PROJECT SUMMARY
Increasing evidence indicates that both zona incerta (ZI) and paraventricular thalamus (PVT) play important
roles in the regulation of feeding. Our previous study reported that activation of ZI GABA neurons and their
projections to PVT rapidly evokes binge-like eating. Food deprivation activates ZI GABA neurons and selective
ablation of ZI GABA neurons suppresses daily food intake and body weight gain in mice, supporting the
importance of ZI GABA neurons in the physiological feeding control. However, it remains largely unknown how
the ZI-PVT pathway is innervated and controlled by other brain areas for the feeding regulation. In this
application, we propose to study how central serotonin (5-HT) signaling targeting both ZI and PVT for the
feeding control. Although the importance of central 5-HT signaling in the satiety regulation is well-known, little
is known what raphe 5-HT projections regulate feeding motivation. Our pilot data show that both ZI and PVT
receive dense 5-HT projections from raphe nuclei, including both dorsal and medial raphe. Food deprivation
depressed the activity of dorsal raphe neurons that project to ZI and PVT. In addition, 5-HT excited PVT
neurons but inhibited ZI neurons as well as ZI-PVT GABA transmission. Based on the significant role of the ZI-
PVT neural pathway in feeding control, we hypothesize that: 1) raphe neurons send 5-HT signaling to modulate
both ZI and PVT neurons, and inhibit ZI-PVT GABA transmission. 2) raphe 5-HT projections to ZI and PVT
regulate feeding motivation and food intake. 3) chronic high-fat high-sugar (HFHS) diet alters 5-HT inhibition
on PVT-projecting ZI neurons and ZI-PVT GABA transmission. Aim 1 of the proposal is focused on the study
about the functional 5-HT neural projections from raphe to both ZI and PVT, and the modulatory effects of 5-
HT signaling on ZI and PVT neurons. Using slice electrophysiology in combination with optogenetics to target
specific neurons in brain slices, we will corroborate the differential modulation of 5-HT signaling on ZI and PVT
neurons as well as ZI-PVT GABA transmission. In Aim 2, we will examine how raphe 5-HT projections to both
ZI and PVT regulate feeding motivation and food intake. In the proposed experiments for the behavioral study,
we will use optogenetic tools to manipulate raphe 5-HT neurons and their projections to ZI and PVT. We will
also use slice electrophysiology and c-fos immunoreactivity to study how ZI- and PVT-projecting 5-HT neurons
respond to the metabolic states, revealing the role of raphe 5-HT projections to ZI and PVT in the physiological
feeding regulation. In Aim 3, we will study how chronic HFHS diets alter 5-HT inhibition on PVT-projecting ZI
neurons and ZI-PVT GABA transmission. Together, the proposal in this application will elucidate a novel role
of 5-HT signaling in the regulation of food intake by targeting both ZI and PVT. Also, the findings from this
project will help further understand how dysfunctional brain 5-HT signaling is involved in overeating and obesity.
