The role of GABAergic neuron subtypes in stabilizing and flexibly resetting head-direction signals in the Presubicular cortex – VIPattract

Head direction (HD) neurons function as the brain’s compass, forming our inner representation of the external world. The HD signal is internally generated, driven by vestibular information, and it is anchored to stable visual cues in the environment. How specific brain microcircuits combine the stable maintenance of the HD signal as well as flexibility upon reorientation, is unknown. We will study this mechanism in the parahippocampal cortex, where vestibular based HD information and visual information converge.

The HD system is hypothesized to function like a continuous attractor, in which the HD signal is maintained by the peak location of a stable, persistent activity pattern. Recent work in Desdemona Fricker’s group has shown that bump attractors can be achieved through precisely timed interactions between GABAergic inhibitory neurons and excitatory HD cells. This project will pinpoint the network mechanisms of the presubicular cortical HD system to sustain persistent activity and for flexible resetting by salient visual cues. Our goal is to understand the roles of GABAergic neuron subtypes such as inhibitory somatostatin (SOM)-expressing, and disinhibitory vasoactive intestinal polypeptide (VIP)-expressing neurons. We propose to record, model and manipulate populations of HD neurons and GABAergic neurons, and to define synaptic and circuit interactions underlying landmark updating. Cell-type specific calcium imaging will be used to monitor head direction related population activity in behaving mice. Cellular mechanisms will be clarified in slice experiments. Results will be incorporated in our existing network model to further uncover the link between activity, connectivity and the bump state. Our hypothesis is that inhibition stabilizes, and disinhibition gates resetting of the head direction attractor network.

Schizophrenia can be considered as an attractor disease. The disruption of GABAergic cells has been suggested as a mechanism underlying the dysregulations of cortical activity patterns and perceptual functions, that are hallmarks of psychiatric diseases. Genetic variants of the human CHRNA5 gene, encoding a nicotinic acetylcholine receptor (nAChR) subunit, have been linked to increased risk for schizophrenia. Our work will include a genetic mouse model with the variation of the human nAChR gene to fill in the intermediate level of investigation, and clarify how impaired cholinergic excitation of VIP neurons affects cortical attractor networks. We ask whether a perturbed balance between internally generated estimates and updates from the external world leads to deficits in HD signaling. VIPattract will help to pave the way for future studies that may focus on disinhibitory GABA neuron function as a potential target for improving some of the defining symptoms of schizophrenia in humans, including cognitive deficits, that critically depend on cortical attractor network function.