D, Horizontal section through the ventral horn (see inset for level), ventral to the section in C. The white arrows mark the lateral and medial boundaries of the lateral motor nuclei. The right side of A, C, and D is contralateral to the stimulated CS system. Scale bars, 1 mm.

Figure 3.

Figure 3.

Stimulation of the CS tract (CST) in the lateral funiculus at C1 (experiment3). These micrographs are similar to those in Figure 2. A, Photomontage of a transverse section through the cervical enlargement. Insets, Nissl-stained section of the dorsal spinal cord (top) and higher magnification view of the boxed area (bottom). B, Horizontal sections through the dorsal horn of the C6-C7 segments (similar level as in Fig. 2_C_). C, Horizontal section through the ventral horn of the C6-C7 segments (similar level as in Fig. 2 D). The sections in C cut through the motor nuclei. The right side of A-C is contralateral to the stimulated CS system. Scale bars: A, A, top inset, B, C, 1 mm; A, bottom inset, 500 μm.

Figure 4.

Figure 4.

Predominantly contralateral CS terminations after reticular formation stimulation (A; experiment 6) and in an 8-week-old control (B; experiment 8). A1, left side (horizontal section), Dense CS axon terminal label in the dorsal horn, contralateral to the side of RF stimulation. No labeling is present on the left side, which is ipsilateral to the RF stimulation site. A2, Horizontal sections through the ipsilateral (left) and contralateral (right) motor nuclei in the ventral horn. No labeling is present in either the contralateral or ipsilateral motor nuclei. The schematic inset shows the levels of the sections. The Nissl-stained section below A2 shows the location of the marking lesion and gliosis associated with the tip of the RF stimulation electrode. B1, Horizontal section through the dorsal horn in an 8-week-old animal. Dense dorsal horn label is present contralaterally only (right side of section). Horizontal sections through the contralateral (B2) and ipsilateral (B3) motor nuclei reveal the absence of a significant label. Scale bars: A1, A2, 200 μm; A, inset, B1-B3, 1 mm.

Figure 1.

Figure 1.

Evoked spinal response. An ensemble average (n = 10 trials) of a surface recording from the sixth cervical segment in a 4-week-old animal is shown. The stimulus was a train of six stimuli at 100 μA. The short vertical marks below the recording trace show the time of occurrence of each stimulus. Calibration, 20 μV.

Figure 7.

Figure 7.

Distribution of CS terminal label from the nonstimulated side. Each diagram shows a camera lucida drawing of label in the dorsal horn and intermediate zone. The dotted line marks the approximate boundary between laminas 6 and 7. The insets show drawings of a single parasagittal section through the injection site; the arrow marks the cruciate sulcus. A, CS axon terminal label after tracer injection into the nonstimulated cortex from an animal that received PT stimulation (experiment 4).B,Asin A but for RF stimulation (experiment 6). C, Nonstimulated animal (PW 8, experiment 9). Scale bar: A-C, 1 mm; insets, 5 mm.

Figure 5.

Figure 5.

The bilaterality index (ratio of ipsilateral to contralateral terminations) at different gray matter locations is shown for CS system stimulation (gray bars; n = 4 animals) and the combined set of control animals (white bar; n = 2 animals with RF stimulation; n = 1 age-matched control). For the CS stimulation experiments, we sampled five sites in the gray matter, as indicated in the inset: superficial dorsal horn (sDH), medial dorsal horn (mDH), intermediate zone (IZ), ventral horn (VH, i.e., territory between lateral and medial motor nuclei), and motor nuclei (MN). For the controls, only the medial dorsal horn was assessed because labeling was too light to quantitatively analyze in the other areas.

Figure 6.

Figure 6.

The density of labeling in CS-stimulated animals decreases gradually within the dorsal and ventral horns (experiment 2). A, C, Polarized dark-field micrographs through the dorsal and ventral horns, respectively. White lines show the axes along which label density was measured. B, D, Gradients of labeling in the dorsal and ventral horns, respectively, from a single animal. Mean values ± SE of five sections (10 samples from each section) are plotted.

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