Review
The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics

https://doi.org/10.1016/j.neubiorev.2003.09.003Get rights and content

Abstract

The prefrontal cortex in rats can be distinguished anatomically from other frontal cortical areas both in terms of cytoarchitectonic characteristics and neural connectivity, and it can be further subdivided into subterritories on the basis of such criteria. Functionally, the prefrontal cortex of rats has been implicated in working memory, attention, response initiation and management of autonomic control and emotion. In humans, dysfunction of prefrontal cortical areas with which the medial prefrontal cortex of the rat is most likely comparable is related to psychopathology including schizophrenia, sociopathy, obsessive-compulsive disorder, depression, and drug abuse. Recent literature points to the relevance of conducting a functional analysis of prefrontal subregions and supports the idea that the area of the medial prefrontal cortex in rats is characterized by its own functional heterogeneity, which may be related to neuroanatomical and neurochemical dissociations. The present review covers recent findings with the intent of correlating these distinct functional differences in the dorso-ventral axis of the rat medial prefrontal cortex with anatomical and neurochemical patterns.

Introduction

The mammalian prefrontal cortex has been classically defined and delineated by anatomical criteria such as cytoarchitectonic features (granular vs. agranular characteristics) [15], connectivity with the mediodorsal thalamic nucleus [1], [6], [71], [73], [76], [105], [111], [161], [168], input of dopaminergic fibers from the ventral mesencephalon, or a combination of these criteria [7], [13], [48], [49], [196], [200], [211]. The rat prefrontal cortex is, in general, tentatively divided into three topologically different regions. First, a medially located cortical region, the medial prefrontal cortex, which constitutes the major portion of the medial wall of the hemisphere anterior and dorsal to the genu of the corpus callosum. Second, a ventrally located cortical region that is termed the orbital prefrontal cortex and that lies in part dorsal to the caudal end of the olfactory bulb in the dorsal bank of the rhinal sulcus. Third, a laterally located cortical region, the lateral or sulcal prefrontal cortex, which is also referred to as the agranular insular cortex and, in rats, is located in the anterior part of the rhinal sulcus [49], [76], [105], [111], [112], [172], [173], [183].

The medial prefrontal cortex will be the main focus of the present review. This part of the prefrontal cortex in rats can be further divided into at least four cytoarchitectonically distinct areas: the medial precentral area (PrCm) or area Fr2, the anterior cingulate area, the prelimbic area, and the infralimbic area [105], [203]. However, on the basis of several anatomical criteria it has been suggested that there exists a main subdivision of the medial prefrontal cortex into a dorsal component, encompassing the FR2, dorsal anterior cingulate areas, and the dorsal part of the prelimbic area, and a ventral component that includes the ventral prelimbic, infralimbic and medial orbital areas (Fig. 1) [11], [74], [191], [220]. Such a distinction between dorsal and ventral subdivisions might be traced back to a phylogenetic origin and, most importantly in the context of the present review, the literature appears to provide ample indications for a concomitant functional–behavioral differentiation of the medial prefrontal cortex into dorsal and ventral parts.

As indicated above, in the context of the present account it is important to realize that the prefrontal cortex evolved from both an archicortical and paleocortical origin [142]. From the archicortical portion arose proisocortical areas 24 (anterior cingulate), 25 (infralimbic), and 32 (prelimbic), which gave rise to both the dorsomedial and dorsolateral prefrontal regions in primates. In fact, the prelimbic cortex of rodents (especially rats) is the equivalent of Brodmann's area 32 in primates (especially macaques) [200]. In the context of the developmental and evolutionary trends recognized by Pandya and colleagues [7], [142], it may be stated that the infralimbic cortex forms the architectonically least developed prefrontal cortical area whereas there is a trend towards further cytoarchitectonic differentiation, as expressed by a clearer and more distinct segregation of cortical layers in the prelimbic and the more dorsally located anterior cingulate and Fr2 areas [105], [106], [203].

In the present review, we will first summarize a series of studies demonstrating that the dorsal and ventral subregions of the medial prefrontal cortex may be involved in different behavioral functions or different aspects of the same function. We will then hypothesize that such a functional distinction is associated with differences not only in cytoarchitectonics, but also in connectivity patterns, neurochemistry and expression of immediate early genes. This review will conclude with the suggestion that because of chemo-anatomical differences in the dorso-ventral axis of the rat medial prefrontal cortex, neurons originating from deep layers of the prelimbic cortex may control a different aspect of subcortical function compared with neurons originating from the superficial layers of the anterior cingulate cortex.

Section snippets

Are there functional grounds for a dissociation between subterritories of the medial prefrontal cortex in the rat?

The medial prefrontal cortex as a whole has been traditionally implicated in attentional processes, working memory and behavioral flexibility. However, a growing body of evidence is currently pointing towards the relevance of conducting a functional analysis of medial prefrontal subregions and supports the contention that the medial frontal cortical wall is characterized by its own functional heterogeneity. In the following paragraphs we will review the recent literature with the intent to

Are there anatomical grounds for a dissociation between subterritories of the medial prefrontal cortex in the rat?

As described in Section 1, the medial prefrontal cortex in rats consists of several cytoarchitectonically distinct subregions that, at least in part, can also be differentiated on the basis of distinct afferent and efferent connectivity patterns with cortical areas as well as with subcortical structures such as the striatum, thalamus, amygdala, hypothalamus and several brain stem nuclei [8], [31], [60], [61], [77], [105], [106], [112], [161], [183], [200], [205]. Although in most of these

Dopamine

As mentioned above (Section 3.4), studies have elegantly demonstrated that the dopamine transporter is densely distributed in the anterior cingulate cortex and only sparsely into the deep layers of the prelimbic cortex [184]. Moreover, these observations are consistent with the lower immunoreactivity and mRNA signal for the dopamine transporter in the ventral tegmental area compared with the substantia nigra [30], [186]. Both anatomical [204] and neurochemical [195] studies indicate that the

Conclusions

The present work reviewed behavioral, neuroanatomical, neurochemical and histochemical evidence to support the existence of a dorso-ventral dissociation within the rat medial prefrontal cortex. The overview of the connectivity of the medial prefrontal cortex leads to the conclusion that this part of the prefrontal cortex can be subdivided not only on the basis of cytoarchitectonics, but also on the basis of differences in connectivity patterns. Borders of cortical areas with similar patterns of

References (220)

  • J.W Dalley et al.

    Deficits in impulse control associated with tonically-elevated serotonergic function in rat prefrontal cortex

    Neuropsychopharmacology

    (2002)
  • F Datiche et al.

    Reciprocal and topographic connections between the piriform and prefrontal cortices in the rat: a tracing study using the B subunit of the cholera toxin

    Brain Res Bull

    (1996)
  • J Day et al.

    Cholinergic activity in the rat hippocampus, cortex and striatum correlates with locomotor activity: an in vivo microdialysis study

    Pharmacol Biochem Behav

    (1991)
  • B Delatour et al.

    Functional role of rat prelimbic–infralimbic cortices is spatial memory: evidence for their involvement in attention and behavioural flexibility

    Behav Brain Res

    (2000)
  • B Delatour et al.

    Involvement of the dorsal anterior cingulate cortex in temporal behavioural sequencing: subregional analysis of the medial prefrontal cortex in rat

    Behav Brain Res

    (2001)
  • A.Y Deutch et al.

    The effects of antipsychotic drugs on Fos protein expression in the prefrontal cortex: cellular localization and pharmacological characterization

    Neuroscience

    (1996)
  • D.C.D Ding et al.

    Differences in the laminar origin of projections from the medial prefrontal cortex to the nucleus accumbens shell and core regions in the rat

    Brain Res

    (2001)
  • I Divac

    Frontal lobe system and spatial reversal in the rat

    Neuropsychologia

    (1971)
  • I Divac et al.

    The prefrontal cortex in the pigeon. Catecholamine histofluorescence

    Neuroscience

    (1985)
  • J.P Donoghue et al.

    Neostriatal projections from individual cortical fields conform to histochemically distinct striatal in the rat

    Brain Res

    (1986)
  • G.E Duncan et al.

    Neuroanatomical characterization of Fos induction in rat behavioral models of anxiety

    Brain Res

    (1996)
  • T.P Durkin

    Spatial working memory over long retention intervals: dependence on sustained cholinergic activation in the septohippocampal or nucleus basalis magnocellularis cortical pathways?

    Neuroscience

    (1994)
  • T.P Durkin et al.

    Septo-hippocampal and NBM-cortical cholinergic neurones exhibit differential time-courses of activation as a function of both type and duration of spatial memory testing in mice

    Behav Brain Res

    (1992)
  • F.P Eckenstein et al.

    An anatomical study of cholinergic innervation in rat cerebral cortex

    Neuroscience

    (1988)
  • G.W Eschweiler et al.

    Left prefrontal activation predicts therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) in major depression

    Psychiat Res

    (2000)
  • M Fendt et al.

    The neuroanatomical and neurochemical basis of conditioned fear

    Neurosci Biobehav Rev

    (1999)
  • F Ferino et al.

    Interhemispheric and subcortical collaterals of medial prefrontal cortical neurons in the rat

    Brain Res

    (1987)
  • A Ferron et al.

    Inhibitory influence of the mesocortical dopaminergic system on the spontaneous activity or excitatory response induced from the thalamic mediodorsal nucleus in the rat medial prefrontal cortex

    Brain Res

    (1984)
  • G.D Fisk et al.

    Descending projections of infralimbic cortex that mediate stimulation-evoked changes in arterial pressure

    Brain Res

    (2000)
  • L.J Freedman et al.

    Thalamic afferents of the rat infralimbic and lateral agranular cortices

    Brain Res Bull

    (1991)
  • M.E Fritts et al.

    Medial prefrontal lesion deficit involving or sparing the prelimbic area in the rat

    Physiol Behav

    (1998)
  • P Gabbott et al.

    Morphological evidence that CA1 hippocampal afferents monosynaptically innervate PV-containing neurons and NADPH-diaphorase reactive cells in the medial prefrontal cortex (Areas 25/32) of the rat

    Brain Res

    (2002)
  • C.R Gerfen et al.

    The basal ganglia

  • H.J Groenewegen et al.

    The prefrontal cortex and the integration of sensory, limbic and autonomic information

  • H.J Groenewegen et al.

    The nucleus accumbens: gateway for limbic structures to reach the motor system?

  • H.J Groenewegen et al.

    Integration and segregation of limbic cortico-striatal loops at the thalamic level

    J Chem Neuroanat

    (1999)
  • G Hedou et al.

    Effects of cocaine on dopamine in subregions of the rat prefrontal cortex and their efferents to subterritories of the nucleus accumbens

    Eur J Pharmacol

    (1999)
  • G Hedou et al.

    Effect of amphetamine on extracellular acetylcholine and monoamine levels in subterritories of the medial prefrontal cortex

    Eur J Pharmacol

    (2000)
  • G Hedou et al.

    Expression of sensitization to amphetamine and dynamics of dopamine neurotransmission in different laminae of the rat medial prefrontal cortex

    Neuropharmacology

    (2001)
  • G Hedou et al.

    Sensitized Fos expression in subterritories of the rat medial prefrontal cortex and nucleus accumbens following amphetamine sensitization as revealed by stereology

    Brain Res

    (2002)
  • A.M Himmelheber et al.

    Effects of local cholinesterase inhibition on acetylcholine release assessed simultaneously in prefrontal and frontoparietal cortex

    Neuroscience

    (1998)
  • M Inoue et al.

    Cholinergic role in monkey dorsolateral prefrontal cortex during bar-press feeding behavior

    Brain Res

    (1983)
  • G.E Jaskiw et al.

    Ibotenic acid lesions of the medial prefrontal cortex potentiate FG-7142-induced attenuation of exploraory activity in the rat

    Pharmacol Biochem Behav

    (1990)
  • A.L Jinks et al.

    Modulation of anxiety-related behaviours following lesions of the prelimbic or infralimbic cortex in the rat

    Brain Res

    (1997)
  • E Jodo et al.

    Activation of locus coeruleus by prefrontal cortex is mediated by excitatory amino acid inputs

    Brain Res

    (1997)
  • K Akert

    Comparative anatomy in the frontal cortex and thalamocortical connections

  • A Aou et al.

    Influence of acetylcholine on neuronal activity in monkey orbitofrontal cortex during bar press feeding task

    Brain Res

    (1983)
  • H Barbas

    Anatomic organization of basoventral and mediodorsal visual recipient prefrontal regions in the rhesus monkey

    J Comp Neurol

    (1988)
  • R.M Beckstead

    Convergent thalamic and mesencephalic projections to the anterior medial cortex in the rat

    J Comp Neurol

    (1976)
  • R.M Beckstead

    An autoradiographic examination of cortico-cortical and subcortical projections of the mediodorsal-projection (prefrontal) cortex in the rat

    J Comp Neurol

    (1979)
  • Cited by (691)

    View all citing articles on Scopus
    View full text