 People with depression are more likely to have chronic pain, and people with chronic pain are more likely to be depressed. Those with depression also often report feeling more intense pain, which can lead to a vicious cycle that's hard to break. Scientists, unfortunately, don't have a good understanding of why this happens. But in a new anesthesiology paper, researchers from China detail a brain circuit in mice that begins to explain this phenomenon and suggest potential treatments. The team used optogenetics and chemogenetics, along with tracing methods to map out neuronal circuits when mice became depressed. In one set of key experiments, mice were restrained in a small tube for six hours a day. After three weeks of chronic restraint stress, mice began to look depressed. They ate less, showed decreased mobility during a swimming test, and displayed greater sensitivity to noxious stimuli. Compared to controls, the brains of depressed mice showed increased activity in specialized neurons that modulate the inhibitory neurotransmitter GABA. These GABA-ergic neurons occurred in the central amygdala, a major pain processing unit, and projected into other neurons in the ventrolateral periaqueductal gray, a checkpoint on the pain signaling pathway from the brain to the site of the injury. Chronic restraint stress also increased the firing rate of these central amygdala neurons, but inhibiting those neurons didn't lead to reduced responses to noxious experimental stimuli. Unexpectedly, selective inhibition increased sensitivity to noxious stimuli while selective activation reduced sensitivity, and neither changed the depressive behaviors of the mice. Additional experiments identified a decrease in the firing activity in ventrolateral periaqueductal gray GABA-ergic neurons in the chronic restraint stress mice compared to controls. Activation of these neurons decreased the animal's tolerance to noxious stimulation, while inhibition increased their tolerance. In contrast, glutamate-modulating neurons in the same area had the opposite response, increasing in activity in the depressed mice. Inhibition of these neurons made the mice more sensitive to noxious stimulation, while activation reduced the sensitivity. Thus, the authors define a brain circuit that operates in depression, in which increased inputs from GABA-ergic neurons from the amygdala disinhibit the periaqueductal gray glutamatergic neurons. With lower excitation of the GABA-ergic neurons in the central gray, there is less inhibition of the pain-promoting glutamatergic neurons. The findings suggest manipulations targeting this circuit could affect painful systems in humans. In particular, it's possible that non-drug approaches such as deep brain stimulation or transcranial magnetic stimulation could be effective tools in helping people with depression and chronic pain.