Dopamine plays a key role in motivation and reward. Dopaminergic neurons in the ventral tegmental area (VTA) signal the discrepancy between expected and actual rewards (i.e., reward prediction error, RPE)1-3, but how they compute such signals is unknown. We recorded the activity of VTA neurons while mice associated different odour cues with appetitive and aversive outcomes. We found three types of neurons based on responses to odours and outcomes: approximately half of the neurons (Type I, 52%) showed phasic excitation after reward-predicting odours and rewards in a manner consistent with RPE coding. The other half of neurons showed persistent activity during the delay between odour and outcome, that was modulated positively (Type II, 31%) or negatively (Type III, 17%) by the value of outcomes. While the activity of Type I neurons was sensitive to actual outcomes (i.e., when the reward was delivered as expected vs. unexpectedly omitted), the activity of Types II and III neurons was determined predominantly by reward-predicting odours. We “tagged” dopaminergic and GABAergic neurons with the light-sensitive protein channelrhodopsin-2 (ChR2) and identified them based on their responses to optical stimulation while recording. All identified dopaminergic neurons were of Type I and all GABAergic neurons were of Type II. These results show that VTA GABAergic neurons signal expected reward, a key variable for dopaminergic neurons to calculate RPE.

SUMMARY Leptin acts in the brain to prevent obesity. The underlying neurocircuitry responsible for this is poorly understood, in part due to incomplete knowledge regarding first order, leptin-responsive neurons. To address this, we and others have been removing leptin receptors from candidate first order neurons. While functionally relevant neurons have been identified, the observed effects have been small suggesting that most first order neurons remain unidentified. Here we take an alternative approach and test whether first order neurons are inhibitory (GABAergic, VGAT+) or excitatory (glutamatergic, VGLUT2+). Remarkably, the vast majority of leptin’s anti-obesity effects are mediated by GABAergic neurons; glutamatergic neurons play only a minor role. Leptin, working directly on presynaptic GABAergic neurons, many of which appear not to express AgRP, reduces inhibitory tone to postsynaptic POMC neurons. As POMC neurons prevent obesity, their disinhibition by leptin action on presynaptic GABAergic neurons likely mediates, at least in part, leptin’s anti-obesity effects.

SummaryHunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to its control. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake1-5. Consistent with their obligatory role in regulating appetite, genetic ablation or pharmacogenetic inhibition of AgRP neurons decreases feeding3,6,7. Excitatory input to AgRP neurons is key in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric state-dependent synaptic plasticity8-10. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing Thyrotropin-releasing hormone (TRH) and Pituitary adenylate cyclase-activating polypeptide (PACAP). Pharmaco-genetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated.