Longitudinal Characterization and Biomarkers of Age and Sex Differences in the Decline of Spatial Memory

Abstract

The current longitudinal study examined factors (sex, physical function, response to novelty, ability to adapt to a shift in light/dark cycle, brain connectivity), which might predict the emergence of impaired memory during aging. Male and female Fisher 344 rats were tested at 6, 12, and 18 months of age. Impaired spatial memory developed in middle-age (12 months), particularly in males, and the propensity for impairment increased with advanced age. A reduced response to novelty was observed over the course of aging, which is inconsistent with cross-sectional studies. This divergence likely resulted from differences in the history of environmental enrichment/impoverishment for cross-sectional and longitudinal studies. Animals that exhibited lower level exploration of the inner region on the open field test exhibited better memory at 12 months. Furthermore, males that exhibited a longer latency to enter a novel environment at 6 months, exhibited better memory at 12 months. For females, memory at 12 months was correlated with the ability to behaviorally adapt to a shift in light/dark cycle. Functional magnetic resonance imaging of the brain, conducted at 12 months, indicated that the decline in memory was associated with altered functional connectivity within different memory systems, most notably between the hippocampus and multiple regions such as the retrosplenial cortex, thalamus, striatum, and amygdala. Overall, some factors, specifically response to novelty at an early age and the capacity to adapt to shifts in light cycle, predicted spatial memory in middle-age, and spatial memory is associated with corresponding changes in brain connectivity. We discuss similarities and differences related to previous longitudinal and cross-sectional studies, as well as the role of sex differences in providing a theoretical framework to guide future longitudinal research on the trajectory of cognitive decline. In addition to demonstrating the power of longitudinal studies, these data highlight the importance of middle-age for identifying potential predictive indicators of sexual dimorphism in the trajectory in brain and cognitive aging.

Reversing age: dual species measurement of epigenetic age with a single clock

“…The decline of cognitive function is a well-characterized feature of increasing age. Learning and memory, which are constituent characteristics of cognitive functions, decline not only in human but also in rats, starting from 12 months of age 38 . Barnes maze was used to measure the latency period required by the rats to escape through the right hole into an escape box.…”

Contextual experience modifies functional connectome indices of topological strength and organization

“…It is well established that the frequency bandwidth of spontaneous BOLD signal oscillations falls within previously characterized infraslow frequencies (<0.5) that cover a large expanse of rat cortex (60,61). Studies in primate visual cortex have also shown that normalized spectral frequencies in the band limited power for gamma (40-100Hz) share a high degree of statistical dependency (mutual information) with the fMRI BOLD signal while alpha (8)(9)(10)(11)(12) Hz), beta (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and higher frequency (0.9-3kHz) multi-unit activity much less so (62).…”

“…The paradigm used here did not generate a memory 'response' by the rats prior or after scanning and this weakens the direct linkage between the network differences between groups and their role in memory structure in the brain. Regarding the experimental paradigm itself, we have previously applied better validated and more system selective experimental paradigms for assessing learning and memory that allowed a priori hypothesis testing of the brain regions involved in memory processing (20,21). We anticipate future studies using similar paradigms here but with the added modification that the memory-retrieving process or the memory-signaling behavior be carried out or measured during a short temporal delay prior to imaging.…”

“…An index of rich club organization, which reflects the presence of a small group of very high degree 'hub' nodes, was observed to be greater in aged versus young male rats, and increased as a function of cognitive training (20). Longitudinal decline in memory was linked to changes in functional connectivity between the dorsal hippocampus and retrosplenial cortex, thalamus, striatum, and amygdala (21). In a study using optimal percolation theory to quantify the collective influence of hub nodes in male rat fMRI networks, Del Ferraro et al (2018) observed that hippocampal CA3-CA1 long-term potentiation (LTP) caused a potent global integration of brain BOLD activation which was weakened by elimination of a low degree node such as the nucleus accumbens (22).…”

Contextual experience modifies functional connectome indices of topological strength and efficiency

“…cortex, thalamus, striatum, and amygdala 19 . In a study using optimal percolation theory to quantify the collective influence of hub nodes in male rat fMRI networks, Del Ferraro et al observed that hippocampal CA3-CA1 long-term potentiation (LTP) caused a potent global integration of brain BOLD activation which was weakened by elimination of a low degree node such as the nucleus accumbens 20 .…”