Cells of the mononuclear phagocytotic system (MPS) are often found near to or within ischemic tissue and can potentially aggravate cellular damage. Hence, visualization of those cells would allow demarcation of putatively affected from intact tissue. Experimental MRI studies have shown that ultrasmall particles of dextran-coated iron oxide (USPIO) are internalized into cells of the MPS. To test if this cell tagging method may be also applied to cerebral infarction, USPIOs were administered to Fisher rats 5.5 h after permanent occlusion of the middle cerebral artery (pMCAO). During the first 2 days USPIO were preferentially found in patches within the lesion and in surrounding areas. On day 4, USPIOs expanded within the core of the lesion. On day 7 they were found predominantly within the boundary area. Histological analysis showed large populations of macrophages containing iron particles in the infarcted tissue. We conclude, therefore, that it is possible to monitor MPS activity after focal cerebral ischemia using USPIOs. Magn Reson Med 46:1018 -1022, 2001.

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Cerebral ischemia provokes tissue damage by two major patho-physiological mechanisms. Direct cell necrosis is induced by diminished access of neurons and glia to essential nutrients such as glucose and oxygen leading to energy failure. A second factor of cellular loss is related to the activation of immune-competent cells within and around the primary infarct. While granulocytes and presumably monocytes are linked to the no-reflow phenomenon, activated microglia cells and monocytes can release cytotoxic substrates, which cause delayed cell death. As a consequence the infarct volume will increase, despite restoration of cerebral perfusion. In the past, visualization of immune competent cells was only possible by histological analysis of post-mortem tissue. However, contrast agents based on small particles of iron oxide are known to accumulate in organs rich in cells with phagocytotic function. These particles can be tracked in vivo by MRI methods based on their relaxation properties. In the present study, the spatio-temporal distribution of USPIO particles was monitored in a rat model of transient cerebral infarction using T1- and T2-weighted MRI sequences. USPIO were detected in vessels at 24 h after administration. At later time points specific accumulation of USPIO was observed within the infarcted hemisphere, with maximal signal enhancement on day 2. Their detectability based on T1-contrast disappeared between day 4 and day 7. Immuno-histochemically (IHC) stains confirmed the presence of macrophages, presumably blood-derived monocytes within areas of T1 signal enhancement. Direct visualization of iron-burdened macrophages by IHC was only possible later than day 3 after occlusion.

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The role of corticogeniculate feedback in the organization, function, and state dependence of visual responses and receptive fields (RFs) is not well understood. We investigated the contribution of the corticogeniculate loop to state-dependent changes of characteristics of the primary visual cortex response by using a novel approach of eliminating corticogeniculate projection neurons with targeted neuronal apoptosis. Experiments were performed in anesthetized cats (N2O plus halothane) with parallel recordings of single units from experimental (right) and control (left) hemispheres approximately 2 weeks after induction of apoptosis. Within the experimental hemispheres, neurons of area 17 and of the dorsal lateral geniculate nucleus (dLGN) showed an unusually enhanced and prolonged tonic visual response during episodes of synchronized (syn) EEG activity, whereas response levels during less synchronized states were almost normal. In addition, dLGN cells showed a reduced tendency for burst firing and a less regular spike interval distribution compared with those of controls. These changes are likely attributable to a tonic depolarization of dLGN relay neurons or, more likely, to a decreased responsiveness of thalamic inhibitory processes to cortical feedback. Cortical neurons also displayed an activity-dependent increase in RF size, in contrast to an almost activity-invariant RF size of controls, a phenomenon likely related to the elimination of collateral, intracortical projections of layer 6 neurons. Together, these results demonstrate that selective chronic elimination of corticogeniculate feedback results in the loss of EEG-correlated differences of visual processing in the remaining thalamocortical network, accompanied by a significant increase in excitability during syn EEG, at the expense of noticeably reduced spatial receptive-field specificity in the remaining cortical neurons.

Reduction in the strength of GABAergic neurotransmission has often been reported following brain lesions. This weakened inhibition is believed to influence neurological deficits, neuronal hyperexcitability and functional recovery after brain injuries. Uncovering the mechanisms underlying the altered inhibition is therefore crucial. In the present study we used an ex vivo-in vitro model of laser lesions in the rat visual cortex to characterize the cellular correlates of changes in GABAergic transmission in the tissue adjacent to the injury. In the first week post-injury the number of VGAT positive GABAergic terminals as well as the expression level of the GABA synthesizing enzymes GAD67 and GAD65 remained unaltered. However, a reduced frequency of miniature inhibitory postsynaptic currents (mIPSCs) together with an increased paired-pulse ratio (PPR) of evoked IPSCs suggested a functional reduction of phasic GABA release. In parallel, we found an enhancement in the GABAA receptor-mediated tonic inhibition. On the basis of these findings, we propose that cortical lesions provoke a shift in GABAergic transmission, decreasing the phasic and reinforcing the tonic component. We therefore suggest that it is not, as traditionally assumed, the overall inhibitory strength to be primarily compromised by a cortical lesion but rather the temporal accuracy of the GABAergic synaptic signaling.

Focal brain injuries are accompanied by processes of functional reorganization that partially compensate the functional loss. In a previous study, extracellular recordings at the border of a laser-induced lesion in the visual cortex of rats showed an enhanced synaptic plasticity, which was mediated by the activity of NR2B-contaning NMDA-receptors (NMDARs) shedding light on the potential cellular mechanisms underlying this reorganization. Given the potentially important contribution of NMDARs in processes of functional reorganization, in the present study, we used the same lesion model to further investigate lesion-induced changes in function and localization of NMDARs in the vicinity of the lesion. The most important finding was a lesion-mediated functional reexpression of nonpostsynaptic, but according to our data, presynaptic or peri-/extrasynaptic NMDARs (preNMDARs), which were undetectable in age-matched (>P21) sham-operated controls. Notably, preNMDARs were able to boost both spontaneous and evoked synaptic glutamatergic transmission. At the postsynaptic site, we also disclosed an increase in the decay time constant of NMDARs mediated currents, which was accompanied by a decreased NR2A/NR2B ratio, as revealed by Western blot analysis. All together these findings provide new insights into the role of NMDARs activity during processes of functional reorganization following a focal lesion in the cerebral cortex.