Grant: Discovery Grants Program - Individual

Adult brain has the innate ability to produce new neurons throughout life. Adult-born neurons provide cellular plasticity to fine tune neural circuitry and adapt to rapidly changed environment. One important neurogenic niche in the adult brain is the subventricular zone (SVZ) of the lateral ventricle. The endogenous neural stem/progenitor cells (NPCs) residing in the SVZ in rodent models produce newborn neurons, which travel to the olfactory bulb (OB), providing the constant cell turnover required for olfactory function. Thus, rodent OB neurogenesis and olfactory function is an excellent model to study adult SVZ NPC function and its regulation. Our long term goal is to uncover cellular and molecular mechanisms that control SVZ NPC function and OB neurogenesis, and how they contribute to the olfactory function. SVZ NPCs have a regional identity and are spatially defined in four sub-regions (dorsal (D), ventral (V), lateral (L) and medial (M)) by distinct transcription factors, Pax6, Nkx2.1, Gsh2 and Zic1, respectively. The spatially distinct SVZ NPCs generate different interneuron subtypes at distinct locations of OB. The mosaic distribution of SVZ NPCs raises an interesting question: Does function of distinct NPC subpopulations are regionally modulated to produce different subtypes of OB interneurons? Our initial exciting results identified mosaic neuronal innervation from four distant brain regions makes direct connection with NPCs, differently, in 4 SVZ sub-regions: 1. hypothalamic ARC region to V-SVZ; 2. hippocampal CA2 region to M-SVZ; 3. superficial cortical region to D-SVZ; and 4. contralateral striatal region to L-SVZ. The goal of current proposal is to dissect the involvement of these neural circuits in regulating regionally distinct SVZ NPC function to produce different OB interneuron subtypes and influence related olfactory function. Since the neural circuit between ARC and V-SVZ  has been well studied before, we will focus on other three neural circuits in the current proposal. For each neural circuit, we will 1) use both retrograde and anterograde tracing tools to validate the neural circuit; 2) determine whether brain region-specific neuronal activity can distinctively regulate sub-region SVZ NPC function; 3) determine whether brain region-specific neuronal activity can explicitly regulate the genesis of OB interneuron subtypes and related olfactory function. In summary, this proposal will provide a thorough understanding of how mosaic neuronal innervation from spatially localized brain regions provide a unique niche microenvironment to the regionally distinct SVZ NPCs, specifically modulating the genesis of OB interneuron subtypes and related olfactory function. Elucidation of this knowledge will provide a mechanistic insight on neural dynamics that attribute to OB subtype interneuron genesis and olfactory development in adult brain.