What, If Anything, Is Rodent Prefrontal Cortex? — TEI-tagged view

LaubachpersName, AmarantepersName, SwansonpersName, WhitepersName (2018date). “What, If Anything, Is Rodent Prefrontal Cortex?.” eNeurotitle·j.

Object of study — the word 'prefrontalterm' - what it refers to in rodentsterm, what it refers to in primatesterm, and whether those are the same thing

Research question — what, if anything, is rodentterm prefrontal cortexterm·def - with the 'if anything' meant literally

Contribution — four independent measurements showing that one anatomical term has no agreed referent, and a proposed crosswalk to the primateterm cingulateterm scheme

Full text — tagged

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What, If Anything, Is Rodentterm Prefrontal Cortexterm·def?

Mark LaubachpersName Mark LaubachpersName 1 Department of Biology and Center for Behavioral Neuroscience, American University, Washington, DC 20016 1, ✉ , Linda M AmarantepersName Linda M AmarantepersName 1 Department of Biology and Center for Behavioral Neuroscience, American University, Washington, DC 20016 1 , Kyra SwansonpersName Kyra SwansonpersName 1 Department of Biology and Center for Behavioral Neuroscience, American University, Washington, DC 20016 1 , Samantha R WhitepersName Samantha R WhitepersName 1 Department of Biology and Center for Behavioral Neuroscience, American University, Washington, DC 20016 1 Department of Biology and Center for Behavioral Neuroscience, American University, Washington, DC 20016 The authors declare no competing financial interests.

Author contributions: M.L., L.M.A., K.S., and S.R.W. designed research; M.L., L.M.A., K.S., and S.R.W. performed research; M.L., L.M.A., K.S., and S.R.W. analyzed data; M.L., L.M.A., K.S., and S.R.W. wrote the paper.

✉ Correspondence should be addressed to Dr. Mark LaubachpersName, Department of Biology, Center for Behavioral Neuroscience American University, 4400 Massachusetts Avenue NW, Washington, DC 20016-8062, E-mail: mark.laubachpersName@american.edu .

✉ Corresponding author.

Received 2018 Aug 13; Revised 2018 Oct 5; Accepted 2018 Oct 9; Prepublished 2018 Oct 18; Collection date 2018 Sep-Oct.

Copyright © 2018 LaubachpersName et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

PMCID: PMC6220587 PMID: 30406193 Visual Abstract Keywords: atlasterm, callosum, cingulated, meta-analysisterm·mth, prefrontalterm, surveyterm·mth Abstract Prefrontal cortexterm·def (PFCterm) means different things to different people. In recent years, there has been a major increase in publications on the PFCterm, especially using mice. However, inconsistencies in the nomenclatureterm and anatomical boundaries of PFCterm areas has made it difficult for researchers to compare data and interpret findings across speciesterm. We conducted a meta-analysisterm·mth of publications on the PFCterm of humansterm and rodentsterm and found dramatic differences in the focus of research on these speciesterm. In addition, we compared anatomical terms and criteria across several common rodentterm brain atlasesterm and found inconsistencies among, and even within, leading atlasesterm. To assess the impact of these issues on the research community, we conducted a surveyterm·mth of established PFCterm researchers on their use of anatomical terms and found little consensusterm. We report on the results of the surveyterm·mth and propose an alternative scheme for interpreting data from rodentterm studies, based on structural analysis of the corpus callosumterm and nomenclatureterm used in research on the anterior cingulateterm cortex (ACCterm) of primatesterm.

Significance Statement Studies on prefrontalterm parts of the rodentterm cerebral cortex have appeared at an increasing rate in recent years. However, there has been no consensusterm on the terms used to describe the rodentterm prefrontal cortexterm·def (PFCterm) or how it relates to the PFCterm of monkeys and humansterm. To address these issues, we conducted a meta-analysisterm·mth of publications on the PFCterm across speciesterm, a review of rodentterm brain atlasesterm, a surveyterm·mth of PFCterm researchers on anatomicterm terms, and an analysis of how speciesterm differences in the corpus callosumterm might help relate PFCterm areas across speciesterm. Addressing these issues may help improve the clarity, rigor, and reproducibilityterm of research on the rodentterm PFCterm.

The anatomicterm term “prefrontalterm” means different things to different people. For neuroscientists studying humansterm and nonhuman primatesterm, prefrontal cortexterm·def (PFCterm) typically means the granular and orbital parts of the frontal cortex. These researchers often use variations of the term anterior cingulateterm cortex (ACCterm) to refer to agranular areas in the medial frontal cortex. By contrast, researchers studying rodentsterm tend to use the term PFCterm to refer to the same medial frontal areas that are often called ACCterm in primatesterm. Confusionterm can arise when the same anatomicterm term applies to different areas in different speciesterm. Anatomicterm terms should mean the same thing across speciesterm. The lack of consensusterm on terms and acronymsterm is apparent, for example, in the NeuroNames database, which seeks to account for anatomicterm terms across speciesterm that are commonly used in neuroscience research ( Bowden et al., 2012 ). For the PFCterm, it has been difficult to incorporate findings made using the latest cutting-edge research tools, which typically depend on rodentterm research, into the larger PFCterm literature. It is easy to dismiss this issue as one of “mere” semantics or terminologyterm, but it has significant, long-term consequences for our field. For instance, it is not uncommon for researchers to use information about one prefrontalterm area in a rodentterm speciesterm to understand a completely different prefrontalterm area in a primateterm speciesterm ( Chen et al., 2013 ; Ferenczi and Deisseroth, 2016 ; Terraneo et al., 2016 ).

Here, we attempt to address this issue by asking a simple question: What, if anything, is rodentterm PFCterm? The phrase “if anything” emphasizes the idea that we are not sure if there is a clear answer to our question. In particular, we do not wish to dispute the idea that rodentsterm have a PFCterm. However, it may be that a standard set of anatomicterm terms, based on established cross-species homologies in the frontal cortex ( Vogt and Paxinos, 2014 ), should be used to describe the “rodentterm PFCterm.” These terms might or might not include the word “prefrontalterm” without implying that the area in question is not a prefrontalterm area. For example, researchers who study monkeys and humansterm know that the orbitofrontal cortex is part of the primateterm PFCterm without the need to include the word “prefrontalterm” in its name. That said, we are well aware of disagreements throughout the history of neuroscience about anatomicterm terms (e.g., V5 vs MT: Zeki, 2004 ) and the fact that there is no accepted “Code of Conduct” for reporting anatomicterm results. (Perhaps there should be.) This article is in four parts. First, we review recent publication trends on PFCterm in humansterm, monkeys, rats, and mice. A meta-analysisterm·mth reveals that humanterm and rodentterm research has diverged to some extent, mostly due to a major focus of humanterm studies on high-level cognitive processes that are associated with granular parts of the lateral PFCterm ( Petrides, 2005 ). These areas do not exist in rodentsterm ( Preuss, 1995 ), and our meta-analysisterm·mth reveals that rodentterm researchers have focused on cognitive functions associated with medial, but not lateral, PFCterm. Second, confusionterm and controversy about rodentterm PFCterm has persisted in part due to the use of multiple sets of anatomicterm terms and acronymsterm to describe areas on the medial wall of the frontal cortex and inconsistencies among, and even within, leading rodentterm brain atlasesterm. We highlight some of these issues. Third, we report on a crowdsourcing effort that was conducted to assess usage of anatomicterm terms for the rodentterm PFCterm. The surveyterm·mth revealed that there is little consensusterm among researchers about what constitutes the rodentterm PFCterm and what terms should be used to describe this cortical region. Finally, we describe differences in the shape of the corpus callosumterm underlying the frontal cortex that might be helpful for comparing medial frontal areas across speciesterm. Our analysis suggests that rodentterm PFCterm areas may readily be understood within a framework that is commonly used to describe the primateterm ACCterm, and consists of dorsal, pregenual (rostral), and subgenual (ventral) regions with clearly dissociable connectivity and functions. To this end, we conclude with some recommendations for reporting anatomicterm data in rodentterm studies that should help resolve issues across labs and improve the rigor and reproducibilityterm of PFCterm research.

Publication Trends in Rodentterm PFCterm Research Publications on the PFCterm have appeared at an increasing rate since 1990 ( Fig. 1 A ). The sudden onset of interest in the PFCterm among neuroscientists was motivated by early studies on the PFCterm of macaque monkeys by research groups headed by Fuster ( Fuster and Alexander, 1971 ) and Goldman-Rakic (for review, see Goldman-Rakic 1995 ). Key findings from these early studies were that neurons in the primateterm dorsolateral PFCterm (Brodmann’s areas 9 and 46) encode spatial “working memory” signals by firing persistently over delay periods ( Funahashi et al., 1989 ) and that the signals were highly sensitive to perturbations of cortical dopamine receptors ( Williams and Goldman-Rakic, 1995 ). In parallel with these neurophysiological studies, early neuroimaging studies (PET and fMRI) implicated the humanterm PFCterm in higher-order cognitive processing such as attention ( Pardo et al., 1991 ) and working memory ( McCarthy et al., 1994 ). Overall, the focus of research on the PFCterm of humansterm and monkeys in the 1990s was the dorsolateral (granular) PFCterm and its role in higher cognitive processing.

Figure 1.

Publication trends in PFCterm research. A , Publications per year on the PFCterm of humansterm, rats, mice, and monkeys from 1945 to 2016. Publication trends on monkey PFCterm (orange line) have remained unchanged and were not further analyzed. B , Publications on the PFCterm of mice are appearing at a higher rate than those on rats in the period from 1990 to 2016.

Perhaps motivated by these findings, publications on the rodentterm PFCterm also appeared at an increasing rate starting around 1990 ( Fig. 1 A ). Early rodentterm studies used neurochemical lesions, instead of neuronal recordings, and focused on determining whether rodentterm PFCterm areas are crucial for a variety of cognitive processes, such as spatial memory ( Shaw and Aggleton, 1993 ), attention ( Muir et al., 1996 ), and reversal learning ( Bussey et al., 1997 ). Given clear differences in PFCterm anatomy across speciesterm, a debate emerged during this period about whether rodentterm PFCterm studies were relevant for understanding the primateterm PFCterm, which generally meant the dorsolateral cortex, and especially areas around the principal sulcus in macaques.

Early definitionsterm of prefrontal cortexterm·def in rodentsterm were based on a classic study by Rose and Woolsey (1948) , who argued that prefrontalterm areas should be defined as having connections with the mediodorsal nucleus of the thalamus (MD). This view was supported by anatomicterm studies such as Krettek and Price (1977) , Groenewegen (1988) , and Condé et al. (1990) and served as the basis for early claims that the rat prefrontal cortexterm·def had functions similar to the primateterm dorsolateral PFCterm and was crucial for spatial working memory ( Kolb, 1984 , 1990 ). However, more recent studies challenged both the anatomicterm and behavioral bases of this view.

For example, the efferent projections of the thalamic nucleus MD include the “medial precentral area” ( Groenewegen, 1988 ), also known as “medial agranular cortex” or “M2.” In contrast to the prelimbicterm and infralimbicterm areas, the medial precentral area was found to receive inputs from sensorimotor parts of the cerebral cortex ( Reep et al., 1990 ; Van Eden et al., 1992 ; Condé et al., 1995 ), project to sensorimotor subcortical regions ( Reep et al., 1987 ), and produce movements of the eyes, neck, and jaws when electrically stimulated ( Neafsey et al., 1986 ). As such, it became thought of as potentially analogous to the frontal eye fields of macaque monkeys ( Reep et al., 1987 ) and raised problems for the PFCterm definitionterm of Rose and Woolsey.

Nucleus MD also projects to orbital regions of the frontal cortex, areas denoted as MO, VO, and LO ( Groenewegen, 1988 ). The connectivity of these regions were studied in monkeys and rats by Price and colleagues ( An et al., 1998 ; Bandler et al., 2000 ; Floyd et al., 2000 , 2001 ). In a review by Ongür and Price (2000) on anatomically defined networks within the frontal cortex, the “rat” orbital areas were held out of a proposed “orbital network” (based on patterns of connectivity in monkeys and humansterm) because of the connectivity of the rat areas with “visceral” structures such as the hypothalamus and periaqueductal gray. Such connections are not associated with the primateterm OFC or dorsolateral PFCterm, raising more problems for the PFCterm definitionterm of Rose and Woolsey.

In parallel with these anatomicterm studies, a number of behavioral studies emerged that challenged the idea that the rodentterm PFCterm cortex mediated spatial working memory ( Kolb, 1984 ). Lesions of the prelimbicterm cortex were found to impair spatial delayed alternation in the T-maze ( Brito et al., 1982 ) and operant chambers ( van Haaren et al., 1988 ; Dunnett et al., 1999 ). However, these effects were transient in nature ( Delatour and Gisquet-Verrier, 2001 ) and may have been due to reductions in spontaneous alternation ( Delatour and Gisquet-Verrier, 1996 ). Moreover, lesions of mPFCterm did not impair performance in another test of spatial working memory, the radial arm maze ( Delatour and Gisquet-Verrier, 1996 ; Ragozzino et al., 1998 ; Gisquet-Verrier and Delatour, 2006 ). Together, these findings led to the idea that the rodentterm PFCterm is important for “working-with-memory” but not spatial memory per se ( Moscovitch and Winocur, 1992 ).

To address the emerging issue of how the frontal cortex of rodentsterm related to the prefrontal cortexterm·def of primatesterm, Preuss (1995) wrote a thoughtful review on cross-species issues and concluded that rodentsterm “probably do not provide useful models of humanterm dorsolateral frontal lobe function” but “might prove valuable” for understanding other humanterm frontal areas, such as the cingulateterm and premotor cortices. Several reviews by anatomists and behavioral neuroscientists appeared several years after the publication of Preuss’ manuscript ( Brown and Bowman, 2002 ; Heidbreder and Groenewegen, 2003 ; Uylings et al., 2003 ; Dalley et al., 2004 ) and argued for common functions, as opposed to common structures, among rodentterm and primateterm PFCterm areas. As a consequence of these competing views, the meaning of the word “prefrontal” in rodent studiesterm·def remained unclear. However, since the publication of Preuss’s article, one clear change is apparent: the disappearance of the rodentterm orbital areas (MO, VO, and LO) from the prefrontalterm taxonomy. A major driver for this change might have been a study by Schoenbaum et al. (1998) that reported data from this part of the rat cortex as some of the first evidence for the encoding of expected outcomes. These researchers referred to the cortical region as “OFC” and this term has largely been used since that time.

In recent years, two lines of research have emerged that may eventually solve the dilemma of what is prefrontal cortexterm·def in rodentsterm. Both are based on measures of connectivity and not function. One was developed by Rogier Mars and colleagues using various measures of functional and structural connectivity ( Mars et al., 2013 , 2016 ; Neubert et al., 2015 ). The most recent platform for this approach is capable of revealing common patterns of whole brain connectivity in monkeys and humansterm ( Mars et al., 2018 ) and might be an excellent approach for understanding the problem of the rodentterm PFCterm. Additionally, a tract-tracing approach was developed by Heilbronner et al. (2016) , focused on corticostriatal connectivity, and revealed clear common patterns of connections for cortical regions such as the prelimbicterm cortex.

In parallel with these anatomicterm findings on the PFCterm, new insights into PFCterm function emerged as methods for chronic multi-electrode recordings in behaving rodentsterm emerged in the late 1990s. These methods allowed for examining the functional properties of PFCterm neurons in rodentsterm performing presumed PFC-dependent behavioral tasks. A hunt for “Goldman-Rakic” neurons in rats was undertaken by several labs.

However, no group found evidence for substantial numbers of neurons in the rodentterm PFCterm neurons firing persistently over delay periods to encode spatial information ( Jung et al., 1998 ; Baeg et al., 2003 ). When persistent activity was found, it was associated with behaviors such as holding down a lever ( Narayanan and LaubachpersName, 2006 ) or maintaining stable body position ( Cowen and McNaughton, 2007 ) over a delay period. These signals from the rat PFCterm were more in line with early studies on the primateterm ACCterm ( Niki and Watanabe, 1979 ; who reporting ramping activity over delay periods in an action timing task) than on the dorsolateral PFCterm. As a result, many rat researchers shifted away from studying spatial processing (with some exceptions; Spellman et al., 2015 ), to issues associated with the primateterm ACCterm and OFC, such as sequencing actions and outcomes (monkey: Procyk et al., 2000 ; rat: Lapish et al., 2008 ), performance monitoring and adjustment (monkey: Ito et al., 2003 ; rat: Narayanan and LaubachpersName, 2008 ), and encoding changes in reward contingencies during learning (monkey: Tremblay and Schultz, 1999 ; Wallis and Miller, 2003 ; Rudebeck et al., 2013 ; rat: Schoenbaum et al., 1999 ; Takahashi et al., 2009 ; van Duuren et al., 2009 ; Sul et al., 2010 ).

During the late 2000s, there was a sudden increase in publications on the mouse PFCterm ( Fig. 1 A ). This trend was likely driven by advances in genetic models of humanterm mental illness ( Sigurdsson et al., 2010 ) and new research tools such as optogenetics ( Covington et al., 2010 ). Given recent publication rates ( Fig. 1 B ), there are projected to be more studies published on the mouse PFCterm than the rat PFCterm by the end of the current decade. We wondered whether some of the same issues that plagued early PFCterm studies in rats had reemerged in the mouse literature (e.g., claims that mouse PFCterm is dlPFCterm and has a role in spatial working memory). We conducted a meta-analysisterm·mth of recent publications on the PFCterm in mice, rats, monkeys, and humansterm by examining word frequencies in articles published since 2000. Word cloudsterm·mth for the most common terms in the abstracts of these articles are shown in Figure 2 . Terms are color coded by meaning (pharmacological terms in purple; anatomicterm terms in orange; diseases and medical conditions in blue; psychological constructs in green; other terms in red). The word cloudsterm·mth show that research on the PFCterm of primatesterm and rodentsterm is focused on different issues. Humanterm and monkey PFCterm research emphasizes the dorsolateral PFCterm, cognitive issues such as working memory, and diseases such as schizophrenia. By contrast, rat and mouse PFCterm research emphasizes the medial PFCterm, dopamine, and gene expression. Our meta-analysisterm·mth suggests that the word “prefrontalterm” really does mean different things to humanterm and rodentterm researchers.

Figure 2.

Research focus of prefrontalterm publications. Word cloudsterm·mth with functional color grouping for papers published on the PFCterm of mice, rats, monkeys, and humansterm since 2000. Pharmacological terms are purple. Anatomicterm terms are orange. Terms associated with diseases and other medical conditions are blue. Psychological constructs are green. Other terms are red.

Differences in word frequencies within a speciesterm are easy to see in word cloudsterm·mth. However, word cloudsterm·mth do not allow so readily for comparing word frequencies across speciesterm, as the viewer has to search for a given term in each word cloudterm·mth and then compare the size of each word across a series of figure panels. A more direct method for comparing terms across speciesterm is to plot the relative frequencyterm·var of each term using Hinton plots, which were developed for visualizing weights of hidden units in neural networks ( Hinton and Shallice, 1991 ). To make Hinton plots of the word frequencies for each functional category of terms, we determined what words were the ten most common in the collection of mouse papers and then added in new terms that were included in the ten most common terms from the other speciesterm. This approach revealed that anatomicterm terms were the most diverse, with 22 terms needed to account for all four speciesterm. By contrast, disease-related terms were least diverse, with just 12 terms needed to account for the ten most common terms across speciesterm. These reduced list of leading terms (12–22) were then used for the Hinton plots, and those for anatomicterm, neurochemical, and disease related terms are shown in Figure 3 A .

Figure 3.

Word frequencies across speciesterm. A , Hinton plots for anatomicterm, neurochemical, and disease-related terms in papers focused on the prefrontal cortexterm·def of mice, rats, monkeys, and humansterm. In each plot, columns denote speciesterm and rows denote terms. The relative frequencyterm·var of each term is represented by a square, and the size of the square is defined as the word count divided by total wordsterm·stat. Plots are color coded using the same colors as in Figure 2. Most notable, was the use of certain anatomicterm terms in monkey studies (e.g., FEF, OFC, vlPFC) that are not common in the humanterm or rodentterm literature. B , Bar plots of the most common terms for rodentsterm (mice and rats) and primatesterm (monkeys and humansterm). Anatomicterm terms were sharply divided across orders (rodentsterm versus primatesterm). Rodentterm studies were focused on the “mPFCterm,” and primateterm studies were focused on the “dlPFCterm.” By contrast, publications focused on neurotransmitters such as dopamine and serotonin were more common in rodentterm studies, but the relative frequencies of these terms were not discordant across speciesterm. A somewhat different finding was apparent in relative word frequencies for diseases and disorders. Rodentterm studies, especially in rats, more often addressed stress than studies in primatesterm, and primateterm studies more often addressed schizophrenia compared to the rodentterm literature.

The plots revealed interesting insights into the use of specific terms within and among speciesterm. For example, several anatomicterm terms were quite common in the monkey literature (e.g., FEF, OFC, parietal, vlPFC) and not so common in the other speciesterm, including the humanterm PFCterm literature. In a similar way, the common rodentterm terms prelimbicterm and infralimbicterm were largely absent from the monkey and humanterm literature. The most common term in rodentsterm was “mPFCterm” and the most common term in primatesterm was “dlPFCterm.” The discordance in these terms was further emphasized in a new bar plot shown in Figure 3 B , top plot.

The situation with neurochemicals (transmitters and drugs) was less discordant. Some exceptions were dopamine (a bit overemphasized in rodentterm studies), ethanol but not alcohol (ethanol overemphasized in rodentterm studies, alcohol equally common across speciesterm), and N-acetylaspartic acid (NAA) only occurring in humanterm studies, where it has been used as a marker for neurodegenerative disorders. The two most common neurochemical terms, dopamine and serotonin, showed similar overall relative frequencies across speciesterm, with the exception of dopamine. It has been used more in studies of the rat PFCterm than other speciesterm, including in comparison to the mouse literature. This point is depicted in a new bar plot in Figure 3 B , middle plot.

Usage of terms associated with diseases and disorders was the least diverse across speciesterm. Yet, two terms showed up with divergent frequencies in rodentsterm and primatesterm. Schizophrenia is a major term in all speciesterm and, perhaps not surprisingly, especially in studies of the humanterm PFCterm. By contrast, stress was the most common disease-related term in the rat literature, perhaps due to the utility of classic behavioral assays such as restraint and the forced swim test in rodentsterm. The relative frequencies of these terms were further emphasized in a new bar plot in Figure 3 B , lower plot.

PFCterm Nomenclatureterm in Rodentsterm Rodentterm PFCterm is agranular in most speciesterm and there is evidence for homologies, based on cytoarchitecture, among medial parts of the PFCterm, especially the anterior cingulateterm cortex (ACCterm), in rodentsterm, humansterm, and monkeys ( Vogt and Gabriel, 1993 ; Vogt et al., 2013 ; Vogt and Paxinos, 2014 ). There have been numerous publications on the medial PFCterm in humansterm (3652 publications according to a PubMed search in June 2018, with some researchers referring to the area as ventromedial prefrontalterm or ventromedial frontal cortex) and rodentsterm (4811 publications). Yet, confusionterm and controversy about the relevance of these rodentterm studies has persisted. We think that controversy about rodentterm PFCterm has persisted for three reasons, all of which reflect confusionterm about anatomicterm nomenclatureterm and not actual physical or physiologic issues. First, the core areas that compose the rodentterm PFCterm are characterized using two different nomenclaturesterm (mPFCterm and ACCterm). Second, multiple terms and acronymsterm are used in prominent brain atlasesterm, and the boundaries for the named areas are inconsistent across atlasesterm. Third, hybrid termsterm·def, such as prelimbicterm medial prefrontal cortexterm·def, have recently emerged in the literature, which are not used in humanterm or non-human primateterm studies. We discuss these issues below and argue that these issues have led to limited collaborationterm between rodentterm and humanterm researchers, evidenced by the small number of publications done in the same behavioral task across speciesterm.

Dual citizenship Rodentterm studies are considered to be “prefrontalterm” when they report data from three cytoarchitectonically defined parts of the frontal cortex: the prelimbicterm, infralimbicterm, and anterior cingulateterm areas. Studies in humansterm and monkeys consider these regions to be part of the mPFCterm, which also includes Walker’s area 10 ( Walker, 1940 ) and the medial parts of area 9, which do not exist in rodentsterm ( Semendeferi et al., 2001 ). A second scheme for cortical nomenclatureterm considers the three rodentterm medial frontal areas as part of the anterior cingulateterm cortex ( Vogt and Gabriel, 1993 ). As such, two distinct anatomicterm terms, ACCterm and mPFCterm, can be used to describe the same three cortical regions. Previous versions of stereotaxic atlasesterm ( Paxinos and Watson, 1982 ; Zilles, 1985 ) referred to the more dorsal and caudal cingulateterm areas as being the cingulateterm cortex, while using the terms “prelimbicterm” and “infralimbicterm” to describe the rostral medial wall regions of the cortex, which may explain why some rodentterm studies report functional differences between the ACCterm and mPFCterm ( Seamans et al., 1995 ). As our surveyterm·mth described below revealed, it seems that some rodentterm PFCterm researchers are aware of, or seemingly prefer, one naming scheme and not the other. This issue has been a major factor in the lack of clarity about the rodentterm PFCterm, and it is confusing to non-PFC researchers.

Alphabet soup/lines in the sand Brain atlasesterm have not made it any easier to define the rodentterm PFCterm. Anatomists have used cytoarchitectural criteria to describe medial parts of the rodentterm frontal cortex as “cingulateterm cortex” in leading brain atlasesterm ( Zilles, 1985 ; Paxinos and Watson, 1986 , 1998 ; SwansonpersName, 1992 ). However, a wide range of terms and acronymsterm have been used to describe these areas. For example, three different acronymsterm have been used to describe the prelimbicterm cortex: PL, PrL, and Cg3 ( Fig. 4 ). Similar to our comments above about the use of the word “prefrontalterm” across speciesterm and dual membership in the mPFCterm and ACCterm nomenclaturesterm, it would be ideal if a single set of anatomicterm terms, and associated acronymsterm, were used to define these cortical regions. The most recent version of the commonly used Paxinos and Watson (2014) rat atlasterm stated “The nomenclatureterm of the rodentterm cingulateterm cortex and related areas has been a major problem for some decades” (page XV). Both mouse ( Paxinos and Franklin, 2012 ) and rat ( Paxinos and Watson, 2014 ) atlasesterm were revised in collaborationterm with a leading cingulateterm cortex anatomist, Brent Vogt ( Vogt and Gabriel, 1993 ; Vogt et al., 2013 ; Vogt and Paxinos, 2014 ), to use slightly different anatomicterm boundaries along the medial wall cortex and label areas with Brodmann’s numbers, e.g., area 32term instead of PL and area 24 instead of Cg1 ( Fig. 4 ). The idea behind these changes, according to the authors, was to make the anatomy more in line with studies in primatesterm (humansterm and monkeys). Unfortunately, a PubMed search reveals that the latest editions of the Paxinos atlasesterm ( Paxinos and Franklin, 2012 ; Paxinos and Watson, 2014 ) have not been used in many recent studies, and labs still use terms from earlier versions of the Paxinos atlasesterm (e.g., 279 publications with “prelimbicterm” and four papers with “area 32term” in the title of studies using rats or mice, based on a PubMed search in October, 2018).

Figure 4.

Anatomicterm terms for rodentterm PFCterm areas. A , Sections from the 4th (1998) and 7th (2014) editions of the commonly used Paxinos and Watson rat brain atlasterm are shown for the most rostral part of the rodentterm PFCterm. The 4th edition of the atlasterm characterized the medial PFCterm areas as the prelimbicterm (PrL) and medial orbital (MO) areas. These terms are still used in many recent publications. The 7th edition revised these regions using terms based on Brodmann’s numbers, as dorsal and ventral parts of area 32term, but the medial orbital term was retained. B , Sections from the middle parts of the rodentterm PFCterm contain more distinct cytoarchitectural areas. Anterior cingulateterm (Cg1), PrL, and infralimbicterm (IL) were used in the 4th edition of the atlasterm. Areas 24 (a and b), 33, and 25 were used in the 7th edition. C , Sections from the most caudal level of the rodentterm PFCterm, just anterior to bregma. The areas denoted as Cg1 and Cg2 were relabeled as areas 24a and 24b, respectively, and a new region (to rodentterm atlasesterm) “area 33” emerged. D , The locations of the sections in A–C are depicted in a midsagittal section. Please note that it was not possible to use atlasterm sections at the same anterior-posterior locations due to changes in the content of the editions of the atlasesterm. For example, the 4th edition did not include a section at +4.6 AP and the 7th edition did not include a section at +4.2 AP.

It is also worth noting that there are two different sets of rodentterm atlasesterm which stem from either the Paxinos or SwansonpersName initial rat atlasterm. The terminologyterm and structures found in Paxinos and Franklin (2012) mouse atlasterm are based off of Paxinos and Watson (1998) rat atlasterm, while the Allen Brain mouse reference atlasterm is largely based off of the SwansonpersName (2004) rat atlasterm (see Appendix 3 in Allen Institute for Brain Science, 2008 ; Lein et al., 2007 ). Therefore, differences in rodentterm PFCterm nomenclatureterm are often due to using either the Paxinos or SwansonpersName atlasesterm.

Obfuscation, beclouding, and abstrusity The three terms in the subheading of this section are synonyms for a lack of clarity in writing. At least they are single words. In recent years, two sets of hybrid termsterm·def have emerged in the recent literature (since 2005) for denoting prefrontalterm regions in rodentsterm. These terms combine the names of the cortical fields, prelimbicterm and infralimbicterm, with the term prefrontal cortexterm·def, e.g., “prelimbicterm prefrontal cortexterm·def” or “prelimbicterm medial prefrontal cortexterm·def.” Together with the various terms and acronymsterm described above for the Paxinos and SwansonpersName atlasesterm, it is clear that there are too many terms being used to describe the prefrontalterm parts of the rodentterm cortex. We hope that these alternative terms can be eliminated from future publications, as they are redundant, do not add clarity, and make it more difficult to track new findings and incorporate them into the existing literature.

Why can’t we be friends?

The anatomicterm issues described above have made it difficult for researchers with expertise on different speciesterm to compare their data and, with only a few exceptions ( Narayanan et al., 2013 ; Parker et al., 2015 ; Hyman et al., 2017 ), rodentterm research groups have not collaborated with humanterm or monkey labs to understand medial PFCterm function. When such collaborationsterm have been done, it has been difficult to agree on how to characterize the rodentterm areas in relation to medial areas of the humanterm mPFCterm. For example, in a study done through collaborationterm between rodentterm and humanterm researchers ( Narayanan et al., 2013 ), data from the prelimbicterm area were characterized as “medial frontal cortex” instead of the ACCterm or mPFCterm. Medial frontal cortex has not been commonly used to describe this area in the literature, with just 48 papers (<1% of all medial PFCterm papers) published using the term for rodentterm studies.

In summary, the question “What, if anything, is rodentterm prefrontal cortexterm·def?” is not easy to address due to major confusionterm about the anatomicterm terms that are commonly used to define the prefrontal cortexterm·def in rodentsterm. These issues should be resolved as open-source brain atlasesterm, such as the Allen Brain Atlasterm, are being developed and are becoming the dominant mode of reporting anatomicterm results for studies on the rodentterm (mouse) brain.

Crowdsourcing the PFCterm We recently conducted a crowdsourcing effort to assess usage of anatomicterm terms for the rodentterm prefrontal cortexterm·def. We reached out directly via email to several leading humanterm, monkey, and rodentterm PFCterm researchers and also requested via social media for anyone with an informed opinion on rodentterm PFCterm to fill out a surveyterm·mth on the topic. In brief, the surveyterm·mth questions inquired about the functional and anatomicterm extent of the rodentterm PFCterm and the specifics of anatomicterm terms within PFCterm. We also allowed surveyterm·mth responders to input their confidence levels on each given topic or question. We received 38 surveyterm·mth responses from a wide range of PFCterm researchers. Even with this small, self-selected sample of opinions, the surveyterm·mth revealed that there is little consensusterm among researchers about what constitutes the rodentterm PFCterm and what terms should be used to describe this cortical region. Three major issues that emerged from the surveyterm·mth are described below.

What is the prelimbicterm cortex?

We asked respondents whether the prelimbicterm area is part of the anterior cingulateterm cortex in rodentsterm ( Fig. 5 A ). Surprisingly, a minority of respondents indicated that the prelimbicterm cortex is part of the ACCterm ( Fig. 5 C ), despite publications by anatomists that support that designation ( Vogt and Gabriel, 1993 ; Vogt et al., 2013 ; Vogt and Paxinos, 2014 ). The prelimbicterm area has been perhaps the most studied part of the rodentterm PFCterm, and we were shocked by this outcome of the surveyterm·mth. One respondent wrote: “Depends on whose definitionterm of the ACCterm is used.” We are not aware of anatomicterm studies or reviews on the ACCterm that do not include the prelimbicterm cortex (also known as area 32term) as a core component of the ACCterm (e.g., the first anatomicterm collection dedicated to the ACCterm: Vogt and Gabriel, 1993 ). The relevance of the prelimbicterm area as part of the ACCterm, i.e., pregenual ACCterm (pACC), is discussed below.

Figure 5.

Crowdsourcing the rodentterm PFCterm. A , B , 38 respondents were asked questions about how different cytoarchitectural areas fit into the concept of rodentterm PFCterm. Major questions included “Is the prelimbicterm cortex part of the ACCterm?,” “Which areas comprise the dorsomedial and ventromedial PFCterm?,” “Is M2 part of the PFCterm?,” and if two distinct levels of the medial wall cortex are part of the PFCterm (located anterior to the genu of the corpus callosumterm, blue box in B ; located below bregma, red box in B ). C , Only 8 of 32 (25%) respondents working with rodentsterm said that the prelimbicterm cortex is part of the ACCterm. Eight of 20 (40%) respondents working with primatesterm answered this question positively. No differences were apparent in the respondents’ confidence in this answer. Given the small sample size, the difference between rodentterm and primateterm researchers was not significant (proportions testterm·stat: χ 2 = 0.69, df = 1, p = 0.4058). This outcome was surprising given that the prelimbicterm cortex has been considered as a core ACCterm region ( Vogt and Gabriel, 1993 ). D , There was almost universal agreement that Cg1 is part of the dmPFC (32 of 36 said yes) and IL is part of the vmPFC (33 of 36 said yes). Respondents were divided about how to characterize PL, with 24 of 36 saying it is part of dmPFC and 16 of 36 saying it is part of vmPFC (six respondents included PL in both dmPFC and vmPFC!). E , All respondents agreed that the pregenual region (blue box in B ) is part of the rodentterm PFCterm. Roughly 25% of respondents felt that the medial wall cortex at bregma (red box in B ) and the secondary motor cortex (M2) are PFCterm regions.

dmPFC versus vmPFC These acronymsterm are used to describe data from the dorsal and ventral parts of the mPFCterm. These terms were first used, to our knowledge, in some of the first reversible inactivation and multielectrode recording studies on this part of the rat frontal cortex ( Narayanan and LaubachpersName, 2006 ). More recently, they have been commonly used in studies of the mouse PFCterm. To assess how researchers use the terms dmPFC and vmPFC, we included questions in our surveyterm·mth about the terms ( Fig. 5 A ). Respondents were evenly split on what areas comprise the dmPFC and vmPFC ( Fig. 5 D ), with one in six respondents actually including prelimbicterm cortex in both areas. (A basis for this might be anatomicterm studies, Gabbott et al., 2005 , which have reported differences in anatomicterm connections of the dorsal and ventral aspects of the prelimbicterm cortex.) Rather than using these confusing terms (dmPFC and vmPFC), we suggest that research articles state exactly where the experiment was done (e.g., dorsal half of prelimbicterm cortex instead of dmPFC).

Rostral-caudal limits on the mPFCterm There may be a differing perception of the anatomicterm extent of rodentterm mPFCterm on a rostral to caudal basis. Figure 5 B shows two areas that have been characterized as medial PFCterm in the literature. One area is located anterior to the genu of the corpus callosumterm (prelimbicterm cortex, blue). The other area is within the cingulateterm cortex (red), directly below a major skull landmark used for stereotaxic surgeries in rodentsterm (bregma). All respondents said that the rostral region is mPFCterm ( Fig. 5 E ). Additionally, 25% said that the caudal region is mPFCterm. This is surprising given that the caudal area is immediately adjacent to the primary motor cortex for the forelimb ( Donoghue and Wise, 1982 ) and is considered as part of the mid, not anterior, cingulateterm cortex ( Vogt, 2016 ).

Lateral limits of the rodentterm PFCterm The area immediately dorsal and lateral to the classic mPFCterm/ACCterm area Cg1 has been called several names (medial precentral cortex, PrCm; medial agranular cortex, AGm, and secondary motor cortex, M2 or MOs). In recent years, data from this area have been characterized as “prefrontalterm” ( Savage et al., 2017 ). Some researchers have been careful to omit the “pre” from prefrontalterm when describing this area ( Siniscalchi et al., 2016 ; for review, see Barthas and Kwan, 2017 ). This is reasonable as several studies have reported projections to muscles controlling jaw and tongue movements ( Yoshida et al., 2009 ) and electrical stimulation producing movements of the whiskers ( Brecht et al., 2004 ), and head/neck ( Erlich et al., 2011 ). The region contains numerous neurons that project to the spinal cord ( Li et al., 1990 ), far more than exist in the adjacent classic PFCterm regions. When data are obtained from this region, some researchers have referred to the area as medial frontal cortex, as opposed to medial medial pre frontal cortex ( AmarantepersName et al., 2017 ). To assess appreciation of whether this area is part of rodentterm PFCterm, we included a question about it in our surveyterm·mth and found that ∼25% of respondents said that M2 is part of the rodentterm PFCterm ( Fig. 5 E ).

In summary, our surveyterm·mth of prefrontalterm nomenclatureterm supports our claim that there is confusionterm and controversy, even among PFCterm researchers, about what defines prefrontal cortexterm·def in rodentsterm. This may be driven by inconsistencies between different rodentterm brain atlasesterm, between atlasesterm and peer-reviewed anatomicterm studies and between different PFC-focused labs (e.g., some use mPFCterm for rostral medial cortex and ACCterm for caudal medial cortex, others call the whole area mPFCterm). These issues really need to be addressed to advance our understanding of PFCterm structure and function in rodentsterm and to motivate collaborationterm among labs, especially those working in different speciesterm.

Evolutionary Homology: From Flat to Curved Brains We would like to propose an alternative way to think about rodentterm PFCterm, which may help with incorporating findings across speciesterm into an integrated field of PFCterm research. Our proposal is based on a major difference between the brains of rodentsterm and primatesterm, putting size aside for the time being. In rodentterm brains, points from rostral to caudal are contained within a horizontal plane. In contrast, extant primateterm brains are curved, i.e., concave from front to back ( Fig. 6 A ). However, extinct basal primatesterm, known as plesiadapiforms, had linear brain plans similar to living rodentsterm ( Long et al., 2015 ). The consequences of these gross changes in brain shape may provide a clue for relating medial PFCterm regions across speciesterm. A similar mechanism was proposed by Vogt and Paxinos (2014) , where they suggest that the expansion of the humanterm midcingulate cortex (MCC), and the addition of the posterior cingulateterm cortex (PCC), leads to a displacement of the ACCterm both rostrally and ventrally around the genu of the corpus callosumterm. Further evidence for this idea comes from a recent computational and physical modeling study of cortical expansion ( Tallinen et al., 2016 ) that suggested that cortical convolutions arise from compressive stress. In their studies on the formation of gyri, this study found that compressive stress was especially pronounced within the frontal and temporal lobes and that compressive effects are maximum at angles that are perpendicular to the angle of maximum curvature, Figure 6.

Proposed cross-species homologies. A , Rodentterm brains are flat. Modern primateterm brains are curved. B , Quantification of the curvature of anterior corpus callosumterm (using the Kappa library for FIJI). The point of maximum curvature along the superior edge of the anterior third of the corpus callosumterm is 1.84 times more curved in humansterm (K = 0.263) than in rats (K = 0.143). Interior angles with vertex at the point of maximum curvature. The rat callosum has obtuse interior angles. The humanterm callosum has acute interior angles. C , Directionality analysis (using FIJI) of the anterior third of the callosum reveals unimodality in rat with a peak of approximately -52°. The humanterm CC peaks at -26° and 16°, indicative of its parabolic shape. A third peak at ∼54° is due to the internal angle of the rostrum. Images used for the directionality analysis are shown on the left and directions are encoded with false color (rainbow colormap with red equal to -90° and violet equal to +90°). D , Locations of three main parts of the rodentterm PFCterm (Cg1, blue; PL, red; IL, purple) shown on a midsagittal section (0.4 mm ML). E , Rotation of the three points representing each cortical region by the measured curvature of the humanterm callosum shifts the rodentterm PFCterm areas into approximate locations associated with the major divisions of the humanterm medial frontal cortex. This analysis suggests that (1) the area called Cg1 in rodentsterm may be homologous to the anterior part of the midcingulate cortex (aMCC) in primatesterm, (2) the area called PL in rodentsterm may be homologous to the called pACC (pregenual ACCterm) in primatesterm, and (3) the area called IL in rodentsterm may be homologous to the area called sACC (subgenual ACCterm) in primatesterm.

In addition to the increase in prefrontalterm tissue volume and development of granular cytoarchitecture, another speciesterm difference is the expansion and curvature of the corpus callosumterm in primatesterm ( Fig. 6 B , C ). By measuring the curvature of the primateterm callosum and applying it to points in space representing the three main parts of the rodentterm medial PFCterm, we found that the three rodentterm areas rotate to the locations associated with the three major functional zones of the primateterm ACCterm: the subgenual region (sACC), the pregenual region (pACC), and the mid-anterior cingulateterm cortex (MCC; compare our Fig. 6 E with Shackman et al., 2011 , their Fig. 1 C ; see Table 1 ). Thinking of rodentterm PFCterm in terms of these primateterm regions of the ACCterm should help clarify cross-species findings and might motivate humanterm and monkey researchers to add simple behavioral tasks to their studies so that results can be better related across speciesterm.

TABLE 1.

Terms and acronymsterm used to describe prefrontalterm areas in humansterm, monkeys, and rodentsterm Humanterm/monkey term Rodentterm term (Paxinos atlasesterm, pre-2013) Rodentterm term ( SwansonpersName, 2004 ; Allen Brain Atlasterm) Brodmann’s term Midcingulate cortex (MCC) ACCterm, Cg1, Cg2 ACAd Area 24 Pregenual ACCterm (pACC) PrL, PL, Cg3 PL Area 32term Subgenual ACCterm (sACC) IL ILA Area 25 Suggestions for Future Studies on the Rodentterm PFCterm We would like to close this perspective with some suggestions for improving the clarity, rigor, and reproducibilityterm of rodentterm PFCterm research. First, we recognize the difficulty in convincing an entire field to change their preferred terminologyterm for rodentterm PFCterm. To reduce confusionterm rodentterm researchers should at least clarify the precise anatomicterm location (e.g., when reporting data from neural recordings, use precise terms such as “prelimbicterm” instead of the more generic “ACCterm” or “mPFCterm” and/or estimated distances from landmarks such as bregma, e.g., 3.2 mm) of their data in publications on rodentterm prefrontal cortexterm·def, should always report specific coordinatesterm used in surgery (along with along with information on the strain, sex, and age of subjects), and should always provide images showing locations of experimental probes and viral fields for single animals and in group summaries. Second, hybrid termsterm·def such as “infralimbicterm medial prefrontalterm” should not be used, and the community (especially journalterm editors and manuscript reviewers) should speak up when such unnecessary and confusion-generating terms appear in a preprint or manuscript that is under consideration for publication. Third, and most important, there is a serious need for community engagement to address the lack of clarity and resulting confusionterm generated by rodentterm PFCterm researchers not having adopted strict standards for anatomicterm details. This might best be addressed through a dedicated workshop to foster consensusterm on the use of precise anatomicterm terms for the rodentterm PFCterm, involving leading rodentterm PFCterm research labs, expert neuroanatomists, funding partners (NIH), foundations with a vested interest in rodentterm neuroanatomy (e.g., Allen Brain), and editors from leading neuroscience journalsterm.

Information on Meta-Analysisterm·mth, Surveyterm·mth, and Anatomicterm Measurements PubMed citations, word frequencies, and word cloudsterm·mth PubMed was searched for publications on the prefrontal cortexterm·def in humansterm, monkeys, rats, and mice using search terms such as “(prefrontal cortexterm·def) AND (primateterm[tiab] OR monkey[tiab])” between the years 2000 and 2017. Timelines for the plots in Figure 1 A were saved into CSV files and plotted using Python code. Publication counts were removed for 2017, given apparent incomplete posting of all papers to PubMed for this most recent complete year. Word cloudsterm·mth were generated for these searches using the freely available reference manager Zotero ( https://www.zotero.org/ ).

Bibliographies were created for each set of search terms using lists of PMIDs, imported into Zotero using the “Add items by identifier” tool, and saved in CSV (comma-separated values) formats. Custom-written Python code was used to select up to 10,000 of the most recent publications for each speciesterm. Then, abstracts were extracted and the resulting text was filtered to remove common stop wordsterm·var (a, the, and, etc.); common science termsterm·var (experiment, hypothesis, subjects, etc.); and species-specific wordsterm·var (monkey, rat, mouse, etc.). The remaining text was then processed in R using the text-mining library (‘tm’) to create matrices of words and number of appearances. Results were then manually sorted into functional categories in Excel: neurochemical terms (neurotransmitters and drugs), anatomicterm terms (regions of pfcterm and other brain areas), disease-related terms (diseases, disorders, and conditions), psychological functions (associated function), and other terms (e.g., gene and expression). The matrix of sorted words and their frequencies were then imported into Python, where word cloudsterm·mth were made using the word cloudterm·mth library ( https://github.com/amueller/word_cloud ).

Dictionaries were created for each of the functional categories and used to assign common colors to words in each category.

Surveyterm·mth on the rodentterm PFCterm The surveyterm·mth consisted of questions about the inclusion of various parts of the rodentterm frontal cortex as “prefrontalterm” areas. Images from atlasesterm were used to query the rostral-to-caudal and medial-to-lateral limits of the prefrontal cortexterm·def and to clarify inclusion into the dorsomedial and ventromedial PFCterm in rats and macaque monkeys. The surveyterm·mth was sent to attendees of the Computational Properties of the Prefrontal Cortexterm·def (CPPC) conference and was also advertised via Twitter. For data analysis, responses were only considered if the respondent has been first or last author on at least one journalterm article on the prefrontal cortexterm·def. Surveyterm·mth results were collated into a spreadsheet and analyzed using a custom-written Jupyter notebook using the following Python libraries: numpy, matplotlib, seaborn, and pandas. Statistical analysis of results was conducted in R, and were done in the same Python notebook using the rpy2 library. Surveyterm·mth results and analysis/plotting code are available on request of the corresponding author.

Participants Linda AmarantepersName, Bruno Averbeck, Mark Baxter, Sebastien Bouret, Kevin Braunscheidel, Hannah Clarke, Michael Cole, Ilka Diester, Fabricio Do Monte, David Euston, Joshua Gordon, Sarah Heilbronner, Cyril Herry, Clay Holroyd, Nicole Horst, James Hyman, Sara Keefer, Christoph Kellendonk, Alex Kwan, Ryan LaLumiere, Christopher Lapish, Martin Pare, David Moorman, Nandakumar Narayanan, Nate Powell, Emmanuel Procyk, David Redish, Trevor Robbins, Peter Rudebeck, Jerome Sallet, Jeremy Seamans, Melissa Sharpe, Michael Siniscalchi, Elena Vazey, Mark Walton, Charlie Wilson, Steve Wise, and John Woodward Analysis of callosum structure in humansterm and rats The humanterm callosum was obtained from Aboitiz and Montiel (2003) . The rat callosum was obtained from Paxinos Atlasterm 6th edition. Directionality of the outer edge of the anterior third was assessed using the Directionality package in FIJI ( https://imagej.net/Directionality ).

Curvature of the dorsal edge was analyzed using the Kappa package in FIJI ( https://github.com/brouhardlab/Kappa/ ). Angles were calculated using the point of highest curvature as the vertex. Both the angle using points along the outer edge of the callosum and the angle using the midpoint of the width of the callosum were calculated in FIJI.

Synthesis Reviewing Editor: Mark Baxter, Mount Sinai School of Medicine Decisions are customarily a result of the Reviewing Editor and the peer reviewers coming together and discussing their recommendations until a consensusterm is reached. When revisions are invited, a fact-based synthesis statement explaining their decision and outlining what is needed to prepare a revision will be listed below. The following reviewer(s) agreed to reveal their identity: Alicia Izquierdo.

Thank you for submitting your paper “What, if anything, is rodentterm prefrontal cortexterm·def?” to eNeuro. I have consulted two reviewers for their comments on the manuscript. We are all enthusiastic about the meta-analytic approach and the illustration of confusionterm surrounding rodentterm prefrontal cortexterm·def. We have a few changes to suggest to the paper, but they should be straightforward to address. I am separating them into more substantive comments and minor word choice/editing.

Substantive: - As far as PFCterm nomenclatureterm goes, Figure 1 Uylings et al. (2003) showed the extent for what different groups considered PFCterm in rat until that time. Krettek and Price (1977) included LO and AIv and later Groenenwegen (1988) expanded to include VO MO. It wasn't until Preuss (1995) that these areas disappeared from PFCterm taxonomy. Yet I could find no mention of this in the manuscript, and I think LO AIv and perhaps also VO and MO deserves some attention.

- I do think Vogt and Paxinos (2014) could be credited a bit more for the curvature idea presented in this manuscript, since they have previously offered a mechanism (expansion of midcingulate cortex) in their 2014 paper comparing mouse, rat, and humanterm: “The substantial expansion of MCC and addition of PCC in the humanterm results in a major displacement of ACCterm rostrally and ventrally around the genu of the corpus callosumterm.”

- It would be useful to have more description of the methodology used to generate the word cloudsterm·mth. How did the meta-analysisterm·mth capture all of the rodentterm articles if so many anatomical terms are in common use - were multiple search terms used? And if so, what were they? Did the word cloudsterm·mth include entire articles, abstracts or just titles? How were terms grouped into clusters of ‘anatomical’, ‘disease and medical’, etc.?

Minor: - If possible, it would be nice to see a monkey word cloudterm·mth.

- In the word cloudsterm·mth, the different themes across speciesterm must be largely due to different tools available in each. I think the authors' point is how this leads to differences in ideas and theories, but their views here aren't fully spelled out. It might even be interesting to exclude technique-driven words (e.g. gene / connectivity) or directly compare frequencies of the same words across speciesterm, to get a sense of the conceptual differences in the fields.

- The NCBI web link appears to be broken.

- The authors write in the introduction, “For instance, it is not uncommon for researchers to use information about one prefrontalterm area in macaque monkeys (or humansterm) in an attempt to understand a completely different prefrontalterm area in a rodentterm speciesterm.” A citation is not necessary, but it would be great to have an example of such an instance.

- There should be some mention somewhere that the labels we use are based on cytoarchitectonic subdivisions.

- The authors do a great job of pointing out different criteria for what could be considered homology, “common functions, as opposed to common structures,” but there is another approach based on connectivity with subcortical structures- Heilbronner et al. Biol Psychiatry 2016; that the authors may choose to cite.

- “.. our meta-analysisterm·mth reveals that rodentterm researchers have not focused on cognitive functions associated with lateral, but not medial, PFCterm.” This is a double-negative, awkward phrasing.

- “As a result, many rat researchers shifted away from studying spatial processing to issues associated with the ACCterm, such as sequencing actions and outcomes (monkey: Procyk et al., 2000; rat: Lapish et al., 2008) and performance monitoring and adjustment (monkey: Ito et al., 2003; rat: Narayanan and LaubachpersName, 2008).” Are there other such examples that the authors can pull from in other PFCterm subregions across monkey and rat? As currently presented, the manuscript is quite ACC-centric.

- “there should be more studies published on the mouse PFCterm than the rat PFCterm by the end of the current decade.” The way this is written makes it sound more advisory than a prediction, suggest “there are projected to be more studies...” or some such phrasing.

- Top of page 10, there is the assertion that authors typically don't provide enough information on location of PFCterm targets. But how often are stereotaxic coordinatesterm not included, or representative images not included? I would say this is fairly rare and likely not to contribute to the confusionterm/controversies.

Author Response Thank you for submitting your paper “What, if anything, is rodentterm prefrontal cortexterm·def?” to eNeuro. I have consulted two reviewers for their comments on the manuscript. We are all enthusiastic about the meta-analytic approach and the illustration of confusionterm surrounding rodentterm prefrontal cortexterm·def. We have a few changes to suggest to the paper, but they should be straightforward to address. I am separating them into more substantive comments and minor word choice/editing. Thank you very much for this very useful feedback on our manuscript. The clarity of the proposed changes made it easy for us to do revisions, and we believe that the manuscript is much better thanks to the review process. We addressed each of the substantive and minor points that were raised. We also made some minor changes to the manuscript that are described at the end of our response to the reviews. We hope that you will now find the manuscript acceptable for publication in eNeuro.

-The authors Substantive: - As far as PFCterm nomenclatureterm goes, Figure 1 Uylings et al. (2003) showed the extent for what different groups considered PFCterm in rat until that time. Krettek and Price (1977) included LO and AIv and later Groenenwegen (1988) expanded to include VO MO. It wasn't until Preuss (1995) that these areas disappeared from PFCterm taxonomy. Yet I could find no mention of this in the manuscript, and I think LO AIv and perhaps also VO and MO deserves some attention. Thank you for raising this issue. We modified the text in the ‘Publication trends’ section of the manuscript to address this issue. Fairly extensive text was added after the sentence starting “Given clear differences in PFCterm anatomy across speciesterm...” and before the sentence starting “Preuss (1995) wrote a thoughtful review...” to address this issue. The text is shown below: “Early definitionsterm of prefrontal cortexterm·def in rodentsterm were based on a classic study by Rose and Woolsey (1948), who argued that prefrontalterm areas should be defined as having connections with the mediodorsal nucleus of the thalamus (MD). This view was supported by anatomical studies such as Krettek and Price (1977), Groenewegen (1988), and Conde et al. (1990), and served as the basis for early claims that the rat prefrontal cortexterm·def had functions similar to the primateterm dorsolateral PFCterm and was crucial for spatial working memory (Kolb, 1984, 1990). However, more recent studies challenged both the anatomical and behavioral bases of this view. For example, the efferent projections of the thalamic nucleus MD include the ‘medial precentral area’ (Groenewegen, 1988), aka ‘medial agranular cortex’ or ‘M2’. In contrast to the prelimbicterm and infralimbicterm areas, the ‘medial precentral area’ was found to receive inputs from sensorimotor parts of the cerebral cortex (Reep et al., 1990; Van Eden et al., 1992; Conde et al., 1995), project to sensorimotor subcortical regions (Reep et al., 1987), and produce movements of the eyes, neck, and jaws when electrically stimulated (Neafsey et al., 1986). As such, it became thought of as potentially analogous to the frontal eye fields of macaque monkeys (Reep et al., 1987) and raised problems for the PFCterm definitionterm of Rose and Woolsey. Nucleus MD also projects to orbital regions of the frontal cortex, areas denoted as MO, VO, and LO (Groenewegen, 1988). The connectivity of these regions were studied in monkeys and rats by Price and colleagues (e.g. An et al., 1998; Floyd et al., 2000; Bandler et al., 2000). In a review by Ongur and Price (2000) on anatomically defined networks within the frontal cortex, the ‘rat’ orbital areas were held out of a proposed ‘orbital network’ (based on patterns of connectivity in monkeys and humansterm) because of the connectivity of the rat areas with ‘visceral’ structures such as the hypothalamus and periaqueductal gray. Such connections are not associated with the primateterm OFC or dorsolateral PFCterm, raising more problems for the PFCterm definitionterm of Rose and Woolsey. In parallel with these anatomical studies, a number of behavioral studies emerged that challenged the idea that the rodentterm PFCterm cortex mediated spatial working memory (Kolb, 1984). Lesions of the prelimbicterm cortex were found to impair spatial delayed alternation in the T-maze (Brito et al., 1982) and operant chambers (van Haaren et al., 1988; Dunnett et al., 1999). However, these effects were transient in nature (Delatour and Gisquet- Verrier, 2001) and may have been due to reductions in spontaneous alternation (Delatour and Gisquet-Verrier, 1996). Moreover, lesions of mPFCterm did not impair performance in another test of spatial working memory, the radial arm maze (Delatour and Gisquet-Verrier, 1996; Ragozzino et al., 1998; Gisquet-Verrier and Delatour, 2006). Together, these findings led to the idea that the rodentterm PFCterm is important for ‘workingwith- memory’ but not spatial memory per se (Moscovitch and Winocur, 1992).

To address the emerging issue of how the frontal cortex of rodentsterm related to the prefrontal cortexterm·def of primatesterm, Preuss (1995) wrote a thoughtful review...” In addition to this new text, we also modified this section of the manuscript by concluding with your observation that terms such as MO, VO, and LO “disappeared from PFCterm taxonomy” and became referred to as ‘OFC’ following an influential paper by Schoenbaum, Chiba, and Gallagher (1998) that provided the first evidence for ‘outcome encoding’ by the rodentterm OFC.

“As a consequence of these competing views, the meaning of the word ‘prefrontalterm’ in rodentterm studies remained unclear. However, since the publication of Preuss's article, one clear change in the literature was the disappearance of the rodentterm orbital areas (MO, VO, and LO) from the prefrontalterm taxonomy. A major driver for this change might have been a study by Schoenbaum and colleagues (1998) that reported data from this part of the rat cortex as some of the first evidence for the encoding of expected outcomes. These researchers referred to the cortical region as ‘OFC’ and this term has largely been used since that time.”

- I do think Vogt and Paxinos (2014) could be credited a bit more for the curvature idea presented in this manuscript, since they have previously offered a mechanism (expansion of midcingulate cortex) in their 2014 paper comparing mouse, rat, and humanterm: “The substantial expansion of MCC and addition of PCC in the humanterm results in a major displacement of ACCterm rostrally and ventrally around the genu of the corpus callosumterm.” Thank you for bringing this up, and we agree that their figure 6 diagram is a great example of the influence of the corpus callosumterm in shaping the cingulateterm cortex. We have added into the text in the paragraph on Evolutionary Homology (pp. 13) to attribute the MCC expansion mechanism to Vogt and Paxinos: “A similar mechanism was proposed by Vogt and Paxinos (2014), where they suggest that the expansion of the humanterm mid-cingulate cortex (MCC) -- and the addition of the posterior cingulateterm cortex (PCC) - leads to a displacement of the ACCterm both rostrally and ventrally around the genu of the corpus callosumterm.”

- It would be useful to have more description of the methodology used to generate the word cloudsterm·mth. How did the meta-analysisterm·mth capture all of the rodentterm articles if so many anatomical terms are in common use - were multiple search terms used? And if so, what were they? Did the word cloudsterm·mth include entire articles, abstracts or just titles? How were terms grouped into clusters of ‘anatomical’, ‘disease and medical’, etc.?

Thanks for asking about these details. The original text was underdeveloped. The section on how we made word cloudsterm·mth was expanded using the text below. We only used the term ‘prefrontalterm’ in the title-or-abstract [tiab] to find papers and so it is possible that we missed some rodentterm studies that did not denote the study as on the prefrontal cortexterm·def. The search strategy is described below as well as the text that was used (abstracts only) and details on how groupings were made (manually). We hope that the expanded text addresses your concerns. PubMed citations, word frequencies, and word cloudsterm·mth: PubMed was searched for publications on the prefrontal cortexterm·def in humansterm, monkeys, rats, and mice using search terms such as “(prefrontal cortexterm·def) AND (primateterm[tiab] OR monkey[tiab])” between the years 2000 and 2017. Timelines for the plots in Figure 1A were saved into CSV files and plotted using Python code. Publication counts were removed for 2017, given apparent incomplete posting of all papers to PubMed for this most recent complete year. Word cloudsterm·mth were generated for these searches using the freely available reference manager Zotero (https://www.zotero.org/). Bibliographies were created for each set of search terms using lists of PMIDs, imported into Zotero using the “Add items by identifier” tool, and saved in CSV (comma-separated values) formats. Custom-written Python code was used to select up to 10,000 of the most recent publications for each speciesterm. Then, abstracts were extracted and the resulting text was filtered to remove common stop wordsterm·var (a, the, and, etc.); common science termsterm·var (experiment, hypothesis, subjects, etc.); and species specific wordsterm·var (monkey, rat, mouse, etc.). The remaining text was then processed in R using the text-mining library (‘tm’) to create matrices of words and number of appearances. Results were then manually sorted into functional categories in Excel: neurochemical terms (neurotransmitters and drugs), anatomical terms (regions of pfcterm and other brain areas), disease-related terms (diseases, disorders, and conditions), psychological functions (associated function), and other terms (e.g. gene and expression). The matrix of sorted words and their frequencies were then imported into Python, where word cloudsterm·mth were made using the wordcloud library (https://github.com/amueller/word_cloud). Dictionaries were created for each of the functional categories and used to assign common colors to words in each category. Minor: - If possible, it would be nice to see a monkey word cloudterm·mth. Thank you for this suggestion. We made a comparable word cloudterm·mth for the monkey literature. It is quite revealing, and strongly supports a dichotomy between rodentterm and primateterm PFCterm research. We added the new word cloudterm·mth to the manuscript. With four word cloudsterm·mth, the original Figure 1 became quite massive. So, we split the figure into two, with the new Figure 1 showing publications trends and the new Figure 2 showing the word cloudsterm·mth.

- In the word cloudsterm·mth, the different themes across speciesterm must be largely due to different tools available in each. I think the authors' point is how this leads to differences in ideas and theories, but their views here aren't fully spelled out. It might even be interesting to exclude techniquedriven words (e.g. gene / connectivity) or directly compare frequencies of the same words across speciesterm, to get a sense of the conceptual differences in the fields. This is an excellent point. We considered removing technique-related terms such as gene, expression, and connectivity; however, their presence revealed major differences in research foci across speciesterm. For example, not surprisingly, expression was more common in publications on mice.

To directly compare frequencies of the same terms across speciesterm, we created a new figure (Figure 3) that depicts relative word frequencies in adjacent columns using Hinton plots and in bar plots for select words that were most common overall. The new text below was added to the manuscript to summarize the new plots and findings. Differences in word frequencies within a speciesterm are easy to see in word cloudsterm·mth. However, word cloudsterm·mth do not allow so readily for comparing word frequencies across speciesterm, as the viewer has to search for a given term in each word cloudterm·mth and then compare the size of each word across a series of figure panels. A more direct method for comparing terms across speciesterm is to plot the relative frequencyterm·var of each term using Hinton plots, which were developed for visualizing weights of hidden units in neural networks (Hinton and Shallice, 1991). To make Hinton plots of the word frequencies for each functional category of terms, we determined what words were the ten most common in the collection of mouse papers, and then added in new terms that were included in the ten most common terms from the other speciesterm. This approach revealed that anatomical terms were the most diverse, with 22 terms needed to account for all four speciesterm. By contrast, disease-related terms were least diverse, with just 12 terms needed to account for the ten most common terms across speciesterm. These reduced list of leading terms (12-22) were then used for the Hinton plots, and those for anatomical, neurochemical, and disease related terms are shown in Figure 3A.

The plots revealed interesting insights into the use of specific terms within and among speciesterm. For example, several anatomical terms were quite common in the monkey literature (e.g. FEF, OFC, parietal, vlPFC) and not so common in the other speciesterm, including the humanterm PFCterm literature. In a similar way, the common rodentterm terms prelimbicterm and infralimbicterm were largely absent from the monkey and humanterm literature. The most common term in rodentsterm was ‘mPFCterm’ and the most common term in primatesterm was ‘dlPFCterm’. The discordance in these terms was further emphasized in a new bar plot shown in Figure 3B (top plot).

The situation with neurochemicals (transmitters and drugs) was less discordant. Some exceptions were dopamine (a bit overemphasized in rodentterm studies), ethanol but not alcohol (ethanol overemphasized in rodentterm studies, alcohol equally common across speciesterm), and N-Acetylaspartic acid (NAA) only occurring in humanterm studies, where it has been used as a marker for neurodegenerative disorders. The two most common neurochemical terms, dopamine and serotonin, showed similar overall relative frequencies across speciesterm, with the exception of dopamine. It has been used more in studies of the rat PFCterm than other speciesterm, including in comparison to the mouse literature. This point is depicted in a new bar plot in Figure 3B (middle plot). Usage of terms associated with diseases and disorders was the least diverse across speciesterm. Yet, two terms showed up with divergent frequencies in rodentsterm and primatesterm. Schizophrenia is a major term in all speciesterm and, perhaps not surprisingly, especially in studies of the humanterm PFCterm. By contrast, stress was the most common disease-related term in the rat literature, perhaps due to the utility of classic behavioral assays such as restraint and the forced swim test in rodentsterm. The relative frequencies of these terms was further emphasized in a new bar plot in Figure 3B (lower plot).

- The NCBI web link appears to be broken. The link was to a website called FLink that was discontinued by the NIH during the time when this manuscript was under review. Instructions for using standard PubMed and Zotero instead have been included in the revised manuscript, as described above in our response to the third substantive issue.

- The authors write in the introduction, “For instance, it is not uncommon for researchers to use information about one prefrontalterm area in macaque monkeys (or humansterm) in an attempt to understand a completely different prefrontalterm area in a rodentterm speciesterm.” A citation is not necessary, but it would be great to have an example of such an instance. We were initially reluctant to include references for this point, but understand the request and the need to document our statements. The following studies have been cited in the revised manuscript. In fact, they translated results in the opposite direction suggested by our text, and so we have revised the text in the new version of the manuscript. The studies cited below went from rodentterm prelimbicterm cortex to humanterm dlPFCterm. The first manuscript is a preview article highlighting findings from the second paper, which is a clinical pilot study on the humanterm dlPFCterm. It was based on findings from the third paper, which was done on the rodentterm mPFCterm (prelimbicterm cortex). Ferenczi and Deisseroth, 2016 - PMID: 26780510 Terraneo et al., 2016 - PMID: 26655188 Chen et al., 2013 - PMID: 23552889 - There should be some mention somewhere that the labels we use are based on cytoarchitectonic subdivisions. Thank you for pointing this out. A comment on this issue was added on page 9 in the section “PFCterm nomenclatureterm in rodentsterm” and on page 10 in the ‘Alphbet soup’ subsection. - The authors do a great job of pointing out different criteria for what could be considered homology, “common functions, as opposed to common structures,” but there is another approach based on connectivity with subcortical structures- Heilbronner et al. Biol Psychiatry 2016; that the authors may choose to cite. Thank you for mentioning this study, and we agree that it should be included. We also cited a promising approach for cross-species anatomy developed by Rogier Mars and colleagues: e.g. https://elifesciences.org/articles/35237. Text was added immediately after the heavily revised section about the Preuss study (p. 6), and is shown below: “In recent years, two lines of research have emerged that may eventually solve the dilemma of what is prefrontal cortexterm·def in rodentsterm. Both are based on measures of connectivity, and not function. One was developed by Rogier Mars and colleagues using various measures of functional and structural connectivity (Mars et al., 2013; Neubert et al., 2015; Mars et al., 2016). The most recent platform for this approach is capable of revealing common patterns of whole brain connectivity in monkeys and humansterm (Mars et al., 2018), and might be an excellent approach for understanding the problem of the rodentterm PFCterm. Additionally, a tract-tracing approach was developed by Heilbronner et al. (2016), focused on corticostriatal connectivity, and revealed clear common patterns of connections for cortical regions such as the prelimbicterm cortex.” - “.. our meta-analysisterm·mth reveals that rodentterm researchers have not focused on cognitive functions associated with lateral, but not medial, PFCterm.” This is a double-negative, awkward phrasing. Thanks for catching this issue. We revised the text as follows: “...our meta-analysisterm·mth reveals that rodentterm researchers have focused on cognitive functions associated with medial, but not lateral, PFCterm.” - “As a result, many rat researchers shifted away from studying spatial processing to issues associated with the ACCterm, such as sequencing actions and outcomes (monkey: Procyk et al., 2000; rat: Lapish et al., 2008) and performance monitoring and adjustment (monkey: Ito et al., 2003; rat: Narayanan and LaubachpersName, 2008).” Are there other such examples that the authors can pull from in other PFCterm subregions across monkey and rat? As currently presented, the manuscript is quite ACC-centric. Thanks for raising this important point. We focused on ACC-related studies given our view that the literature for OFC has diverged and there is no other PFCterm in rodentsterm. To address this issue, we added some text about the OFC and also a citation to some more recent work that continued to emphasize spatial coding by rodentterm mPFCterm/ACCterm. The text was revised as follows: “As a result, many rat researchers shifted away from studying spatial processing (with some exceptions, e.g. Spellman et al., 2015), to issues associated with the primateterm ACCterm and OFC, such as sequencing actions and outcomes (monkey: Procyk et al., 2000; rat: Lapish et al., 2008), and performance monitoring and adjustment (monkey: Ito et al., 2003; rat: Narayanan and LaubachpersName, 2008), and encoding changes in reward contingencies during learning (monkey: Tremblay and Schultz, 1999; Wallis and Miller, 2003; Rudebeck et al., 2013; rat: Schoenbaum et al., 1999; Takahashi et al., 2009; van Duuren et al., 2009; Sul et al., 2010).” CHANGES HIGHLIGHTED IN RED - “there should be more studies published on the mouse PFCterm than the rat PFCterm by the end of the current decade.” The way this is written makes it sound more advisory than a prediction, suggest “there are projected to be more studies...” or some such phrasing. We have changed the phrasing on this to instead say “Given recent publication rates (Figure 1B), there are projected to be more studies published on the mouse PFCterm than the rat PFCterm” - Top of page 10, there is the assertion that authors typically don't provide enough information on location of PFCterm targets. But how often are stereotaxic coordinatesterm not included, or representative images not included? I would say this is fairly rare and likely not to contribute to the confusionterm/controversies. Indeed, this point is correct for stereotaxic coordinatesterm. We went back and checked the last 20 papers published on rodentterm PFCterm using PubMed and found that all studies reported stereotaxic coordinatesterm and most showed some example of localization of electrodes, optrodes, or infusion cannula. Therefore, we modified the text to focus on the specific issue of the acronymsterm dmPFC and vmPFC. “Rather than using these confusing terms (dmPFC and vmPFC), we suggest that research articles state exactly where the experiment was done (e.g. dorsal half of prelimbicterm cortex instead of dmPFC).” Additional changes: 1. The anatomical term used in Figure 6, and related text on pages 14-15, was changed to denote the region of the cingulateterm cortex above the corpus callosumterm as MCC, instead of dACC. The anatomical basis for this change is described in Vogt, 2016. 2. An early motivation for our manuscript was a study by Tallinen and colleagues (2016), which reported evidence for the rotational (or shearing) forces that might have resulted in changes in the shape of the corpus callosumterm. We omitted this study from the original version of our manuscript, but added a comment about it in the ‘Evolutionary homology’ section (p 14) of the revised manuscript. “Further evidence for this idea comes from a recent computational and physical modeling study of cortical expansion (Tallinen et al., 2016) that suggested that cortical convolutions arise from compressive stress. In their studies on the formation of gyri, this study found that compressive stress was especially pronounced within the frontal and temporal lobes, and that compressive effects are maximum at angles that are perpendicular to the angle of maximum curvature,” 3. We received feedback from the manuscript while it was under review from a mouse researcher who noted we did not consider leading mouse atlasesterm when discussing changes to rodentterm atlasesterm. We included these changes throughout the manuscript to add in details about the Paxinos and Franklin mouse atlasterm and more details on the Allen Brain atlasterm. Interestingly, these atlasesterm were apparently all derived from rat atlasesterm. 4. We became aware of a project called NeuroNames during the period when our manuscript was under review. This project is a database of definitionsterm used for neuroanatomical structures and acronymsterm that was created with the intention to “resolve ambiguities of neuroanatomical nomenclatureterm”. We added a comment about this project in the first paragraph of the revised manuscript.