The dentate gyrus is one of two regions in the adult brain that continuously incorporates new neurons throughout the lifetime of mammals. These new neurons, which add to the principal excitatory neuron population in the dentate gyrus, pass through several different morphological and functional states prior to fully integrating into the network. Previous behavioral and computational studies have suggested that this gradual incorporation of new neurons has the potential to have a substantial impact on cognition. While theoretical studies have demonstrated that these neurons may contribute novel forms of information into memories, including temporal information, there is little direct biological evidence showing what the effects of neurogenesis are on animal behavior. This proposal will address the function of adult neurogenesis from several different and important perspectives. First, a novel genetic mouse model that provides temporal selectivity will be used to knockout neurogenesis. This mouse line will allow examination of the functional role of adult-born neurons of specific ages. Such temporal specificity is important given recent theoretical arguments for age-dependent functions for maturing neurons. Second, the long-term specialization of adult-born neurons will be examined by labeling different populations of neurons which will be exposed to different experiences during their maturation. According to both theoretical modeling of adult neurogenesis and preliminary observations, this study should demonstrate that adult-born neurons will preferentially respond to environments that they experience shortly after they are born. Finally, this proposal will investigate the effects of dopamine - a behaviorally-regulated neurotransmitter - on the function of the dentate gyrus involving both existing and adult-born neurons. Preliminary data suggests that dopamine, which has been associated with both rewarding and aversive stimuli, has effects on both immature and mature dentate gyrus neurons. This proposal will explore both the extent of and the mechanisms underlying these effects. Adult neurogenesis has been shown to be associated with several neurological conditions, including depression, aging, and schizophrenia. The studies described in this proposal will serve to help elucidate mechanisms by which neurogenesis affects cognition and memory. Determining the functional impact of new neurons in the adult brain is an important initial step for understanding how adult neurogenesis is involved in these pathological conditions.
The goal of this proposal is to investigate the function of adult neurogenesis in the hippocampus of the adult brain. We will determine how newly born neurons affect the ability for the brain to form new memories during behavior and what type of information these new neurons will encode later in life. The findings of this study will increase our understanding of the adult neurogenesis process which has been implicated in neurological conditions such as aging, depression, and schizophrenia.
|Gonçalves, J Tiago; Bloyd, Cooper W; Shtrahman, Matthew et al. (2016) In vivo imaging of dendritic pruning in dentate granule cells. Nat Neurosci 19:788-91|
|Johnston, Stephen T; Shtrahman, Matthew; Parylak, Sarah et al. (2016) Paradox of pattern separation and adult neurogenesis: A dual role for new neurons balancing memory resolution and robustness. Neurobiol Learn Mem 129:60-8|
|Pei, Liming; Mu, Yangling; Leblanc, Mathias et al. (2015) Dependence of hippocampal function on ERR?-regulated mitochondrial metabolism. Cell Metab 21:628-36|
|Schafer, Simon T; Han, Jinju; Pena, Monique et al. (2015) The Wnt adaptor protein ATP6AP2 regulates multiple stages of adult hippocampal neurogenesis. J Neurosci 35:4983-98|
|Clemenson, Gregory D; Lee, Star W; Deng, Wei et al. (2015) Enrichment rescues contextual discrimination deficit associated with immediate shock. Hippocampus 25:385-92|
|Kim, Hyung Joon; Denli, Ahmet M; Wright, Rebecca et al. (2015) REST Regulates Non-Cell-Autonomous Neuronal Differentiation and Maturation of Neural Progenitor Cells via Secretogranin II. J Neurosci 35:14872-84|
|Aimone, James B; Li, Yan; Lee, Star W et al. (2014) Regulation and function of adult neurogenesis: from genes to cognition. Physiol Rev 94:991-1026|
|Zhao, Chunmei; Jou, Jessica; Wolff, Lisa J et al. (2014) Spine morphogenesis in newborn granule cells is differentially regulated in the outer and middle molecular layers. J Comp Neurol 522:2756-66|
|Deng, Wei; Mayford, Mark; Gage, Fred H (2013) Selection of distinct populations of dentate granule cells in response to inputs as a mechanism for pattern separation in mice. Elife 2:e00312|
|Ge, Woo-Ping; Miyawaki, Atsushi; Gage, Fred H et al. (2012) Local generation of glia is a major astrocyte source in postnatal cortex. Nature 484:376-80|
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