Specific regions within the adult mammalian brain maintain the ability to generate neurons. The largest of these, the ventricular-subventricular zone (V-SVZ), comprises the entire lateral wall of the lateral ventricles. Here, a subset of glial fibrillary acid protein (GFAP)-positive astrocytes (B cells) gives rise to neurons and oligodendrocytes throughout life. This process of neurogenesis involves quiescent B cells becoming proliferative (epidermal growth factor receptor (EGFR)-positive) and giving rise to neuroblasts via transit amplifying precursors. The neuroblasts then migrate through the rostral migratory stream (RMS) to the olfactory bulbs (OBs), where they mature into neurons. Studying the stem cells in the V-SVZ has been hindered by the shortage of molecular markers to selectively target them. Using microarray and qPCR analysis of putative quiescent neural stem cells we determined that they were enriched for PDGFRβ mRNA. We used immunostaining to determine the in vivo identity of PDGFRβ+ cells, and discovered that only GFAP+ cells within the V-SVZ stem cell lineage express PDGFRβ. Moreover, these PDGFRβ+ B cells contact the ventricle at the center of ependymal pinwheel structures and the vast majority of them are EGFR-. Importantly, the V-SVZ/RMS/OBcore axis was highly enriched for PDGFRβ expression compared with other brain regions. Detailed morphological analyses of PDGFRβ+ B cells revealed primary cilia at their apical process in contact with the ventricle and long radial processes contacting blood vessels deep within the V-SVZ, both of which are characteristics of adult neural stem cells. When PDGFRβ+ cells were lineage traced in vivo they formed olfactory bulb neurons. Using fluorescence-activated cell sorting (FACS) to purify PDGFRβ+ astrocytes we discovered this receptor is expressed by all adult V-SVZ neural stem cells, including a novel population of EGFR+ PDGFRβ+ cells which correspond to the activated neural stem cells. RNA-sequencing analysis of the purified populations revealed that PDGFRβ+ EGFR+ cells possess a transcriptional profile intermediate between quiescent neural stem cells and actively proliferating GFAP- progenitor cells. Finally, when PDGFRβ is deleted in adult GFAP+ NSCs we observe a decrease in EGFR+ and Dcx+ progenitor cells, together with an increase in quiescent GFAP+ astrocytes. A larger proportion of these mutant cells come in contact with the ventricular lumen, suggesting that PDGFRβ is required for V-SVZ astrocytes to act as stem cells, possibly by mediating interactions with their niche. Taken together, these data identify PDGFRβ as a novel marker for adult V-SVZ neural stem cells that is an important regulator of their stem cell capabilities.

The intracranial system consists of three main basic components - the brain, the blood and the cerebrospinal fluid. The physiological processes of each of these individual components are complex and they are closely related to each other. Understanding them is important to explain the mechanisms behind neurostructural disorders such as hydrocephalus. This research project consists of three interrelated studies, which examine the mechanical properties of the brain at the macroscopic level, the mechanics of the brain during hydrocephalus and the study of fluid hydrodynamics in both the normal and hydrocephalic ventricles. The first of these characterizes the porous properties of the brain tissues. Results from this study show that the elastic modulus of the white matter is approximately 350Pa. The permeability of the tissue is similar to what has been previously reported in the literature and is of the order of 10-12m4/Ns. Information presented here is useful for the computational modeling of hydrocephalus using finite element analysis. The second study consists of a three dimensional finite element brain model. The mechanical properties of the brain found from the previous studies were used in the construction of this model. Results from this study have implications for mechanics behind the neurological dysfunction as observed in the hydrocephalic patient. Stress fields in the tissues predicted by the model presented in this study closely match the distribution of histological damage, focused in the white matter. The last study models the cerebrospinal fluid hydrodynamics in both the normal and abnormal ventricular system. The models created in this study were used to understand the pressure in the ventricular compartments. In this study, the hydrodynamic changes that occur in the cerebral ventricular system due to restrictions of the fluid flow at different locations of the cerebral aqueduct were determined. Information presented in this study may be important in the design of more effective shunts. The pressure that is associated with the fluid flow in the ventricles is only of the order of a few Pascals. This suggests that large transmantle pressure gradient may not be present in hydrocephalus.

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