Use-Dependent Dendritic Regrowth Is Limited after Unilateral Controlled Cortical Impact to the Forelimb Sensorimotor Cortex

Abstract

Compensatory neural plasticity occurs in both hemispheres following unilateral cortical damage incurred by seizures, stroke, and focal lesions. Plasticity is thought to play a role in recovery of function, and is important for the utility of rehabilitation strategies. Such effects have not been well described in models of traumatic brain injury (TBI). We examined changes in immunoreactivity for neural structural and plasticity-relevant proteins in the area surrounding a controlled cortical impact (CCI) to the forelimb sensorimotor cortex (FL-SMC), and in the contralateral homotopic cortex over time (3-28 days). CCI resulted in considerable motor deficits in the forelimb contralateral to injury, and increased reliance on the ipsilateral forelimb. The density of dendritic processes, visualized with immunostaining for microtubule-associated protein-2 (MAP-2), were bilaterally decreased at all time points. Synaptophysin (SYN) immunoreactivity increased transiently in the injured hemisphere, but this reflected an atypical labeling pattern, and it was unchanged in the contralateral hemisphere compared to uninjured controls. The lack of compensatory neuronal structural plasticity in the contralateral homotopic cortex, despite behavioral asymmetries, is in contrast to previous findings in stroke models. In the cortex surrounding the injury (but not the contralateral cortex), decreases in dendrites were accompanied by neurodegeneration, as indicated by Fluoro-Jade B (FJB) staining, and increased expression of the growth-inhibitory protein Nogo-A. These studies indicate that, following unilateral CCI, the cortex undergoes neuronal structural degradation in both hemispheres out to 28 days post-injury, which may be indicative of compromised compensatory plasticity. This is likely to be an important consideration in designing therapeutic strategies aimed at enhancing plasticity following TBI.

Combinatorial Motor Training Results in Functional Reorganization of Remaining Motor Cortex after Controlled Cortical Impact in Rats

“…Two of our recent studies indicate that this assumption is flawed. 14,15 After a unilateral controlled cortical impact (CCI) over the caudal motor cortex (CMC) in rats, there are long-term forelimb impairments, similar to what is found following other models of damage to the motor cortex; however, we found that neural remodeling was severely blunted post-CCI compared to similarly placed and sized ischemic lesions.…”

“…57,58 The fact that wrist and elbow movements are primarily elicited above 60 uA indicates that, even 41 days post-CCI, the motor cortex is highly dysfunctional, further supporting our previous findings that dendrites in peri-injury remaining MC are sparse, and NOGO is upregulated compared to control animals. 14 Nishibe and colleagues 58 found that wrist movements in the RMC post-CCI over the CMC required, on average, 11-20 uA more current compared to non-CCI controls. It is also possible that intracortical and corticospinal white matter damage, ongoing neuroinflammation, or other inhibitory mechanisms underlie the reduced motor cortex representation and higher movement thresholds post-CCI.…”

“…14,[16][17][18] Further, we also recently reported that motor treatments that have been found to improve forelimb function after ischemic stroke (reaching alone and forelimb constraint alone), were not effective post-CCI over the forelimb area of the CMC unless they were combined. 15 Skilled forelimb reaching, voluntary aerobic exercise, and nonimpaired forelimb constraint individually have been shown to enhance recovery or enhance neural plasticity in animal models of stroke and focal lesions.…”

Experimental Traumatic Brain Injury Alters Ethanol Consumption and Sensitivity

“…Numerous studies have demonstrated features of neuronal plasticity after TBI in regions including the cortex and hippocampus. [50][51][52][53][54][55] Evidence of acute neuroplasticity in both the hippocampus and cortex has also been reported after acute ethanol exposure in rodents. 56 Disruption of this observed ethanol-induced neuroplasticity by impairment in the protein kinase A (PKA) signaling pathway, for example, results in heightened sensitivity to ethanol, which is manifested as extended sedation durations.…”

Cortical Reorganization after Experimental Traumatic Brain Injury: A Functional Autoradiography Study

“…12,46,47 Though the mechanism for this remapping is uncertain, the short timescale precludes the idea of structural remodeling occurring to reshape the map because, unlike in stroke or lesioning studies, 10,48-51 compensatory structural neuronal plasticity does not occur in the contralesional cortex after CCI injury. 52 However, this does not necessarily rule out that compensatory motor learning associated with over-reliance of the unaffected limb 49,53 might occur to activate contralesional circuits without any major structural remodeling. The extreme asymmetry of limb use early after brain injury 44,52 and the finding that the maladaptive effects of nonparetic limb use depend upon the contralesional cortex 54 would support this as a potential mechanism.…”