Where is Cingulate Cortex? A Cross-Species View
Authors: Sabrina van Heukelum, Rogier B. Mars, Martin Guthrie, Jan K. Buitelaar, Christian F. Beckmann, Paul H.E. Tiesinga, Brent A. Vogt, Jeffrey C. Glennon, Martha N. Havenith
Journal: Trends in Neurosciences (2020)

Cingulate cortex is a hub of cognitive and emotional control, and it is highly preserved across mammals. As such, much of our knowledge on cingulate cortex relies on a synthesis of findings across species.One crucial obstacle to such cross-species comparisons is a striking discrepancy in anatomical definitions. In most mammals, the border between subregions of the cingulate cortex is drawn along the rostrocaudal axis, but in mice and rats it has been routinely drawn perpendicularly to this axis.This rarely discussed discrepancy has given rise to apparent inconsistencies in cingulate cortex structure and function, within and across species.A homologous nomenclature of cingulate cortex across species was proposed in 2005, but has so far been rarely used in relevant studies.We argue that applying the homologous definition aligns the structure and function of rodent cingulate cortex with that of other species. It also better reflects the inherent structure of rodent cingulate cortex itself. To compare findings across species, neuroscience relies on cross-species homologies, particularly in terms of brain areas. For cingulate cortex, a structure implicated in behavioural adaptation and control, a homologous definition across mammals is available – but currently not employed by most rodent researchers. The standard partitioning of rodent cingulate cortex is inconsistent with that in any other model species, including humans. Reviewing the existing literature, we show that the homologous definition better aligns results of rodent studies with those of other species, and reveals a clearer structural and functional organisation within rodent cingulate cortex itself. Based on these insights, we call for widespread adoption of the homologous nomenclature, and reinterpretation of previous studies originally based on the nonhomologous partitioning of rodent cingulate cortex. To compare findings across species, neuroscience relies on cross-species homologies, particularly in terms of brain areas. For cingulate cortex, a structure implicated in behavioural adaptation and control, a homologous definition across mammals is available – but currently not employed by most rodent researchers. The standard partitioning of rodent cingulate cortex is inconsistent with that in any other model species, including humans. Reviewing the existing literature, we show that the homologous definition better aligns results of rodent studies with those of other species, and reveals a clearer structural and functional organisation within rodent cingulate cortex itself. Based on these insights, we call for widespread adoption of the homologous nomenclature, and reinterpretation of previous studies originally based on the nonhomologous partitioning of rodent cingulate cortex. Evolutionary success depends on the ability to operate flexibly in a changing environment. This encompasses skills such as planning tasks, selecting among sensory inputs, inhibiting learned actions, and over-riding automatic behaviours. Such operations are mediated to a large extent by prefrontal circuits [1.Rainer G. Behavioral flexibility and the frontal lobe.Neuron. 2007; 53: 321-323Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Prefrontal cortex consists of several substructures, among them the cingulate cortex. Cingulate cortex plays a particularly central role in various functions related to behavioural flexibility, ranging from autonomic regulation to action selection and performance monitoring – both in health [2.Allman J.M. et al.The anterior cingulate cortex.Ann. N. Y. Acad. Sci. 2006; 935: 107-117Crossref Google Scholar, 3.Etkin A. et al.Emotional processing in anterior cingulate and medial prefrontal cortex.Trends Cogn. 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While evidence broadly suggests that cingulate cortex can be divided into a number of structurally and functionally distinct regions [5.Vogt B.A. Cingulate Neurobiology and Disease. Oxford University Press, 2009Google Scholar,8.Vogt B.A. Submodalities of emotion in the context of cingulate subregions.Cortex. 2014; 59: 197-202Crossref PubMed Scopus (38) Google Scholar,9.Vogt B.A. et al.Structural and functional dichotomy of human midcingulate cortex.Eur. J. Neurosci. 2003; 18: 3134-3144Crossref PubMed Scopus (319) Google Scholar], the definition of these regions has undergone several changes throughout the past century. In the past decades, the field has begun to converge on a partitioning system that divides cingulate cortex into several regions along the rostrocaudal axis. The two most anterior of these regions are referred to as anterior cingulate cortex (ACC) and midcingulate cortex (MCC), or alternatively have often been described as ventral ACC (vACC) and dorsal ACC (dACC) (for clarity, we will adhere to the ACC/MCC designation throughout the article (see Box 1 for details on the history of partitioning systems for cingulate cortex). This nomenclature has successfully been implemented across species, including nonhuman primates and rabbits, but has rarely been used in mice and rats (Figure 1, Key Figure).Box 1History of Human Cingulate CortexHuman cingulate cortex has undergone several remappings over the past century. Brodmann [121.Brodmann K. Beiträge zur histologischen lokalisation der grosshirnrinde. III. mitteilung: die rindenfelder der niederen affen.J. Psychol. Neurol. 1909; 4: 177-226Google Scholar] originally divided it into precingulate and postcingulate cortex, with precingulate cortex corresponding to what researchers have since referred to as the ACC and postcingulate cortex corresponding to what today is known as posterior cingulate cortex (PCC). However, in the early 1990s, following the advent of functional neuroimaging methods, studies failed to demonstrate a uniform activation of the ACC in a variety of contexts [122.Goodwin G.M. Neuropsychological and neuroimaging evidence for the involvement of the frontal lobes in depression.J. Psychopharmacol. 1997; 11: 115-122Crossref PubMed Scopus (169) Google Scholar, 123.Grossman M. et al.Attention and sentence processing deficits in Parkinson's disease: the role of anterior cingulate cortex.Cereb. Cortex. 1992; 2: 513-525Crossref PubMed Google Scholar, 124.Nordahl T.E. et al.Regional cerebral metabolic asymmetries replicated in an independent group of patients with panic disorder.Biol. Psychiatry. 1998; 44: 998-1006Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 125.Paus T. et al.Role of the human anterior cingulate cortex in the control of oculomotor, manual, and speech responses: a positron emission tomography study.J. Neurophysiol. 1993; 70: 453-469Crossref PubMed Scopus (696) Google Scholar, 126.Vogt B.A. et al.Functional heterogeneity in cingulate cortex: the anterior executive and posterior evaluative regions.Cereb. Cortex. 1992; 2: 435-443Crossref PubMed Google Scholar]. For instance, emotional processing; for example, in tasks involving emotive facial expressions or emotionally charged voices, results in activation of a portion of perigenual ACC; whereas cognitive processing, for example, in stimulus–response selection tasks under cognitive load, results in activation of the posterior part of ACC, adjacent to the PCC [3.Etkin A. et al.Emotional processing in anterior cingulate and medial prefrontal cortex.Trends Cogn. Sci. 2011; 15: 85-93Abstract Full Text Full Text PDF PubMed Scopus (1590) Google Scholar,27.Bush G. et al.Cognitive and emotional influences in anterior cingulate cortex.Trends Cogn. Sci. 2000; 4: 215-222Abstract Full Text Full Text PDF PubMed Scopus (4296) Google Scholar].To account for this observed dichotomy in activation patterns, ACC was subsequently subdivided into vACC (indicating the anterior segment, surrounding the genu of the corpus callosum; also referred to as rostral ACC) and dorsal ACC (indicating the posterior part, dorsal to the corpus callosum and adjacent to PCC; [127.Devinsky O. et al.Contributions of anterior cingulate cortex to behaviour.Brain. 1995; 118: 279-306Crossref PubMed Google Scholar]). Around the same time, Vogt [5.Vogt B.A. Cingulate Neurobiology and Disease. Oxford University Press, 2009Google Scholar,119.Wang S. et al.The roles of the anterior cingulate cortex and its dopamine receptors in self-paced cost–benefit decision making in rats.Learn. Behav. 2016; 45: 89-99Crossref Scopus (4) Google Scholar] argued that based on anatomical features such as cytoarchitectural borders, receptor distribution, and connectivity profile, as well as on functional divisions, vACC differ from each other to an extent that suggests they should be regarded as distinct structures altogether, rather than as subdivisions of the same 'anterior cingulate' structure. To this end, Vogt [128.Vogt B.A. Structural organization of cingulate cortex: areas, neurons, and somatodendritic transmitter receptors.in: Neurobiology of Cingulate Cortex and Limbic Thalamus. Birkhäuser Boston, 1993: 19-70Crossref Google Scholar] introduced a nomenclature by which vACC is referred to as ACC and dACC is considered part of midcingulate cortex (MCC (see Figure 1 in main text). Since the publication of Vogt's book on the cingulate cortex in 2009 [5.Vogt B.A. Cingulate Neurobiology and Disease. Oxford University Press, 2009Google Scholar], which was based on a wide-ranging synthesis of the literature available at the time, argued in favour of a clear distinction between ACC and MCC, the scientific community has increasingly adopted this nomenclature. This transition has proved useful, laying the ground for integrating data on differences in function, connectivity, and potential malfunctions into a comprehensive model of ACC and MCC functioning [15.Vogt B.A. Midcingulate cortex: structure, connections, homologies, functions and diseases.J. Chem. Neuroanat. 2016; 74: 28-46Crossref PubMed Google Scholar]. Furthermore, cross-species comparisons were bolstered as ACC and MCC could be identified consistently in the primate, rabbit, and rodent brains [15.Vogt B.A. Midcingulate cortex: structure, connections, homologies, functions and diseases.J. Chem. Neuroanat. 2016; 74: 28-46Crossref PubMed Google Scholar]. Human cingulate cortex has undergone several remappings over the past century. Brodmann [121.Brodmann K. Beiträge zur histologischen lokalisation der grosshirnrinde. III. mitteilung: die rindenfelder der niederen affen.J. Psychol. Neurol. 1909; 4: 177-226Google Scholar] originally divided it into precingulate and postcingulate cortex, with precingulate cortex corresponding to what researchers have since referred to as the ACC and postcingulate cortex corresponding to what today is known as posterior cingulate cortex (PCC). However, in the early 1990s, following the advent of functional neuroimaging methods, studies failed to demonstrate a uniform activation of the ACC in a variety of contexts [122.Goodwin G.M. Neuropsychological and neuroimaging evidence for the involvement of the frontal lobes in depression.J. Psychopharmacol. 1997; 11: 115-122Crossref PubMed Scopus (169) Google Scholar, 123.Grossman M. et al.Attention and sentence processing deficits in Parkinson's disease: the role of anterior cingulate cortex.Cereb. Cortex. 1992; 2: 513-525Crossref PubMed Google Scholar, 124.Nordahl T.E. et al.Regional cerebral metabolic asymmetries replicated in an independent group of patients with panic disorder.Biol. Psychiatry. 1998; 44: 998-1006Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 125.Paus T. et al.Role of the human anterior cingulate cortex in the control of oculomotor, manual, and speech responses: a positron emission tomography study.J. Neurophysiol. 1993; 70: 453-469Crossref PubMed Scopus (696) Google Scholar, 126.Vogt B.A. et al.Functional heterogeneity in cingulate cortex: the anterior executive and posterior evaluative regions.Cereb. Cortex. 1992; 2: 435-443Crossref PubMed Google Scholar]. For instance, emotional processing; for example, in tasks involving emotive facial expressions or emotionally charged voices, results in activation of a portion of perigenual ACC; whereas cognitive processing, for example, in stimulus–response selection tasks under cognitive load, results in activation of the posterior part of ACC, adjacent to the PCC [3.Etkin A. et al.Emotional processing in anterior cingulate and medial prefrontal cortex.Trends Cogn. Sci. 2011; 15: 85-93Abstract Full Text Full Text PDF PubMed Scopus (1590) Google Scholar,27.Bush G. et al.Cognitive and emotional influences in anterior cingulate cortex.Trends Cogn. Sci. 2000; 4: 215-222Abstract Full Text Full Text PDF PubMed Scopus (4296) Google Scholar]. To account for this observed dichotomy in activation patterns, ACC was subsequently subdivided into vACC (indicating the anterior segment, surrounding the genu of the corpus callosum; also referred to as rostral ACC) and dorsal ACC (indicating the posterior part, dorsal to the corpus callosum and adjacent to PCC; [127.Devinsky O. et al.Contributions of anterior cingulate cortex to behaviour.Brain. 1995; 118: 279-306Crossref PubMed Google Scholar]). Around the same time, Vogt [5.Vogt B.A. Cingulate Neurobiology and Disease. Oxford University Press, 2009Google Scholar,119.Wang S. et al.The roles of the anterior cingulate cortex and its dopamine receptors in self-paced cost–benefit decision making in rats.Learn. Behav. 2016; 45: 89-99Crossref Scopus (4) Google Scholar] argued that based on anatomical features such as cytoarchitectural borders, receptor distribution, and connectivity profile, as well as on functional divisions, vACC differ from each other to an extent that suggests they should be regarded as distinct structures altogether, rather than as subdivisions of the same 'anterior cingulate' structure. To this end, Vogt [128.Vogt B.A. Structural organization of cingulate cortex: areas, neurons, and somatodendritic transmitter receptors.in: Neurobiology of Cingulate Cortex and Limbic Thalamus. Birkhäuser Boston, 1993: 19-70Crossref Google Scholar] introduced a nomenclature by which vACC is referred to as ACC and dACC is considered part of midcingulate cortex (MCC (see Figure 1 in main text). Since the publication of Vogt's book on the cingulate cortex in 2009 [5.Vogt B.A. Cingulate Neurobiology and Disease. Oxford University Press, 2009Google Scholar], which was based on a wide-ranging synthesis of the literature available at the time, argued in favour of a clear distinction between ACC and MCC, the scientific community has increasingly adopted this nomenclature. This transition has proved useful, laying the ground for integrating data on differences in function, connectivity, and potential malfunctions into a comprehensive model of ACC and MCC functioning [15.Vogt B.A. Midcingulate cortex: structure, connections, homologies, functions and diseases.J. Chem. Neuroanat. 2016; 74: 28-46Crossref PubMed Google Scholar]. Furthermore, cross-species comparisons were bolstered as ACC and MCC could be identified consistently in the primate, rabbit, and rodent brains [15.Vogt B.A. Midcingulate cortex: structure, connections, homologies, functions and diseases.J. Chem. Neuroanat. 2016; 74: 28-46Crossref PubMed Google Scholar]. Even though studies in mice and rats have played a key role in elucidating neuronal mechanisms by which cingulate cortex drives behavioural regulation [8.Vogt B.A. Submodalities of emotion in the context of cingulate subregions.Cortex. 2014; 59: 197-202Crossref PubMed Scopus (38) Google Scholar], the anatomical partitioning system they most commonly use, as discussed in more detail later, cannot be directly translated to findings in virtually any other species, in terms of both structure and function [10.Laubach M. et al.What, if anything, is rodent prefrontal cortex?.eNeuro. 2018; 5ENEURO.0315-18.2018Crossref Scopus (29) Google Scholar, 11.Vogt B.A. Paxinos G. Cytoarchitecture of mouse and rat cingulate cortex with human homologies.Brain Struct. Funct. 2014; 219: 185-192Crossref PubMed Scopus (135) Google Scholar, 12.Lee I.-S. et al.A new animal model of placebo analgesia: involvement of the dopaminergic system in reward learning.Sci. 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By tracking the appearance of terms such as prefrontal cortex and cingulate cortex in >10 000 studies in several species including humans, primates, and rodents, the authors were able to explicitly demonstrate the lack of consensus on anatomical definitions. While this constitutes a crucial step towards a more unified approach, their review (partly in view of its breadth) did not address how well different nomenclatures reflect the actual anatomical/functional boundaries within cingulate cortex. Here, we set out to add this perspective. To this end, we directly compare the structural and functional distinctiveness of cingulate cortex regions based either on the homologous ACC/MCC or the nonhomologous Cg1/Cg2 nomenclature of rodent cingulate cortex. Our comparisons suggest that applying the ACC/MCC definition not only reconciles findings on cingulate cortex across species, but also clarifies the functional and structural organization within rodent cingulate cortex itself. In the following sections, we first briefly introduce the structure and function of human ACC/MCC as a benchmark, then discuss competing nomenclatures of rodent cingulate cortex and their functional implications. We conclude with recommendations for how future studies on cingulate cortex may provide new grounds for cross-species comparison and synergy. Human ACC encompasses the frontal third of cingulate cortex, surrounding the rostral part of the corpus callosum (A24a–c, A25, A32, and A33), while MCC occupies the middle third of the cingulate cortex (A24a′–c′, A32′, and A33′). Both ACC and MCC can be subdivided into two subregions – pregenual (pACC) and subgenual ACC (sACC), and anterior MCC (aMCC) and posterior MCC (pMCC; Figure 2A , zoom-in inset). While human cingulate cortex additionally contains other regions – specifically, posterior cingulate cortex and retrosplenial cortex (RSC) – this article focuses solely on ACC/MCC and their homologous definition across species. In this section, we mainly summarize diffusion-weighted magnetic resonance imaging studies that investigated the connectivity patterns of human ACC and MCC. Due to the limited spatial resolution of these techniques, it is difficult to make specific statements about the exact laminar origin and termination of projections. We thus use the term connectivity to refer to the existence of tracts between ACC/MCC and other brain regions. Like all prefrontal areas, ACC and MCC are both highly connected with frontal cortex: they show strong connections with orbitofrontal cortex (OFC), ventromedial prefrontal cortex (vmPFC), and dorsolateral prefrontal cortex (dlPFC) [22.Beckmann M. et al.Connectivity-based parcellation of human cingulate cortex and its relation to functional specialization.J. Neurosci. 2009; 29: 1175-1190Crossref PubMed Scopus (513) Google Scholar, 23.Koski L. Paus T. Functional connectivity of the anterior cingulate cortex within the human frontal lobe: a brain-mapping meta-analysis.Exp. Brain Res. 2000; 133: 55-65Crossref PubMed Google Scholar, 24.Neubert F.-X. et al.Connectivity reveals relationship of brain areas for reward-guided learning and decision making in human and monkey frontal cortex.Proc. Natl. Acad. Sci. 2015; 112: E2695-E2704Crossref PubMed Scopus (0) Google Scholar]. Apart from this, the connectivity patterns of ACC and MCC relate to distinct functional purposes. ACC strongly connects to areas involved in processing emotional salience, motivation, and autonomic function, such as the amygdala and vmPFC. Connections to autonomic brainstem nuclei are mostly centred in sACC, while extensive connections to amygdala, hypothalamus, nucleus accumbens (NAc), and periaqueductal grey (PAG) are seen throughout sACC and pACC. By contrast, MCC mainly connects to areas involved in action control and decision making, such as dlPFC, sensorimotor and parietal cortex, as well as motor cortices and pontine and PAG nuclei. MCC also contains the cingulospinal motor area. While aMCC receives moderate amygdalar input, this input is absent in pMCC. Unlike ACC, MCC is not part of the default-mode network, but is considered to be part of the salience network [25.Palomero-Gallagher N. et al.Cytology and receptor architecture of human anterior cingulate cortex.J. Comp. Neurol. 2008; 508: 906-926Crossref PubMed Scopus (0) Google Scholar,26.Seeley W.W. et al.Dissociable intrinsic connectivity networks for salience processing and executive control.J. Neurosci. 2007; 27: 2349-2356Crossref PubMed Scopus (3730) Google Scholar]. Figure 2B summarizes the connectivity profiles of ACC and MCC. The functional importance of human ACC and MCC was first highlighted by studies of patients with ACC and/or MCC lesions, who were reported to suffer from diverse symptoms, including apathy, as well as dysregulation of autonomic functions, emotion, attention, and error monitoring [27.Bush G. et al.Cognitive and emotional influences in anterior cingulate cortex.Trends Cogn. Sci. 2000; 4: 215-222Abstract Full Text Full Text PDF PubMed Scopus (4296) Google Scholar,28.Løvstad M. et al.Anterior cingulate cortex and cognitive control: Neuropsychological and electrophysiological findings in two patients with lesions to dorsomedial prefrontal cortex.Brain Cogn. 2012; 80: 237-249Crossref PubMed Scopus (0) Google Scholar]. In the past few decades, neuroimaging work has expanded on these initial findings, demonstrating that ACC serves as a processing hub for the regulation of autonomic responses, as well as assessing emotional and motivational aspects of internal and external information [29.Stevens F.L. et al.Anterior cingulate cortex: unique role in cognition and emotion.J. Neuropsychiatry. 2011; 23: 121-125Crossref PubMed Scopus (152) Google Scholar]. For instance, emotional contexts such as seeing emotional faces or listening to emotionally charged voices, reliably activate ACC [30.Killgore W.D.S. Yurgelun-Todd D.A. Activation of the amygdala and anterior cingulate during nonconscious processing of sad versus happy faces.NeuroImage. 2004; 21: 1215-1223Crossref PubMed Scopus (215) Google Scholar]. Consistent with ACC's strong interconnection with autonomic brainstem nuclei, one of the most robust findings across species is that electrical stimulation of ACC depresses autonomic activity [31.Cechetto D.F. Cortical control of the autonomic nervous system.Exp. Physiol. 2013; 99: 326-331Crossref PubMed Scopus (55) Google Scholar], leading to reduced blood pressure/heart rate, and respiratory inhibition. MCC, by contrast, has been highlighted to play a role in different facets of cognitive control, such as response selection, attentional processing, monitoring conflict, and detecting errors [3.Etkin A. et al.Emotional processing in anterior cingulate and medial prefrontal cortex.Trends Cogn. Sci. 2011; 15: 85-93Abstract Full Text Full Text PDF PubMed Scopus (1590) Google Scholar,27.Bush G. et al.Cognitive and emotional influences in anterior cingulate cortex.Trends Cogn. Sci. 2000; 4: 215-222Abstract Full Text Full Text PDF PubMed Scopus (4296) Google Scholar]. MCC's role in decision-making seems to be especially pronounced in reward-based decision-making [32.Rushworth M.F. Behrens T.E. Choice, uncertainty and value in prefrontal and cingulate cortex.Nat. Neurosci. 2008; 11: 389-397Crossref PubMed Scopus (540) Google Scholar,33.Heilbronner S.R. Hayden B.Y. Dorsal anterior cingulate cortex: a bottom-up view.Annu. Rev. Neurosci. 2016; 39: 149-170Crossref PubMed Google Scholar]. Given the strong activation of this area in a multitude of task domains, an overarching theory is difficult to establish and has been the topic of intense debate [34.Kolling N. et al.Multiple signals in anterior cingulate cortex.Curr. Opin. Neurobiol. 2016; 37: 36-43Crossref PubMed Scopus (99) Google Scholar,35.Shenhav A. et al.Dorsal anterior cingulate cortex and the value of control.Nat. Neurosci. 2016; 19: 1286-1291Crossref PubMed Google Scholar]. Overall, MCC activity seems to relate to multiple aspects of updating beliefs and internal models of the environment to guide decision-making [36.Kolling N. et al.Value, search, persistence and model updating in anterior cingulate cortex.Nat. Neurosci. 2016; 19: 1280-1285Crossref PubMed Scopus (136) Google Scholar]. Studies using sophisticated task designs have also shown that ACC and MCC are often active during the same task but code for complementary task-related parameters [37.Kolling N. et al.Prospection, perseverance, and insight in sequential behavior.Neuron. 2018; 99: 1069-1082.e1067Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. Figure 3 summarizes to which behavioural aspects ACC and MCC have been found to contribute. The most popular partitioning system for rodent cingulate cortex defines two subareas: Cg1 and Cg2, located dorsally to each other (Figure 4A ). Cg1 encompasses A24b and A24b′ and Cg2 consists of A24a and A24a′. A25 and A32, which are considered as part of ACC in other mammals, are not part of either Cg1 or Cg2, but treated as separate areas [infralimbic cortex (IL) and prelimibic cortex (PL), respectively; Figure 4A]. As Figure 1, Figure 4 show, although this definition can be applied consistently in rats and mice, it is not homologous to the ACC/MCC definition used in other mammals [5.Vogt B.A. Cingulate Neurobiology and Disease.