Exploring the Role and Sensitivity of the Hippocampal Dentate Gyrus: From Addiction-Relevant Memories to the Influence of Space Radiation on Hippocampal Neurogenesis
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The hippocampus and its subregion the dentate gyrus (DG) are involved in learning and memory. Adult hippocampal neurogenesis, which takes place in the DG, is also thought to contribute to learning and memory. Understanding the neural basis of learning and memory could help in a wide range of situations, from helping addicts break the cycle of substance abuse to ensuring appropriate astronaut action during spaceflight missions. This doctoral dissertation spans this wide range by using animal models relevant to addiction and spaceflight to improve understanding of the DG and adult neurogenesis, and obliquely, of learning and memory. After an introductory chapter, I show morphine-context reward memories are established via drug/context associations (D/CA, Chapter 2), and require adult neurogenesis for extinction of young reward memories (Chapter 3). Using conditioned place preference, a behavioral test classically used to assess drug strength, and the immediate early gene cFos as an indirect marker of neuronal activity, I found that morphine-paired mice sequestered to a morphine-paired context had more DG cFos+ cells than those sequestered to a saline-paired context or other controls. Thus, the retrieval of D/CA memory is accompanied by activation of hippocampal DG neurons. Surprisingly, image-guided cranial irradiation (IG-IR) prevented extinction of young, but not old, morphine D/CA memories without affecting retrieval. These data suggest that deficits in adult neurogenesis may contribute to stronger D/CA reward memory. The second section of my dissertation (Chapter 4) examines the influence of space radiation on adult neurogenesis. I find acute and fractionated space radiation similarly diminish adult neurogenesis, but neither decrease neural stem cell number, the putative source of new neurons. Thus, while spaceflight mission success may be hampered by space radiation due to diminished neurogenesis, my data raise the possibility that neurogenesis may recover overtime. Taken together, my data show an impaired DG (and perhaps neurogenesis) diminishes extinction of morphine-context reward memories, and that adult neurogenesis is decreased (perhaps reversibly) by space radiation. In my final chapter (Chapter 5), I discuss implications of these data for the fields of learning/memory and neuroscience in general, and suggest future directions that may help addicts recover and allow astronauts to perform optimally during spaceflight missions.