Monika Liguz-Lecznar

Influence of Inflammation on Poststroke Plasticity

Age-related brain injuries including stroke are a leading cause of morbidity and mental disability worldwide. Most patients who survive stroke experience some degree of recovery. The restoration of lost functions can be explained by neuronal plasticity, understood as brain ability to reorganize and remodel itself in response to changed environmental requirements. However, stroke triggers a cascade of events which may prevent the normal development of the plastic changes. One of them may be inflammatory response initiated immediately after stroke, which has been found to contribute to neuronal injury. Some recent evidence though has suggested that inflammatory reaction can be also neuroprotective. This paper attempts to discuss the influence of poststroke inflammatory response on brain plasticity and stroke outcome. We also describe the recent anti-inflammatory strategies that have been effective for recovery in experimental stroke.

Somatostatin and Somatostatin-Containing Neurons in Shaping Neuronal Activity and Plasticity.

Since its discovery over four decades ago, somatostatin (SOM) receives growing scientific and clinical interest. Being localized in the nervous system in a subset of interneurons somatostatin acts as a neurotransmitter or neuromodulator and its role in the fine-tuning of neuronal activity and involvement in synaptic plasticity and memory formation are widely recognized in the recent literature. Combining transgenic animals with electrophysiological, anatomical and molecular methods allowed to characterize several subpopulations of somatostatin-containing interneurons possessing specific anatomical and physiological features engaged in controlling the output of cortical excitatory neurons. Special characteristic and connectivity of somatostatin-containing neurons set them up as significant players in shaping activity and plasticity of the nervous system. However, somatostatin is not just a marker of particular interneuronal subpopulation. Somatostatin itself acts pre- and postsynaptically, modulating excitability and neuronal responses. In the present review, we combine the knowledge regarding somatostatin and somatostatin-containing interneurons, trying to incorporate it into the current view concerning the role of the somatostatinergic system in cortical plasticity.

Involvement of retrosplenial cortex in classical conditioning

The cingulate cortex, which comprises of two major subdivisions - anterior cingulate cortex (CG) and retrosplenial cortex (RSP), is implicated in many cognitive functions. The RSP is an important node in the systemic integration network. Studies point to its role in learning that involves spatial stimuli and navigation. Relatively little is known about its involvement in simple learning such as classical conditioning. We examined the involvement of the two cytoarchitectonic divisions, agranular and granular, of the rostral and caudal RSP in a delay conditioning, where stimulation of the facial vibrissae was paired with a tail shock. During the conditioning session the [(14)C]-2-deoxyglucose (2DG) brain mapping was performed. Effectiveness of conditioning was assessed with frequency of head movements, which decreased in the course of the conditioning. 2DG uptake in RSP and additionally in CG was examined in conditioned, pseudoconditioned and stimulated control groups. The metabolic labeling was elevated in caudal and rostral both RSP and CG in the conditioned group, but not in animals which received CS or UCS alone. Comparison between conditioned and pseudoconditioned groups showed the specific activation by associative learning in both divisions of the rostral RSP and rostral CG. Counts of c-Fos expressing nuclei confirmed activation of the rostral RSP in the CS+UCS group. These data support the concept of RSP as structure that, besides its recognized role in visuospatial learning, monitors and reacts to activity of brain systems responsible for other types of learning and, together with CG, subserve cognitive processes, with simple associative learning among them.

Dissociation of synaptic zinc level and zinc transporter 3 expression during postnatal development and after sensory deprivation in the barrel cortex of mice.

In the neocortex, synaptic zinc level is regulated by sensory experience. Previously, we found that trimming of mystacial vibrissae resulted in an increase of synaptic zinc level in corresponding deprived barrels in the cortex of mice. The present study focused on the relationship between synaptic zinc and zinc transporter 3 (ZnT3) protein expression in the barrel cortex of mice during postnatal development and after sensory deprivation of selected vibrissae. Using immunocytochemistry and western blot analysis, we found that ZnT3 expression is delayed as compared with the onset of synaptic zinc and presynaptic markers, such as synapsin I and synaptophysin. Further, neither long-term deprivation in young mice nor short deprivation in adult mice, that resulted in an increase of synaptic zinc level, produced alterations in ZnT3, synapsin I or synaptophysin expression in deprived barrels. These results suggest that in the barrel cortex ZnT3, synapsin I or synaptophysin are not determinant for the activity-dependent regulation of the synaptic zinc level.

Matrix metalloproteinase inhibition counteracts impairment of cortical experience‐dependent plasticity after photothrombotic stroke

Matrix metalloproteinases (MMPs) are fine modulators of brain plasticity and pathophysiology. The inhibition of MMPs shortly after ischaemic stroke reduces the infarct size and has beneficial effects on post‐stroke behavioural recovery. Our previous studies have shown that photothrombotic cortical stroke disrupts use‐dependent plasticity in the neighbouring cortex. The aim of the present study was to check whether the inhibition of MMPs after photothrombosis rescued the plastic capacity of the barrel cortex. To induce plasticity in adult mice, a unilateral deprivation of all vibrissae except row C was applied. The deprivation started immediately after stroke and lasted 7 days. This procedure, in control (non‐stroke) animals, results in an enlargement of functional representation of the spared row, as shown with [14C]2‐deoxyglucose uptake mapping. In mice with stroke induced by photothrombosis in the vicinity of the barrel cortex, vibrissae deprivation did not result in an enlargement of the cortical representation of the spared row C of vibrissae, which confirmed our previous results. However, when mice were injected with the broad‐spectrum inhibitor of MMPs FN‐439 (10 mg/kg, i.v.) immediately before a stroke, an enlargement of the representation of the spared row similar to the enlargement found in sham mice was observed. These results indicate the involvement of MMPs in the impairment of use‐dependent plasticity in the vicinity of an ischaemic lesion.

Impairment of experience-dependent cortical plasticity in aged mice

This study addresses the relationship between aging and experience-dependent plasticity in the mouse somatosensory cortex. Plasticity in the cortical representation of vibrissae (whiskers) was investigated in young (3 months), mature (14 months) and old (2 years) mice using [14C]2-deoxyglucose (2-DG) autoradiography. Plastic changes were evoked using two experimental paradigms. The deprivation-based protocol included unilateral deprivation of all but one row of whiskers for a week. In the conditioning protocol the animals were subjected to classical conditioning, where tactile stimulation of one row of whiskers was paired with an aversive stimulus. Both procedures evoked functional plasticity in the young group, expressed as a widening of the functional cortical representation of the spared or conditioned row. Aging had a differential effect on these two forms of plasticity. Conditioning-related plasticity was more vulnerable to aging: the plastic change was not detectable in mature animals, even though they acquired the behavioral response. Deprivation-induced plasticity also declined with age, but some effects were persistent in the oldest animals.

Experience-dependent brain plasticity after stroke: effect of ibuprofen and poststroke delay

Despite indications that brain plasticity may be enhanced after stroke, we have described impairment of experience‐dependent plasticity in rat cerebral cortex neighboring the stroke‐induced lesion. Photothrombotic stroke was centered behind the barrel cortex in one cerebral hemisphere of rats. Plasticity of cortical representation of one row of vibrissae was induced by sensory deprivation of all surrounding whiskers for 1 month, and visualized with [14C]‐2‐deoxyglucose autoradiography. In control rats deprivation resulted in an enlargement of functional cortical representation of the spared row of vibrissae. After a focal stroke neighbouring the barrel cortex, no plasticity of the spared row representation was found. Investigation of plastic changes with deprivation initiated 1 week and 1 month after stroke have shown that later poststroke onset of deprivation resulted in a partial recovery of cortical plasticity in the barrel field. Western blot analysis of proinflammatory enzyme cyclooxygenase‐2 (COX‐2) expression revealed its strong upregulation in the barrel cortex 24 h after stroke. When chronic treatment with the anti‐inflammatory drug ibuprofen (10 mg/kg or 20 mg/kg) accompanied deprivation, plasticity was restored. Ibuprofen applied before the ischemia also prevented the poststroke upregulation of COX‐2. The results strongly suggest that poststroke impairment of experience‐dependent cortical plasticity is caused by stroke‐induced inflammatory reactions that subside with poststroke delay and can be at least partially ameliorated by pharmacological treatment.

Bilateral Plasticity of Vibrissae SII Representation Induced by Classical Conditioning in Mice

The somatosensory cortex in mice contains primary (SI) and secondary (SII) areas, differing in somatotopic precision, topographic organization, and function. The role of SII in somatosensory processing is still poorly understood. SII is activated bilaterally during attentional tasks and is considered to play a role in tactile memory and sensorimotor integration. We measured the plasticity of SII activation after associative learning based on classical conditioning, in which unilateral stimulation of one row of vibrissae was paired with a tail shock. The training consisted of three daily 10 min sessions, during which 40 pairings were delivered. Cortical activation driven by stimulation of vibrissae was mapped with 2-[14C]deoxyglucose (2DG) autoradiography 1 d after the end of conditioning. We reported previously that the conditioning procedure resulted in unilateral enlargement of 2DG-labeled cortical representation of the “trained” row of vibrissae in SI. Here, we measured the width and intensity of the labeled region in SII. We found that both measured parameters in SII increased bilaterally. The increase was observed in cortical layers II/III and IV. Apparently, plasticity in SII is not a simple reflection of changes in SI. It may be attributable to bilateral integrative role of SII, its lesser topographical specificity, and strong involvement in attentional processing.

Functional assessment of sensory functions after photothrombotic stroke in the barrel field of mice

Motor, sensory and cognitive deficits are common impairments observed in human stroke as well as in animal stroke models. Using a battery of behavioural tests we assessed sensorimotor deficits after photothrombotic stroke localized within or beyond cortical representation of mouse sensory vibrissae. We found restricted, modality specific behavioural consequences in the acute post-stroke period. Among incorporated tests, adhesive removal test, novelty exploration test and sensory labyrinth task were sensitive to the somatosensory cortical deficits. Injured animals explored new objects significantly longer, they also needed distinctly more time to contact and to remove the adhesive tape placed on whiskers contralateral to the infarct. Moreover, we observed that after stroke animals were unable to solve the sensory labyrinth depending only upon tactile sensation from whiskers with injured cortical representation. Spontaneous recovery could be observed within the first post-stroke week for adhesive tape removal and within 14 days for labyrinth performance. However, for the novel object exploration we did not observed the recovery for the period of 18 days after stroke. Moreover, new object exploration test performance differed between the somatosensory and visual cortical impairments. We suggest that those three tests might be valuable in assessing the usefulness of therapies designed to support brain repair after experimental stroke.

Learning-Dependent Plasticity of the Barrel Cortex Is Impaired by Restricting GABA-Ergic Transmission

Experience-induced plastic changes in the cerebral cortex are accompanied by alterations in excitatory and inhibitory transmission. Increased excitatory drive, necessary for plasticity, precedes the occurrence of plastic change, while decreased inhibitory signaling often facilitates plasticity. However, an increase of inhibitory interactions was noted in some instances of experience-dependent changes. We previously reported an increase in the number of inhibitory markers in the barrel cortex of mice after fear conditioning engaging vibrissae, observed concurrently with enlargement of the cortical representational area of the row of vibrissae receiving conditioned stimulus (CS). We also observed that an increase of GABA level accompanied the conditioning. Here, to find whether unaltered GABAergic signaling is necessary for learning-dependent rewiring in the murine barrel cortex, we locally decreased GABA production in the barrel cortex or reduced transmission through GABAA receptors (GABAARs) at the time of the conditioning. Injections of 3-mercaptopropionic acid (3-MPA), an inhibitor of glutamic acid decarboxylase (GAD), into the barrel cortex prevented learning-induced enlargement of the conditioned vibrissae representation. A similar effect was observed after injection of gabazine, an antagonist of GABAARs. At the behavioral level, consistent conditioned response (cessation of head movements in response to CS) was impaired. These results show that appropriate functioning of the GABAergic system is required for both manifestation of functional cortical representation plasticity and for the development of a conditioned response.