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C3 - Dependency of inter-areal functional connectivity as assessed by fMRI on network oscillations

Principal investigator(s):

Klinik für Psychiatrie und Psychotherapie
Medizinische Fakultät Mannheim, Universität Heidelberg
Zentralinstitut für Seelische Gesundheit (ZI)
J5, D-68159 Mannheim


Projects within the BCCN:

Firstly, we successfully established optogenetic BOLD imaging (og-fMRI) at our 9.4 T high field animal scanning facility. This included investigations necessary to understand basic effects of stimulation and heating covarying with laser pulse protocols and laser power, changes of the hemodynamic response function with og-fMRI, as well as establishing complex post-processing protocols. Three substeps had been necessary to achieve a valid establishment of og-fMRI: 1) Establishing resting state fMRI (rs-fMRI) of the default network and of PFC-HC networks (Schwarz et al. 2013a; Schwarz et al. 2013b). We systematically characterized the rat brain connectivity signature derived from low-frequency resting blood oxygenation level-dependent (BOLD) oscillations associated with and within the hippocampal-prefrontal network, using an array of small seed locations within the relatively large anatomical structures comprising this system. Inter alia an analogous system to the human default mode network including posterior cingulate and anterior cingulate/medial-prefrontal cortex was identified. 2) Establishing of group statistics for optogenetic fMRI (og-fMRI; Lebhardt et al. 2016). For the first time, we employed this technique for studying the brain response to stimulation of the mouse hippocampus. A viral vector expressing the light-sensitive channel Channelrhodopsin-2 (ChR2) was injected into the left hippocampus of mice (N=10). ChR2 expression was restricted to glutamatergic cells. Functional magnetic resonance imaging was performed during local laser stimulation. We compared trains of light pulses repeated for short (1s) and long (30s) durations (“burst“ vs. “block” design). The burst stimulation was used to study the hemodynamic response function (HRF). The hemodynamic response in the mouse hippocampus had an earlier peak and a shorter duration compared to those observed in humans. Photostimulation was associated with significantly increased BOLD signal in the ipsilateral hippocampus and the septum. Compared to the block design, burst stimulation yielded more widespread BOLD activation, also including the contralateral hippocampus, nucleus accumbens and amygdala. In conclusion, the anatomical distribution of signal changes depends on the temporal pattern of the laser application. The characterization of the HRF in mouse hippocampus may enable more precise interpretation of future fMRI experiments. 3) Establishing optogenetic functional connectivity fMRI (og-FC-fMRI) in the rat. We used the chance to test animals carrying an optogenetically modified oxytocinergic network for this purpose (by courtesy of V. Grinevich). To selectively excite oxytocin neurons and their axons recombinant adeno-associated virus (channelrhodopsin-2-mCherry driven by 2.6kb oxytocin promoter) were injected into the hypothalamic nuclei (paraventricular, supraoptic and accessory nuclei). Meanwhile, we improved group analysis of our experiments with hippocampal optogenetic stimulation: We used multiregion psychophysiological interaction (PPI) modeling, a well-established technique that can be used to determine whether the connectivity between a pair of regions increases during a given context or task. In our context, we took LASER stimulation ON as a task. Furthermore, we applied graph theory analysis as a methodology to obtain information of local and global network changes with oxytocinergic og-fMRI after LASER stimulation of the amygdala and the hypothalamic nuclei.
Finally, we performed og-fMRI in Negative Cognitive State rats, a model of treatment-resistant depression. An inhibitory light-sensitive ion channel was introduced into the lateral habenula (LHb) by viral transduction. Neural activity and connectivity were assessed before, during and after laser stimulation. In this animal model a connectivity decrease in the default mode network (DMN) was observed, following laser-induced LHb perturbation, which indicates a causal link between LHb down-regulation and reduction in DMN connectivity.
Beyond two pending specific publications, we expect that our results will lead to advances of our mechanistic understanding of LHb inhibition as a promising therapeutic principle. This could reinforce the idea of a highly specific intervention ameliorating so far treatment-resistant depression.

Participating groups:

Key publications:

Lebhardt P, Hohenberg CC, Weber-Fahr W, Kelsch W, Sartorius A (2016) Optogenetic fMRI in the mouse hippocampus: hemodynamic response to brief glutamatergic stimuli J Cereb Blood Flow Metab. 2016 Mar;36(3):629-38 .
Schwarz AJ, Gass N, Sartorius A, Zheng L, Spedding M, Schenker E, Risterucci C, Meyer-Lindenberg A, Weber-Fahr W (2013) The low-frequency blood oxygenation level-dependent functional connectivity signature of the hippocampal-prefrontal network in the rat brain Neuroscience. 2013 Jan 3;228:243-58 .
Schwarz AJ, Gass N, Sartorius A, Risterucci C, Spedding M, Schenker E, Meyer-Lindenberg A, Weber-Fahr W (2013) Anti-correlated cortical networks of intrinsic connectivity in the rat brain Brain Connect. 2013;3(5):503-11 .