Post-traumatic stress disorder (PTSD) is twice as common in women as in men; it is a major public health problem whose neurobiological basis is unknown. In preclinical studies using fear conditioning and extinction paradigms, women and female animals with low estrogen levels exhibit impaired extinction retrieval, but the mechanisms that underlie these hormone-based discrepancies have not been identified. There is much evidence that estrogen can modulate dopaminergic transmission, and here we tested the hypothesis that dopamine-estrogen interactions drive extinction processes in females. Intact male and female rats were trained on cued fear conditioning, and received an intraperitoneal injection of a D1 agonist or vehicle before extinction learning. As reported previously, females that underwent extinction during low estrogen estrous phases (estrus/metaestrus/diestrus (EMD)) froze more during extinction retrieval than those that had been in the high-estrogen phase (proestrus; PRO). However, D1 stimulation reversed this relationship, impairing extinction retrieval in PRO and enhancing it in EMD. We also combined retrograde tracing and fluorescent immunohistochemistry to measure c-fos expression in infralimbic (IL) projections to the basolateral area of the amygdala (BLA), a neural pathway known to be critical to extinction retrieval. Again we observed diverging, estrous-dependent effects; SKF treatment induced a positive correlation between freezing and IL-BLA circuit activation in EMD animals, and a negative correlation in PRO animals. These results show for the first time that hormone-dependent extinction deficits can be overcome with non-hormone-based interventions, and suggest a circuit-specific mechanism by which these behavioral effects occur.

Human orientation in novel and familiar environments is a complex skill that can involve numerous different strategies. To date, a comprehensive account of how these strategies interrelate at the behavioural level has not been documented, impeding the development of elaborate systems neuroscience models of spatial orientation. Here, we describe a virtual environment test battery designed to assess five of the core strategies used by humans to orient. Our results indicate that the ability to form a cognitive map is highly related to more basic orientation strategies, supporting previous proposals that encoding a cognitive map requires inputs from multiple domains of spatial processing. These findings provide a topology of numerous primary orientation strategies used by humans during orientation and will allow researchers to elaborate on neural models of spatial cognition that currently do not account for how different orientation strategies integrate over time based on environmental conditions.

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