Hypothalamic neuronal activation in non-human primates drives naturalistic goal-directed eating behavior

Maladaptive feeding behavior is the primary cause of modern obesity. While the causal influence of the lateral hypothalamic area (LHA) on eating behavior has been established in rodents, there is currently no primate-based evidence available on naturalistic eating behaviors. We investigated the role of LHA GABAergic (LHAGABA) neurons in eating using chemogenetics in three macaques. LHAGABA neuron activation significantly increased naturalistic goal-directed behaviors and food motivation, predominantly for palatable food. Positron emission tomography and magnetic resonance spectroscopy validated chemogenetic activation. Resting-state functional magnetic resonance imaging revealed that the functional connectivity (FC) between the LHA and frontal areas was increased, while the FC between the frontal cortices was decreased after LHAGABA neuron activation. Thus, our study elucidates the role of LHAGABA neurons in eating and obesity therapeutics for primates and humans. [Display omitted] •The role of LHAGABA neurons on macaque’s naturalistic eating behavior was investigated•Chemogenetic activation increased goal-directed behaviors, mainly for palatable food•PET and MRS functionally validated chemogenetic activation•Rs-fMRI revealed increased LHA-frontal FC, with decreased FC within frontal cortices Ha et al. demonstrate that activation of LHAGABA neurons in macaques drives naturalistic goal-directed eating behavior and motivation, predominantly for palatable food. The chemogenetic activation was functionally validated via PET and MRS. Further, rs-fMRI showed increased FC between LHA and frontal area, while the FC between frontal cortices was decreased.