The dentate gyrus contributes to hippocampal memory encoding by transforming dense cortical patterns of sensory and spatial information into sparse neural representations of specific contexts. There is now overwhelming evidence that continual adult neurogenesis in the dentate gyrus in important for the ability to discriminate spatial contexts, but it is not clear how newly generated neurons contribute to dentate circuit function. Most theories have focused on the fact that newly-generated immature neurons have distinct physiological properties that potentially endow them with unique processing capabilities compared to larger population of mature neurons. Alternatively, an emerging idea is that adult-born neurons promote wide-spread plasticity of the pre-existing cortical-dentate circuit by modifying the function of existing neurons in a manner that promotes sparse activity. This could occur either by indirect circuit actions like feedback inhibition, as well as via direct interactions with existing excitatory synaptic connectivity. We recently showed that selectively increasing the number of adult-born neurons in mouse dentate gyrus reduces the excitatory synaptic connectivity of mature neurons, resulting in both functional and anatomical changes in entorhinal-dentate circuitry. These results and existing literature support a model wherein a static pool of cortical pre-synaptic terminals is dynamically distributed between newly integrating adult-born neurons and developmentally- generated mature neurons. The goal of this project is to test the overarching hypothesis that synaptic integration of adult-born neurons has disproportionate effects on circuit function via redistribution of cortical synaptic connectivity. First, we will map and quantify the presynaptic changes that accompany neurogenesis-induced loss of cortical synapses with mature neurons. Second, we will test the prediction that availability of cortical presynaptic terminals is a limiting factor in the integration of newborn GCs that potentially contributes to the reduced rate new neuron maturation across adulthood. Finally, we will test potential consequences of synaptic redistribution on the sparsity of neural activity and synaptic plasticity, and the requirement for synaptic redistribution for neurogenesis-sensitive behaviors. We will use a combination of viral manipulations, electrophysiology, imaging and behavioral analysis to test the prediction that synaptic re- distribution limits the integration of adult-born neurons during adulthood and sparsifies neural activity, as well as contributes to behaviors that are sensitive to neurogenesis. Together our results will generate fundamental new knowledge about the role of neurogenesis in cortical-dentate circuitry, and potentially provide insight into how this circuit changes across adulthood as neurogenesis declines. Understanding how neurogenesis contributes to hippocampal function is important for devising strategies to counteract the consequences of disrupted neurogenesis that occurs during aging and many neurological conditions.
The goal of this project is to understand how new neurons in the adult dentate gyrus contribute to brain function. The results of these studies will expand our knowledge of a brain process that is critical for normal cognitive function and that is altered in many neurological conditions including epilepsy, stress-related depression and psychiatric diseases.
| Gonzalez, Jose Carlos; Epps, S Alisha; Markwardt, Sean J et al. (2018) Constitutive and Synaptic Activation of GIRK Channels Differentiates Mature and Newborn Dentate Granule Cells. J Neurosci 38:6513-6526 |
| Froula, Jessica M; Henderson, Benjamin W; Gonzalez, Jose Carlos et al. (2018) ?-Synuclein fibril-induced paradoxical structural and functional defects in hippocampal neurons. Acta Neuropathol Commun 6:35 |
| Nietz, Angela K; Vaden, Jada H; Coddington, Luke T et al. (2017) Non-synaptic signaling from cerebellar climbing fibers modulates Golgi cell activity. Elife 6: |
| Laszczyk, Ann M; Fox-Quick, Stephanie; Vo, Hai T et al. (2017) Klotho regulates postnatal neurogenesis and protects against age-related spatial memory loss. Neurobiol Aging 59:41-54 |
| Adlaf, Elena W; Vaden, Ryan J; Niver, Anastasia J et al. (2017) Adult-born neurons modify excitatory synaptic transmission to existing neurons. Elife 6: |
| Dieni, Cristina V; Panichi, Roberto; Aimone, James B et al. (2016) Low excitatory innervation balances high intrinsic excitability of immature dentate neurons. Nat Commun 7:11313 |
| Enikolopov, Grigori; Overstreet-Wadiche, Linda; Ge, Shaoyu (2015) Viral and transgenic reporters and genetic analysis of adult neurogenesis. Cold Spring Harb Perspect Biol 7:a018804 |
| Overstreet-Wadiche, Linda; McBain, Chris J (2015) Neurogliaform cells in cortical circuits. Nat Rev Neurosci 16:458-68 |
| Wadiche, Jacques I; Overstreet-Wadiche, Linda (2015) New neurons don't talk back. Neuron 85:3-5 |
| Hallengren, Jada J; Vaden, Ryan J (2014) Sodium-potassium ATPase emerges as a player in hippocampal phenotypes of Angelman syndrome mice. J Neurophysiol 112:5-8 |
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