Validation of a novel cerebellar-striatal satiety circuit in human

ABSTRACT The goal of this project is to test the hypothesis that a cerebellar-striatal circuit regulates satiety in humans. Obesity currently affects 42% of U.S. adults, with projections that by 2030, 50% of U.S. adults will have obesity. These trends forecast a parallel increase in risk of obesity-related morbidity and mortality. Behavior, emergent from brain function, likely governs several primary sources of obesity, yet therapeutic intervention based on known brain circuits has not yielded dramatic success, suggesting a need to identify and rigorously evaluate neural circuits associated with appetite and food intake. We used a reverse-translational approach to identify the cerebellum as a regulator of appetite and feeding behavior. Animal studies determined that this effect is due to cerebellar regulation of food related reward activity in ventral striatum (VS). Our prior studies of this circuit in humans have been observational. Rigorous examination of the causal role of this circuit in modulating reward- related food intake in humans requires well-designed acute, mechanistic, state-of-the-art neuromodulation studies. Our group has evidence that cerebellar transcranial magnetic stimulation (TMS) can selectively modulate network function in cerebellar networks in healthy adults, and when applied therapeutically, can reduce symptom severity in patient populations. Thus, given the nascent nature of human data collected to date, we will integrate TMS and neuroimaging techniques to validate the role of the cerebellar-VS circuit in satiation in humans. We hypothesize that TMS modulation of the cerebellar-VS circuit will elicit neural and behavioral responses that are consistent with state-dependent cerebellar-induced satiation. These include increases in cerebellar activation, reductions in VS activation, and reduced food reward behaviors and intake. This proposal will innovatively combine cerebellar TMS with neuroimaging and behavioral measures of food-related reward under varying appetitive states. We will study the acute impact of cerebellar TMS on the satiation response to palatable food in neural systems and behavioral endpoints using a double-blinded, randomized, sham-controlled, mechanistic parallel trial involving cerebellar TMS neuromodulation in 150 healthy adults with BMIs spanning the healthy weight to obese range. The approach, completed under fasted and fed states to identify state-specific functioning of the cerebellar-VS circuit, will include functional MRI to ascertain neural reactivity to high-palatable food in the cerebellum and VS, as measures of target engagement. Food reward behavior will be measured using objective assessments and subjective ratings, in addition to ad libitum intake of palatable food. This proposal has public health impact because it will provide a mechanistic understanding of how this novel cerebellar-ventral striatal circuit functions to induce a reward-related satiation response in humans, which in turn will allow development of obesity therapeutics that target these validated and novel neurobiological pathways.