Oxytocin, dopamine, and the amygdala: a neurofunctional model of social cognitive deficits in schizophrenia

Abstract

Until recently, the social cognitive impairment in schizophrenia has been underappreciated and remains essentially untreated. Deficits in emotional processing, social perception and knowledge, theory of mind, and attributional bias may contribute to functional social cognitive impairments in schizophrenia. The amygdala has been implicated as a key component of social cognitive circuitry in both animal and human studies. In addition, structural and functional studies of schizophrenia reproducibly demonstrate abnormalities in the amygdala and dopaminergic signaling. Finally, the neurohormone oxytocin plays an important role in multiple social behaviors in several mammals, including humans. We propose a model of social cognitive dysfunction in schizophrenia and discuss its therapeutic implications. The model comprises abnormalities in oxytocinergic and dopaminergic signaling in the amygdala that result in impaired emotional salience processing with consequent social cognitive deficits.

Fig. 1.

The Amygdala Serves as the Central Integrative Unit in this Portion of the Emotional-Processing System. Emotional stimuli evoke emotional responses mediated via the pictured neurocircuitry. Emotional stimuli activate amygdala efferents based on the stimuli's valence. Threatening stimuli may activate connections with brainstem autonomic systems that initiate sympathetic and hypothalamic-pituitary-adrenal axis activity associated with the fear response. In contrast, received prosocial or trust behaviors may activate efferent output from the amygdala to oxytocinergic (OT) systems. The OT systems in turn feedback through the amygdala to dampen the brainstem autonomic response in addition to acting on dopaminergic systems (eg, ventral tegmental area, ventral striatum, and nucleus accumbens) to assign salience to perceived trust behaviors that might cumulatively facilitate a response of prosocial behaviors and bonding. Amygdala interactions with the prefrontal cortex may both direct cortical activity, such as allowing visual attention to be focused on emotionally salient features of the environment, and comprise a feedback loop that allows theory of mind and social perception to occur. The higher cortical regions plan and carry out the behavioral response. In persons with schizophrenia, the system is changed by functional alterations in the amygdala and prefrontal cortex as well as in oxytocinergic and dopaminergic systems. Aberrant amygdala input to OT centers may result in diminished OT inhibition of brainstem autonomic activity via nuclei in the amygdala. Altered OT input to dopamine systems coupled with dopaminergic overactivity may cause assignment of emotional salience to inappropriate stimuli. This may prevent the integrated signaling that comprises the feedback loop between the amygdala and the prefrontal cortex, thus making appropriate direction of attention, social perception, and theory of mind difficult to achieve. The resultant emotional response will vary with illness severity and subtype but may include multiple deficits such as social withdrawal, blunted affect, incongruous emotional responses, and paranoia.