Neonatal adoptive transfer of lymphocytes rescues social behaviour during adolescence in immune-deficient mice.

Accumulating evidence has shown that lymphocytes modulate behaviour and cognition by direct interactions with the central nervous system. Studies have shown that reconstitution by adoptive transfer of lymphocytes from wild type into immune-deficient mice restores a number of neurobehavioural deficits observed in these models. Moreover, it has been shown that these effects are mostly mediated by T lymphocytes. Studies of adoptive transfer thus far have employed adult mice, but whether lymphocytes may also modulate behaviour during development remains unknown. In this study, neonate lymphocyte-deficient Rag2-/- mice were reconstituted within 48 hours after birth with lymphoid cells from transgenic donors expressing green fluorescent protein, allowing for their identification in various tissues in recipient mice while retaining all functional aspects. Adolescent Rag2-/- and reconstituted Rag2-/- along with C57BL/6J wild-type mice underwent a series of behavioural tests, including open field, social interaction and sucrose preference tests. At 12 weeks, they were evaluated in the Morris water maze (MWM). Reconstituted mice showed changes in almost all aspects of behaviour that were assessed, with a remarkable complete rescue of impaired social behaviour displayed by adolescent Rag2-/- mice. Consistent with previous reports in adult mice, neonatal reconstitution in Rag2-/- mice restored spatial memory in the MWM. The presence of donor lymphocytes in the brain of neonatally reconstituted Rag2-/- mice was confirmed at various developmental points. These findings provide evidence that lymphocytes colonize the brain during post-natal development and modulate behaviour across the lifespan supporting a role for adaptive immunity during brain maturation.

Time and frequency dependent changes in resting state EEG functional connectivity following lipopolysaccharide challenge in rats.

Research has shown that inflammatory processes affect brain function and behavior through several neuroimmune pathways. However, high order brain functions affected by inflammation largely remain to be defined. Resting state functional connectivity of synchronized oscillatory activity is a valid approach to understand network processing and high order brain function under different experimental conditions. In the present study multi-electrode EEG recording in awake, freely moving rats was used to study resting state connectivity after administration of lipopolysaccharides (LPS). Male Wistar rats were implanted with 10 cortical surface electrodes and administered with LPS (2 mg/kg) and monitored for symptoms of sickness at 3, 6 and 24 h. Resting state connectivity and power were computed at baseline, 6 and 24 h. Three prominent connectivity bands were identified using a method resistant to spurious correlation: alpha (5-15 Hz), beta-gamma (20-80 Hz), and high frequency oscillation (150-200 Hz). The most prominent connectivity band, alpha, was strongly reduced 6 h after LPS administration, and returned to baseline at 24 h. Beta-gamma connectivity was also reduced at 6 h and remained reduced at 24 h. Interestingly, high frequency oscillation connectivity remained unchanged at 6 h and was impaired 24 h after LPS challenge. Expected elevations in delta and theta power were observed at 6 h after LPS administration, when behavioral symptoms of sickness were maximal. Notably, gamma and high frequency power were reduced 6 h after LPS and returned to baseline by 24 h, when the effects on connectivity were more evident. Finally, increases in cross-frequency coupling elicited by LPS were detected at 6 h for theta-gamma and at 24 h for theta-high frequency oscillations. These studies show that LPS challenge profoundly affects EEG connectivity across all identified bands in a time-dependent manner indicating that inflammatory processes disrupt both bottom-up and top-down communication across the cortex during the peak and resolution of inflammation.

Quantitative Analysis of Kynurenine Aminotransferase II in the Adult Rat Brain Reveals High Expression in Proliferative Zones and Corpus Callosum.

Kynurenic acid, a metabolite of the kynurenine pathway of tryptophan degradation, acts as an endogenous antagonist of alpha7 nicotinic and NMDA receptors and is implicated in a number of neurophysiological and neuropathological processes including cognition and neurodegenerative events. Therefore, kynurenine aminotransferase II (KAT II/AADAT), the enzyme responsible for the formation of the majority of neuroactive kynurenic acid in the brain, has prompted significant interest. Using immunohistochemistry, this enzyme was localized primarily in astrocytes throughout the adult rat brain, but detailed neuroanatomical studies are lacking. Here, we employed quantitative in situ hybridization to analyze the relative expression of KAT II mRNA in the brain of rats under normal conditions and 6 h after the administration of lipopolysaccharides (LPSs). Specific hybridization signals for KAT II were detected, with the highest expression in the subventricular zone (SVZ), the rostral migratory stream and the floor of the third ventricle followed by the corpus callosum and the hippocampus. This pattern of mRNA expression was paralleled by differential protein expression, determined by serial dilutions of antibodies (up to 1:1 million), and was confirmed to be primarily astrocytic in nature. The mRNA signal in the SVZ and the hippocampus was substantially increased by the LPS treatment without detectable changes elsewhere. These results demonstrate that KAT II is expressed in the rat brain in a region-specific manner and that gene expression is sensitive to inflammatory processes. This suggests an unrecognized role for kynurenic acid in the brain's germinal zones.

Cellular neuroinflammation in a lateral forceps compression model of spinal cord injury.

Postinjury inflammation has been implicated in secondary degeneration following injury to the spinal cord. The cellular inflammatory response to injury has not been described in the lateral compression injury model, although various types of compression injuries account for ∼20% of human spinal cord injuries (SCI). Here, we used forceps to induce a moderate compression injury to the thoracic spinal cord of female Sprague-Dawley rats. We evaluated innate and adaptive components of the inflammatory response at various times postinjury using immunohistochemical techniques. We show that components of innate immunity (e.g., macrophages and dendritic cells) peak between 1 and 2 weeks postinjury but persist through 42 days postinjury (dpi). CD163 and CD206 expression, associated with an anti-inflammatory, reparative phenotype, was upregulated on activated macrophages in the injury site, as were MHC class II antigens. The expression of MHC class II antigens is necessary for the initiation of adaptive immunity and was accompanied by an influx of T cells. T cells were initially restricted to gray matter at the injury epicenter but were later observed throughout the lesioned parenchyma. In summary, we demonstrate that lateral forceps compression of the spinal cord produces a neuroinflammatory response similar to that described in human spinal cord trauma and in other experimental models of spinal cord trauma, thus is an appropriate model to study secondary neurodegeneration in SCI.