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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH090258-04
Application #
8432505
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Panchision, David M
Project Start
2010-04-02
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
4
Fiscal Year
2013
Total Cost
$452,628
Indirect Cost
$215,028
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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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

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