Sex Differences in the Development of the Rodent Corticolimbic System

Abstract

In recent years, a growing body of research has shown sex differences in the prevalence and symptomatology of psychopathologies, such as depression, anxiety, and fearrelated 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 sexdependent 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.

Effects of a 33-ion sequential beam galactic cosmic ray analog on male mouse behavior and evaluation of CDDO-EA as a radiation countermeasure

“…This is particularly important limitation since over half the current astronaut class is female and there are sex-dependent differences in CNS sensitivity to charged particle radiation [9,82]. It is also important from a fundamental neurobiological perspective; female and male rodents differ in key developmental and behavioral aspects, in their response to stress, and in both their performance in and strategies for completing many "classical" behavioral paradigms [83][84][85][86][87]. Indeed, given the lower level of within-cage aggression in group-housed conspecific female vs. male mice (see next point), studies on female mice likely will have lower attrition than is reported here and elsewhere in male rodents [9].…”

Effects of Early Life Stress on the Developing Basolateral Amygdala-Prefrontal Cortex Circuit: The Emerging Role of Local Inhibition and Perineuronal Nets

“…Sex differences in the development of the rodent corticolimbic circuit and its specific components has been recently elegantly reviewed ( Premachandran et al, 2020 ) and sex effects have been outlined at the level of the amygdala, mPFC and hippocampus in terms of differences in volume, morphology, synaptic organization, cell proliferation, microglia, and GABAergic signaling. Morphological and functional changes over the course of development have been studied mostly in the dorsal hippocampus, reporting both transient, and long-term effects of sex on this structure.…”

“…Morphological and functional changes over the course of development have been studied mostly in the dorsal hippocampus, reporting both transient, and long-term effects of sex on this structure. Interestingly, females undergo an earlier switch in GABA A -mediated excitation to inhibition during the first postnatal week in rodents, occurring between PND4–7 compared to PND8–14 in males ( Premachandran et al, 2020 ). This difference in the timing of inhibition onset might be critical to determine further developmental processes in this structure and to identify potential windows of sensitivity to external stimuli.…”

Early Development of the GABAergic System and the Associated Risks of Neonatal Anesthesia

“…In humans, the mature state of these synapses is not reached until the onset of puberty in the hippocampus and the end of adolescence in the neocortex [ 103 ]. Although, it is expected that the mature characteristics of these synapses will be achieved more rapidly in females, compared to males in certain brain regions [ 104 ]. Therefore, similarly to the development of the GABA-driven force, drastic GABAergic synaptic development may also commence during infancy, however, this process may last significantly longer.…”