Transcriptional plasticity in the hippocampus and its role in conditioned place avoidance learning




Harris, Rayna Michelle

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For centuries, scientists and philosophers have sought to understand how the brain uses memory to drive changes in behavior. One challenge is that memory cannot be physically isolated. Memory is an instance in which an organism's current behavior is determined by some aspect of its previous experience4. It an emergent property that researchers observe as an overt change at one or more levels of biological organization. Recent advances in molecular biology and neuroscience pushed our understanding past the concept of the neural doctrine (single neurons are the brain’s information processing unit of organization) and the central dogma of molecular biology (function is coded by the process DNA->RNA->Protein) which alone do not solve the problem of understanding how the brain stores and recalls memories that change animal behavior. Identifying the molecular basis of individual phenotypic variation is a major challenge for modern molecular neuroscientists. This research provides fundamental new insights into how transcriptional and electrophysiological variation arises both within the major principal cell class of the hippocampus that are crucial for learning, memory, and cognition. The first research chapter provides a thorough description of how a conditioned place avoidance paradigm and its associated stressors alter transcriptomic and synaptic activity in the hippocampus. I found that DG responds strongly with an upregulation of transcription factors in response to consistently reinforced place avoidance training. While CA1 responds to cognitive and stressful manipulations with up and down-regulation of biochemical pathways that are important for synaptic signaling. The second research chapter provides insight into how genetic manipulation alters behavior, physiology, and gene expression. I thoroughly explore and describe the effects of FMR1 gene knockout on avoidance learning, synaptic physiology, and gene expression. The main behavioral finding was that FMR1-KO mice use strategy for place avoidance that does not utilize hippocampal-dependent mechanisms of memory. Unexpectedly, learning was not as strong during initial training as expected based on published literature and the previous chapter; therefore, the results of these experiments should be interpreted with that caution. FMRP loss in mice has been shown to cause abnormal synaptic and structural plasticity in CA1 pyramidal cells and has been associated with impaired hippocampal function as well as cognitive deficits. To focus only on the effect of genotype and to better understand the transcriptional effects of gene-knockdown, I narrow my examination to the CA1 of naive animals (those without cognitive training to increase learning and memory). I detected minor changes in genes that encode proteins known to interact with FMRP directly. I found that downregulation of expression of Cacna1g, Efcab6, Serpina3n, and Sstr3 genes is robust by conducting open and reproducible analysis of primary and public data. Finally, the third thesis chapter provides a deeper understanding of how new technological methods for RNA sequencing influence our ability to detect stability and plasticity in hippocampal transcriptomes. This study constitutes a significant contribution to our understanding of how experimental techniques may or may not mask our ability to identify biologically meaningful signatures of the molecular mechanisms regulating behavior and brain function.


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