Interrogating vestibulo-cerebellar circuits involved in spatial orientation – InVest

We will be using anatomical tracings to identify the vestibular sub-circuits upstream of the ascending vestibular pathway involved in the updating of head direction coding. Optogenetic perturbations of these sub-circuits coupled with electrophysiological recordings and tests of spatial navigation will be used to demonstrate their role in head direction coding. Finally electrophysiological recordings will be used to understand the nature of the computations in these sub-circuits. All experiments will be performed in rats and will conform to the principles of the 3Rs (replace, reduce, refine).

The work performed so far has consisted in technical developments necessary for the implementation of experiments.

The actual phase of experimentation and data collection will start shortly.

Fayat R, Delgado Betancourt V, Goyallon T, Petremann M, Liaudet P, Descossy V, Reveret L and Dugué GP. 2021, Sensors. 21(18):6318. doi: 10.3390/s21186318

Spatial cognition relies upon an ensemble of forebrain circuits encoding the location, speed an orientation of the body in space. Among them, several neuronal populations encode head direction in the earth-horizontal plane (perpendicular to gravity). The activity of these head direction (HD) cells is largely updated by the vestibular system, which collects and analyzes sensory inputs from motion sensors localized in the inner ear (the vestibular organs). Because they carry strong ambiguities, these inputs are however inappropriate, as such, for updating HD cells. Indeed, vestibular organs, which measure accelerations and rotations in a reference frame tied to the head, are unable to provide an explicit description of head kinematics in a terrestrial reference frame. This leads to the following fundamental question : how does the brain transform ambiguous vestibular inputs into explicit signals for the updating of HD cells ?

A series of observations have led to the hypothesis that the brain is able to solve vestibular ambiguities in the first stations of central vestibular information processing : the brainstem vestibular nuclei (VN) and the vestibular subdivision of the cerebellum (VC). Results obtained by the project coordinator in rats have shown in particular that a number of VC output neurons (the Purkinje cells) encode head rotations about an axis defined relative to gravity. Our working hypothesis is that the inhibitory influence of such cells on their VN target neurons could subtract the earth-horizontal component of head rotation from the rotation signals received by these cells from the vestibular organs ; the result of this subtraction would be the earth-vertical component of head rotation, a signal perfectly suited for the updating of HD cells.

To test this hypothesis and understand the computations performed by the vestibular system upstream of HD cells, our work will aim at identifying, characterizing and manipulating VN and VC subcircuits communicating with HD cells. Our consortium gathers three teams with complementary technical and scientific skills : Guillaume Dugué (partner 1, coordinator), specialist of VC physiology, Francesca Sargolini (partner 2), specialist of rodent spatial cognition, and Mathieu Beranek (partner 3), specialist of VN physiology.

Our project is divided into three tasks, each lead by a different partner. Task 1 (partner 1) will consist in identifying VN neurons projecting to the supragenual nucleus (SG), one of the first relay stations toward HD cells, as well as their presynaptic VC Purkinje cells using retrograde viral tracings. Task 2 (partner 2), will aim at characterizing the effects of optogenetic perturbations of these neurons on HD cells of the anterodorsal thalamus and on spatial navigation. Task 3 (partner 3) will intend to characterize SG-projecting VN subcircuits, and to describe their sensitivity as well as the one of their presynaptic VC Purkinje cells to head movements using in vivo electrophysiology.

This project, based on a series of strong and experimentally testable hypotheses, will tackle a major blindspot in our knowledge of the neuronal bases of spatial cognition : the mechanisms by which the brain builds explicit representations of body kinematics in space from ambiguous sensory information. It should refine our understanding of the coupling between the vestibular system and spatial cognition and potentially shed a new light on how vestibular dysfunctions lead to orientation disorders.