Research report
Dissociable 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

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Abstract

It is becoming increasingly apparent that multiple functions of the frontal cortex such as inhibitory control and executive attention are likely sustained by its functionally distinct and interacting sub-regions but the precise localization of dissociable executive processes has proved difficult and controversial. In the present series of studies, we investigated the behavioural effects of bilateral excitotoxic lesions of different regions of the rat neocortex in the 5-choice serial reaction time task. Whereas lesions of the dorsal anterior cingulate cortex (ACC) impaired performance of the task as revealed by a reduction in discriminative accuracy, lesions made to distinct ventral regions of the frontal cortex showed selective deficits in inhibitory measures of control. Specifically, the infralimbic lesion produced increases in premature responding that was accompanied by fast response latencies. By comparison, the orbitofrontal lesion showed perseverative tendencies particularly when the inter-trial interval was made long and unpredictable, a challenge that would normally promote premature responding instead. These different behavioural effects following dorsal and ventral lesions of the rodent frontal cortex signifies the integrity of the frontal cortex in multiple executive mechanisms that work independently and complementarily by which performance is optimized. Furthermore, these data provide new insights into the functional organization of the rodent frontal cortex with a particular emphasis on localization of function.

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.

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