Gene expression changes of interconnected spared cortical neurons 7 days after ischemic infarct of the primary motor cortex in the rat

Abstract

After cortical injury resulting from stroke, some recovery can occur and may involve spared areas of the cerebral cortex reorganizing to assume functions previously controlled by the damaged cortical areas. No studies have specifically assessed gene expression changes in remote neurons with axonal processes that terminate in the infarcted tissue, i.e., the subset of neurons most likely to be involved in regenerative processes. By physiologically identifying the primary motor area controlling forelimb function in adult rats (caudal forelimb area = CFA), and injecting a retrograde tract-tracer, we labeled neurons within the non-primary motor cortex (rostral forelimb area = RFA) that project to CFA. Then, 7 days after a CFA infarct (n = 6), we used laser capture microdissection techniques to harvest labeled neurons in RFA. Healthy, uninjured rats served as controls (n = 6). Biological interactions and functions of gene profiling were investigated by Affymetrix Microarray, and Ingenuity Pathway Analysis. A total of 143 up- and 128 down-regulated genes showed significant changes (fold change ≥1.3 and p <0.05). The canonical pathway, “Axonal Guidance Signaling,” was overrepresented (p value = 0.002). Significantly overrepresented functions included: branching of neurites, organization of cytoskeleton, dendritic growth and branching, organization of cytoplasm, guidance of neurites, development of cellular protrusions, density of dendritic spines, and shape change (p = 0.000151–0.0487). As previous studies have shown that spared motor areas are important in recovery following injury to the primary motor area, the results suggest that these gene expression changes in remote, interconnected neurons may underlie reorganization and recovery mechanisms.

Distal axotomy enhances retrograde presynaptic excitability onto injured pyramidal neurons via trans-synaptic signaling

“…We used a model system to study the cellular mechanisms of synaptic remodeling following axon injury; this model recapitulated several hallmarks of neurons subjected to axonal injury in vivo, including chromatolysis 6,21 , retrograde spine loss 4,22,23 , retrograde hyper-excitability [1][2][3] , and disinhibition 2, 9, 10 . Axotomy-induced transcriptional changes in this in vitro model are also consistent with in vivo findings 7,20 . Because of the ability to separate neuronal compartments, this tool facilitates the investigation of axotomy-induced retrograde signaling intrinsic to neurons and the resulting effects to interneuronal communication.…”

The interaction between training and plasticity in the poststroke brain

“…During the post-stroke SP, there are widespread gene activations in peri-infarct cortex and surrounding areas that are independent of behavior [24,49-54]. Notably, these genes are very similar to those important for neuronal growth, dendritic spine development, and synaptogenesis during early brain development.…”

Fluoxetine Maintains a State of Heightened Responsiveness to Motor Training Early After Stroke in a Mouse Model

“…5–8 We have previously referred to this period of spontaneous recovery and increased responsiveness to motor training as the post-stroke “sensitive period.” 9 The sensitive period is a unique, time-limited environment of heightened plasticity characterized by molecular, 8, 10 physiological, 11, 12 and structural changes 13, 14 that are qualitatively and quantitatively distinct to plasticity mechanisms in the absence of stroke or in the presence of a chronic stroke. 6, 9 That there is a causal link between the unique short-lived plasticity milieu after stroke and the amount of recovery from hemiparesis in this same period is supported by rodent experiments that have manipulated plasticity in the sensitive period, for example by increasing 15, 16 or decreasing BDNF, 17 which augments or prevents recovery, respectively.…”