Developmental emergence of persistent memory for contextual and auditory fear in mice.

The ability to generate memories that persist throughout a lifetime (that is, memory persistence) emerges in early development across species. Although it has been shown that persistent fear memories emerge between late infancy and adolescence in mice, it is unclear exactly when this transition takes place, and whether two major fear conditioning tasks, contextual and auditory fear, share the same time line of developmental onset. Here, we compared the ontogeny of remote contextual and auditory fear in C57BL/6J mice across early life. Mice at postnatal day (P)15, 21, 25, 28, and 30 underwent either contextual or auditory fear training and were tested for fear retrieval 1 or 30 d later. We found that mice displayed 30-d memory for context- and tone-fear starting at P25. We did not find sex differences in the ontogeny of either type of fear memory. Furthermore, 30-d contextual fear retrieval led to an increase in the number of c-Fos positive cells in the prelimbic region of the prefrontal cortex only at an age in which the contextual fear memory was successfully retrieved. These data delineate a precise time line for the emergence of persistent contextual and auditory fear memories in mice and suggest that the prelimbic cortex is only recruited for remote memory recall upon the onset of memory persistence.

Sex Differences in the Development of the Rodent Corticolimbic System.

In recent years, a growing body of research has shown sex differences in the prevalence and symptomatology of psychopathologies, such as depression, anxiety, and fear-related disorders, all of which show high incidence rates in early life. This has highlighted the importance of including female subjects in animal studies, as well as delineating sex differences in neural processing across development. Of particular interest is the corticolimbic system, comprising the hippocampus, amygdala, and medial prefrontal cortex. In rodents, these corticolimbic regions undergo dynamic changes in early life, and disruption to their normative development is believed to underlie the age and sex-dependent effects of stress on affective processing. In this review, we consolidate research on sex differences in the hippocampus, amygdala, and medial prefrontal cortex across early development. First, we briefly introduce current principles on sexual differentiation of the rodent brain. We then showcase corticolimbic regional sex differences in volume, morphology, synaptic organization, cell proliferation, microglia, and GABAergic signaling, and explain how these differences are influenced by perinatal and pubertal gonadal hormones. In compiling this research, we outline evidence of what and when sex differences emerge in the developing corticolimbic system, and illustrate how temporal dynamics of its maturational trajectory may differ in male and female rodents. This will help provide insight into potential neural mechanisms underlying sex-specific critical windows for stress susceptibility and behavioral emergence.