Neural Circuit Control of Postnatal Quiescent Neural Stem Cell Activation

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ABSTRACT It has become increasingly clear that systemic signals and external stimuli can alter neurodevelopmental programs, and that early developmental defects become significant contributors to behavioral sequelae later in life. Despite our current understanding of neurogenesis control, it remains largely unclear what functions neural circuit activity patterns may exert on NSC proliferation and differentiation during development. The rodent postnatal lateral ventricular (LV) germinal matrix/neurogenic niche is a specialized environment housing GFAP+ astrocytes functioning as NSCs, producing mainly GABAergic interneurons. It is analogous to the postnatal human LV germinal matrix, where robust neurogenesis persists for up to two years after birth. The postnatal LV niche serves as an excellent model system to study molecular mechanisms regulating neurogenesis, both in health and in disease states. Postnatal LV neurogenesis is regulated by NSC-intrinsic mechanisms, interacting with extracellular/niche-driven cues. It has been generally accepted that these local effects are responsible for sustaining neurogenesis, though behavioral paradigms and disease states have suggested possibilities for neural circuit-level modulations. It is currently unclear if activity patterns from groups of neurons, or discrete neural circuits, can respond to external stimuli and control NSC proliferation in the postnatal brain. We have identified long-range neuronal projections that can provide excitatory drive to local neurons within the postnatal LV niche. Our preliminary results have uncovered putative downstream targets of this previously undescribed neural circuit, the quiescent NSCs, suggesting an exciting connection between external inputs and NSC activation. We plan to further explore these observations by determining the following: 1) the cellular identity of the postnatal LV quiescent NSCs; 2) which brain regions can serve as a relay for external stimuli to induce LV NSC proliferation; and 3) which postnatal radial glial progenitors, and their activity-dependent maturation process, are responsible for constructing the neural circuits to direct quiescent NSC activation. Our proposal explores a direct connection between neuronal activity patterns from discrete circuits and postnatal NSC proliferation. To make this research question tractable, we have developed new mouse reagents, as well as experimental platforms to measure the interactions between patterns of neuronal activity and NSC proliferation. We believe findings from these experiments will significantly advance our understanding of how neural circuit activity controls stem cell proliferation in the postnatal brain in health and disease.