Sex differences in the dynamic epigenetic regulation of learning and memory.

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Males and females are physiologically different, and often exhibit distinct behavioural responses to environmental stimuli. Yet, there is a significant lack of knowledge regarding how the sexes differ in the biological mechanisms that regulate behaviour, a deficit that can likely be attributed to the large focus on male responses in preclinical research. As a result, innate sex differences in gene regulation, cell signaling, and brain systems communication mechanisms that underlie behavior have been poorly characterized. Thus, the long-term objective of this research program is to evaluate sex differences in the dynamic neurobiological changes, from the gene up to the system, that regulate behaviour. Animal behavior serves as a bridge between the molecular and physiological aspects of biology with the environment, and plays a critical role in biological adaptations. It is known that while salient stimuli can result in long-term stable biological changes, they can also induce dynamic changes of shorter duration, both processes of which play pivotal roles in behavioural variation. A key principle that has recently emerged from behavioural neuroscience research is that is that dynamic changes in the epigenetic regulation of gene expression in response to environmental stimuli play a critical role in the manifestation of specific behaviours, such as learning and memory. There is an almost complete lack of knowledge, however, regarding sex differences in the epigenetic regulation of learning and memory processes. Therefore, aligning with the overall objective of the research program, in this proposal we will evaluate sex differences in the dynamic epigenetic changes that occur at the gene for brain derived neurotrophic factor (bdnf), a protein widely shown to positively contribute to learning and memory. Sex differences in temporal changes in histone acetylation will first be evaluated at various bdnf gene protomers in specific sub-regions of the prefrontal cortex and hippocampus during spatial and reversal learning. Next, we will evaluate the transient changes in bdnf mRNA expression in these brain sub-regions during learning, and assess DNA methylation patterns at specific bdnf promoters and associated exons. Finally, as neuronal communication within, and between, the prefrontal cortex and hippocampus are critical to learning and memory processes, we will evaluate how altering histone acetylation and DNA methylation in these regions impacts on neuronal oscillatory activity during learning in male and female rats. The findings from this research will not only improve our knowledge of the fundamental differences between the male and female brain, but will also provide an additional level of understanding on how learning and memory may be differentially regulated in the two sexes.