Testing Amyloid Cross-Toxicity in the Vertebrate Brain.

While amyloid proteins such as amyloid ß (Aß),α-synuclein, tau, and lysozyme are known to be prion-like; emerging data have revealed that they are also able to seed the misfolding of prion-like proteins differing in sequence. In the present study, we have developed a tool designed to test neurohistochemical outcomes associated with the entry of an amyloid protein into heterotypic neurons, i.e., neurons that do not express the invading amyloid and, instead, endogenously express amyloids differing in sequence. The stereotaxic introduction of Aß into the rodent tegmental area of the mid-brain revealed that the foreign amyloid had infiltrated into nigral neurons. Furthermore, Aß was found colocalized with α-synuclein, an amyloid endogenous to the substantia nigra and differing in sequence relative to Aß. Disruption of α-synuclein status in the substantia nigra is associated with Parkinson's disease onset and progress. In addition to the study findings, a significant inroad to future neurodegenerative research was made via the stereotaxic introduction of the foreign amyloid. This technique limits the presence of confounding neurometabolic variables that may be prevalent in transgenic animal models of cross-toxicity and, thereby, better addresses the role of individual neuronal factors in cross-toxicity. Finally, the data from this work may help reconcile the high frequency of clinical comorbidity seen in neurodegenerative diseases.

Traumatic Brain Injury Occludes Training-Dependent Cortical Reorganization in the Contralesional Hemisphere.

Rehabilitative training drives plasticity in the ipsilesional (injured) motor cortex that is believed to support recovery of motor function after either stroke or traumatic brain injury (TBI). In addition, adaptive plasticity in the contralesional (uninjured) motor cortex has been well-characterized in the context of stroke. While similar rehabilitation-dependent plasticity in the intact hemisphere may occur after TBI, this has yet to be thoroughly explored. In this study, we investigated the effects of TBI and forelimb training on reorganization of movement representations in the intact motor cortex. Rats were trained to proficiency on the isometric pull task and then received a controlled cortical impact (CCI) in the left motor cortex to impair function of the trained right forelimb. After TBI, animals underwent forelimb training on the pull task for 2 months. At the end of training, intracortical microstimulation was used to document the organization of the intact motor cortex (the contralesional hemisphere). TBI significantly decreased the cortical area eliciting movements of the impaired forelimb in untrained animals. In the absence of TBI, training significantly increased forelimb map area, compared with in untrained controls. However, training of the impaired forelimb after TBI was insufficient to increase forelimb map area. These findings are consistent with other studies showing impaired rehabilitation-dependent plasticity after TBI and provide a novel characterization of TBI on rehabilitation-dependent plasticity in contralesional motor circuits.

Forelimb training drives transient map reorganization in ipsilateral motor cortex.

Skilled motor training results in reorganization of contralateral motor cortex movement representations. The ipsilateral motor cortex is believed to play a role in skilled motor control, but little is known about how training influences reorganization of ipsilateral motor representations of the trained limb. To determine whether training results in reorganization of ipsilateral motor cortex maps, rats were trained to perform the isometric pull task, an automated motor task that requires skilled forelimb use. After either 3 or 6 months of training, intracortical microstimulation (ICMS) mapping was performed to document motor representations of the trained forelimb in the hemisphere ipsilateral to that limb. Motor training for 3 months resulted in a robust expansion of right forelimb representation in the right motor cortex, demonstrating that skilled motor training drives map plasticity ipsilateral to the trained limb. After 6 months of training, the right forelimb representation in the right motor cortex was significantly smaller than the representation observed in rats trained for 3 months and similar to untrained controls, consistent with a normalization of motor cortex maps. Forelimb map area was not correlated with performance on the trained task, suggesting that task performance is maintained despite normalization of cortical maps. This study provides new insights into how the ipsilateral cortex changes in response to skilled learning and may inform rehabilitative strategies to enhance cortical plasticity to support recovery after brain injury.

Vagus Nerve Stimulation Delivered with Motor Training Enhances Recovery of Function after Traumatic Brain Injury.

Traumatic Brain Injury (TBI) is one of the largest health problems in the United States, and affects nearly 2 million people every year. The effects of TBI, including weakness and loss of coordination, can be debilitating and last years after the initial injury. Recovery of motor function is often incomplete. We have developed a method using electrical stimulation of the vagus nerve paired with forelimb use by which we have demonstrated enhanced recovery from ischemic and hemorrhagic stroke. Here we have tested the hypothesis that vagus nerve stimulation (VNS) paired with physical rehabilitation could enhance functional recovery after TBI. We trained rats to pull on a handle to receive a food reward. Following training, they received a controlled-cortical impact (CCI) in the forelimb area of motor cortex opposite the trained forelimb, and were then randomized into two treatment groups. One group of animals received VNS paired with rehabilitative therapy, whereas another group received rehabilitative therapy without VNS. Following CCI, volitional forelimb strength and task success rate in all animals were significantly reduced. VNS paired with rehabilitative therapy over a period of 5 weeks significantly increased recovery of both forelimb strength and success rate on the isometric pull task compared with rehabilitative training without VNS. No significant improvement was observed in the Rehab group. Our findings indicate that VNS paired with rehabilitative therapy enhances functional motor recovery after TBI.

Controlled-cortical impact reduces volitional forelimb strength in rats.

Traumatic brain injury (TBI) is one of the largest health problems in the United States and affects both cognitive and motor function. Although weakness is common in TBI patients, few studies have demonstrated a reduction in strength in models of brain injury. We have developed a behavioral method to measure volitional forelimb strength and quantify forelimb weakness following traumatic brain injury. In this paper, we report the ability of the isometric pull task to measure both acute and chronic impairments in forelimb motor function following a controlled cortical impact (CCI) in rodents. Following CCI, volitional forelimb strength is reduced by 36% and remains significantly reduced after 6 weeks of post-lesion training. We also show that CCI results in impairment of multiple additional measures of forelimb function for several weeks post-injury.