New neurons are continually born and are incorporated into the mature circuitry of the adult central nervous system. The hippocampal dentate gyrus is a brain region where there is a substantial level of neurogenesis in adult birds and mammals. This brain region is important for encoding new memories. Increased hippocampal neurogenesis has been correlated with enhanced learning. Enhanced neurogenesis is elicited by exercise and antidepressant medications - treatments that are known to be important for enhancing mood in depressed patients. The ability to generate new neurons is unique to two regions in the central nervous system. Further, it is the lack of this ability throughout most central nervous system regions that results in a poor ability to recover from brain injuries and neurodegenerative disorders. While much work has focused on the birth of new neurons in the hippocampal brain region there has been less emphasis on the mechanisms by which new neurons survive and integrate into the mature synaptic circuitry. It is known that neural activity can enhance the integration of newborn neurons into the dentate gyrus.
In aim 1 we propose to examine the mechanisms by which activity influences the integration and survival of newborn neurons in the adult central nervous system. Specifically we will use brain slices from animals expressing a genetically encoded marker of newborn neurons and examine how stimulation affects growth, synapse formation, and synapse function of newborn neurons. We will use live-imaging methods to measure growth and synapse formation and electrophysiological recordings to measure synapse formation and function.
In aim 2 we propose to study the molecular mechanisms important for integration. We can target newborn neurons for genetic modification by injecting molecularly engineered viruses into the brains of live mice. With this approach we can knockdown genes that we hypothesize to be important for integration and examine the effect genetic manipulation on the growth and synapse formation of the newborn neurons. The results of the proposed experiments will expand our knowledge about how activity and genetic expression influence the ability of newborn neurons to survive in the adult central nervous system. An understanding of how new neurons integrate into mature synaptic circuitry is fundamental to our understanding of the brain. I believe that this knowledge will be important to develop therapies to enhance cognitive abilities in the learning impaired, mood in depressed patients, and functionally replace damaged neurons in patients with acquired brain injuries or neurodegenerative disorders. ? ?
| Luikart, Bryan W; Perederiy, Julia V; Westbrook, Gary L (2012) Dentate gyrus neurogenesis, integration and microRNAs. Behav Brain Res 227:348-55 |
| Luikart, Bryan W; Bensen, AeSoon L; Washburn, Eric K et al. (2011) miR-132 mediates the integration of newborn neurons into the adult dentate gyrus. PLoS One 6:e19077 |
| Luikart, Bryan W; Schnell, Eric; Washburn, Eric K et al. (2011) Pten knockdown in vivo increases excitatory drive onto dentate granule cells. J Neurosci 31:4345-54 |
| Luikart, Bryan W; Zhang, Wei; Wayman, Gary A et al. (2008) Neurotrophin-dependent dendritic filopodial motility: a convergence on PI3K signaling. J Neurosci 28:7006-12 |
