Sex Differences in Cognitive Flexibility and Resting Brain Networks in Middle-Aged Marmosets

Abstract

Sex differences in human cognitive performance are well characterized. However, the neural correlates of these differences remain elusive. This issue may be clarified using nonhuman primates, for which sociocultural influences are minimized. We used the marmoset ( Callithrix jacchus ) to investigate sex differences in two aspects of executive function: reversal learning and intradimensional/extradimensional (ID/ED) set shifting. Stress reactivity and motor function were also assessed. In agreement with human literature, females needed more trials than males to acquire the reversals. No sex differences in ED set shifting or motivational measures were observed. The findings suggest enhanced habit formation in females, perhaps due to striatal estrogenic effects. Both sexes showed increased urinary cortisol during social separation stressor, but females showed an earlier increase in cortisol and a greater increase in agitated locomotion, possibly indicating enhanced stress reactivity. Independent of sex, basal cortisol predicted cognitive performance. No sex differences were found in motor performance. Associations between brain networks and reversal learning performance were investigated using resting state fMRI. Resting state functional connectivity (rsFC) analyses revealed sex differences in cognitive networks, with differences in overall neural network metrics and specific regions, including the prefrontal cortex, caudate, putamen, and nucleus accumbens. Correlations between cognitive flexibility and neural connectivity indicate that sex differences in cognitive flexibility are related to sex-dependent patterns of resting brain networks. Overall, our findings reveal sex differences in reversal learning, brain networks, and their relationship in the marmoset, positioning this species as an excellent model to investigate the biological basis of cognitive sex differences.

Baseline cortisol levels and social behavior differ as a function of handedness in marmosets (Callithrix jacchus)

“…With regard to cognitive flexibility, as assessed by reversal learning, we found that performance was equivalent between left‐, right‐handers and ambidextrous marmosets. Independent of hand preference, however, females obtained poorer performance than males, a finding that we have reported previously (LaClair et al, ; Lacreuse et al, ; Workman et al, ). The lack of handedness influence on cognitive performance is consistent with several reports in humans (e.g., Corballis et al, ) and nonhuman primates including marmosets (e.g., Cameron & Rogers, ).…”

“…For cognitive performance, a main effect of Sex F (1, 21) = 10.90, p = .003) on RI indicated that females were slower than males in acquiring the reversals, compared to the simple discriminations, a finding reported elsewhere (LaClair et al, ; Lacreuse et al, ; Workman et al, ). However, neither Hand Preference ( F (2, 21) = 0.14, p = 0.87) nor the interaction between Sex and Hand Preference ( F (2, 21) = 0.017, p = .98; see Figure ) significantly affected RI.…”

“…Because few monkeys provided urine within the first 2 hr of separation, cortisol values were averaged for baseline (15 min before separation), middle separation (3–5 hours), end of the separation (last 2 hours), and postseparation (24 hr postseparation). The stress reactivity data of a subset of animals have been reported in LaClair et al ().…”

“…The cognitive data were collected throughout 2016, with data from a subset of monkeys presented in several papers (LaClair et al, ; Lacreuse, Moore, LaClair, Payne, & King, ; Workman et al, ). For most monkeys, cognitive performance was assessed in a reversal learning task administered on a touchscreen (CANTAB battery, see Spinelli et al, ) and described in details in Workman et al ().…”

Sex-dependent effects of chronic exercise on cognitive flexibility in aging mice

“…There is some evidence of sex differences within the literature regarding cognitive flexibility in young adults and even in children under the age of 3, with males generally performing better (Evans & Hampson, 2015;Overman, 2004). Consistent with this, a recent report in middle-aged marmosets showed that males are faster to acquire reversal learning (Laclair et al, 2019). These studies all highlighted the PFC as the main driver of observed sex differences in these reversal tasks, but did not undertake further investigations of the role of the hippocampus.…”