Unambiguous evidence of ongoing neurogenesis has revolutionized views of neuroplasticity in the adult brain. Continual generation of adult-born dentate granule cells (abGCs) in the dentate gyrus (DG) has received particular attention due to the hippocampus' role in learning, memory and cognition. Dentate granule cells (GCs) perform cognitive functions such as pattern separation and novelty detection in spatial environments through the use of a sparse neural code. However, the nature of sparseness in GC activity is enigmatic: more than 95% of GCs do not fire in any environment, while the remaining 5% are active in all environments. Computational models and in vivo studies suggest that abGCs are preferentially activated and may comprise the majority of these functional GCs. This theory has not been sufficiently tested, and if found to be supported, the mechanisms mediating this preferential activation of abGCs are unknown. Dysregulation of abGC neurogenesis has been observed in animal models of temporal lobe epilepsy (TLE). Early following brain injuries that induce TLE, there is an increased production accompanied by aberrant integration of abGCs. It is unclear whether these aberrantly integrated cells promote or protect against seizure activity, as the exact contributions of newborn cells to hippocampal circuit function are unknown. The CENTRAL hypothesis of this proposal is that abGCs are important regulators of dentate gyrus circuit function in both the normal and epileptic brain, and furthermore, that their functional contributions in these two states is distinct. To test this hypothesis, we will conduct studies focused on two specific aims, which are:
Aim 1) Determine whether immature abGCs are preferentially activated by afferent stimulation, and Aim 2) Determine whether abGCs contribute to the degradation in the specificity of cellular activation by afferent stimulation evident in the dentate gyrus of animals with epilepsy. Through the use of state-of-the-art optical and electrical recordings, and genetic strategies, we will examine the relative circuit contributions and physiology of both newborn and mature GCs in both nave animals and in an animal model of epilepsy.
Ongoing neurogenesis of dentate granule cells in the hippocampal dentate gyrus is a natural feature of the adult brain, but there is profound dysregulation of this neurogenesis after brain injuries that precipitate epilepsy. The circuit contributions of newborn granule cells in the normal brain are unknown, as are the contributions of aberrantly integrated granule cells born after brain injury. The proposed studies employ cutting edge optical and electrical recording techniques, as well as transgenic strategies to investigate the physiological contributions of neurogenesis to circuit function in the hippocampal dentate gyrus in health and in epilepsy; elucidation of the role of newborn granule cells in epilepsy should enhance our understanding of the disease, and contribute to the development of new therapeutic avenues and insights contributing to the prevention of epileptogenesis and treatment of epilepsy.
| Yu, Esther P; Dengler, Christopher G; Frausto, Shanti F et al. (2013) Protracted postnatal development of sparse, specific dentate granule cell activation in the mouse hippocampus. J Neurosci 33:2947-60 |
