Recent models of episodic memory propose a division of labor among medial temporal lobe cortices comprising the parahippocampal gyrus. Specifically, perirhinal and lateral entorhinal cortices are thought to comprise an object/item information pathway, whereas parahippocampal and medial entorhinal cortices are thought to comprise a spatial/contextual information pathway. Although several studies in human subjects have demonstrated a perirhinal/parahippocampal division, such a division among subregions of the human entorhinal cortex has been elusive. Other recent work has implicated pattern separation computations in the dentate gyrus and CA3 subregions of the hippocampus as a mechanism supporting the resolution of mnemonic interference. However, the nature of contributions of medial temporal lobe cortices to downstream hippocampal computations is largely unknown. We used high-resolution fMRI during a task selectively taxing mnemonic discrimination of object identity or spatial location, designed to differentially engage the two information pathways in the medial temporal lobes. Consistent with animal models, we demonstrate novel evidence for a domain-selective dissociation between lateral and medial entorhinal cortex in humans, and between perirhinal and parahippocampal cortex as a function of information content. Conversely, hippocampal dentate gyrus/CA3 demonstrated signals consistent with resolution of mnemonic interference across domains. These results provide insight into the information processing capacities and hierarchical interference resolution throughout the human medial temporal lobe.T he encoding of episodic memories is known to rely on a network of brain regions within the medial temporal lobes (MTL) (1). Past models of episodic memory have largely focused on the functional role of the hippocampus and its subregions. A wealth of recent evidence has implicated pattern separation, a computation by which overlapping inputs are orthogonalized into nonoverlapping outputs, as a key process in resolving interference among similar memories (2). This computation is widely thought to occur as a function of sparse firing patterns of granule cells of the hippocampal dentate gyrus (DG), which form powerful mossy fiber synapses with large numbers of pyramidal cells in subregion CA3 (3-6). A critical role for the DG in orthogonalizing interfering inputs has been demonstrated in animal studies by using lesions (7-9), NMDA receptor knockouts (10), electrophysiological recordings (11, 12), and human functional MRI (13-15).Numerous studies have provided evidence for selective information processing in cortical areas that project to the hippocampus. Much of this research has focused on perirhinal cortex (PRC) and parahippocampal cortex (PHC, postrhinal in the rat). PRC has been shown to be critical for memory of item or object information, whereas PHC has been shown to play a role in memory of contextual or spatial information both in rats (16-18) and in humans (19)(20)(21). These dissociations are consistent with diff...

The entorhinal cortex (EC) is among the earliest brain areas to deteriorate in Alzheimer's disease (AD). However, the extent to which functional properties of the EC are altered in the aging brain, even in the absence of clinical symptoms, is not understood. Recent human fMRI studies have identified a functional dissociation within the EC, similar to what is found in rodents. Here, we used high-resolution fMRI to identify a specific hypoactivity in the anterolateral EC (alEC) commensurate with major behavioral deficits on an object pattern separation task in asymptomatic older adults. Only subtle deficits were found in a comparable spatial condition, with no associated differences in posteromedial EC between young and older adults. We additionally linked this condition to dentate/CA3 hyperactivity, and the ratio of activity between the regions was associated with object mnemonic discrimination impairment. These results provide novel evidence of alEC-dentate/CA3 circuit dysfunction in cognitively normal aged humans.

There is accumulating evidence that the entorhinal-hippocampal network is important for temporal memory. However, relatively little is known about the precise neurobiological mechanisms underlying memory for time. In particular, whether the lateral entorhinal cortex is involved in temporal processing remains an open question. During high-resolution fMRI scanning, participants watched a ~30-minute episode of a television show. During test, they viewed still-frames and indicated on a continuous timeline the precise time each still-frame was viewed during study. This procedure allowed us to measure error in seconds for each trial. We analyzed fMRI data from retrieval and found that high temporal precision was associated with increased BOLD fMRI activity in the anterolateral entorhinal (a homologue of the lateral entorhinal cortex in rodents) and perirhinal cortices, but not in the posteromedial entorhinal and parahippocampal cortices. This suggests a novel role for the lateral entorhinal cortex in processing of high-precision minute-scale temporal memories.

Physical exercise has beneficial effects on neurocognitive function, including hippocampus-dependent episodic memory. Exercise intensity level can be assessed according to whether it induces a stress response; the most effective exercise for improving hippocampal function remains unclear. Our prior work using a special treadmill running model in animals has shown that stress-free mild exercise increases hippocampal neuronal activity and promotes adult neurogenesis in the dentate gyrus (DG) of the hippocampus, improving spatial memory performance. However, the rapid modification, from mild exercise, on hippocampal memory function and the exact mechanisms for these changes, in particular the impact on pattern separation acting in the DG and CA3 regions, are yet to be elucidated. To this end, we adopted an acute-exercise design in humans, coupled with high-resolution functional MRI techniques, capable of resolving hippocampal subfields. A single 10-min bout of very light-intensity exercise (30%V˙O2peak) results in rapid enhancement in pattern separation and an increase in functional connectivity between hippocampal DG/CA3 and cortical regions (i.e., parahippocampal, angular, and fusiform gyri). Importantly, the magnitude of the enhanced functional connectivity predicted the extent of memory improvement at an individual subject level. These results suggest that brief, very light exercise rapidly enhances hippocampal memory function, possibly by increasing DG/CA3−neocortical functional connectivity.

Previous studies across species have established that the aging process adversely affects certain memory-related brain regions earlier than others. Behavioral tasks targeted at the function of vulnerable regions can provide noninvasive methods for assessing the integrity of particular components of memory throughout the lifespan. The present study modified a previous task designed to separately but concurrently test detailed memory for object identity and spatial location. Memory for objects or items is thought to rely on perirhinal and lateral entorhinal cortices, among the first targets of Alzheimer’s related neurodegeneration. In line with prior work, we split an aged adult sample into “impaired” and “unimpaired” groups on the basis of a standardized word-learning task. The “impaired” group showed widespread difficulty with memory discrimination, whereas the “unimpaired” group showed difficulty with object, but not spatial memory discrimination. These findings support the hypothesized greater age-related impacts on memory for objects or items in older adults, perhaps even with healthy aging.