Neuroblasts migrate long distances in the postnatal subventricular zone (SVZ) and rostral migratory stream (RMS) to the olfactory bulbs. Many fundamental features of SVZ migration are still poorly understood, and we addressed several important questions using two-photon time-lapse microscopy of brain slices from postnatal and adult eGFP(+) transgenic mice. 1) Longitudinal arrays of neuroblasts, so-called chain migration, have never been dynamically visualized in situ. We found that neuroblasts expressing doublecortin-eGFP (Dcx-eGFP) and glutamic acid decarboxylase-eGFP (Gad-eGFP) remained within arrays, which maintained their shape for many hours, despite the fact that there was a wide variety of movement within arrays. 2) In the dorsal SVZ, neuroblasts migrated rostrocaudally as expected, but migration shifted to dorsoventral orientations throughout ventral regions of the lateral ventricle. 3) Whereas polarized bipolar morphology has been a gold standard for inferring migration in histologic sections, our data indicated that migratory morphology was not predictive of motility. 4) Is there local motility in addition to long distance migration? 5) How fast is SVZ migration? Unexpectedly, one-third of motile neuroblasts moved locally in complex exploratory patterns and at average speeds slower than long distance movement. 6) Finally, we tested, and disproved, the hypothesis that all motile cells in the SVZ express doublecortin, indicating that Dcx is not required for migration of all SVZ cell types. These data show that cell motility in the SVZ and RMS is far more complex then previously thought and involves multiple cell types, behaviors, speeds, and directions.

No abstract

No abstract

Plasmacytoid dendritic cells (pDCs) have both stimulatory and regulatory effects on T cells. pDCs are a major CNS-infiltrating dendritic cell population during experimental autoimmune encephalomyelitis but, unlike myeloid dendritic cells, have a minor role in T cell activation and epitope spreading. We show that depletion of pDCs during either the acute or relapse phases of experimental autoimmune encephalomyelitis resulted in exacerbation of disease severity. pDC depletion significantly enhanced CNS but not peripheral CD4+ T cell activation, as well as IL-17 and IFN-γ production. Moreover, CNS pDCs suppressed CNS myeloid dendritic cell-driven production of IL-17, IFN-γ, and IL-10 in an IDO-independent manner. The data demonstrate that pDCs play a critical regulatory role in negatively regulating pathogenic CNS CD4+ T cell responses, highlighting a new role for pDCs in inflammatory autoimmune disease.

Adult subventricular zone (SVZ) neuroblasts migrate in the rostral migratory stream to the olfactory bulbs. Brain lesions generally increase SVZ neurogenesis or gliogenesis and cause SVZ cell emigration to ectopic locations. We showed previously that glia emigrate from the SVZ toward mechanical injuries of the somatosensory cerebral cortex in mice. Here we tested the hypotheses that SVZ neurogenesis increases, that neuroblasts emigrate, and that epidermal growth factor expression increases after cortical injuries. Using immunohistochemistry for phenotypic markers and BrdU, we show that newborn doublecortin-positive SVZ neuroblasts emigrated toward cerebral cortex lesions. However, the number of doublecortin-positive cells in the olfactory bulbs remained constant, suggesting that dorsal emigration was not at the expense of rostral migration. Although newborn neuroblasts emigrated, rates of SVZ neurogenesis did not increase after cortical lesions. Finally, we examined molecules that may regulate emigration and neurogenesis after cortical lesions and found that epidermal growth factor was increased in the SVZ, corpus callosum, and cerebral cortex. These results suggest that after injuries to the cerebral cortex, neuroblasts emigrate from the SVZ, that emigration does not depend either on redirection of SVZ cells or on increased neurogenesis, and that epidermal growth factor may induce SVZ emigration.

Proliferation decreases in the neurogenic subventricular zone (SVZ) of mice after aspiration lesions of the cerebral cortex. We hypothesized that microglial activation may contribute to this given microglial activation attenuates neurogenesis in the hippocampus. Using CD45, CD11b, IB4, and IL-6 immunohistochemistry (IHC), BrdU IHC, and fluorescent bead tracking of peripheral monocytes into the brain, we compared microglial activation in the SVZ to non-neurogenic forebrain regions. SVZ microglia exhibited greater constitutive activation and proliferation than did microglia in non-neurogenic regions. In contrast to the SVZ, the dentate gyrus (DG) contained relatively few CD45(+) cells. After aspiration cerebral cortex lesions, microglia became activated in the cerebral cortex, corpus callosum, and striatum. SVZ microglial activation did not increase, and similarly, microglia in the DG were less activated after injury than in adjacent non-neurogenic regions. We next showed that SVZ microglia are not categorically refractory to activation, since deep cortical contusion injuries increased SVZ microglial activation. Macrophages migrate into the brain during development, but it is unclear if this is recapitulated after injury. Infiltration of microbead-labeled macrophages into the brain did not change after injury, but resident SVZ microglia were induced to migrate toward the injury. Our data show that both constitutive and postlesion levels of microglial activation differ between neurogenic and non-neurogenic regions.

Doublecortin (Dcx) is a microtubule-associated protein expressed by migrating neuroblasts in the embryo and in the adult subventricular zone (SVZ). The adult SVZ contains neuroblasts that migrate in the rostral migratory stream (RMS) to the olfactory bulbs. We have examined the distribution and phenotype of Dcx-positive cells in the adult mouse SVZ and surrounding regions. Chains of Dcx-positive cells in the SVZ were distributed in a tight dorsal population contiguous with the RMS, with a separate ventral population comprised of discontinuous chains. Unexpectedly, Dcx-positive cells were also found outside of the SVZ: dorsally in the corpus callosum, and ventrally in the nucleus accumbens, ventromedial striatum, ventrolateral septum, and bed nucleus of the stria terminalis. Dcx-positive cells outside the SVZ had the morphology of migrating cells, occurred as individual cells or in chain-like clusters, and were more numerous anteriorly. Of the Dcx-positive cells found outside of the SVZ, 47% expressed the immature neuronal protein class III beta-tubulin, 8% expressed NeuN, a marker of mature neurons. Dcx-positive cells did not express molecules found in astrocytes, oligodendrocytes, or microglia. Structural and immunoelectron microscopy revealed that cells with the ultrastructural features of neuroblasts in the SVZ were Dcx+, and that clusters of neuroblasts emanated ventrally from the SVZ into the parenchyma. Our results suggest that the distribution of cells comprising the walls of the lateral ventricle are more heterogeneous than was thought previously, that SVZ cells may migrate dorsally and ventrally away from the SVZ, and that some emigrated cells express a neuronal phenotype.

Xu et al. provide the first study in patients with intractable epilepsy showing a direct correlation between the phenotype, activation state, cytokine profiles, and ability to cause neuronal apoptosis of brain-infiltrating peripherally derived immune cells with seizure severity using an unbiased flow cytometric approach.