The cortical connections of area 25 and its interactions with areas involved in emotion and cognition

The equilibrium between cognition and emotion among shifting prefrontal networks is necessary for flexible behavior in the primate, but the organization of the circuitry involved is largely unknown. The subgenual cingulate area 25 (A25) has been strongly associated with affect and somatic states based on clinical evidence and functional studies in non-human primates. The dorsolateral prefrontal cortex (DLPFC), on the other hand, is associated with cognition and executive function. Both areas are robustly connected with pregenual cingulate area 32 (A32), implicated in both affective and cognitive functions. A32 may thus be positioned to balance activity between these two functionally disparate prefrontal regions. This issue was addressed by mapping the largely unidentified cortical connectome of A25 to understand its position in prefrontal networks. A25 was most strongly connected with other ventromedial and posterior orbitofrontal areas associated with emotions and internal homeostasis. Connectional patterns showed that A25 is a major prefrontal feedback system, positioned to exert a widespread influence on other areas. A25 was also robustly connected with auditory association areas, memory-related medial temporal cortices, and with the interoceptive-related anterior insula. Connectional patterns with memory-related medial areas, the posterior orbitofrontal cortex, and the anterior insula suggest that activity is initiated in A25 and flows in a feedforward pattern to these areas. Weak to sparse connections linked the DLPFC and A25. To determine how affective signals from A25 and cognitive signals from the DLPFC may be integrated in prefrontal circuits, high resolution mapping techniques revealed that A32 densely targeted modulatory inhibitory neurons in the superficial layers and strong inhibitory neurons in the deep layers of A25. These data suggest that A32 can tune activity in A25 cortical columns and convey signals pertaining to ongoing prefrontal processes. The sequential pathway from the DLPFC to A32 may help dampen A25 output by predominant innervation of the strong inhibitory microsystem in the deep layers of A25. These findings indicate that A32 is positioned to recruit or reduce activity in A25 as needed, demonstrating a circuit mechanism for the delicate integration of cognition and emotion and its potential disruption in mood disorders