Optogenetische Kontrolle von epileptischen Anfällen in einem mittels simultaner Kalzium-Messung und fMRT kartierten Netzwerk
Molekulare Biologie und Physiologie von Nerven- und Gliazellen
Zusammenfassung der Projektergebnisse
Epilepsy is regarded as brain network disease. We instituted multimodal methods, fMRI, optical, fiber-based Ca2+ recordings, parallel electrophysiological slice experiments and immunohistochemistry to characterize the epileptic brain network in a spontaneous rat absence epilepsy model, the Genetic Absence epilepsy rat from Strasbourg (GAERS). The ultimate goal was to identify potential epileptic hubs and probe these targets by optogenetic stimulation in order to control seizures in this model. Simultaneous Ca2+ recordings during resting state (rs)-fMRI acquisition allowed for unambiguous identification of brain states: the pre-seizure state and the seizure state. Based on standard BOLD fMRI and one-dimensional line scanning data, a hemodynamic response function appropriate for the analysis of seizure activity in the rat brain was established. Graph theoretical analysis of rs-fMRI data allowed for identification of acute and chronic network changes. The most prominent acute change in network organization during seizures was the segregation of cortical regions from the remaining brain. Subtle differences were observed for retrosplenial cortex (RS), forming more connections beyond cortex in epileptic rats and showing a tendency to lateralization during seizures. A potential role of RS as hub between subcortical and cortical regions in epilepsy was supported by increased numbers of parvalbumin-positive (PV+) interneurons together with enhanced inhibitory synaptic activity and neuronal excitability in pyramidal neurons. General differences in brain networks of GAERS and NEC were already apparent at 3 months of age in the longitudinal rs-fMRI study. Functional brain mapping with manganese-enhanced MRI (MEMRI) indicated involvement of thalamus, basal ganglia, and limbic regions during frequently reoccurring absence seizures in this rat model. Although reliable BOLD responses could be evoked by light stimulation of excitatory opsins ChR2, C1V1, and ultrafast opsins we did not succeed in controlling seizure activity by targeting either the perioral region of the sensory cortex or the RS yet. Light intensities necessary to activate the inhibitory opsin ArchT caused heating artifacts. Targeting inhibitory neurons represent a further strategy, however, commercially available viral constructs with promotors specific for interneurons are rare. Targeting basal ganglia and limbic regions with excitatory opsins remain promising strategies for future experiments.
Projektbezogene Publikationen (Auswahl)
- (2018) Line scanning fMRI reveals earlier onset of optogenetically evoked BOLD response in rat somatosensory cortex as compared to sensory stimulation. NeuroImage,164, 144-154
Albers F, Schmid F, Wachsmuth L, Faber C
(Siehe online unter https://doi.org/10.1016/j.neuroimage.2016.12.059) - (2018). Modulation of Hyperpolarization-Activated Inward Current and Thalamic Activity Modes by Different Cyclic Nucleotides. Frontiers in Cellular Neuroscience, 12: 369
Datunashvili M, Chaudhary R, Zobeiri M, Lüttjohann A, Mergia E, Baumann A, Balfanz S, Budde B, van Luijtelaar G, Pape HC, Koesling D, Budde T
(Siehe online unter https://doi.org/10.3389/fncel.2018.00369) - (2018). Multimodal functional neuroimaging by simultaneous BOLD fMRI and fiber-optic calcium recordings and optogenetic control. Molecular Imag. and Biol., 2018 20(2):171-182
Albers F, Wachsmuth L, van Alst TM, Faber C
(Siehe online unter https://doi.org/10.1007/s11307-017-1130-6) - Balfanz S, Meuth P, Chetkovich DM, Pape HC, Baumann A, van Luijtelaar G, Budde T (2018) Modulation of thalamocortical oscillations by TRIP8b, an auxiliary subunit for HCN channels. Brain Struct Funct. 2018 Apr;223(3):1537-1564
Zobeiri M, Chaudhary R, Datunashvili M, Heuermann RJ, Lüttjohann A, Narayanan V, Balfanz S, Meuth P, Chetkovich DM, Pape HC, Baumann A, van Luijtelaar G, Budde T
(Siehe online unter https://doi.org/10.1007/s00429-017-1559-z) - (2019) Anesthesia differentially modulates neural and vascular contributions to the BOLD Signal. NeuroImage, 195: 89-103
van Alst T, Wachsmuth L, Datunashvili M, Albers F, Just N, Budde T, Faber, C
(Siehe online unter https://doi.org/10.1016/j.neuroimage.2019.03.057) - (2019) Functional MRI readouts from BOLD and diffusion measurements differentially respond to optogenetic activation and tissue heating, Frontiers in Neuroscience-Brain Imaging Methods, Front. Neurosci., 2019 (10) |13:1104
Albers F, Wachsmuth L, Schache D, Lambers H, Faber C
(Siehe online unter https://doi.org/10.3389/fnins.2019.01104) - (2019) The Brain Network in a Model of Thalamocortical Dysrhythmia. Brain Connectivity, 9: 273-284
Zobeiri M, van Luijtelaar G, Budde T, Sysoev IV
(Siehe online unter https://doi.org/10.1089/brain.2018.0621) - (2020) A cortical rat hemodynamic response function for improved detection of BOLD activation under common experimental conditions, Neuroimage, 208: 116446
Lambers H, Segeroth M, Albers F, Wachsmuth L, Faber C
(Siehe online unter https://doi.org/10.1016/j.neuroimage.2019.116446) - (2020) Myelination- and immune-mediated MR- based brain network correlates. Journal of Neuroinflammation, 17: 186
Cerina M, Muthuraman M, Gallus M, Koirala N, Dik A, Wachsmuth L, Hundehege P, Schiffler P, Tenberge JG, Fleischer V, Gonzalez-Escamilla G, Narayanan V, Krämer J, Faber C, Budde T, Groppa S, Meuth
(Siehe online unter https://doi.org/10.1186/s12974-020-01827-z) - (2021) Retrosplenial cortex contributes to network changes during seizures in the GAERS absence epilepsy rat model. Cerebral Cortex Communications
Wachsmuth L, Datunashvili M, Kemper K, Franziska Albers F, Lambers H, Lüttjohann A, Kreitz S, Budde T, Faber C
(Siehe online unter https://doi.org/10.1093/texcom/tgab023)
