Neurocognitive mechanisms and pathological impairments of pattern separation processes in the human hippocampus

• Applicant: Aarti Swaminathan, Ph.D.
• Subject Area: Human Cognitive and Systems Neuroscience ; Cognitive, Systems and Behavioural Neurobiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 549665162

The crucial role of dentate gyrus in encoding and retrieval of hippocampal-dependent memories has been widely investigated in rodents. Many studies have also explored the neural mechanisms of how the hippocampus distinguishes similar experiences. Multisensory information from the entorhinal cortex is streamlined by sparsely-firing granule cells in the dentate gyrus (DG), the main input structure of the hippocampus, via the process of ‘pattern separation’. The pattern separation in the DG enables the hippocampus to disentangle similar memories and is complemented by ‘pattern completion’ in the recurrent networks of the CA3 region, whereby memory traces are retrieved from partial or noisy cues. Recent studies in rodents have started to investigate the role of the neighboring hilar region, especially the excitatory mossy cells, in the DG-CA3 network. However, it is much less clear whether similar network mechanisms play a role in humans, partly because of the difficulty in obtaining direct electrophysiological recordings from the human hippocampus. Functional magnetic resonance imaging (fMRI) studies in healthy participants and first evidence from intracranial EEG (iEEG) studies in presurgical epilepsy patients have revealed specific reactivations in the hippocampus and neocortex during a mnemonic discrimination task. Hippocampal ripples, known to occur during sleep and waking states, are prominent synchronous oscillations (80-140 Hz in humans) involved in the consolidation of episodic memories. The influence of ripples during pattern separation and their interaction with stimulus specific network patterns and with oscillations in the theta/gamma frequency range are still largely unknown. We propose to study hippocampal and cortical activity during a pattern separation task in presurgical patients using iEEG. Specifically, we will address three fundamental questions: First, we will study the stimulus-specific representations during the encoding and recall phases of a mnemonic discrimination task involving associative learning and their relationship to oscillations in the theta/gamma band and ripples. Second, we will conduct microelectrode recordings to assess single-neuron activity and investigate its relationship to the ongoing population activity assessed with iEEG. Third, given the occurrence of hyper-excitation and pathological ripples in the hippocampal network in temporal lobe epilepsy (TLE), we will elucidate possible differences in encoding and retrieval between the healthy and the epileptic hemispheres in unilateral temporal lobe epilepsy. Understanding the cellular and network mechanisms underlying memory in humans and their impairment during epilepsy will provide us important insights into the neural foundations of human memory in health and disease.

• DFG Programme: WBP Position