A Hypothalamic Circuit that Bidirectionally Regulates Hunger in Anticipation of Future Changes in Energy State
1 BIDMC Endorcrinology Research
2 University of Iowa, Neuroscience and Pharmacology
3 University of Virginia, Biology
Hunger, the drive to seek and consume food, is represented in the activity of hypothalamic AgRP neurons. Excitatory input to AgRP neurons from the paraventricular nucleus of the hypothalamus (PVH) is important for energy balance, but the information transmitted through this pathway to regulate hunger is unknown, largely due to a lack of genetic access. Using single-cell RNA sequencing, mouse transgenics and activity manipulation, we show that a transcriptionally unique neuron cluster in the paraventricular nucleus (PVH-Sim2 neurons) provides excitatory input to AgRP neurons and drives food intake. By recording the activity of PVH-Sim2 neurons, we show that they transmit feedforward signals that anticipate future energy state in response to changes in food (but not water) availability. Specifically, removal of food rapidly and transiently increased PVH-Sim2 activity, whereas returning food to a fasted mouse inhibited it. Importantly, inhibiting PVH-Sim2 neurons delayed the activation of AgRP neurons during fasting, demonstrating the functional importance of this circuit in the activation of hunger. Moreover, at a longer timescale, PVH-Sim2 neurons are essential for sustaining food intake, since chronic inhibition of PVH-Sim2 activity led to reduced body weight and food intake, accompanied by reduced energy expenditure. Together, this work identifies a genetically specified circuit that is essential for normal energy balance, and transmits feedforward signals that enable the brain to predict and prevent deviations from homeostasis.