CONTRIBUTION OF INHIBITORY NEURONS OF THE ANTERIOR INSULAR CORTEX TO ANXIETY-RELATED BEHAVIORS IN MICE

Anxiety serves as an adaptive response to potential threats but becomes maladaptive when persistent without immediate or potential danger. Converging clinical and preclinical evidence implicate that the insular cortex (insula) contributes to anxiety regulation. Indeed, patients with anxiety disorders exhibit heightened insula responses to threat. Consistently, in mice, anterior insula excitatory neurons show increased activity when mice are located in anxiogenic environments, and anterior insula pharmacological inhibition reduces anxiety-like behaviors. Although GABAergic interneurons comprise about 20% of insula neurons and powerfully constrain excitatory dynamics, their contribution to insula-mediated anxiety remains unknown.
This project dissects the relative roles of excitatory and inhibitory neurons of the anterior insula in anxiety-related behaviors. We used cell-type-specific fiber photometry to record calcium activity from excitatory and inhibitory populations, either separately (single color) or simultaneously (dual-color) across anterior and posterior insula of both hemispheres. Animals were recorded during behavioral assays enabling us to resolve population-specific activity patterns across insular subregions. Photometry recordings revealed a coordinated increase in activity of both excitatory and inhibitory neural populations in the right anterior insula, when mice were in anxiogenic environments of anxiety assays.
To test the causal role of neural population of the insula we used chemogenetics (DREADDs) to bilaterally inhibit excitatory neurons (hM4Di) or activate inhibitory neurons (hM3Dq) in the anterior insula. Chemogenetic inhibition was confirmed with in vivo electrophysiology after deschloroclozapine administration (0.1 mg/kg).
Together, our findings implicate the right anterior inhibitory microcircuits in the control of anxiety, opening the path to assess their contribution to anxiety dysregulation.