Presubicular bursting and visual anchoring of the head direction signal – BURST

In a first set of experiment, we will record presubicular neurons while animals are navigating in an open field arena, using juxtacellular recordings. This technique also allows to reconstruct cellular morphologies. We will test how head direction signals depend on visual information, by recording cells in normal light condition, and in darkness.
In a second set of experiment we will test how the signal of presubicular neurons depends on vestibular and visual inputs. We will use a setup where these sensory inputs can be tightly controlled. Awake head-fixed mice will be maintained at the center of a vestibular turntable surrounded by a dome and a projector. Records will be carried out with Neuropixels probes or tetrodes.
The convergence of visual and vestibular inputs to the presubiculum will be examined ex vivo. Long range inputs will be determined with retrograde tracing techniques. A combination of optogenetics and patch clamp recordings is used to define the cell-type specific functional connectivity. We also aim to carry out cell-type specific phamacogenetic manipulation experiments in order to obtain causal evidence.

The work performed so far has focused on in vivo recordings in behaving animals in Berlin, and on the ex vivo characterization of converging vestibular and visual pathways in the presubiculum, in Paris. We have also begun to set up the necessary conditions to perform in vivo recordings in head fixed conditions in the Paris lab.

Burst firing will be analyzed using the ISI analysis, and the burstiness will be correlated with the modulation of firing by head direction. We will examine if bursting layer 4 cells discharge preferentially during visual updating. In vivo results will be confronted with layer 4 recordings in the slice preparation, and their recruitment following double stimulation of ATN and RSC inputs.

-/-

Knowing where we are, where we have come from and where we are going is crucial to behavior. Our sense of orientation derives from combining multiple types of sensory information with our memory of known places, and it is closely linked to networks that subserve episodic memory storage throughout life (Buzsáki and Moser 2013). How these networks encode spatial orientation depends strongly on vision, but the cellular and circuit basis for this visual anchoring of our sense of orientation remains unknown.
We will focus on the presubiculum, which functions as an internal compass. Cells in the presubiculum code for head direction. This signal originates from the lateral mammillary nucleus (hypothalamus), where vestibular signals are transformed into head-direction signals and are transferred to presubiculum via the anterodorsal thalamic nucleus. This directional signal is anchored to external visual landmark allowing a coherent activity of the network. Presubicular lesions disrupt the control of head-direction signals by visual landmarks. Neurons in the different presubicular layers have distinct targets and we are particularly interested in the direct feedback to the lateral mammillary nucleus, that seems to rely on intrinsic bursting neurons of layer 4 (Yoder et al. 2015; Huang et al. 2017). Our project evolves around the idea that a burst feedback signal has a key role for visual updating of the head direction signal.
In this bilateral collaboration between our two laboratories in Paris and Berlin, we aim to elucidate how cells and circuits interact dynamically to produce a visual anchoring for our sense of orientation. This project combines in vivo single-cell physiology during behavior with analysis of cellular properties and microcircuit synaptic connectivity in vitro. We pose the following questions:
1) Does the presubicular feedback to the upstream regions of the head-direction system indeed occur via layer 4 bursting cells in vivo?
2) What are the cellular and microcircuit mechanisms leading to layer 4 neuron recruitment and burst firing?
3) What is the signal carried by layer 4 cells and does it reflect the combinations of vestibular and visual sensory inputs?
4) Is presubicular layer 4 bursting required for providing the visual landmark control of the head-direction signal?
5) How do the synaptic short-term dynamics of feedback synapses contribute to the relay of feedback signals?
The project is timely because of the recent demonstration of an internally organized network of the head-direction sense (Peyrache et al. 2015). What distinguishes our approach from previous studies is that we will combine high-end in vivo recordings with synaptic physiology and optogenetics to elucidate cellular integration of visual and vestibular signals. The tight collaboration of two labs with complementary expertise will enable such bridging between synaptic, cellular and systems neuroscience.