Stem cells, metamorphosis, and regeneration in the nervous system
Thus far, it has not been possible to rebuild or regenerate functional neuronal networks in the mature mammalian brain. We are interested in understanding regenerative capacities in the nervous system, using rodent neurogenesis and fly metamorphosis as model systems. A major part of our current efforts is focused on how to sustain neurogenesis in the adult brain.
Since we are taught that we can’t just upgrade our brains by replacing or adding new neurons, how does it keep up as we fill it with new experiences/tasks/skills? Is this accomplished purely by strengthening/weakening/remodeling of existing connections between cells, or could we complement these processes by making and integrating new useful neurons?
We are studying the assembly and function of a neural stem cell niche in the adult rodent brain leading to this possibility. In addition to molecular analyses of lateral ventricular (LV) niche homeostasis under physiological and injury conditions, through a chemical screen we found that cholinergic modulators have robust effects on adult LV neurogenesis ex vivo. In search of potential sources for acetylcholine (ACh) in the LV niche, we uncovered direct cholinergic innervation from previously undescribed subependymal ChAT+ (subep-ChAT+) neurons. These novel cholinergic neurons display morphological and functional differences from neighboring striatal counterparts, and releases ACh into the LV niche in activity-dependent fashion. Our genetic, optogenetic, and electrophysiology experiments showed that subep-ChAT+ neuron activity can directly control adult LV neurogenic proliferation.
Contrary to the view that adult LV neurogenesis is primarily directed by stem-cell intrinsic and local signals, including neurotransmitters acting through bulk-release mechanisms, we have discovered an undescribed gateway connecting neural network activity states to LV NSC proliferation. We are interested in what lies beyond this gateway, and there are many questions to answer going forward, with potentials for modulating neuroregenerative capacities in health and after injury.
Contributions of NSCs and their progeny to brain repair and remodeling after injury
Our strategies to disrupt the rodent LV neurogenic niche revealed that resident NSCs have considerable plasticity, and can participate in local remodeling and cortical injury repair. We are investigating the underlying mechanisms regulating this plasticity. We are interested in how systemic cues can influence the differentiation of adult NSCs into either neurons or astrocytes, and how this process can functionally impact brain homeostasis in both health (integration of newborn neurons into mature neural circuits) and after brain injury. We discovered that cortical injury induces LV niche switching from neurogenesis to robust astrogenesis, producing distinct Thbs4hi astrocytes migrating to the injury site. This astrogenesis response is critical for proper glial scar formation to stop cortical bleeding after injury. Our ability to modify adult NSC progeny fates, under physiological and injury conditions, gives us unique opportunities to tackle brain injury repair, a challenging and medically important problem. Our approaches include a combination of mouse genetics, molecular analyses, live-cell imaging, electrophysiology and optogenetics, and collaborations with neural trauma colleagues.