The goal of this project is to understand how the plasticity of adult-born neurons may be harnessed to modify learning and mood regulation. During the training phase (K99) of the award, the candidate augmented his extensive background experience in developmental neurobiology, molecular biology and mouse genetics with a rigorous training in behavioral neuroscience as applied to the study of cognition and emotion in mice. The candidate employed a novel genetic gain of function approach to demonstrate the impact of selectively increasing adult hippocampal neurogenesis on cognition and mood. In the independent (ROO) phase, the candidate will explore the effects of manipulating the properties of adult-born dentate granule neurons, rather than their number, on dentate gyrus dependent functions. The candidate will build on recent work showing that the transcription factor Kruppel-like factor 9 regulates dentate granule neuronal maturation.
The Specific Aims will assess how genetic over expression of Kruppel-like factor 9 in adult neural stem cells and dentate granule neurons influences their maturation and hippocampal functions in normal mice and mouse models of depression. Although a growing literature documents the unique properties of new neurons, how these properties of new neurons relate to fundamental mnemonic processes such as pattern separation and the role of the dentate gyrus in mood regulation is poorly understood. Therefore, the experiments proposed here will attempt to causally link discrete changes in cell-type properties with circuit functions and behavior.
The proposed research will help determine the therapeutic impact of stimulating adult hippocampal neurogenesis for ameliorating cognitive impairments in psychiatric disorders and for treatment of depression. It may result in the development of fast acting novel treatments that target discrete components of adult hippocampal neurogenesis and are encumbered by fewer side effects.
|McAvoy, Kathleen; Russo, Craig; Kim, Shannen et al. (2015) Fluoxetine induces input-specific hippocampal dendritic spine remodeling along the septotemporal axis in adulthood and middle age. Hippocampus 25:1429-46|
|Hill, Alexis S; Sahay, Amar; Hen, René (2015) Increasing Adult Hippocampal Neurogenesis is Sufficient to Reduce Anxiety and Depression-Like Behaviors. Neuropsychopharmacology 40:2368-78|
|Ikrar, Taruna; Guo, Nannan; He, Kaiwen et al. (2013) Adult neurogenesis modifies excitability of the dentate gyrus. Front Neural Circuits 7:204|
|Tata, Purushothama Rao; Mou, Hongmei; Pardo-Saganta, Ana et al. (2013) Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature 503:218-23|
|Ho, N F; Hooker, J M; Sahay, A et al. (2013) In vivo imaging of adult human hippocampal neurogenesis: progress, pitfalls and promise. Mol Psychiatry 18:404-16|
|Kheirbek, Mazen A; Klemenhagen, Kristen C; Sahay, Amar et al. (2012) Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders. Nat Neurosci 15:1613-20|
|Sahay, Amar; Wilson, Donald A; Hen, Rene (2011) Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron 70:582-8|