Differential regulation of observational fear and neural oscillations by serotonin and dopamine in the mouse anterior cingulate cortex

The aberrant regulation of serotonin (5-HT) and dopamine (DA) in the brain has been implicated in neuropsychiatric disorders associated with marked impairments in empathy, such as schizophrenia and autism. Many psychiatric drugs bind to both types of receptors, and the anterior cingulate cortex (ACC) is known to be centrally involved with empathy. However, the relationship between the 5-HT/DA system in the ACC and empathic behavior is not yet well known. We investigated the role of 5-HT/DA in empathy-like behavior and in the regulation of ACC neural activity. An observational fear learning task was conducted following microinjections of 5-HT, DA, 5-HT and DA, methysergide (5-HT receptor antagonist), SCH-23390 (DA D-1 receptor antagonist), or haloperidol (DA D-2 receptor antagonist) into the mouse ACC. The ACC neural activity influenced by 5-HT and DA was electrophysiologically characterized in vitro and in vivo. The microinjection of haloperidol, but not methysergide or SCH-23390, decreased the fear response of observing mice. The administration of 5-HT and 5-HT and DA together, but not DA alone, reduced the freezing response of observing mice. 5-HT enhanced delta-band activity and reduced alpha- and gamma-band activities in the ACC, whereas DA reduced only alpha-band activity. Based on entropy, reduced complexity of ACC neural activity was observed with 5-HT treatment. The current results demonstrated that DA D-2 receptors in the ACC are required for observational fear learning, whereas increased 5-HT levels disrupt observational fear and alter the regularity of ACC neural oscillations.