Previously, we showed that the ventral premotor cortex (PMv) underwent neurophysiological remodeling after injury to the primary motor cortex (M1). In the present study, we examined cortical connections of PMv after such lesions. The neuroanatomical tract tracer biotinylated dextran amine was injected into the PMv hand area at least 5 months after ischemic injury to the M1 hand area. Comparison of labeling patterns between experimental and control animals demonstrated extensive proliferation of novel PMv terminal fields and the appearance of retrogradely labeled cell bodies within area 1/2 of the primary somatosensory cortex after M1 injury. Furthermore, evidence was found for alterations in the trajectory of PMv intracortical axons near the site of the lesion. The results suggest that M1 injury results in axonal sprouting near the ischemic injury and the establishment of novel connections within a distant target. These results support the hypothesis that, after a cortical injury, such as occurs after stroke, cortical areas distant from the injury undergo major neuroanatomical reorganization. Our results reveal an extraordinary anatomical rewiring capacity in the adult CNS after injury that may potentially play a role in recovery.
Stroke is often characterized by incomplete recovery and chronic motor impairments. A nonhuman primate model of cortical ischemia was used to evaluate the feasibility of using device-assisted cortical stimulation combined with rehabilitative training to enhance behavioral recovery and cortical plasticity. Following pre-infarct training on a unimanual motor task, maps of movement representations in primary motor cortex were derived. Then, an ischemic infarct was produced which destroyed the hand representation. Several weeks later, a second cortical map was derived to guide implantation of a surface electrode over peri-infarct motor cortex. After several months of spontaneous recovery, monkeys underwent subthreshold electrical stimulation combined with rehabilitative training for several weeks. Post-therapy behavioral performance was tracked for several additional months. A third cortical map was derived several weeks post-therapy to examine changes in motor representations. Monkeys showed significant improvements in motor performance (success, speed, and efficiency) following therapy, which persisted for several months. Cortical mapping revealed large-scale emergence of new hand representations in peri-infarct motor cortex, primarily in cortical tissue underlying the electrode. Results support the feasibility of using a therapy approach combining peri-infarct electrical stimulation with rehabilitative training to alleviate chronic motor deficits and promote recovery from cortical ischemic injury.
After a cortical lesion, cortical areas distant from the site of injury are known to undergo physiological and anatomical changes. However, the mechanisms through which reorganization of distant cortical areas is initiated are poorly understood. In a previous publication, we showed that the ventral premotor cortex (PMv) undergoes physiological reorganization after a lesion destroying the majority of the primary motor cortex (M1) distal forelimb representation (DFL). After large lesions destroying >50% of the M1 DFL, the PMv DFL invariably increased in size, and the amount of the increase was positively correlated with the size of lesion. To determine whether lesions destroying <50% of the M1 DFL followed a similar trajectory, we documented PMv reorganization using intracortical microstimulation techniques after small, ischemic lesions targeting subregions within the M1 DFL. In contrast to earlier results, lesions resulted in a reduction of the PMv DFL regardless of their location. Further, because recent anatomical findings suggest a segregation of PMv connectivity with M1, we examined two lesion characteristics that may drive alterations in PMv physiological reorganization: location of the lesion with respect to PMv connectivity and relative size of the lesion. The results suggest that after a lesion in the M1 DFL, the induction of representational plasticity in PMv, as evaluated using intracortical microstimulation, is related more to the size of the lesion than to the disruption of its intracortical connections.
Vascular endothelial growth factor (VEGF) is thought to contribute to both neuroprotection and angiogenesis after stroke. While increased expression of VEGF has been demonstrated in animal models after experimental ischemia, these studies have focused almost exclusively on the infarct and peri-infarct regions. The present study investigated the association of VEGF to neurons in remote cortical areas at three days after an infarct in primary motor cortex (M1). Although these remote areas are outside of the direct influence of the ischemic injury, remote plasticity has been implicated in recovery of function. For this study, intracortical microstimulation techniques identified primary and premotor cortical areas in a non-human primate. A focal ischemic infarct was induced in the M1 hand representation, and neurons and VEGF protein were identified using immunohistochemical procedures. Stereological techniques quantitatively assessed neuronal-VEGF association in the infarct and peri-infarct regions, M1 hindlimb, M1 orofacial, and ventral premotor hand representations, as well as non-motor control regions. The results indicate that VEGF protein significantly increased association to neurons in specific remote cortical areas outside of the infarct and peri-infarct regions. The increased association of VEGF to neurons was restricted to cortical areas that are functionally and/or behaviorally related to the area of infarct. There was no significant increase in M1 orofacial region or in non-motor control regions. We hypothesize that enhancement of neuronal VEGF in these functionally related remote cortical areas may be involved in recovery of function after stroke, through either neuroprotection or the induction of remote angiogenesis.
Uterine innervation undergoes profound remodeling during puberty, pregnancy, and after parturition. However, the extent to which uterine innervation may change during the estrous cycle is uncertain. The objective of the present study was to determine whether nerve fiber density of the uterine horn is altered during the estrous cycle and, if so, which subpopulations are affected. Immunostaining for the pan-neuronal marker protein gene product (PGP) 9.5 revealed fibers within the vascular zone, myometrium, and endometrium, with greater density in the ovarian and cervical regions than in the middle. In most structures, nerve density was reduced during estrus. This could not be accounted for by increased target volume, as the reduction in longitudinal muscle innervation persisted after correction for changes in target size. Immunostaining for vasoactive intestinal polypeptide-immunoreactive parasympathetic nerves revealed fibers associated predominantly with the vascular zone and circular muscle within the cervical region. No cyclical variation was detected. Calcitonin gene-related peptide-immunoreactive nerves were present within all structures, and density was highest at the ovarian end. These fibers also did not vary significantly through estrous. Dopamine beta-hydroxylase-immunoreactive sympathetic nerves innervated all structures, with greater density in the ovarian end. These fibers were reduced substantially during estrus, but the decline was also significant in proestrus, thus preceding that detected by using the pan-neuronal marker. We conclude that the estrous cycle in rat is accompanied by structural remodeling of sympathetic nerves by way of retraction or degeneration of terminal fibers during estrus. The structural loss of the terminal axon apparently is preceded by depletion of catecholamine-synthesizing enzyme.
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