Converging Prefronto-Insula-Amygdala Pathways in Negative Emotion Regulation in Marmoset Monkeys

Impaired regulation of emotional responses to potential threat is a core feature of affective disorders. However, while the subcortical circuitry responsible for processing and expression of fear has been well characterized, the top-down control of this circuitry is less well understood. Our recent studies demonstrated that heightened emotionality, as measured both physiologically and behaviorally, during conditioned fear and innate/social threat was induced, independently, by excitotoxic lesions of either the anterior orbitofrontal cortex (antOFC) or ventrolateral prefrontal cortex (vlPFC). An important outstanding question is whether the antOFC and vlPFC act on common or distinct downstream targets to regulate negative emotion.

The question was addressed by combining localized excitotoxic lesions in the PFC of a nonhuman primate and functional neuroimaging ([¹⁸F]fluorodeoxyglucose positron emission tomography) with a fear-regulating extinction paradigm. Marmoset monkeys with unilateral lesions of either the antOFC or vlPFC were scanned immediately following exposure to a fearful or safe context, and differences in [¹⁸F]fluorodeoxyglucose uptake were evaluated.

[¹⁸F]fluorodeoxyglucose uptake in the insula and amygdala of the intact hemisphere was significantly increased in response to the fearful context compared with the safe context. Such discrimination between the two contexts was not reflected in the activity of the insula-amygdala of the antOFC or vlPFC-lesioned hemisphere. Instead, uptake was at an intermediate level in both contexts.

These findings demonstrate that the distinct control functions of the antOFC and vlPFC converge on the same downstream targets to promote emotion regulation, taking us closer to a mechanistic understanding of different forms of anxiety.