Abstract
Subcallosal area 25 is one of the least understood regions of the anterior cingulate cortex, but activity in this area is emerging as a crucial correlate of mood and affective disorder symptomatology. The cortical and subcortical connectivity of area 25 suggests it may act as an interface between the bioregulatory and emotional states that are aberrant in disorders such as depression. However, evidence for such a role is limited because of uncertainty over the functional homologue of area 25 in rodents, which hinders cross-species translation. This emphasizes the need for causal manipulations in monkeys in which area 25, and the prefrontal and cingulate regions in which it is embedded, resemble those of humans more than rodents. In this review, we consider physiological and behavioral evidence from non-pathological and pathological studies in humans and from manipulations of area 25 in monkeys and its putative homologue, the infralimbic cortex (IL), in rodents. We highlight the similarities between area 25 function in monkeys and IL function in rodents with respect to the regulation of reward-driven responses, but also the apparent inconsistencies in the regulation of threat responses, not only between the rodent and monkey literatures, but also within the rodent literature. Overall, we provide evidence for a causal role of area 25 in both the enhanced negative affect and decreased positive affect that is characteristic of affective disorders, and the cardiovascular and endocrine perturbations that accompany these mood changes. We end with a brief consideration of how future studies should be tailored to best translate these findings into the clinic.
Highlights
Area 25 is found within the subcallosal cortex and is one of the least understood regions of the anterior cingulate cortex (ACC)
Suggestions that elevated area 25 activity may be relevant to disorders of enhanced negative emotion, in part, derive from studies implicating subregions of the scACC in transient states of sadness induced in healthy control subjects
Inactivation with GABA A and B agonists (i) reduced the expression of behavioral and cardiovascular conditioned threat responses during Pavlovian discriminative conditioning when a previously neutral stimulus became associated with an aversive event (i.e., a loud noise and (ii) accelerated extinction of conditioned cardiovascular and behavioral responses, when the conditioned stimulus no longer predicted the aversive event [38]. These findings suggest that non-human primate area 25 normally acts to drive Pavlovian cardiovascular and behavioral responses during threatening situations
Summary
Area 25 is found within the subcallosal cortex and is one of the least understood regions of the anterior cingulate cortex (ACC). Based on tracing studies in rhesus macaques (Figure 1A), area 25 is densely connected with neighboring ventromedial and posterior orbitofrontal cortex (OFC), involved in affective evaluation and a moderate pathway. 2 of 322 of 33 tracing studies in rhesus macaques (Figure 1A), area 25 is densely connected with neighboring ventromedial and posterior cortex (OFC), of involved inarea affective evaluation and a linking it to fronto-polar area 10orbitofrontal and cognition. As will be seen later in the descriptions of functional effects of the rodent IL compared to the monkey area 25, potential differences do emerge, suggesting that the assumption of functional homology between these regions may be premature Another issue hampering translation is that, often when describing activation foci within the subcallosal zone, human neuroimaging studies do not differentiate between the distinct cytoarchitectonic regions present within this zone [18]. By careful comparison with studies of IL in rodents we can begin to piece together the functions of this region, determine the extent of functional homology, and inform future studies in humans
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