Exercise and Hippocampal Memory Systems

Abstract

No medications prevent or reverse age-related cognitive decline. Physical activity (PA) enhances memory in rodents, but findings are mixed in human studies. As a result, exercise guidelines specific for brain health are absent. Here, we re-examine results from human studies, and suggest the use of more sensitive tasks to evaluate PA effects on age-related changes in the hippocampus, such as relational memory and mnemonic discrimination. We discuss recent advances from rodent and human studies into the underlying mechanisms at both the central and peripheral levels, including neurotrophins and myokines that could contribute to improved memory. Finally, we suggest guidelines for future research to help expedite well-founded PA recommendations for the public.

Keywords: aging; growth factors; hippocampus; myokines; neurogenesis; pattern separation; physical activity; relational memory.

Figure 1, Key Figure:. Human PA and fitness affect hippocampal memories and networks

(A) Bar graph shows the proportion of statistically significant effects in favor of improved memory for aerobic compared to control groups in training studies with older adults. Ratios indicate absolute number of positive effects relative to all studies. See SI IV-V for more information. (B) In non-spatial relational tasks, letters symbolize items, which could take the form of words, faces, scenes, etc. Participants are tested for memory of relations compared to recombined or novel pairs. The spatial relational reconstruction task requires retrieval of object-location pairs and inter-relations. A signature error involves swapping item identity with correct locations [162]. Mnemonic discrimination tasks test memory precision. Participants incidentally encode objects and are tested on memory for repeats (targets), similar objects (lures), or new objects (foils) [39, 163, 164]. (C) Association networks modified by aging and PA. Network links and bar graphs are colored according to network. Links show connections within each network. Only the default network includes aspects of the hippocampal and medial temporal lobe memory system, as approximated in the oval inset. The figure to the right of the inset illustrates a different view of the relative positioning of medial temporal lobe structures (ph, parahippocampus; erc, entorhinal cortex; prc, perirhinal cortex). The dentate gyrus and CA sub-regions are coiled together along the long axis of the hippocampus. Young>Old functional connectome indicates the links that were stronger for young adults [76], and the bar graph shows the percentage of links within each network in favor of young adults. The functional connectome below shows links that were stronger with greater fitness, and the bar graph shows the percentage of links within each network having a positive association with fitness. Of all the networks with connections that are weaker for older adults, the hippocampal-cortical default network had the greatest percentage (15.38%) that were stronger with greater fitness [76].

Figure 2:. Effects of PA on hippocampal circuits and pattern separation in mice.

In mice voluntary wheel running increases the number of new hippocampal neurons and modifies their network. (A) Using viral vectors to trace the structures that project directly to adult-born neurons it was observed that running enhances entorhinal cortex innervation of adult-born dentate granule cells [58]. Control and running afferent circuitry are depicted in a 3D reconstruction of photomicrographs taken throughout the dorso-ventral extent of hippocampal-entorhinal cortex slices derived from young adult male mice. In control conditions, afferent traced cells (labeled with rabies virus expressing MCherry, red) that project directly to new neurons, are observed in the lateral entorhinal cortex (LEC) and perirhinal cortex (PRC), and only sparsely in the caudomedial entorhinal cortex (CEnt). Exercise increases the input from the CEnt and LEC onto the adult-born granule cells. Nuclei are stained with 4′,6-diamidino-2-phenylindole (DAPI), blue [58]. (B) LEC input to new neurons is important for pattern separation. (B, C) Mice are trained in the touchscreen to distinguish between two identical stimuli spaced apart (big) closely together (small) to evaluate pattern separation. The ability to differentiate which icon is associated with reward in the more challenging, small separation condition, is (B) reduced following LEC lesion [48], and (C) enhanced by running [53]. (D) Model showing the relative contribution of the regions that directly innervate adult-born granule cells under control and exercise conditions [58].