Domain selectivity and age-related vulnerability in the human medial temporal lobes
The medial temporal lobes (MTL) comprise a set of brain regions known to be critical for the formation of memories. Different regions of the MTL support distinct aspects of experience, with the perirhinal and lateral entorhinal cortices comprising a “what” information pathway supporting local features (such as objects), and the parahippocampal and medial entorhinal cortices comprising a “where” pathway supporting configurational features (such as space or context). Importantly, both pathways converge on the hippocampus, where domain-general pattern separation has been hypothesized to occur.. These regions – chiefly perirhinal and lateral entorhinal cortices – are known to be susceptible to the earliest stages of age-related neuropathology. An understanding the distinct contributions of the regions of the MTL will help to elucidate their function in the service of memory, as well as their roles in age-related cognitive decline. However, evidence for functional subdivisions of the human entorhinal cortex, their contributions to hippocampal computations such as pattern separation, and their roles in neurocognitive aging is severely lacking.
In a series of behavioral and functional magnetic resonance imaging (MRI) experience, we sought to fill these gaps in knowledge. First, in a behavioral experiment, we developed a spatial mnemonic discrimination paradigm, modeled after work in rodents studying pattern separation. This complemented prior object discrimination paradigms studying human memory, and showed age-related deficits consistent with a decline in pattern separation ability. Next, in a high-resolution functional MRI study, we used an object vs. spatial mnemonic discrimination paradigm to show dissociable functional roles of lateral and medial entorhinal cortex in human subjects. We next used the object vs. spatial paradigm to investigate whether cognitively normal aging asymmetrically affected performance on the two tasks. We found that older adults are relatively more impaired at object than spatial discrimination, consistent with selective vulnerability of perirhinal and/or lateral entorhinal cortices. Finally, in a high-resolution functional MRI study, we replicated the aforementioned selective object discrimination deficits, and furthermore demonstrated associated hypoactivity in the lateral entorhinal cortex. We additionally replicated prior reports of hyperactivity in the dentate/CA3 subfields of the hippocampus, and furthermore found that the ratio of relative activity between dentate/CA3 and lateral entorhinal cortex predicted the extent of object discrimination impairment. In sum, the studies presented here provide novel evidence for dissociable functional roles of lateral and medial entorhinal cortex in humans, and suggest that the lateral entorhinal cortex-dentate/CA3 circuit is selectively disrupted in aging.