Sex Differences in Retrieval of Context Fear: Behavioral and Neural Mechanisms

Abstract

The behavioral and neural mechanisms underlying consolidation and retrieval of fear-related memories have been defined over many years. However, the majority of established theories of learning and memory have been based on data derived from predominantly male animals. Throughout this dissertation, I examined how females differ from males behaviorally and in brain regions engaged during retrieval of context fear. In chapter 2, I assessed whether males and females differ in foreground context fear conditioning, generalization to a similar, safe context and determined the neural correlates of retrieval in males and females. I found that females showed higher levels of freezing behavior than males and exhibited greater generalized context fear. Further, I demonstrated that ventral hippocampus is required for retrieval of context fear memories in males and females but that males preferentially engaged dorsal hippocampus following retrieval of context fear memory whereas females preferentially engaged ventral hippocampus and amygdala. If males and females differ in context fear conditioning and engagement of brain regions when memory is recalled at recent time points, they may also differ in retrieval of remote context fear. Therefore, in chapter 3 I examined sex differences in retrieval of remote context fear and determined neural correlates of remote retrieval. I found that females but not males trained with background fear conditioning (tone), show reduced freezing to the context at remote time points. Further, I demonstrated that as in retrieval of recent context fear memories, females preferentially engaged ventral hippocampus and basal amygdala, and also engaged retrosplenial cortex after retrieval of background context fear memory compared with males. Together, chapter 2 and 3 suggest that retrieval and its neural correlates differ between males and females at both recent and remote time points. Therefore, it is likely that males and females engage in distinct cognitive strategies to retrieve context fear. One way to assess sex differences in strategy of retrieval is to examine whether the context-shock association is similarly retrieved in both sexes. In chapter 4 I examined this using a blocking task and extinction paradigm. I show that despite strong context fear memory in both sexes, only males showed blocking to the tone. In extinction, sex differences in patterns of freezing were observed within session where females start off lower in freezing at the beginning of each session and show an increase in freezing throughout the session. While chapters 2-4 provide data to suggest that females differ in hippocampal mechanisms normally activated by retrieval in males, it still remains unclear as to which mechanisms females engage to retrieve context fear memories that may be separate from males. In chapter 5 I use RNA-sequencing as an unbiased approach to identify differential expression of genes in ventral hippocampus of males and females following retrieval and during consolidation of context fear compared with naïve. Despite similar behavior between the sexes during learning and retrieval, I identify a diverse transcriptional profile in ventral hippocampus of males and females following retrieval, during consolidation and at baseline. Collectively, these data determine sex-specific mechanisms associated with retrieval of a context fear memory and move the field closer from pointing out where males and females differ in learning and memory to understanding and defining how and why.