Periaqueductal Gray Sheds Light on Dark Areas of Psychopathology

New animal/rodent data that utilize modern functional track tracing with optogenetics and designer receptors exclusively activated by designer drugs (DREADDS) technology show that the periaqueductal gray (PAG) is a rich substrate for the integration of active and passive responses to threat. Human data suggest that the PAG may be dysregulated in psychopathology that drives maladaptive behavior. The neural circuit that connects the frontal cortex, amygdala, PAG, and pons medulla is hypothesized to be a focal point for psychopathology where stress and threat converge to usurp decision making for stimulus-appropriate motivated behavior. Neurons in the periaqueductal gray (PAG) integrate negative emotions with the autonomic, neuroendocrine, and immune systems to facilitate responses to threat. Modern functional track tracing in animals and optogenetic and chemogenetic techniques show that the PAG is a rich substrate for the integration of active and passive responses to threat. In humans, the same regions of the PAG that give rise to adaptive anger/fight, fear/panic, depression/shutdown, pain, and predatory behaviors in response to challenging situations or overwhelming threats can become activated pathologically, resulting in symptoms that resemble those of psychiatric disorders. This review coalesces human and animal studies to link PAG neuropathways to specific elements of psychiatric diagnoses. The insights gained from this overview may eventually lead to new therapeutic interventions. Neurons in the periaqueductal gray (PAG) integrate negative emotions with the autonomic, neuroendocrine, and immune systems to facilitate responses to threat. Modern functional track tracing in animals and optogenetic and chemogenetic techniques show that the PAG is a rich substrate for the integration of active and passive responses to threat. In humans, the same regions of the PAG that give rise to adaptive anger/fight, fear/panic, depression/shutdown, pain, and predatory behaviors in response to challenging situations or overwhelming threats can become activated pathologically, resulting in symptoms that resemble those of psychiatric disorders. This review coalesces human and animal studies to link PAG neuropathways to specific elements of psychiatric diagnoses. The insights gained from this overview may eventually lead to new therapeutic interventions.