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.
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|Shimozaki, Koji; Zhang, Chun-Li; Suh, Hoonkyo et al. (2012) SRY-box-containing gene 2 regulation of nuclear receptor tailless (Tlx) transcription in adult neural stem cells. J Biol Chem 287:5969-78|
|Li, Yan; Aimone, James B; Xu, Xiangming et al. (2012) Development of GABAergic inputs controls the contribution of maturing neurons to the adult hippocampal network. Proc Natl Acad Sci U S A 109:4290-5|
|Lee, Star W; Clemenson, Gregory D; Gage, Fred H (2012) New neurons in an aged brain. Behav Brain Res 227:497-507|
|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|
|Aimone, James B; Deng, Wei; Gage, Fred H (2011) Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron 70:589-96|
|Mu, Yangling; Zhao, Chunmei; Gage, Fred H (2011) Dopaminergic modulation of cortical inputs during maturation of adult-born dentate granule cells. J Neurosci 31:4113-23|
|Aimone, James B; Deng, Wei; Gage, Fred H (2010) Adult neurogenesis: integrating theories and separating functions. Trends Cogn Sci 14:325-37|
|Ma, Dengke K; Marchetto, Maria Carolina; Guo, Junjie U et al. (2010) Epigenetic choreographers of neurogenesis in the adult mammalian brain. Nat Neurosci 13:1338-44|
|Mathews, Emily A; Morgenstern, Nicolas A; Piatti, Veronica C et al. (2010) A distinctive layering pattern of mouse dentate granule cells is generated by developmental and adult neurogenesis. J Comp Neurol 518:4479-90|
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