The Role of Adult Hippocampal Neurogenesis on the Effects of Antidepressant Action

For more than 100 years, neuroscientists assumed that there was no generation of new neurons in the adult brain. However, in 1965, scientists claimed new neurons are formed in the adult brain. Subsequently, the 1990s sparked a period of intensive work by researchers who strived to unveil factors controlling hippocampal neurogenesis and investigate the functions of newly-formed neurons. Unfortunately, there is still no consensus on what functions these new neurons perform. The hippocampus is considered a key anatomical structure for learning and emotion. Thus, scientists have assumed that the functions of newly form neurons in the adult hippocampus were also linked to learning and emotion. Indeed, several publications have already shown learning or emotionally aberrant phenotypes by using different animal models which feature absent or depleted neurogenesis. However, these models disrupt cell proliferation rather than specifically target newly formed neurons in hippocampus. Despite all the work that has been done and published, the functions of newly formed neurons is still largely unclear due to lacking of convincing animal models to approach this issue. In this proposal, my aim is to investigate the functional role of adult neurogenesis by using inducible Tbr2 knock out mice. From my pilot experiment, I already succeeded to demonstrate Tbr2 is essential for the hippocampal neurogenesis. I did this in adult mice by crossing the Tbr2 flox mice with GLAST-CreERt2 mice. Subsequently, I induced the knocking down of Tbr2 by tamoxeifen injection. It selective depleted the neurogenesis in hippocampus, but not in the olfactory bulb. I am going to use this mouse model to test the prevailing hypothesis that the function of new neurons in hippocampus is involved in antidepressant action. This hypothesis had made a big impact in the psychiatry and neuroscience fields. However, others and I have previously cast doubt on this. First of all, I am going to give these absent hippocampal neurogenesis mice fluoxetine in the drinking water. I shall then test antidepressant-like behavior 30 days later, including open field test, force swimming test, and novelty suppressive feeding. This experiment will provide the answer whether new neurons are required for the antidepressant action. The second part of this project, I am going to find the candidate genes which contribute to hippocampal neurogenesis by using expression microarray from Tbr2 wildtype and knock out mice. I will then use in situ hybridization to select the genes expressed in the subgranular zone of dentate gyrus where the neurogenesis occurs. This information will provide me the target genes which follow Tbr2 expression to build the possible neurogenesis molecular pathway for my future study.

Project ID:PC10005-0026
External Project ID:NSC100-2320-B182-003