Elsevier

Brain Research

Volume 765, Issue 1, 8 August 1997, Pages 37-50
Brain Research

Research report
Effects of electrolytic lesions of the medial prefrontal cortex or its subfields on 4-arm baited, 8-arm radial maze, two-way active avoidance and conditioned fear tasks in the rat

https://doi.org/10.1016/S0006-8993(97)00334-XGet rights and content

Abstract

The present study tested the effects of electrolytic lesions in two mPFC subregions, the dorsal anterior cingulate area (dACA) and prelimbic cortex, as well as the effects of a larger medial prefrontal cortex (mPFC) lesion which included both subregions, on 4-arm baited, 4-arm unbaited, 8-arm radial maze task and its reversal (Experiments 1 and 4), two-way active avoidance (Experiments 2 and 5) and conditioned emotional response (Experiments 3 and 6). Rats with large or small lesions of the mPFC learned the location of the 4 baited arms in the training and reversal stages of the radial maze task similarly to sham rats, indicating that these lesions did not affect animals' capacity to process and remember spatial information. dACA and mPFC lesions produced a transient deficit in the acquisition of the radial maze task, suggestive of an involvement of these regions in mnemonic processes. However, in view of the normal performance of these groups by the end of training and during reversal, this deficit is better interpreted as stemming from a difficulty to learn the memory-based strategy used to solve the task. Only mPFC lesion led to better avoidance performance at the beginning of training and tended to increase response during the presentation of a stimulus previously paired with shock, compared to sham rats. Both effects can be taken as an indication of reduced emotionality following mPFC lesion. The results are discussed in relation to known behavioral functions of the mPFC and the suggested functional specialization within this region.

Introduction

The rat medial prefrontal cortex (mPFC) has connections with diverse brain regions involved in perceptual, motor, cognitive, and autonomic-limbic functions 33, 53, 54, 63, 72. This diversity is paralleled by multiplicity of function ascribed to the mPFC. Thus, the mPFC has been implicated in various cognitive functions, such as rule learning and the ability to use and shift between behavioral strategies 2, 10, 36, 75, in working memory 17, 36, 68(although less agreement exists with regard to this function; e.g. 60, 76), in spatial learning (e.g. 37, 38, 39, 64), and in emotional processes, particularly in the aversive domain 23, 29, 30, 31, 32, 49, 50, 55.

The mPFC is a heterogeneous structure containing several cytoarchitectonically distinct subregions [71], which include along its dorsoventral axis the agranular medial cortex (AGm) (or Fr2 of [79]) (which has been suggested to include areas homologous to the primate premotor cortex, supplementary motor area, and frontal eye field 45, 46, 51, 52, 58, 70), dorsal anterior cingulate area (dACA), prelimbic cortex (PL), and infralimbic cortex (the latter is not considered by some writers to be part of the PFC, see [79]) 6, 12, 26, 28, 44, 61, 62, 70. These subregions differ in their pattern of connectivity 27, 32, 51, 52, 53, 54, 63, 67, 70, 74, thus implying functional distinction. However, the establishment of structure–function relationships for these subregions still lags behind the anatomical refinement.

Most of the evidence used to ascribe different functions to different mPFC subregions has several shortcomings: (1) Some structure–function relationships are based on comparisons of partial and complete mPFC lesions, which may confound selective involvement of the different subregions and a 'mass action'. For example, Dunnett [17]reported that lesions of the pregenual shoulder area (AGm and dACA) result in a delay-specific deficit in the delayed non-match to sample task, implicating these regions in working memory, while larger lesions, including in addition the more ventral regions of the mPFC, result in a non-delay-dependent deficit, suggesting that the more ventral regions of the mPFC are involved in the acquisition of the more general aspects of the task (see also 19, 34, 64, 68, 78). (2) Other conclusions are based on comparisons between different lesions in different experiments. For example, Brito et al.'s [3]conclusion that the PL cortex, rather than the shoulder area, is the critical site for spatial delayed alternation is not derived from a single study comparing the two lesions. (3) Finally, even studies using small mPFC lesions usually damage more than one mPFC subdivision (e.g. 8, 9, 19, 35, 76, but see [47]).

The present experiments sought to compare the behavioral functions of two mPFC subregions, dACA and PL. Anatomically, these regions differ in several sets of connections. The PL cortex has more extensive connections with autonomic and limbic brain regions compared with the dACA 32, 33, 43, 51, 53, 54, 63, 66, 67, 72, while the dACA has more extensive connections with second-order association areas, posterior parietal cortex, and premotor areas 26, 41, 42, 63, 70, 74. This pattern of connectivity suggests that the PL might be more involved in the autonomic and limbic functions ascribed to the mPFC, while the dACA might be more involved in the cognitive functions ascribed to the mPFC.

Behavioral results thus far give only partial support to this suggestion. Thus, manipulations of the ventral mPFC (including PL) but not the dorsal mPFC (including dACA) result in alterations of autonomic responses, particularly those evoked by stress (e.g. 29, 30, 31, 32, 41, 51, 54), although both regions appear to play a role in unconditioned and conditioned fear or anxiety 23, 47, 49, 50. There is a controversy with regard to the involvement of the shoulder area and PL cortex in the acquisition of spatial-delayed-alternation, a task involving both rule learning and working memory, and in which both regions have been implicated (shoulder area: 8, 18, 56; PL: 3, 4, 24, 68). Some studies which assessed working memory in operant chambers suggested that the shoulder area might be more involved in the working memory component of the task, while the PL cortex might be more involved in the more general aspects of the task 17, 58, 73, but others concluded that the shoulder area is involved in the acquisition of skill- and rule-based behavior [77]. In addition, lesions of the ventral and dorsal mPFC (including PL and dACA, respectively) were found to induce similar effects on behavioral flexibility [9].

The present study tested the effects of electrolytic lesions in two mPFC subregions, the dACA and PL, on 4-arm baited, 4-arm unbaited, 8-arm radial maze task and its reversal (Experiment 1), two-way active avoidance (Experiment 2) and conditioned emotional response (CER; Experiment 3), as well as the effects of a larger mPFC lesion, which included both subregions, on these tasks (Experiments 4, 5, and 6, respectively). We have chosen the avoidance and CER tasks to test the involvement of the mPFC and its subregions in emotional processes 7, 15, 25, and the radial maze task to test their involvement in working and reference memory. We added a reversal stage to the radial maze task in order to obtain a better assessment of reference memory, since a rat with an impaired reference memory should be less affected by reversal.

Section snippets

Subjects

Male Wistar rats (Tel-Aviv University Medical School, Israel) approximately 4 months old, weighing 300–420 g, were housed in pairs under reversed cycle lighting (lights on 1900–0700). Animals were maintained on ad lib food and water except for a week prior to and during the radial maze and CER tasks (see below).

Surgery

Rats were anesthetized with an i.p. injection of Equithesin (3.0 ml/kg). They were placed in a stereotaxic frame and an incision was made into the scalp to expose the skull. The vertical

Anatomical

Representative reconstruction of the dACA and PL lesions is presented in Plate I, columns A and B, respectively. The dACA lesions obtained were triangular in cross-section and elongated in the anteroposterior axis. In most animals the lesion extended A–P 4.2–2.2 mm anterior to bregma. Restricted damage to the most dorsal aspect of Cg3 (PL) and the most medial aspect of Fr2 (AGm) was detected in most of the rats. The PL lesions obtained were circular in cross-section and elongated in the

Discussion

Rats with large or small lesions of the mPFC learned the location of the 4 baited arms in the radial maze task similarly to sham rats, as reflected in similar acquisition curves of the RME and W-RME. dACA and mPFC lesions slowed down the acquisition of the 4-arm baited, 8-arm radial maze task, as a result of a slower rate of reduction in WME. However, impaired performance of the dACA and mPFC rats on the working memory component of the task was evident at the initial stages of training, whereas

Acknowledgements

This research was supported by grants from the Israel Academy of Sciences and Humanities, the Ministry of Science and The Arts, Israel and the Commission of the European Community, and the Josef Buchmann Doctoral Fellowship Fund to D.J.

References (79)

  • R.J. Frysztak et al.

    The effect of medial frontal cortex lesions on cardiovascular conditioned emotional responses in the rat

    Brain Res.

    (1994)
  • S. Granon et al.

    Effortful information processing in a spontaneous spatial situation by rats with medial prefrontal lesions

    Behav. Brain Res.

    (1996)
  • H.J. Groenewegen

    Organization of the afferent connections of the mediodorsal thalamic nucleus in the rat, related to the MD-prefrontal topography

    Neuroscience

    (1988)
  • R.R. Holson

    Mesial prefrontal cortical lesions and timidity in rats.I. Reactivity to aversive stimuli

    Physiol. Behav.

    (1986)
  • R.R. Holson et al.

    Mesial prefrontal cortical lesions and timidity in rats.II. Reactivity to novel stimuli

    Physiol. Behav.

    (1986)
  • R.R. Holson

    Mesial prefrontal cortical lesions and timidity in rats.III Behavior in a semi-natural environment

    Physiol. Behav.

    (1986)
  • K.M. Hurley-Gius et al.

    The medial frontal cortex and gastric motility: Microstimulation results and their possible significance for the overall pattern of organization of rat frontal and parietal cortex

    Brain Res.

    (1986)
  • D. Joel et al.

    Electrolytic lesions of the medial prefrontal cortex in rats disrupt performance on an analog of the wisconsin card sorting test but do not disrupt latent inhibition: implications for animal models of schizophrenia

    Behav. Brain Res.

    (1997)
  • B. Kolb et al.

    Dissociation of the contributions of the prefrontal cortex and dorsomedial thalamic necleus to spatially guided behavior in the rat

    Behav. Brain Res.

    (1982)
  • B. Kolb

    Functions of the frontal cortex of the rat: A comparative review

    Brain Res. Rev.

    (1984)
  • C.M. Leonard

    The prefrontal cortex of the ratI. Cortical projection of the mediodorsal nucleus. II. Efferent connection

    Brain Res.

    (1969)
  • H. Maaswinkel et al.

    Effects of an electrolytic lesion of the prelimbic area on anxiety-related and cognitive tasks in the rat

    Behav. Brain Res.

    (1996)
  • M.A. Morgan et al.

    Extinction of emotional learning — contribution of medial prefrontal cortex

    Neurosci. Lett.

    (1993)
  • E.J. Neafsey et al.

    The organization of the rat motor cortex: A microstimulation mapping study

    Brain Res. Rev.

    (1986)
  • E.J. Neafsey et al.

    The topographical organization of neurons in the rat medial frontal, insular and olfactory cortex projecting to the solitary nucleus, olfactory bulb, periaqueductal gray and superior colliculus

    Brain Res.

    (1986)
  • B. Poucet et al.

    Septum and medial frontal cortex contribution to spatial problem-solving

    Behav. Brain Res.

    (1990)
  • J.D. Sokolowski et al.

    Effects of dopamine depletions in the medial prefrontal cortex on active avoidance and escape in the rat

    Brain Res.

    (1994)
  • L.W. Swanson et al.

    Neural mechanisms for the functional coupling of autonomic, endocrine and somatomotor responses in adaptive behavior

    Brain Res. Rev.

    (1981)
  • G. Winocur

    A comparison of normal old rats and young adult rats with lesions to the hippocampus or prefrontal cortex on a test of matching-to-sample

    Neuropsychologia

    (1992)
  • C. Wolf et al.

    Large and small medial frontal cortex lesions and spatial performance of the rat

    Brain Res. Bull.

    (1987)
  • G.N.O. Brito et al.

    Prelimbic cortex, mediodorsal thalamus, septum, and delayed alternation in rats

    Exp. Brin Res.

    (1982)
  • J.M. de Brabander et al.

    Comparison of the effects of neonatal and adult medial prefrontal cortex lesions on food hoarding and spatial delayed alternation

    Behav. Brain Res.

    (1991)
  • L.D. Devenport et al.

    Sampling behavior in the radial maze and operant chamber: Role of the hippocampus and prefrontal area

    Behav. Neurosci.

    (1988)
  • I. Divac et al.

    Mesial cortical lesions and fear behavior in the wild rat

    Physiological Psychology

    (1984)
  • J.P. Donoghue et al.

    Afferent connections of the lateral agranular field of the rat motor cortex

    J. Comp. Neurol.

    (1983)
  • P. Driscoll and K., Battig, Behavioral, emotional and neurochemical profiles of rats selected for extreme differences...
  • P. Driscoll et al.

    A genetically-based model for divergent stress responses: Behavioral, neurochemical and hormonal aspects

    Adv. Anim. Breeding Genet.

    (1990)
  • P. Driscoll et al.

    Effects of prenatal diazepam on two-way avoidance behavior, swimming navigation and brain levels of benzodiazepine-like molecules in male Roman high- and low-avoidance rats

    Psychopharmacology

    (1995)
  • S.B. Dunnett et al.

    Delay-dependent short-term memory deficits in aged rats

    Psychopharmacology

    (1988)
  • Cited by (67)

    • Paired-housing selectively facilitates within-session extinction of avoidance behavior, and increases c-Fos expression in the medial prefrontal cortex, in anxiety vulnerable Wistar-Kyoto rats

      2016, Physiology and Behavior
      Citation Excerpt :

      Foremost, increased levels of mPFC activation have been consistently observed in outbred controls during the extinction of fear [27,32], and avoidance [15]. Lesions of the mPFC increase the rate of acquisition, and inhibit the extinction, of active avoidance [8,16]. Thus anxiety vulnerability may, in part, be the product of inherent abnormalities of the mPFC.

    • Preventing long-lasting fear recovery using bilateral alternating sensory stimulation: A translational study

      2016, Neuroscience
      Citation Excerpt :

      For instance, it is well documented that the prelimbic (PL) and infralimbic (IL) areas of the medial prefrontal cortex (mPFC) are involved in long-lasting expression or inhibition of conditioned fear responses following extinction learning (for review see Sotres-Bayon and Quirk, 2010; Courtin et al., 2013). Lesional and inactivation of the PL were associated with a reduction in conditioned fear responses (Joel et al., 1997; Akirav et al., 2006; Blum et al., 2006; Sierra-Mercado et al., 2006; Corcoran and Quirk, 2007). In contrast, the same manipulations applied to the IL induced high-fear levels (Quirk et al., 2000; Lebron et al., 2004; Tian et al., 2011).

    • CGMP-dependent protein kinase type II knockout mice exhibit working memory impairments, decreased repetitive behavior, and increased anxiety-like traits

      2014, Neurobiology of Learning and Memory
      Citation Excerpt :

      We selected the RAM assay to assess working memory in cGKII KO animals, a process that has been well-studied as relying upon various subregions of the PFC (D’Ardenne et al., 2012; Funahashi & Kubota, 1994; George, Mandyam, Wee, & Koob, 2008; McCarthy et al., 1996; Nielsen-Bohlman & Knight, 1999; Perlstein, Dixit, Carter, Noll, & Cohen, 2003). Lesions to dorsal anterior cingulate cortex have produced deficits in acquisition of this task in rats and others have shown that the prelimbic region is also important for RAM working memory tasks (Joel, Tarrasch, Feldon, & Weiner, 1997; Taylor, Latimer, & Winn, 2003). These data are also consistent with other studies showing that inhibition of PKA in the PFC, another kinase that phosphorylates the same residue on GluA1, also produces working memory deficits (Aujla & Beninger, 2001; Serulle et al., 2007).

    View all citing articles on Scopus
    View full text