Rodent Cingulate Cortex

From a regional perspective, ACC includes areas 25, d32, v32, 33 and 24, MCC is comprised of dorsal and ventral area 24', and retrosplenial cortex areas 29a, 29b, a29c, p29c, a30 and p30. The laminar organization of each of these areas has been reported by Vogt and Paxinos (2014). Notice that rodents do not have a posterior cingulate cortex present in primates which is comprised in primates of areas 23 and 31.

In terms of equivalencies with the previous Paxinos and Watson rat atlases, there are similarities but they are not equivalent (van Heukelum et al., 2020; see for additional references). This group refers to the present nomenclature as the “homologous definition.” The earlier nomenclature typically applied in rodents divides cingulate cortex into cingulate area 1 (Cg1) and cingulate area 2 (Cg2), drawing the border between Cg1 and Cg2 perpendicularly to that between ACC and MCC as applied in other mammals. The most popular partitioning system for rodent cingulate cortex defines these two subareas (Cg1 and Cg2) located dorsal to each other. Cg1 encompasses areas 24b and 24b′ and Cg2 consists of areas 24a and A24a′. Areas 25 and 32, which are considered part of ACC in other mammals, are not part of either Cg1 or Cg2, but treated as separate areas IL and PL. As a result, both Cg1 and Cg2 cover parts of what would be considered ACC and MCC in other mammals. Although this definition can be applied consistently in rats and mice, it is not homologous to the ACC/MCC definition used in other mammals. This discrepancy arises because the border between ACC and MCC is drawn perpendicularly to that between Cg1 and Cg2. In other words, while areas 24 and 24′ form the border between ACC and MCC in other mammals, in rats and mice, they are each covered by both Cg1 and Cg2, whereas areas 25 and 32 (part of ACC) are excluded by both Cg1 and Cg2. This approach creates a fundamental obstacle for cross-species comparisons because most studies of rodent cingulate cortex do not investigate ACC and MCC independently, whereas studies in other species do.

To compare and synthesize findings across species, studies have sometimes treated rodent Cg1 and/or Cg2 as directly comparable to human ACC; mostly without assigning a direct counterpart to human MCC; on other occasions, Cg1 and Cg2 have been equated to MCC; and in still other cases, rodent Cg1 has been treated as the counterpart of human dorsal ACC and Cg2 as the counterpart of human ventral ACC. All of these approaches overlook the fact that the border between Cg1 and Cg2 is defined perpendicularly to both the border between ACC/MCC and between dACC/vACC, so that results gained using the Cg1/Cg2 nomenclature will necessarily represent a mix of data that would have been studied separately under the ACC/MCC nomenclature/maps.

It is important to recognize that as the field evolves the rodent maps we have presented are being verified by other groups based on connectivities; i.e., independent of cytoarchitecture. van Heukelum and colleagues (2020) also explored connectivities based on the two nomenclatures from studies that investigated either the afferent or efferent connection profile of cingulate cortex. They observed that rodent Cg1/Cg2 shows a mixed connectivity pattern, with both Cg1 and Cg2 being moderately connected to a wide range of areas, including subcortical and cortical structures involved in many functions such as pain processing and performing cognitively demanding tasks. By contrast, when using the ACC/MCC nomenclature, rodent ACC and MCC show connectivity patterns that are noticeably better demarcated and better matched to that observed in humans. Centered in area 32 but extending throughout ACC, there is strong connectivity with structures involved in processing emotional information, such as the orbitofrontal cortex (OFC), hypothalamus, amygdala, and autonomic brainstem nuclei. Rodent ACC further connects with cortical areas involved in sensory processing, RSC, and monoaminergic brainstem nuclei. Rodent MCC, by contrast, has limited connections to amygdala and hypothalamus, while being strongly connected to parietal association cortex, RSC, motor cortices, and pontine nuclei. As in humans, the border between MCC area 24′ and ACC area 24 is outlined by a difference in overall connection density with area 24 having denser connections as well as a divergence of thalamic targets.

One reason for this difference in connection specificity between the two nomenclatures/maps is that the Cg1/Cg2 designations do not include areas 25 and 32, which maintain strong and specific reciprocal connections to the amygdala, OFC, insula, and autonomic brainstem nuclei. Most importantly, given that in this nomenclature both Cg1 and Cg2 span parts of area 24 in ACC and area 24′ in MCC, differentially strong connections to areas 24 and 24′, respectively, will appear as uniformly intermediate across Cg1/Cg2. In other words, connectivity differences that in the ACC/MCC nomenclature/maps define the border between separate areas and connect roughly equally to Cg1 and Cg2, suggesting that the ACC/MCC nomenclature is better suited to highlight intrinsic connectivity differences among cingulate cortex regions.

Schaeffer et al. (2020) used connectivities to define cingulate regions in a data-driven hierarchical clustering approach to intrinsically define the functional boundaries of the medial prefrontal cortex (MFC) in rats, marmosets, and humans, independent of a priori assumptions about the organization of an area (e.g., cytoarchitecture). They mapped the functional connectivity fingerprints of these functional clusters with defined brain regions extrinsic to the MFC. The results demonstrated a remarkably similar intrinsic functional organization of the MFC across the three species, but also revealed clear differences between rodent and primate interareal patterns of connectivity. The MFC clusters of the rat brain showed preferential functional connectivity with motor-related regions (M1 and S1), whereas MFC clusters of marmosets and humans showed connectivity more broadly distributed across cortical and subcortical regions. The four-cluster solution across the three species corresponded strikingly well to the cytoarchitectonic boundaries for each species. This data driven approach suggests that the functional boundaries in the MFC consistently correspond well with the cytoarchitectonic boundaries in both rats and primates. Generally, the rats showed progressively less similar interareal connectivity with humans or marmosets as the clusters moved into areas 32 and 24. This transition was marked by relatively high connectivity with the S1 and M1 in rats, while the primate patterns of connectivity were distributed across the insula, striatum, and auditory cortex (cluster 3, ∼area 24) than auditory and posterior parietal cortex (cluster 4; ∼area 24 posterior.)

Overall, these studies show an essential convergence of cytoarchitectural and connectivity information, the former of which provides a strong starting point for functional studies of cingulate cortex. The final summary of Vogt and Paxinos (2014) is shown here as an initial guide to such work.

Emotion (e.g., fear) and pain both activate the anterior midcingulate cortex so it is not surprising that the pain domain is influenced by emotion. Indeed, fear of movement is often a feature of chronic low back pain. Patients often report that the simple process of getting out of bed in the morning causes them anxiety and pain. It appears that fear-responsive cingulate cortex projects to the cingulate premotor areas in the cingulate sulcus and this is a key mechanism for avoiding painful events.

Emotional trauma includes PTSD that impacts aMCC which shrinks in the face of PTSD and abuse. Why this shrinkage occurs is not known but it may be due to a loss of neurons and thus this part of cingulate circuitry is lost to uncover latent pain activity. As aMCC has projections from the back into the cingulate motor areas, this provides a means by which pain is localized to the back. It is also the case that nerve compression itself causes damage to the nerve that innervate the back as well as intracellular protein expression. Since adolescent physical abuse often involves spanking/beating of the buttocks this also would tend to infame the nerves that innervate this tissue.

The family structure itself has an impact on adolescent views of their abuse. Abused adolescents perceive their families as significantly less adaptable, less cohesive, and less balanced than non-abused adolescents. Fathers and mothers of abused adolescents are viewed as less caring; abuse group fathers are also viewed as more overprotective. Adolescent neglect is primarily associated with extrafamilial difficulties and social isolation. Adolescent physical abuse has been linked more with rigidity in family relations, poorer maternal understanding of child developmental skills, and adolescent externalizing behaviors. In contrast, adolescent sexual abuse is related to maternal emotional problems and adolescent internalizing behaviors. In general, maltreated adolescents experience lower levels of family cohesion, more attention problems, and more daily stress than their non-maltreated counterparts. These problems lead to suicidal ideation, depression and anxiety disorders.