Experience with the "good" limb induces aberrant synaptic plasticity in the perilesion cortex after stroke.

Following unilateral stroke, the contralateral (paretic) body side is often severely impaired, and individuals naturally learn to rely more on the nonparetic body side, which involves learning new skills with it. Such compensatory hyper-reliance on the "good" body side, however, can limit functional improvements of the paretic side. In rats, motor skill training with the nonparetic forelimb (NPT) following a unilateral infarct lessens the efficacy of rehabilitative training, and reduces neuronal activation in perilesion motor cortex. However, the underlying mechanisms remain unclear. In the present study, we investigated how forelimb movement representations and synaptic restructuring in perilesion motor cortex respond to NPT and their relationship with behavioral outcomes. Forelimb representations were diminished as a result of NPT, as revealed with intracortical microstimulation mapping. Using transmission electron microscopy and stereological analyses, we found that densities of axodendritic synapses, especially axo-spinous synapses, as well as multiple synaptic boutons were increased in the perilesion cortex by NPT. The synaptic density was negatively correlated with the functional outcome of the paretic limb, as revealed in reaching performance. Furthermore, in animals with NPT, there was dissociation between astrocytic morphological features and axo-spinous synaptic density in perilesion motor cortex, compared with controls. These findings demonstrate that skill learning with the nonparetic limb following unilateral brain damage results in aberrant synaptogenesis, potentially of transcallosal projections, and this seems to hamper the functionality of the perilesion motor cortex and the paretic forelimb.

Subventricular zone cytogenesis provides trophic support for neural repair in a mouse model of stroke.

Stroke enhances proliferation of neural precursor cells within the subventricular zone (SVZ) and induces ectopic migration of newborn cells towards the site of injury. Here, we characterize the identity of cells arising from the SVZ after stroke and uncover a mechanism through which they facilitate neural repair and functional recovery. With genetic lineage tracing, we show that SVZ-derived cells that migrate towards cortical photothrombotic stroke in mice are predominantly undifferentiated precursors. We find that ablation of neural precursor cells or conditional knockout of VEGF impairs neuronal and vascular reparative responses and worsens recovery. Replacement of VEGF is sufficient to induce neural repair and recovery. We also provide evidence that CXCL12 from peri-infarct vasculature signals to CXCR4-expressing cells arising from the SVZ to direct their ectopic migration. These results support a model in which vasculature surrounding the site of injury attracts cells from the SVZ, and these cells subsequently provide trophic support that drives neural repair and recovery.

Skill learning induced plasticity of motor cortical representations is time and age-dependent.

Movement representations in the motor cortex can reorganize to support motor skill learning during young adulthood. However, little is known about how motor representations change during aging or whether their change is influenced by continued practice of a skill after it is learned. We used intracortical microstimulation to characterize the organization of the forelimb motor cortex in young and aged C57/BL6 mice after short (2-4 weeks) or long (8 weeks) durations of training on a skilled reaching task or control procedures. In young mice, a short duration of reach training increased the area of proximal forelimb movement representations at the expense of distal representations. Following a longer training duration, ratios of proximal to distal movements returned to baseline, even with ongoing practice and skill maintenance. However, lingering changes were evident in thresholds for eliciting distal forelimb movements, which declined over the longer training period. In aged mice, movement representations and movement thresholds failed to change after either duration of training. Furthermore, there was an age-related loss of digit representations and performance decrements on other sensorimotor tests. Nevertheless, in quantitative measures of reaching success, aged mice learned and performed the skilled reaching task at least as well as younger mice. These results indicate that experience-driven topographical reorganization of motor cortex varies with age, as well as time, and is partially dissociable from behavioral performance. They also support an enduring capacity to learn new manual skills during aging, even as more youthful forms of cortical plasticity and sensorimotor function are lost.

The organization of the forelimb representation of the C57BL/6 mouse motor cortex as defined by intracortical microstimulation and cytoarchitecture.

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.

Growth and pruning of mushroom body Kenyon cell dendrites during worker behavioral development in the paper wasp, Polybia aequatorialis (Hymenoptera: Vespidae).

Adult workers of some social insect species show dramatic behavioral changes as they pass through a sequence of task specializations. In the paper wasp, Polybia aequatorialis, female workers begin adult life within the nest tending brood, progress to maintaining and defending the nest exterior, and ultimately leave the nest to forage. The mushroom body (MB) calyx neuropil increases in volume as workers progress from in-nest to foraging tasks. In other social Hymenoptera (bees and ants), MB Kenyon cell dendrites, axons and synapses change with the transition to foraging, but these neuronal effects had not been studied in wasps. Furthermore, the on-nest worker of Polybia wasps, an intermediate task specialization not identified in bees or ants, provides the opportunity to study pre-foraging worker class transitions. We asked whether Kenyon cell dendritic arborization varies with the task specialization of Polybia workers observed in the field near Monteverde, Costa Rica. Golgi-impregnated arbors in the lip and collar calyces, which receive a predominance of olfactory and visual input, respectively, were quantified using Sholl's concentric circles and a novel application of virtual spherical probes. Arbors of the lip varied in a manner reminiscent of honeybees, with foragers having the largest and in-nest workers having the smallest arbors. In contrast, arbors of the collar were largest in foragers but smallest in on-nest workers. Thus, progression through task specializations in P. aequatorialis involves subregion specific dendritic growth and regression in the MB neuropil. These results may reflect the sensitivity of Kenyon cell dendritic structure to specialization dependent social and sensory experience.

Cortical Stimulation Concurrent With Skilled Motor Training Improves Forelimb Function and Enhances Motor Cortical Reorganization Following Controlled Cortical Impact.

BACKGROUND: Electrical and magnetic brain stimulation can improve motor function following stroke in humans, rats, and nonhuman primates, especially when paired with rehabilitative training (RT). Previously, we found in rodent stroke models that epidural electrical cortical stimulation (CS) of the ipsilesional motor cortex (MC) combined with motor RT enhances motor function and motor cortical plasticity. It was unknown whether CS following experimental traumatic brain injury (TBI) would have similar effects. OBJECTIVE: To test the effects of CS combined with motor training after moderate/severe TBI on behavioral outcome and motor cortical organization. METHODS: Following unilateral controlled cortical impact (CCI) over the caudal forelimb area of the MC in adult male rats, forelimb reach training was administered daily for 9 weeks concurrently with subthreshold, 100-Hz monopolar CS or no-stimulation control procedures. The rate and magnitude of behavioral improvements and changes in forelimb movement representations in the injured MC as revealed by intracortical microstimulation were measured. RESULTS: CCI resulted in severe motor impairments persisting throughout the 9 weeks of training in both groups, but CS-treated animals had significantly greater behavioral improvements. CS also increased wrist motor cortical representation, one of the main movements used in the training task, when compared with RT alone. However, the overall recovery level was modest, leaving animals still extremely impaired. CONCLUSIONS: These data suggest that CS may be useful for improving rehabilitation efficacy after TBI but also raise the possibility that the CS parameters that are highly effective following stroke are suboptimal after moderate/severe TBI.

Long-lasting functional disabilities in middle-aged rats with small cerebral infarcts.

Recommendations from experts and recently established guidelines on how to improve the face and predictive validity of animal models of stroke have stressed the importance of using older animals and long-term behavioral-functional endpoints rather than relying almost exclusively on acute measures of infarct volume in young animals. The objective of the present study was to determine whether we could produce occlusions in older rats with an acceptable mortality rate and then detect reliable, long-lasting functional deficits. A reversible intraluminar suture middle cerebral artery occlusion (MCAO) procedure was used to produce small infarcts in middle-aged rats. This resulted in an acceptable mortality rate, and robust disabilities were detected in functional assays, although the degree of total tissue loss measured 90 d after MCAO was quite modest. Infarcted animals were functionally impaired relative to sham control animals even 90 d after the occlusions, and when animals were subgrouped based on amount of tissue loss, MCAO animals with only 4% tissue loss exhibited enduring neurological-behavioral impairments relative to sham-operated controls, and the functional impairments in the group with the largest infarcts (20% tissue loss) were more severe than the functional impairments in the rats with 4% tissue loss. These results suggest that this model, using reversible MCAO to produce small infarcts and long-lasting functional-behavioral deficits in older rats, may represent an advance in the relatively higher-throughput modeling of stroke and its recovery in rodents and may be useful in the development and characterization of future stroke therapies.

Mushroom body structural change is associated with division of labor in eusocial wasp workers (Polybia aequatorialis, Hymenoptera: Vespidae).

Highly eusocial insect workers exhibit age-related division of labor. Adults begin working inside the nest, moving to the nest periphery and later to foraging. Passage through this task sequence is associated with neuroanatomical changes in the mushroom bodies (MB) of honey bee (Apis) and ant (Camponotus) workers. We asked whether eusocial wasp workers (Polybia aequatorialis) exhibit similar changes in adult neuroanatomy. Wasps were identified as working in-nest, on-nest, or foraging. The volumes of the somata of workers' MB intrinsic neurons (Kenyon cells), and of the neuropils containing the Kenyon cell dendritic arbors (calyces), were estimated using stereological methods. In-nest workers had significantly smaller calyx to Kenyon cell volume ratios than on-nest and foraging workers. Age-related task specializations in Polybia workers are associated with major neuroanatomical reorganization in the mushroom bodies.