A small chemical in the brain is the difference between eating and wasting away.

Whether or not a mouse eats food placed in front of it depends on a complex circuit in the brain.

Control of feeding behavior and body weight is a complicated business. The field has been dominated by studies investigating the role of hormones and neuropeptides for the last 15 years. Yet the roles of glutamate and GABA, two major neurotransmitters in the brain, have been largely ignored. But now, HHMI investigator Richard Palmiter has shown that GABA plays a critical role in maintenance of feeding behavior.

A group of neurons in the arcuate nucleus, a part of the brain's hypothalamus, has long drawn the attention of scientists looking for the neural circuits that control eating. These neurons synthesize protein messengers that promote eating, called agouti-related peptide (AgRP) and neuropeptide Y (NPY). Though these peptides were strong candidates for eating regulators, there was a hitch: animals without them eat normally. Yet killing the neurons that make them induces starvation; mice won't even consume food put directly into their mouths. “So the neurons must be making something that's critical, and it's probably not AgRP or NPY,” says Palmiter, at the University of Washington.

In a series of experiments published in Cell on June 26, 2009, the authors fingered GABA, a neurotransmitter that inhibits neuronal activity throughout the brain, as the missing ingredient. After selectively killing the AgRP/NPY neurons, Palmiter and colleagues observed that the activity of many postsynaptic neurons, in an area of the brain called the parabrachial nucleus, was greatly elevated. They postulated that the sudden loss of GABA from AgRP/NPY neurons was responsible and showed that they could prevent starvation by supplementing mice with a drug that activates GABA receptors. Conversely, blocking GABA receptors there led normal mice to starve.

Although it's unclear how hyperactivity in the parabrachial nucleus halts eating, the results reveal a pathway critical for food consumption, one that Palmiter will further delineate by identifying the transmitters involved in activating the nucleus and the targets of the parabrachial nucleus. Judging by how quickly appetites can be suppressed, he may not have to look far. “I think this is a pretty short circuit,” he says. “But that would just be my gut feeling.”

Photo: Phanie / Photo Researchers, Inc.