The relationships between sex differences in learning strategy in early life and neurochemical and neuroarchitectural endpoints in multiple memory systems
Rodents solve dual-solution tasks that require navigation to a goal by adopting either a hippocampus-dependent place strategy or a striatum-dependent stimulus–response strategy. The current experiments investigated the preference for learning strategy as a function of biological sex and anxiety level in rats prior to the onset of puberty, before the activational effects of gonadal hormones influence these processes. In the first experiment, a significant proportion of prepubertal males preferred a stimulus-response strategy on a dual-solution visible platform water maze task at 28 days of age, in contrast to age-matched prepubertal females or adult males. In the second experiment, prepubertal males categorized as high in trait anxiety on an open field task exhibited a bias toward stimulus–response strategy, whereas age-matched females exhibited no preference in strategy regardless of anxiety level. In the third experiment, pups were separated from dams for either 15 or 180 min per day during the first 2 weeks of life and tested for anxiety and learning strategy preference. Prolonged maternal separations were linked to elevated anxiety and a bias for stimulus-response strategy in prepubertal males but not females. In the fourth experiment, prepubertal males and rats preferring a stimulus-response strategy expressed a lower ratio of muscarinic binding in the hippocampus relative to the striatum compared to prepubertal females and place learners, respectively. In the fifth experiment, prepubertal females masculinized by injections of testosterone shortly after birth preferred a stimulus-response strategy similar to that of prepubertal males and unlike vehicle-treated females. In the sixth experiment, prepubertal females expressed greater dendritic complexity and spine density in the CA1 region of the hippocampus than males at the exact age at which sex differences in learning strategy preference were found in the first five experiments. This series of experiments indicates that, in contrast to prepubertal female rats, prepubertal males displayed a clear preference for a striatum-based stimulus-response strategy when learning a dual-solution task. Furthermore, several variables were identified as contributing to this sex difference, including the impact of male anxiety on strategy preference, lower male hippocampus-to-striatum ratios of muscarinic binding, and delayed structural development of the male hippocampus.