The Human Dentate Gyrus Plays a Necessary Role in Discriminating New Memories

Abstract

Episodic memory provides us with the ability to re-experience unique events in rich detail. For this to occur, we must be able to 1) behaviorally "pattern separate" or discriminate new from old experiences, and 2) "pattern complete" or reinstate memories from partial cues. I report a rare individual with a specific lesion to the dentate gyrus of his hippocampus who has difficulty distinguishing between studied targets and unstudied lures that are visually similar. In addition, he displays a heightened tendency to recognize studied scenes from degraded pictures. These results provide the first direct evidence in humans that discriminating new memories cannot wholly function without an intact dentate gyrus and that this mnemonic ability is dissociable from, but likely interacts with, completion processes in the CA3 subfield of the hippocampus.iii Acknowledgements

Focal CA3 hippocampal subfield atrophy following LGI1 VGKC-complex antibody limbic encephalitis

“…CA3 is also associated with the capacity to reconstruct and recall distinctive, precise details of newly acquired episodic memories (Chadwick et al , 2014), and these operations can be assessed with extended assays of autobiographical episodic memory such as the autobiographical interview (Levine et al , 2002; Addis et al , 2007). The loss of internal detail on the autobiographical interview likely reflected a loss of such CA3-mediated features of episodic memory, and is compatible with evidence that focal lesions involving human CA1 or the dentate gyrus (Bartsch et al , 2011; Baker et al , 2016), the other two subfields of hippocampal trisynaptic circuit that subtends episodic memory, are sufficient to induce severe episodic amnesia. Future studies will need to address the impact of the observed focal atrophy on other CA3-mediated reconstructive, computational, and episodic mechanisms alongside work identifying the specific pathomechanisms in humans, because these data will be key to developing optimized approaches to prevention, detection, intervention, and clinical management.…”

“…Focal lesions in CA1 have been associated with transient epileptic amnesia (Bartsch et al , 2011), whereas in a recent case study involving hypoxic-ischaemic brain injury, the lesion profile was confined to the bilateral dentate gyrus and a portion of CA3 (Baker et al , 2016). In both cases, the subfield lesions were associated with episodic amnesia (Bartsch et al , 2011; Baker et al , 2016).…”

“…Focal lesions in CA1 have been associated with transient epileptic amnesia (Bartsch et al , 2011), whereas in a recent case study involving hypoxic-ischaemic brain injury, the lesion profile was confined to the bilateral dentate gyrus and a portion of CA3 (Baker et al , 2016). In both cases, the subfield lesions were associated with episodic amnesia (Bartsch et al , 2011; Baker et al , 2016). To our knowledge, pathology confined to human CA3 has not been previously reported in vivo , but evidence from molecular imaging in a rodent model and functional MRI in humans indicates CA3 activity is associated with episodic retrieval (Bonnici et al , 2013; Lux et al , 2016).…”

“…In addition, whole-brain, voxel-by-voxel morphometry was conducted on high-resolution (600 µm isotropic) T 1 -weighted images to test for grey matter reductions across the rest of the brain. Finally, to the extent that CA3 interacts with CA1 and the dentate gyrus to support episodic memory (Baker et al , 2016), we tested the hypothesis that CA3 and/or CA1 atrophy would be linked with selective deficits in the retrieval of experiential, first person components of episodic but not semantic memory detail for the same event.…”

Integrating new findings and examining clinical applications of pattern separation

“…Recently, ultrahigh-resolution 7T fMRI was used to demonstrate that the DG, but not other hippocampal subfields or medial temporal cortices, exhibits distinct neural patterns for similar items, thus suggesting that the human DG is perhaps selectively engaged in pattern separation 57 . Interestingly, patient B.L., a 54-year-old man with selective bilateral ischemic lesions to the DG subregion of the hippocampus, was found to have impaired performance on a mnemonic discrimination task, which further suggests that the DG is required for pattern separation 58 .…”