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Differential Involvement of Electrically Coupled Networks in Brain Oscillations

Final Report Summary - DIECNBO (Differential Involvement of Electrically Coupled Networks in Brain Oscillations)

It is generally accepted that the brain generates behaviour by the electrical activity of neurons. Still, the link between these two items remains largely unknown. The context of this project is the study of relationships between behaviour and electrical activity of neuronal assemblies, in the rodent.

The initial scientific objective of the outgoing period was to determine the impact of interneuron and pyramidal cell electrical coupling on hippocampal oscillations and spatial navigation in the rodent. During the first half of the outgoing phase, the first step of the objective was completed, and data analysis revealed that our main hypothesis was infirmed: brain oscillations and in particular, ripples) were not disrupted in mice permanently lacking either interneuron only, or interneuron and pyramidal cell electrical coupling, but showed only subtle changes in their current source density profile. This negative result, combined with a shortage in our supply of genetically modified mice, led to reconsider the feasibility of the rest of the outgoing phase's objective. At this point, new objectives were defined: addressing the question of the mechanisms of brain oscillations using an emerging powerful technique, optogenetics. The principle of this technique is to combine molecular tools (viral vectors), genetically modified animals, laser-stimulation through optic fibers and multi-channel recordings in the behaving animal to answer long standing questions that no traditional stimulation technique could have assessed before for lack of specificity.

Therefore, during the rest of the outgoing phase, we optimised cell-type specific expression of channelrhodopsin (a light-sensitive ion channel) into different septo-hippocampal neurons, using viral vectors and transgenic mice. We also developed a set-up to stimulate specifically this neuronal population while recording the hippocampal oscillations in vivo (in anesthetised, or awake head-restrained, or freely moving animals), by bringing laser-source light into the brain of the animal through optic fibers, or homemade 'optrodes' (an optic fiber attached to a silicon probe). We have been able to stimulate specifically three different septo-hippocampal populations (cholinergic, GABAergic and Thy1 neurons) and analyze their specific impact on hippocampal oscillations. One of the main results is a differential effect of selective stimulation of cholinergic neurons during anesthesia compared to behaving animals.

The objective of the return phase was to import the technique learned during the outgoing phase and apply it to the scientific questions studied in the return laboratory. This was achieved by the design of a state-of-the-art 256-channel multi-recording system combined with video-acquisition of rodent behavior. In parallel, we developed a long-term project to study the transfer of information in the basal ganglia in physiological as well as pathological conditions, rooted in the recent conceptual advances made by the return laboratory team. Indeed, in vitro electrophysiology and quantitative anatomy performed in Dr Venance's laboratory, together with collaborative modeling studies all point towards a critical role of striatal GABAergic interneurons in gating cortico-striatal information processing during learning. Thanks to the transfer of technology realised during the return phase, we are now able to start dissecting the role of striatal GABAergic interneurons subpopulations in behaving animals during a procedural learning task.