Dopamine transmission in the anterior insula shapes the neural coding of anxiety

The insular cortex (or insula), and particularly its anterior region, plays a crucial role in the control of emotional valence and anxiety (Etkin & Wager, 2007; Méndez-Ruette et al., 2019; Nicolas et al., 2023). While dopamine neurotransmission is known to modulate anxiety levels in humans (Hjorth et al., 2021) and animal models (de la Mora et al., 2010; Bananej et al., 2012; Zarrindast & Khakpai, 2015; DeGroot et al., 2020; Godino et al., 2023), its regulatory effects on the anterior insula remained unexplored. Here, using a multifaceted approach, we uncovered how dopamine shapes anterior insula function in anxiety and valence processing. First, we revealed a high density of neurons expressing type-1 dopamine receptors (D1) in the insula, particularly important in the anterior insula, and seven times greater than the density of neurons expressing type-2 dopamine receptors (D2). Few neurons co-expressed Drd1 and Drd2 mRNAs in the anterior and posterior insula, and the density of Drd1+ neurons in the anterior insula was twice higher among inhibitory neurons than excitatory neurons. Second, we found that pharmacological activation of D1 in the anterior insula is anxiogenic, suggesting a direct link between insular dopamine signaling and anxiety-related behaviors. Using fiber-photometry recordings, we identified that the amplitude of dopamine release onto D1+ neurons in the anterior insula while mice were in anxiogenic spaces or receiving mild foot shocks was both positively correlated with mice level of trait anxiety. Population dynamics and deep-learning analyses of anterior insula single-unit recordings uncovered distinct coding patterns of anxiety-provoking and safe environments, as well as tastants of positive and negative valence. Remarkably, systemic D1 activation, which heightens anxiety- related behaviors, dampens this coding dichotomy by increasing coding variability for protected spaces while increasing the coding reliability for anxiogenic spaces. Interestingly, the coding reliability of anxiogenic areas was positively correlated with mice level of trait anxiety, and we observed a trend towards a positive correlation between the coding reliability of a negative tastants, and mice level of anxiety. Altogether, our findings provide a new model of neural population coding of anxiety and emotional valence and unravel D1-dependent coding mechanisms in the mouse anterior insula.