In Vivo Monitoring of Adult Neurogenesis in Health and Disease

Abstract

Adult neurogenesis, i.e., the generation of new neurons in the adult brain, presents an enormous potential for regenerative therapies of the central nervous system. While 5-bromo-2′-deoxyuridine labeling and subsequent histology or immunohistochemistry for cell-type-specific markers is still the gold standard in studies of neurogenesis, novel techniques, and tools for in vivo imaging of neurogenesis have been recently developed and successfully applied. Here, we review the latest progress on these developments, in particular in the area of magnetic resonance imaging (MRI) and optical imaging. In vivo in situ labeling of neural progenitor cells (NPCs) with micron-sized iron oxide particles enables longitudinal visualization of endogenous progenitor cell migration by MRI. The possibility of genetic labeling for cellular MRI was demonstrated by using the iron storage protein ferritin as the MR reporter-gene. However, reliable and consistent results using ferritin imaging for monitoring endogenous progenitor cell migration have not yet been reported. In contrast, genetic labeling of NPCs with a fluorescent or bioluminescent reporter has led to the development of some powerful tools for in vivo imaging of neurogenesis. Here, two strategies, i.e., viral labeling of stem/progenitor cells and transgenic approaches, have been used. In addition, the use of specific promoters for neuronal progenitor cells such as doublecortin increases the neurogenesis-specificity of the labeling. Naturally, the ultimate challenge will be to develop neurogenesis imaging methods applicable in humans. Therefore, we certainly need to consider other modalities such as positron emission tomography and proton magnetic resonance spectroscopy (1H-MRS), which have already been implemented for both animals and humans. Further improvements of sensitivity and neurogenesis-specificity are nevertheless required for all imaging techniques currently available.

Adult neurogenesis: bridging the gap between mice and humans

“…An alternative approach to measure levels of neurogenesis in humans may be the use of noninvasive imaging strategies based on magnetic resonance imaging (MRI) and positron emission tomography (PET). Several studies have described associations between MRI-measured hippocampal blood volume and specific lipid peaks, as measured by magnetic resonance spectroscopy, with levels of neurogenesis [26][27][28]. However, the specificity and sensitivity of these approaches remain controversial.…”

Neuroplasticity and MRI: A perfect match

“…In order to detect neurogenesis and especially the migration pattern of newly generated cells longitudinally in the living brain, the use of different non-invasive imaging tools have been tested including bioluminescence, PET and MRI-based methods such as MRI reporter genes and iron oxide particles (for review: (Couillard-Despres, Vreys et al 2011)). Most in vivo imaging tools label stem and/or progenitor cells derived from the subventricular zone and trace their travel along the rostral migration stream towards the olfactory bulb.…”

In vivoimaging of endogenous neural stem cells in the adult brain

“…Direct injection of a paramagnetic label such as small particles of iron oxide allows for cell detection using magnetic resonance imaging (MRI) with excellent spatial resolution on the single cell level (Figure 1) [54][55][56][57][58][59] . However, this type of labeling is neither specific for a certain cell type, nor does it reflect cell viability, as only the particles themselves are visualized [53] . Moreover, directly injecting iron oxide in e.g., the lateral ventricles of the brain results in image distortion in the region of injection, allowing only for the detection of cells migrating away from the injection site [54,57,58] .…”

“…Under ideal conditions, optical imaging can specifically detect clusters of about 10³ cells in vivo, but its sensitivity is limited by the relatively poor spatial resolution with shallow tissue penetration [53] . Moreover, the need for transgenic mice limits the potential applications of optical imaging and prohibits its translation into a clinical setting.…”