Causal probing of slow oscillations in rodent models of Alzheimer´s disease: combining optogenetics with multimodal opto-acousto-magnetic imaging

• Applicants: Professor Dr. Albrecht Stroh; Professor Dr. Gil Westmeyer; Privatdozent Xin Yu, Ph.D.
• Subject Area: Anatomy and Physiology ; Cognitive, Systems and Behavioural Neurobiology
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 322164672

Here, the proposed study aims at causally investigating an oscillatory neuronal population activity highly relevant to maintaining cognitive function: the slow oscillation. Slow oscillations of membrane potential in the frequency range below 1 Hz play a major role in memory consolidation. Just recently, a causal link between the dysregulation of slow oscillations in a rodent model of Alzheimer´s disease (AD) to normal network function and behavior could be demonstrated. However, for a truly causal understanding of the therapeutic and diagnostic potential of (dysregulated) slow oscillations in AD, we need to significantly further the available methodological toolbox, as proposed here in this troika collaborative effort. In our preliminary data, we have for the first time identified slow oscillations in brain-wide rodent neuroimaging data (fMRI) using combined Ca2+ recordings as a template, the critical prerequisite for the proposed study. However, we are far from understanding the complex relation of slow wave initiation and dysregulation with respect to disease progression. Importantly, up to now, the temporal sequence of the recruitment of brain circuits such as cortico-thalamic or cortico-hippocampal are not understood, as are the cell-type specificity of the dysregulation of slow oscillations, mainly due to methodological and conceptual roadblocks. Our proposed study, in a pioneering setting, will overcome these limitations and will for the first time causally explore the relation of slow oscillations, recruitment of brain circuits, and disease progression, using highly innovative and complementary imaging methods: 1) applying fast sequences in fMRI to resolve the propagating slow oscillation with a velocity of about 30 mm/s, 2) Developing novel opto-acoustic methods to complement the fMRI approaches, with the potential of an even faster readout, 3) Combining fMRI and optoacoustic approaches with optic-fiber based optogenetics and neuronal Ca2+ recordings, in a closed-loop optogenetic recovery approach, all in a rodent model of AD. The proposed project is driven by the need to address a fundamental question in translational neuroscience, requiring a causal interrogation of neuronal networks and the unique expertise of the PIs and pioneering methodological pedigree.Our common goal is to causally explore an oscillation key to fundamental processes such as memory consolidation; our findings will have true translational value, potentially leading to both, novel diagnostics and novel therapeutic strategies in neurodegenerative disorders such as AD, based on a novel network-centered view.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1665: Resolving and Manipulating Neuronal Networks in the Mammalian Brain - From Correlative to Causal Analysis