Aging and exercise have opposing effects on mnemonic discrimination task performance, which putatively taxes pattern separation mechanisms reliant on the dentate gyrus (DG) subfield of the hippocampus. In young adults, increasing cardiorespiratory fitness (CRF) has been shown to improve mnemonic discrimination task performance and increase left anterior DG/CA3 volume. It is unknown how these variables interact in cognitive aging, yet this knowledge is critical, given the established effects of aging on hippocampal plasticity. To investigate these relationships, 65 older adults (aged 55–85 years) completed a submaximal treadmill test to estimate CRF, a mnemonic discrimination task, and a high‐resolution MRI scan to determine hippocampal subfield volumes. Our older adult sample demonstrated the lowest task accuracy in the condition with the greatest stimuli similarity and left DG/CA3 body volume significantly predicted accuracy in this condition. Our results did not provide support for relationships between CRF and task accuracy or CRF and DG/CA3 volume as evidenced in studies of young adults. Instead, CRF predicted bilateral subiculum volume in older adult women, not men. Altogether, these findings provide further support for a role of the DG in behavioral pattern separation in humans and suggest that CRF may have differential effects on hippocampal subfield integrity in older adult men and women. ClinicalTrials.gov identifiers: (a) Neuroimaging Study of Exercise and Memory Function, NCT02057354; (b) The Entorhinal Cortex and Aerobic Exercise in Aging, NCT02775760; (c) Physical Activity and Cognition Study, NCT02773121.

Rodent and human studies examining the relationship between aerobic exercise, brain structure, and brain function indicate that the hippocampus (HC), a brain region critical for episodic memory, demonstrates striking plasticity in response to exercise.Beyond the hippocampal memory system, human studies also indicate that aerobic exercise and cardiorespiratory fitness (CRF) are associated with individual differences in large-scale brain networks responsible for broad cognitive domains. Examining network activity in large-scale resting-state brain networks may provide a link connecting the observed relationships between aerobic exercise, hippocampal plasticity, and cognitive enhancement within broad cognitive domains. Previously, CRF has been associated with increased functional connectivity of the default mode network (DMN), specifically in older adults. However, how CRF relates to the magnitude and directionality of connectivity, or effective connectivity, between the HC and other DMN nodes remains unknown. We used resting-state fMRI and conditional Granger causality analysis (CGCA) to test the hypothesis that CRF positively predicts effective connectivity between the HC and other DMN nodes in healthy young adults.Twenty-six participants (ages 18-35 years) underwent a treadmill test to determine CRF by estimating its primary determinant, maximal oxygen uptake (VO 2max ), and a 10-min resting-state fMRI scan to examine DMN effective connectivity. We identified the DMN using group independent component analysis and examined effective connectivity between nodes using CGCA. Linear regression analyses demonstrated that CRF significantly predicts causal influence from the HC to the ventromedial prefrontal cortex, posterior cingulate cortex, and lateral temporal cortex and to the HC from the dorsomedial prefrontal cortex. The observed relationship between CRF and Corey A. Kronman and Kathryn L. Kern share the first authorship.

Spatial navigation is a cognitive skill critical for accomplishing daily goal-directed behavior in a complex environment; however, older adults exhibit marked decline in navigation performance with age. Neuroprotective interventions that enhance the functional integrity of navigation-linked brain regions, such as those in the medial temporal lobe memory system, may preserve spatial navigation performance in older adults. Importantly, a well-established body of literature suggests that cardiorespiratory fitness has measurable effects on neurobiological integrity in the medial temporal lobes, as well as in other brain areas implicated in spatial navigation, such as the precuneus and cerebellum. However, whether cardiorespiratory fitness modulates brain activity in these regions during navigation in older adults remains unknown. Thus, the primary objective of the current study was to examine cardiorespiratory fitness as a modulator of fMRI activity in navigation-linked brain regions in cognitively healthy older adults. To accomplish this objective, cognitively intact participants (N = 22, aged 60–80 years) underwent cardiorespiratory fitness testing to estimate maximal oxygen uptake (V·O2max) and underwent whole-brain high-resolution fMRI while performing a virtual reality navigation task. Our older adult sample demonstrated significant fMRI signal in the right and left retrosplenial cortex, right precuneus, right and left inferior parietal cortex, right and left cerebellum lobule VIIa Crus I and II, right fusiform gyrus, right parahippocampal cortex, right lingual gyrus, and right hippocampus during encoding of a virtual environment. Most importantly, in women but not men (N = 16), cardiorespiratory fitness was positively associated with fMRI activity in the right cerebellum lobule VIIa Crus I and II, but not other navigation-linked brain areas. These findings suggest that the influence of cardiorespiratory fitness on brain function extends beyond the hippocampus, as observed in other work, to the cerebellum lobule VIIa Crus I and II, a component of the cerebellum that has recently been linked to cognition and more specifically, spatial processing.

Background Cognitive aging is associated with impaired episodic memory formation (Small et al., 1999), which requires the neurocomputational process of pattern separation to disambiguate similar stimulus input. Pattern separation relies on the dentate gyrus (DG) (Yassa & Stark, 2011), a hippocampal subfield that is susceptible to age‐related change (Small et al., 2011). Cognitive aging is also associated with impaired performance on putative measures of behavioral pattern separation (Yassa et al., 2010), called mnemonic discrimination tasks in humans. Prior work using high‐resolution fMRI suggests that age‐related impairments in mnemonic discrimination are linked to aberrant activation patterns in the DG/CA3 (Yassa et al., 2010). Whereas aging is associated with impaired DG integrity and mnemonic discrimination ability, cardiorespiratory fitness is associated with enhanced DG integrity and improved mnemonic discrimination ability. Given that cardiorespiratory fitness has been positively linked to DG/CA3 integrity in young adults (Nauer et al., 2019), it is conceivable that in older adults, cardiorespiratory fitness will modulate age‐related changes in DG/CA3 activation, which in turn, will dampen age‐related impairments in mnemonic discrimination. Methods 18 older adults (55‐85 years) and 18 young adults (18‐35 years) underwent a submaximal treadmill test to estimate cardiorespiratory fitness and high‐resolution fMRI to examine hippocampal subfield BOLD signal during encoding and retrieval of a mnemonic discrimination task (MDT). Results In older adults, we found increased right DG/CA3 BOLD signal in incorrect mnemonic discrimination trials contrasted with correct mnemonic discrimination trials, specifically during stimulus retrieval. Additionally, in both young and older adults, we found that right DG/CA3 BOLD signal in the mnemonic discrimination fMRI contrast during stimulus encoding marginally significantly predicted MDT corrected accuracy. Finally, in both young and older adults, fitness significantly negatively predicted left DG/CA3 BOLD signal in the mnemonic discrimination fMRI contrast during stimulus retrieval. Conclusions These results suggest that DG/CA3 BOLD signal relates to performance on a MDT designed to tax pattern separation, and that cardiorespiratory fitness modulates BOLD signal in these subregions. Altogether, these results suggest a link between fitness, DG/CA3 functional integrity, and mnemonic discrimination that may be critical to understanding how to dampen age‐related impairments in episodic memory.

Cognitive aging is associated with reduced integrity of the medial temporal lobe memory system. A key facet of episodic memory that demonstrates behavioral impairment with aging is pattern separation (PS), or the disambiguation of similar stimuli during neural encoding. PS is supported by the dentate gyrus (DG), a subfield of the hippocampus that demonstrates striking plasticity in response to exercise. Recent work from our laboratory has demonstrated that increasing cardiorespiratory fitness (CRF) through exercise training is associated with increased left anterior DG/CA3 volume and improved PS task performance in young adults. However, how these variables interact in cognitive aging is unknown, yet critical, given that aging is associated with impairments in hippocampal plasticity and PS task performance. Based on our findings in young adults, we predicted that CRF would positively correlate with DG/CA3 volume and PS task performance in older adults. Secondly, given the suggested role of the DG in PS task performance in humans, we predicted that DG/CA3 volume would significantly correlate with PS task performance. Sixty‐four participants aged 55–85 years underwent a submaximal treadmill test to estimate maximal oxygen uptake (VO2MAX), which operationally defined CRF, an MRI scan to examine volume of the hippocampal subfields, and a behavioral task designed to tax PS at parametrically varying levels of stimulus similarity (10, 30, 50%). There was a significant effect of similarity on PS task performance, with participants demonstrating lowest task accuracy in the condition theoretically placing the highest taxation on PS (50%). Left DG/CA3 body volume significantly predicted performance in the 50% condition. However, there was no relationship between CRF and PS task performance. Furthermore, while CRF did not predict DG/CA3 volume, it did significantly predict right and left subiculum volume, which may be unique to female participants between the ages of 60–80 years. Altogether, these findings provide support for a role of the DG in PS in older adults and suggest a relationship between CRF and hippocampal subfield volume that may be unique to the bilateral subiculum in female older adults. Support or Funding Information This work was supported by NIH grant R00 AG036845 (Schon), R21 AG049968 (Schon), and the BU Clinical and Translational Science Institute (1UL1TR001430).