Does the brain possess a mechanism for generating genetic diversity that could support memory storage? This proposal aims to test the idea that DNA recombination/repair mechanisms play a specific part in memory storage in the brain. Gene rearrangements may be used in the brain as a mechanism to generate experience-dependent protein diversity that could contribute to the storage of information acquired throughout a lifetime. DNA recombination may serve as a mechanism upstream of transcription to regulate the expression and function of a specific set of genes important for long-lasting memory storage. Thus, epigenetic, transcriptional, and recombinational mechanisms of gene regulation in memory do not exclude one another, but most likely complement each other. At this point, the most intriguing questions related to the idea of gene recombination and memory formation in the brain are what are the factors that mediate such a process in neurons and, more importantly, what are the genes that are subjected to this kind of regulation in response to learning. In this proposal, we focus on consolidation mechanisms of conditioned taste aversion (CTA), a behavioral paradigm characterized by the ability of many animals to learn to avoid certain substances after experiencing an unpleasant or harmful somatic (visceral) reaction.
Aim # 1 of this proposal addresses the role of amygdalar DNA recombination mechanisms in consolidation of CTA in rats by using or gene knockdown approaches, both targeting the function of putative recombination effector enzymes, Flap Structure-Specific Endonuclease-1 (FEN-1) and DNA ligase IV.
AIM # 2 examines amygdalar genomic rearrangement of putative DNA recombination target genes, such as protocadherin p9. Particularly, experiments will determine if the protocadherin 09 gene undergoes CTArelated genomic rearrangement in amygdala neurons. Overall, these studies will establish that DNA recombination/repair processes are part of the initial mechanisms utilized by the brain for the long-lasting storage of information, characterize the function of specific factors involved in this processes, and help demonstrate that specific gene targets undergo genomic rearrangement during memory formation.
|Castro-Pérez, Edgardo; Soto-Soto, Emilio; Pérez-Carambot, Marizabeth et al. (2016) Identification and Characterization of the V(D)J Recombination Activating Gene 1 in Long-Term Memory of Context Fear Conditioning. Neural Plast 2016:1752176|
|Santos-Soto, Iván J; Chorna, Nataliya; Carballeira, Néstor M et al. (2013) Voluntary running in young adult mice reduces anxiety-like behavior and increases the accumulation of bioactive lipids in the cerebral cortex. PLoS One 8:e81459|
|Aldavert-Vera, Laura; Huguet, Gemma; Costa-Miserachs, David et al. (2013) Intracranial self-stimulation facilitates active-avoidance retention and induces expression of c-Fos and Nurr1 in rat brain memory systems. Behav Brain Res 250:46-57|
|Chorna, Nataliya E; Santos-Soto, Iván J; Carballeira, Nestor M et al. (2013) Fatty acid synthase as a factor required for exercise-induced cognitive enhancement and dentate gyrus cellular proliferation. PLoS One 8:e77845|
|Huguet, G; Aldavert-Vera, L; Kadar, E et al. (2009) Intracranial self-stimulation to the lateral hypothalamus, a memory improving treatment, results in hippocampal changes in gene expression. Neuroscience 162:359-74|
|Saavedra-Rodríguez, Lorena; Vázquez, Adrinel; Ortiz-Zuazaga, Humberto G et al. (2009) Identification of flap structure-specific endonuclease 1 as a factor involved in long-term memory formation of aversive learning. J Neurosci 29:5726-37|