Research reportDissociable aspects of performance on the 5-choice serial reaction time task following lesions of the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: differential effects on selectivity, impulsivity and compulsivity
Introduction
The ability to inhibit inappropriate responses in complex situations is a fundamental aspect of executive control. Abnormalities of response inhibition are associated with frontal pathology, resulting in widespread disorganization of behaviour. However, attempts to localize mechanisms of response inhibition within the prefrontal cortex of human subjects have been controversial [20] not only because neuropathological cases often comprise brain damage that is indiscriminate and non-selective, but also because of the difficulty in defining the precise nature of response inhibitory deficits. For example, response inhibition may lead to impulsive behaviour (that is, actions that occur without foresight, usually disadvantageously) perhaps akin to the risky behaviour in patients with damage to the ventromedial damage as observed in risk taking gambling tasks [6], [7] or to perseverative behaviour (an apparently aimless, ‘compulsive’ repetition of responding) as exemplified by the effects of orbitofrontal cortex (OFC) lesions on reversal learning tasks [18], [32], [33]. In addition, perseveration and impulsivity are both intimately related to executive attentional processes that enable accurate response selection in the face of distraction and interference [46], [54] and is also compromised following selective frontal lesions [22], [50]. Consequently, inhibitory deficits of perseveration and impulsivity, as well as inattention, all contribute to classic dysexcutive syndromes such as in ADHD, schizophrenia and Parkinson’s disease [2], [14], [45] as well as in compulsive drug taking [27], [59] and obsessive-compulsive disorder [4].
Converging evidence from humans and monkeys suggests that the dorsal prefrontal cortex is critical for the on-line maintenance and selection of responses particularly under high attentional demands [24], [28], [29], [49], [54]. By comparison, response inhibition operates within the ventral regions of the frontal cortex [6], [18], [33], [48]. Several lines of evidence have suggested that the rodent brain can also be similarly functionally divided along its dorso-ventral axis [10], [34], [37], [42], [53]. Consistent with this approach, we have recently reported a dissociation of function between the dorsal pre-genual anterior cingulate (Cg1) cortex and the ventral prelimbic-infralimbic (PL-IL) cortex of the rat in a continuous performance test of attention [40]. Specifically, Cg1 lesioned animals showed poor discriminative accuracy because they were unable to attend to the stimuli or temporally organize their behaviour in order to make a correct response. By contrast, animals with combined PL-IL lesions were unable to maintain flexibility and exhibited increases in the number of perseverative responses only.
Although the IL and PL cortex are often considered as a common functional unit [25], [40], [42], it is the IL and OFC that essentially constitute the ventral surface of the rat frontal cortex and effects of selective lesions of these structures have been less extensively examined. This is of particular interest in light of recent neuroimaging evidence that has associated both compulsive and impulsive behaviours with the ventromedial sector of the frontal cortex which includes the IL and OFC [6], [8], [27], [59], [60]. It is not clear, however, how these independent mechanisms of response control contribute to the cognitive disturbances that are observed in disorders observed in compulsive drug taking, OCD or impulsive ADHD-like disorders.
The aim of the present study was to examine the comparative effects of fibre-sparing IL or OFC lesions in the 5-choice serial reaction time task (5CSRTT). This task is capable of measuring different types of performance that include aspects of attention and inhibition such as compulsive (perseveration) and impulsive (premature) responses. In addition, animals with dorsal anterior cingulate lesions were also included in the series of experiments as this allowed for the direct comparison of the dorsal and ventral divisions of the rat frontal cortex. For each group, in addition to effects on baseline performance on the 5CSRTT we also examined the effects of temporal unpredictability of the target stimuli by introducing ‘challenge’ sessions with variable inter-trial intervals (VITIs).
Section snippets
Subjects
All subjects were male Lister Hooded rats (Charles River, UK), housed in pairs in a temperature controlled room (22 °C), under diurnal conditions (12-h light:12-h dark). Rats were food deprived and maintained at 85% of their free-feeding weight throughout the experiment. All testing occurred at a regular time during the light period and animals were 3 months of age (230–260 g) at the start of behavioural training. All experimental procedures were subject to UK Home Office approval (Project License
Histological analysis
The cytoarchitecture was taken from the atlas by Paxinos and Watson [41]. The largest and smallest of the lesion in each group are depicted in Fig. 1. Fig. 1A shows a diagrammatic reconstruction of the OFC lesion. Two animals had extensive damage which extended from the frontal pole and included the anterior cingulate and prelimbic region. These two animals were discarded from analysis. The remaining seven animals showed extensive neuronal loss in the orbitofrontal region. The lesion started at
Histological analysis
Fig. 1B shows the extent of the lesions in the IL lesion group. Following histological analysis, one animal from the IL group was found to have a unilateral lesion. Another two animals were found to have very large lesions which included most parts of the rostral PL cortex whilst leaving the IL region intact. The data from these three animals were therefore excluded from subsequent behavioural analysis. The remaining animals showed evidence of bilateral IL damage with almost complete neuronal
Histological analysis
The largest and smallest lesions in each group are depicted in Fig. 1C. Histological analysis revealed that in all nine cases the area of the lesion was centred on the appropriate target region of the brain. There was extensive cell loss as a result of the ACC lesion which started at approximately AP +3.7 mm from bregma and extended to AP +1.7 mm. The lesion encroached the most dorsal extent of the PL cortex and there was minimal overlap with the motor cortex. The Sham operated group showed no
Discussion
This is the perhaps the first demonstration that inhibitory processes of response control can be dissociated at the level of the ventral regions of frontal cortex. Specifically, we have shown that lesions of the OFC (medial and lateral regions) predominantly induced ‘compulsive’ perseverative responses in the apertures. By comparison, lesions of the most ventromedial frontal sector, the IL cortex, mainly resulted in inappropriate ‘impulsive’ premature responses that occurred prior to the onset
Acknowledgements
This work was supported by a Programme grant from the Wellcome Trust (T.W.R) completed within the Medical Research Centre for Behavioural and Clinical Neuroscience. We would like to thank David Theobald for assistance with histological preparation. Y.C. was supported by Cambridge Cognition and is now at NIH/NIMH, 49 Convent Drive, Bldg 49, Room 1B80, Bethesda, MD 20892-4415, USA.
References (61)
- et al.
Insensitivity to future consequences following damage to human prefrontal cortex
Cognition
(1994) - et al.
Rodent models of prefrontal function
TINS
(2002) - et al.
Effects of lesions to the ascending noradrenergic neurons on performance on a 5-choice serial reaction time task: implications for theories of dorsal noradrenergic bundle function based on selective attention and arousal
Behav. Brain Res.
(1983) - et al.
Functional role of rat prelimbic-infralimbic cortices in spatial memory: evidence for their involvement in attention and behavioural flexibility
Behav. Brain Res.
(2000) - et al.
Common regions of the human frontal lobe recruited by diverse cognitive demands
Trends Neurosci.
(2000) The basal ganglia
TINS
(1995)- et al.
Toward a neurobiology of obsessive-compulsive disorder
Neuron
(2000) - et al.
Limbic lesions and the problem of stimulus-reinforcement associations
Exp. Neurol.
(1972) - et al.
Cognitive functions of cortical acetylcholine: toward a unifying hypothesis
Brain Res. Rev.
(1997) - et al.
Spatial mapping: definitive disruption by hippocampal or medial frontal cortex damage in rats
Neurosci. Lett.
(1982)
The effects of fornix and medial prefrontal lesions on delayed non-matching-to-sample by rats
Behav. Brain Res.
A comparison of the effects of medial prefrontal, cingulate cortex and cingulum bundle lesions on tests of spatial memory: evidence of a double dissociation between frontal and cingulum bundle contributions
J. Neurosci.
Stop-signal inhibition disrupted by damage to right inferior frontal gyrus in humans
Nat. Neurosci.
Bilateral lesions of the subthalamic nucleus induce multiple deficits in an attentional task in rats
Eur. J. Neurosci.
Brain imaging as a tool in establishing a theory of brain pathology in obsessive compulsive disorder
J. Clin. Psychol.
Object discrimination by rats: the role of frontal and hippocampal systems in retention and reversal
Physiol. Behav.
Emotion, decision-making, and the orbitofrontal cortex
Cereb. Cortex
Different contributions of the human amygdala and ventromedial prefrontal cortex to decision making
J. Neurosci.
Prelimbic cortex, mediodorsal thalamus, septum, and delayed alternation in rats
Exp. Brain Res.
Functional disconnection of a prefrontal cortical-dorsal striatal system disrupts choice reaction time performance: implications for attention function
Behav. Neurosci.
Dissociable contributions of the orbitofrontal and infralimbic cortex to pavlovian autoshaping and discrimination reversal learning: further evidence for the functional heterogeneity of the rodent frontal cortex
J. Neurosci.
Dopaminergic modulation of high-level cognition in Parkinson’s disease: the role of the prefrontal cortex revealed by PET
Brain
Lesions of the prelimbic-infralimbic cortices in rats do not disrupt response selection processes but induce delay-dependent deficits: evidence for a role in working memory?
Behav. Neurosci.
Effects of selective excitotoxic prefrontal lesions on acquisition of nonmatching- and matching-to-place in the T-maze in the rat: differential involvement of the prelimbic-infralimbic and anterior cingulate cortices in providing behavioural flexibility
Eur. J. Neurosci.
Dissociation in prefrontal cortex of affective and attentional shifts
Nature
Spontaneous alternation in rats with lesions in the frontal lobes. An extension of the frontal lobe syndrome
Physiol. Psychol.
Varieties of impulsivity
Psychopharmacology
Central cholinergic systems and cognition
Annu. Rev. Psychol.
Selective roles for hippocampal, prefrontal cortical and ventral striatal circuits in radial-arm maze tasks with or without a delay
J. Neurosci.
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