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

The anterior insula1-3 and dopamine neuromodulation4-11 both play key roles in the control of anxiety, yet how dopamine shapes anterior insula function to regulate anxiety remains unknown. Here we show that dopaminergic neurons of the ventral tegmental area preferentially target the anterior relative to the posterior insula, and that optogenetic activation of these neurons elicits dopamine signals in the anterior insula. Behaviorally, dopamine signals increased in the anterior insula during risk assessment and exploration of exposed spaces. Interestingly, neurons expressing the type-1 dopamine receptor (D1) are enriched in the anterior insula subdivision, where their optogenetic activation is anxiogenic. At the molecular level, direct D1 activation or blockade in the anterior insula bidirectionally controls anxiety, demonstrating a causal anxiogenic function of D1 in the anterior insula. Remarkably, systemic D1 activation also increased anxiety-related behaviors, together with a cellular activation of the anterior insula, and a disruption of neural coding in this region. As an example of the latter, systemic D1 activation oppositely regulated the coding reliability of exposed and protected areas, increasing the reliability of the neural code for exposed spaces. Together, our findings reveal an anterior insula D1-dependent mechanism by which dopamine can control anxiety, providing a framework for investigating dopamine dysregulation in models of anxiety disorders. Our study also introduces quantitative metrics applied to AI-based computational representations of neural activity to identify how neuromodulation reshapes neural coding of behaviors and contexts.