Role of zona incerta neurons in the integration of feeding and fear

The zona incerta (ZI) is a subthalamic region in the brain, which comprises loosely packed albeit mixed population of several neurons. However, an in-depth understanding of anatomical connections of neurons emerging from and /or projecting to the ZI, and the functional implications, remains elusive. The ZI has recently gathered considerable interest because of its role in primal survival-associated instincts, like appetitive drive, hunting, food intake and fear generalization. We therefore aimed to identify and characterize the neuronal subpopulations, which may be involved in emotional and metabolic circuitries and assess the extent of their overlap. For achieving this, we combined the widely known bacteria-derived tetracycline trans-activator controlled genetic tagging system (tet-tag) with Designer Receptors Exclusively Activated by Designer Drugs technology (DREADD). We injected male and female C57BL/6N wild type mice with tet-tag-DREADD vectors for specifically tagging fasting-associated neurons (FANs) and assessed the effect of their activation and inhibition during anxiety and fear-related testing paradigms. Notably, chemo-genetic activation of FANs increased food and water intake in mice whereas, their inhibition produced the opposite effects. Both, chemo-genetic activation and inhibition of FANs did not have an effect on anxiety-related behavior. However, chemo-genetic activation of FANs promoted fear extinction. Overall, our results demonstrate that fasting-induced neural ensembles in the ZI not only modulate food intake but also adapt fear-associated behavioral responses.