LAUSR

Poor outcomes are common in individuals with anxiety and depression, and the brain circuits underlying symptoms and treatment responses remain elusive. To elucidate these neural circuits, experimental studies must specifically manipulate them, which is only possible in animals. Here, we used a chemogenetics strategy involving engineered designer receptors exclusively activated by designer drugs (DREADDs) to activate a region of the marmoset brain that is dysfunctional in human patients with major depressive disorder, called the subcallosal anterior cingulate cortex area 25 (scACC-25). Using this DREADDs system, we identified separate scACC-25 neural circuits that underlie specific components of anhedonia and anxiety in marmosets. Activation of the neural pathway connecting the scACC-25 to the nucleus accumbens (NAc) caused blunting of anticipatory arousal (a form of anhedonia) in marmosets in response to a reward-associated conditioned stimulus in an appetitive Pavlovian discrimination test. Separately, activation of the circuit between the scACC-25 and the amygdala increased a measure of anxiety (the threat response score) when marmosets were presented with an uncertain threat (human intruder test). Using the anhedonia data, we then showed that the fast-acting antidepressant ketamine when infused into the NAc of marmosets prevented anhedonia after scACC-25 activation for more than 1 week. These neurobiological findings provide targets that could contribute to the development of new treatment strategies. Description Separate area 25 brain circuits drive reward- and threat-associated responses in nonhuman primates. Dissecting the neural circuitry of depression There is still much to learn about the brain circuits involved in depression and anxiety. Here, Wood and colleagues demonstrate that specific connections of a brain region called area 25 directly affect anxiety and anhedonia in marmosets. Using a chemogenetics strategy, the authors showed that activation of area 25 connections to the nucleus accumbens resulted in anhedonia, whereas activation of area 25 connections to the amygdala induced anxiety in the animals. Moreover, the nucleus accumbens was a target for the response of marmosets to the fast-acting antidepressant ketamine. These findings may help to elucidate more effective treatment strategies for depression and anxiety. —OS