Functional and structural analysis of aberrant adult neurogenesis

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Hippocampal dentate granule cells are among the few neuronal cell types in the brain that are continuously generated throughout adulthood. Although the functional significance of neurogenesis remains unclear, recent work suggests that adult-born neurons transiently exhibit physiological characteristics (i.e. heightened excitability and plasticity) that enable them to contribute to specific forms of hippocampal-dependent behaviors, including contextual learning, cognitive flexibility, and pattern separation. It is well established that memory and learning-related impairments are overrepresented in individuals afflicted with epilepsy. Interestingly, previous work has shown that seizures dramatically increase the accumulation of new neurons in the dentate gyrus. Given that the dentate gyrus also operates as a “gate” that regulates the flow of information entering into the hippocampus, an unexplored question is whether atypical neurogenesis secondary to recurrent seizures might contribute to alterations in hippocampal-mediated behavior. The aim of this proposal will be to examine the functional impact of aberrant seizure-induced neurogenesis on behavior and cognitive performance. To address this question, we will use an animal model called kindling, in which daily electrical stimulation of certain brain regions results in the gradual progression of motor seizures. We have previously found that kindling causes dramatic changes in neurogenesis that alters hippocampal function--a process that may contribute to impairments in learning and memory function, as well as emotional behavior. To extend on these observations, we will assess the impact of kindling on behaviors that require functional neurogenesis, such as pattern separation and contextual discrimination. We will also map the anatomy and neurochemical characteristics of synaptic inputs on newborn neurons after kindling, and determine if kindling affects the integration of these cells into circuits that are involved in learning and memory. Finally, we will examine whether blocking aberrant neurogenesis can reverse the behavioral consequences of kindling. The studies outlined in this proposal will provide insight into the fundamental mechanisms that govern adult neurogenesis and how newborn neurons can influence behavior under normal and pathological conditions.