Post by Lincoln Tracy
What's the science?
The motivation for natural rewards is mediated by both classic homeostatic circuits as well as mesolimbic dopaminergic circuits in the brain. It is not known how external rewards influence homeostatic circuits in the hypothalamus to alter behavior. Within the hypothalamus, agouti-related protein (AgRP-) and pro-opiomelanocortin (POMC)-expressing neurons play a key role in the control of food intake. The former subset of neurons is inhibited by food intake, while the latter subset of neurons is activated by food intake. Therefore, stimulating these subsets of neurons increases or decreases food intake, respectively. But does alcohol—a calorie-containing drug—use similar mechanisms to influence the activity of these hypothalamic neurons and food intake? This week in Neuron, Alhadeff and colleagues describe the different pathways utilized by drugs and nutrients as part of the coordinated regulation of hypothalamic feeding and midbrain reward circuits in mice.
How did they do it?
First, the authors engineered mice to express a calcium indicator in AgRP and POMC neurons in the hypothalamus. This allowed them to measure calcium fluorescence from these neurons as a proxy measure of neural activity using fiber photometry. Second, they examined AgRP and POMC neuronal activity in response to forced alcohol consumption by injecting alcohol through a catheter into the upper part of the stomach of the mice. Third, they tested how unrestricted alcohol drinking affected AgRP and POMC activity as alcohol is normally consumed on a voluntary basis. Fourth, they used optogenetics to test whether stimulating AgRP neurons led to increased alcohol consumption. Fifth, they investigated the role of the vagus nerve in how the AgRP neurons in the brain communicate with the gut. They severed the vagus nerve and examined whether the neuropeptides cholecystokinin (CCK) and peptide YY (PYY) modulated AgRP activity. Sixth, they looked at the effects of short- (hours) and long-term (two weeks) alcohol consumption on food intake in food-deprived and non-food-deprived mice. Finally, they injected several recreational drugs that suppress appetite—cocaine, amphetamine, and nicotine—into the abdomen of the mice to determine their effects on AgRP, POMC, and dopaminergic neuronal activity.
What did they find?
First, the authors found that injecting alcohol into the stomach of the mice reduced AgRP neuron activity in a dose-dependent fashion—meaning that the more alcohol that was injected, the less the AgRP were active. The injected alcohol had no effect on the POMC neurons. Second, they found that drinking alcohol reduced AgRP activity—but had no effect on POMC neuronal activity. These results imply that alcohol consumption sends different signals to the brain, compared to other nutrients. Third, they found that using light to stimulate the AgRP neurons did not influence the amount of alcohol that was consumed—but it did increase glucose intake. This finding suggests that the brain—at the level of AgRP neurons—does not associate alcohol with calories. Fourth, they found that severing the vagus nerve eliminated the effects of CCK and PYY on AgRP neuronal activity, implying that vagal neurotransmission—not central action—mediates the suppression of AgRP neurons. Fifth, they observed that only the food-deprived mice—and not the non-food-deprived mice—showed reduced food consumption after alcohol consumption. Sixth, they found that cocaine, amphetamine, and nicotine all reduced activity of the AgRP and POMC neurons and increased dopaminergic signaling in the nucleus accumbens.
What's the impact?
These findings show that there are both vagal-dependent and vagal-independent methods for reward signaling in the brain, and reveal the presence of bidirectional, modulatory network effects across brain circuits involving the hypothalamus and midbrain. This research also shows that drugs of abuse can robustly inhibit AgRP neurons independent of calories, which opens the door for the potential use of pharmacotherapeutics to modulate AgRP activity. Future research will be required to determine if and how drugs of abuse affect neural activity in other brain regions that control food intake and reward behavior. By improving our understanding of how nutrient-rich and nutrient-poor substances alter brain reward circuit activity, this research provides new targets for the development of weight loss and addiction therapies.
Alhadeff et al. Natural and Drug Rewards Engage Distinct Pathways that Converge on Coordinated Hypothalamic and Reward Circuits. Neuron (2019). Access the original scientific publication here.