Endogenous activity regulates the early development of adult-born neurons in the mouse olfactory bulb

Thousands of adult-born neurons are added to the mouse olfactory bulb on a daily basis. The mechanisms underlying the migration, morphogenesis and survival of adult-born neurons are not well understood. In the present work, we studied the roles of endogenous and sensory-driven neuronal activity in the in vivo development of adult-born neurons in the mouse olfactory bulb. We utilized the overexpression of potassium channel, Kv1.2 or Kir2.1, to genetically modify the endogenous activity of adult-born neurons. By using in vivo two-photon Ca2+ imaging in awake mice, we found a ubiquitous presence of spontaneous Ca2+ transients in control and even Kv1.2- and Kir2.1-overexpressing adult-born neurons. The overexpression of Kv1.2 or Kir2.1 selectively changed the spiking behavior of frequently or even continuously active cells by decreasing their fraction as well as their area under the curve and the maximum Twitch-2B ratio. We further monitored the in vivo development of these Kv1.2- and Kir2.1-overexpressing adult-born neurons and discovered that their migration, morphogenesis, odor-evoked responsiveness, and early-phase (14-25 DPI) survival rate were remarkably impaired. Furthermore, whereas Kv1.2-overexpressing adult-born neurons showed similar survival rate as control cells during the late-phase (25-45 DPI) survival, the Kir2.1-overexpressing cells showed significantly lower survival rate. It is probably because, unlike Kv1.2 overexpression which solely altered endogenous activity, Kir2.1 overexpression impaired both endogenous and sensory-driven activity. These data suggest that the survival of adult-born neurons was predominantly regulated by endogenous activity in the early phase and by sensory-driven activity in the late phase. Furthermore, we tested the role of sensory-driven activity in the development of adult-born neurons. The odor-deprived adult-born neurons displayed normal migration and morphology, thus suggesting that sensory-driven activity did not affect the early development of adult-born neurons. Further analysis revealed that the odor-deprived adult-born neurons maintained a normal level of endogenous activity. We also explored the interplay between endogenous and sensory-driven activity. Using in vivo Ca2+ imaging of individual cells, we found that impaired endogenous activity was paralleled by suppressed sensory-driven activity. However, odor deprivation did not change the properties of spontaneous activity in adult-born neurons. This data suggest that endogenous activity is robust in immature adult-born neurons. Finally, we explored which signaling pathway is involved in the development of adult-born neurons. Our results demonstrated that pCREB expression was down-regulated in Kv1.2- and Kir2.1-overexpressing adult-born neurons. We propose that impaired endogenous neuronal activity inhibits Ca2+-pCREB signaling pathway as well as the expression of pCREB-dependent genes. In conclusion, our data demonstrate that endogenous but not sensory-driven activity plays a key role in regulating migration, morphogenesis and early-phase survival of adult-born neurons in the mouse olfactory bulb, and identify an important role of Kv1.2/Kir2.1 in the developmental processes mentioned above. Furthermore, our work also identifies CREB signaling pathway as a mediator of the early development of adult-born neurons. Moreover, sensory-driven activity predominantly regulates neuronal survival in the late phase

Tracking Neural Progenitor Cell Migration in the Rodent Brain Using Magnetic Resonance Imaging

The study of neurogenesis and neural progenitor cells (NPCs) is important across the biomedical spectrum, from learning about normal brain development and studying disease to engineering new strategies in regenerative medicine. In adult mammals, NPCs proliferate in two main areas of the brain, the subventricular zone (SVZ) and the subgranular zone, and continue to migrate even after neurogenesis has ceased within the rest of the brain. In healthy animals, NPCs migrate along the rostral migratory stream (RMS) from the SVZ to the olfactory bulb, and in diseased animals, NPCs migrate toward lesions such as stroke and tumors. Here we review how MRI-based cell tracking using iron oxide particles can be used to monitor and quantify NPC migration in the intact rodent brain, in a serial and relatively non-invasive fashion. NPCs can either be labeled directly in situ by injecting particles into the lateral ventricle or RMS, where NPCs can take up particles, or cells can be harvested and labeled in vitro, then injected into the brain. For in situ labeling experiments, the particle type, injection site, and image analysis methods have been optimized and cell migration toward stroke and multiple sclerosis lesions has been investigated. Delivery of labeled exogenous NPCs has allowed imaging of cell migration toward more sites of neuropathology, which may enable new diagnostic and therapeutic opportunities for as-of-yet untreatable neurological diseases