Robustness of sex-differences in functional connectivity over time in middle-aged marmosets

Abstract

Nonhuman primates (NHPs) are an essential research model for gaining a comprehensive understanding of the neural mechanisms of neurocognitive aging in our own species. In the present study, we used resting state functional connectivity (rsFC) to investigate the relationship between prefrontal cortical and striatal neural interactions, and cognitive flexibility, in unanaesthetized common marmosets (Callithrix jacchus) at two time points during late middle age (8 months apart, similar to a span of 5–6 years in humans). Based on our previous findings, we also determine the reproducibility of connectivity measures over the course of 8 months, particularly previously observed sex differences in rsFC. Male marmosets exhibited remarkably similar patterns of stronger functional connectivity relative to females and greater cognitive flexibility between the two imaging time points. Network analysis revealed that the consistent sex differences in connectivity and related cognitive associations were characterized by greater node strength and/or degree values in several prefrontal, premotor and temporal regions, as well as stronger intra PFC connectivity, in males compared to females. The current study supports the existence of robust sex differences in prefrontal and striatal resting state networks that may contribute to differences in cognitive function and offers insight on the neural systems that may be compromised in cognitive aging and age-related conditions such as mild cognitive impairment and Alzheimer’s disease.

Bridging the rodent to human translational gap: Marmosets as model systems for the study of Alzheimer's disease

“…Relatedly, marmosets are excellent at performing cognitive tasks across several domains, including learning, memory, and attention. In addition, marmosets demonstrate age‐dependent cognitive decline with impairments associated with synaptic loss and reduced spine density 16–17,25–31 . Of interest, sex differences have also been reported with cognitive impairment in aging marmosets, with worse outcomes in aging females relative to aging males both in task performance and functional connectivity measures 30,31 .…”

The marmoset as an important primate model for longitudinal studies of neurocognitive aging

“…Few studies to date have leveraged the advantages of small, short‐lived NHP (Fischer & Austad, 2011) for longitudinal investigations of neurocognitive aging (Pifferi & Aujard, 2019; Rothwell et al, 2021). Longitudinal assessments of cognitive, behavioral, and biological parameters, combined with multiple neuroimaging assessments (Laclair et al, 2019; Nephew et al, 2020) and postmortem neuropathology in the aging marmoset will provide invaluable insight into healthy and pathological aging, including Alzheimer's disease (AD). While transgenic rodent models have advanced our understanding of AD, clinical trials have routinely failed for almost two decades (King, 2018).…”

“…Longitudinal assessments of cognitive, behavioral, and biological parameters, combined with multiple neuroimaging assessments (Laclair et al, 2019;Nephew et al, 2020) and postmortem neuropathology in the aging marmoset will provide invaluable insight into healthy and pathological aging, including Alzheimer's disease (AD).…”

Evaluating depression- and anxiety-like behaviors in non-human primates

“…Like in humans, specific cognitive and learning tests (that can also assess attention) can detect impaired performance in NHPs displaying depression- and anxiety-like behaviors (Sridharan et al, 2012 ; Ash et al, 2020 ; Nephew et al, 2020 ). For rhesus macaques, most of these tests are adaptations of human versions, such as the Wisconsin card sorting task (WCST) and conditioned reward learning (Sridharan et al, 2012 ).…”