Pathologic features of sharp-wave ripples in the hippocampus of rodents and epilepsy patients - a biomarker for memory impairment and a target for memory repair

• Applicant: Dr. Anna Maslarova
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology ; Experimental and Theoretical Network Neuroscience
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 512713434

Significance: Deep brain stimulation provides a neurosurgical treatment option for several psychiatric diseases. Most of the currently implemented stimulation protocols merely inhibit neuronal signal propagation in an all-or-none manner and therefore the results are hardly superior to those of lesional techniques. Recently, however, more targeted modulation of neuronal oscillations timed to identified frequencies of the EEG signal has been highly efficient in treating depression. In rodents, targeted modulation of neuronal oscillations related to memory has been successfully used to boost memory performance. However, it remains to be revealed whether such modulation can also recover impaired memory. Project: The current project aims to identify components of the hippocampal network oscillations that are altered in conditions affecting memory performance and can therefore serve as targets for modulation with electric stimulation. The project is based on a combined approach of an animal model of memory impairment and intracranial EEG (iEEG) from patients suffering from epilepsy. The focus is on hippocampal sharp-wave-ripple (SWR) oscillations, which are known to play a crucial role in memory encoding and retrieval. In patients suffering from drug-resistant focal epilepsy and non-identifiable epileptogenic lesion by non-invasive techniques, iEEG is used to localize the seizure onset zone and plan surgical resection. Such recordings from the hippocampus, which is crucially involved in long-term memory formation, provide an opportunity to study local-field potentials and single-neuron activity related to hippocampal information processing. Memory-related ripples have been recorded in human hippocampus in the intervals between interictal events. However, most studies so far have failed to assign the recordings to a specific hippocampal subregion, which is due to poor recording site localization techniques in humans. One part of this project will be to challenge poor localization by designing a region classifier based on recordings from identified regions in mouse iEEG, utilizing local-field potential and neuronal firing patterns specific to these regions and adapt the classifier to predict recording sites in human iEEG (data is available from the database of the Epilepsy Center at University Hospital Erlangen, Germany). This will allow to look for specific characteristics of SWRs in identified regions of the human hippocampus. The second part of the project will focus on putative neurophysiologic markers of memory impairment: 1) in a mouse model of Alzheimer’s Disease 2) in human iEEG from epilepsy patients. Whether modulation of these parameters can influence behavior and memory performance, will be investigated in mice using optogenetic closed-loop stimulation.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Gyorgy Buzsaki, Ph.D.