Identification of novel neurocircuitry through which leptin targets multiple inputs to the dopamine system to reduce food reward seeking

Abstract BACKGOUND Leptin reduces the motivation to obtain food by modulating activity of the mesolimbic dopamine system upon presentation of cues that predict a food reward. Although leptin directly reduces activity of ventral tegmental (VTA) dopamine neurons, the majority of leptin receptor (LepR)-expressing dopamine neurons do not project to the nucleus accumbens (NAc), the projection implicated in driving food reward seeking. Therefore, the precise locus of leptin action to modulate motivation for a food reward is unresolved. METHODS We used transgenic mice expressing Cre recombinase under control of the LepR promotor, anatomical tracing, optogenetics-assisted patch-clamp electrophysiology, in vivo optogenetics with fiber photometric calcium measurements and chemogenetics to unravel how leptin-targeted neurocircuitry inhibits food reward seeking. RESULTS A large number of dopamine neurons projecting to the NAc are innervated by local VTA LepR-expressing gamma-aminobutyric acid (GABA) neurons. Leptin enhances the activity of these GABA neurons and thereby inhibits NAc-projecting dopamine neurons. In addition, we find that lateral hypothalamic (LH) LepR-expressing neurons projecting to the VTA are inhibited by leptin and that these neurons modulate dopamine neurons indirectly via inhibition of VTA GABA neurons. In accordance with such a disinhibitory function, optogenetically stimulating LH LepR projections to the VTA potently activates dopamine neurons in vivo. Moreover, we found that chemogenetic activation of LH LepR neurons increases the motivation to obtain a food reward only when mice are in positive energy balance. CONCLUSION We identify neurocircuitry through which leptin targets multiple inputs to the dopamine system to reduce food reward seeking.