Monday, December 9, 2024
12/9/2024
PROJECT SUMMARY Zona incerta (ZI), a brain region located between the ventral thalamus and the hypothalamus, has been revealed to regulate food intake by latest findings. We reported that g-aminobutyric acid (GABA) neurons in the ZI regulate food intake through inhibitory projections to paraventricular thalamus (PVT). In addition to GABA neurons, dopamine (DA) neurons have been found in the ZI for decades. However, little is known about their function in the behavioral regulation. In our pilot studies, we used TH-Cre mice to target ZI DA neurons and found that chemogenetic activation of ZI DA neurons potently increased motivation to obtain food reward. Based on our pilot data, we hypothesize that: 1) ZI DA neurons regulate feeding motivation to control food consumption. 2) ZI DA neurons encode feeding behaviors and respond to metabolic hunger signals. 3) the PVT serves as one of the important postsynaptic areas for ZI DA neurons to exert the functional control on feeding. To test our hypothesis, we will use adeno-associated viral vectors (AAVs) to induce Cre-dependent expression of excitatory hM3Dq, inhibitory hM4Di, or ChR2 selectively in ZI DA neurons of TH-Cre mice. Chemogenetic activation and silencing will be employed to selectively manipulate ZI DA neurons for testing their role in the control of food motivation using progressive ratio (PR) schedule of reinforcement and real-time food consumption and meal pattern using Feeding Experimental Devices (FED). We will also use optogenetics to selectively activate ZI DA projections to determine the role of PVT neurons in feeding regulation induced by ZI DA neurons. In addition to the behavioral studies, we will perform slice electrophysiology in combination with optogenetics to dissect functional ZI DA pathways. In vivo fiber photometry will be applied to examine how ZI DA neurons encode feeding behaviors including food seeking and consumption and slice electrophysiology will be used to study the activity response of ZI DA neurons to metabolic hunger signals. Together, the proposed studies in this application will reveal novel ZI DA pathways in feeding control. The expected outcome from the proposed studies will significantly expand our view of how ZI and central DA signaling regulate feeding motivation and food consumption.
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