The organization of forelimb representation areas of the monkey, cat, and rat motor cortices has been studied in depth, but its characterization in the mouse lags far behind. We used intracortical microstimulation (ICMS) and cytoarchitectonics to characterize the general organization of the C57BL/6 mouse motor cortex, and the forelimb representation in more detail. We found that the forelimb region spans a large area of frontal cortex, bordered primarily by vibrissa, neck, shoulder, and hindlimb representations. It included a large caudal forelimb area, dominated by digit representation, and a small rostral forelimb area, containing elbow and wrist representations. When the entire motor cortex was mapped, the forelimb was found to be the largest movement representation, followed by head and hindlimb representations. The ICMS-defined motor cortex spanned cytoarchitecturally identified lateral agranular cortex (AGl) and also extended into medial agranular cortex. Forelimb and hindlimb representations extended into granular cortex in a region that also had cytoarchitectural characteristics of AGl, consistent with the primary motor-somatosensory overlap zone (OL) characterized in rats. Thus, the mouse motor cortex has homologies with the rat in having 2 forelimb representations and an OL but is distinct in the predominance of digit representations.

The motor cortex and spinal cord possess the remarkable ability to alter structure and function in response to differential motor training. Here we review the evidence that the corticospinal system is not only plastic but that the nature and locus of this plasticity is dictated by the specifics of the motor experience. Skill training induces synaptogenesis, synaptic potentiation, and reorganization of movement representations within motor cortex. Endurance training induces angiogenesis in motor cortex, but it does not alter motor map organization or synapse number. Strength training alters spinal motoneuron excitability and induces synaptogenesis within spinal cord, but it does not alter motor map organization. All three training experiences induce changes in spinal reflexes that are dependent on the specific behavioral demands of the task. These results demonstrate that the acquisition of skilled movement induces a reorganization of neural circuitry within motor cortex that supports the production and refinement of skilled movement sequences. We present data that suggest increases in strength may be mediated by an increased capacity for activation and/or recruitment of spinal motoneurons while the increased metabolic demands associated with endurance training induce cortical angiogenesis. Together these results show the robust pattern of anatomic and physiological plasticity that occurs within the corticospinal system in response to differential motor experience. The consequences of such distributed, experience-specific plasticity for the encoding of motor experience by the motor system are discussed.

This study assessed the behavioral and dendritic structural effects of combining subdural motor cortical electrical stimulation with motor skills training following unilateral sensorimotor cortex lesions in adult male rats. Rats were pre-operatively trained on a skilled forelimb reaching task, the Montoya staircase test, and then received endothelin-1 induced ischemic lesions of the sensorimotor cortex. Ten to 14 days later, electrodes were implanted over the peri-lesion cortical surface. Rats subsequently began 10 days of rehabilitative training on the reaching task in 1 of 3 conditions: 1. 50 Hz stimulation during training, 2. 250 Hz stimulation during training or 3. no stimulation. No significant difference in performance was found between the 250 Hz and no stimulation groups. The 50 Hz stimulation group had significantly greater rates of improvement with the impaired forelimb in comparison to 250 Hz and no stimulation groups combined. Fifty Hz stimulated animals also had a significant increase in the surface density of dendritic processes immunoreactive for the cytoskeletal protein, microtubule-associated protein 2, in the peri-lesion cortex compared to the other groups. These results support the efficacy of combining rehabilitative training with cortical electrical stimulation to improve functional outcome and cortical neuronal structural plasticity following sensorimotor cortical damage.

The complement system is implicated in promoting acute secondary injury after traumatic brain injury (TBI), but its role in chronic post-traumatic neuropathology remains unclear. Using various injury-site targeted complement inhibitors that block different complement pathways and activation products, we investigated how complement is involved in neurodegeneration and chronic neuroinflammation after TBI in a clinically relevant setting of complement inhibition. The current paradigm is that complement propagates post-TBI neuropathology predominantly through the terminal membrane attack complex (MAC), but the focus has been on acute outcomes. Following controlled cortical impact in adult male mice, we demonstrate that while inhibition of the MAC (with CR2-CD59) reduces acute deficits, inhibition of C3 activation is required to prevent chronic inflammation and ongoing neuronal loss. Activation of C3 triggered a sustained degenerative mechanism of microglial and astrocyte activation, reduced dendritic and synaptic density, and inhibited neuroblast migration several weeks after TBI. Moreover, inhibiting all complement pathways (with CR2-Crry), or only the alternative complement pathway (with CR2-fH), provided similar and significant improvements in chronic histological, cognitive and functional recovery, indicating a key role for the alternative pathway in propagating chronic post-TBI pathology. Although we confirm a role for the MAC in acute neuronal loss after TBI, this study shows that upstream products of complement activation generated predominantly via the alternative pathway propagate chronic neuroinflammation, thus challenging the current concept that the MAC represents a therapeutic target for treating TBI. A humanized version of CR2fH has been shown to be safe and non-immunogenic in clinical trials.Complement, and specifically the terminal membrane attack complex, has been implicated in secondary injury and neuronal loss after TBI. However, we demonstrate here that upstream complement activation products, generated predominantly via the alternative pathway, are responsible for propagating chronic inflammation and injury following CCI. Chronic inflammatory microgliosis is triggered by sustained complement activation after CCI, and is associated with chronic loss of neurons, dendrites and synapses, a process that continues to occur even 30 days after initial impact. Acute and injury-site targeted inhibition of the alternative pathway significantly improves chronic outcomes, and together these findings modify the conceptual paradigm for targeting the complement system to treat TBI.