Glutamatergic Neurons in the Arcuate Nucleus (ARC) and Regulation of Satiety ARCAgRP neurons are activated by fasting and inhibited by feeding. When turned on, they rapidly and potently drive hunger. ARCPOMC neurons, on the other hand, are viewed as the counterpoint to ARCAgRP neurons. They are regulated in an opposite fashion and their activity leads to opposite effects - decreased hunger. The antagonistic “yin-yang” functions of these two neurons is a constant feature of essentially all proposed models of homeostatic hunger/satiety regulation. At odds with this widely held view, however, is the finding that opto- and chemo-genetic activation of ARCPOMC neurons fails to decrease food intake over a period of less than 8-12 hours of stimulation. Contrast this with the potent effect on hunger observed just minutes following ARCAgRP neuron stimulation. This striking lack of effect strongly suggests that ARCPOMC neurons, by themselves, are not the full counterpoint to ARCAgRP neurons. Based on this, we hypothesize the following: A) A functionally important, presently unknown neural component of the ARC-based homeostatic satiety system is missing from current models. B) Excitatory ARCVGLUT2 neurons not expressing POMC provide this missing component and when stimulated / inhibited, they rapidly increase / decrease satiety. C) Reconciling the known important roles of αMSH and MC4Rs as evidenced by genetic studies, with the inability of acute selective stimulation of ARCPOMC neurons to rapidly affect hunger, we hypothesize that ARCPOMC neurons do not work in isolation but instead decrease hunger by increasing the strength of excitatory synaptic transmission across the ARCVGLUT2 neuron à PVH satiety neuron synapse. We postulate that this occurs via αMSH/MC4R-mediated effects on synaptic plasticity. The following 3 aims are proposed: Aim 1: ARCVGLUT2 satiety neurons – their function, identity and Cre/Flp drivers providing “access”. Aim 2: The interaction between ARCVGLUT2 neurons and the melanocortin system – convergence on PVH satiety neurons and an important role for αMSH/MC4R-driven excitatory synaptic plasticity. Aim 3: ARCVGLUT2 satiety neurons – their regulation and the responsible afferent circuits / mechanisms. As these ARCVGLUT2 neurons exert hitherto unknown strong, bidirectional control over hunger / satiety, it is important to explore their regulation, features and functions as they could provide mechanisms for previously observed phenomenon for which the basis is either unknown or incompletely understood. Examples include, but are not limited to, αMSH/MC4R regulation of hunger (as discussed above), a forebrain site of action for NTS “satiety” neurons, and regulation of hunger by GLP-1R agonists, oxytocin and cannabinoids (via cognate receptors expressed by ARCVGLUT2 neurons). These studies should improve understanding of hunger / satiety.