Involvement of the Rat Medial Prefrontal Cortex in Novelty Detection

Behavioral Neuroscience 2002, Vol. 116, No. 3, 498 –503

Copyright 2002 by the American Psychological Association, Inc. 0735-7044/02/$5.00 DOI: 10.1037//0735-7044.116.3.498

Involvement of the Rat Medial Prefrontal Cortex in Novelty Detection R. Dias and R. C. Honey Cardiff University The prefrontal cortex in humans has been implicated in processes that underlie novelty detection and attention. This study examined the contribution of the rat medial prefrontal cortex to novelty detection using the targeting, or orienting, response (OR) as a behavioral index. Lesions to the medial prefrontal cortex (specifically the prelimbic and infralimbic cortices) influenced neither the OR to a novel visual stimulus from a localized light source (V1), nor the change in this OR over the course of a series of exposures to V1. However, after exposure to V1, the OR to a 2nd visual stimulus from the same source, V2, was more pronounced in control rats than in lesioned rats. These results suggest that the medial prefrontal cortex in the rat contributes to the process of novelty detection.

In our training procedure, rats receive many presentations of one visual stimulus (V1) and occasional presentations of a (relatively) novel stimulus (V2) from the same source as V1. In such a procedure, rats orient to the stimulus when it is novel, and this orienting response (OR) becomes less frequent as the result of repeated exposure to the stimulus (i.e., habituation occurs) and is restored when the stimulus is altered in some way (i.e., dishabituation occurs; Honey, Good, & Manser, 1998; Honey, Watt, & Good, 1998). These changes in the rats’ tendency to orient can be considered overt behavioral indices of the operation of processes involved in novelty detection and attention (see, e.g., Honey & Good, 2000a, 2000b). If the rat medial prefrontal cortex (specifically, the prelimbic and infralimbic cortices) contributes to the operation of these processes, then the behavior of rats with lesions to these structures in this simple task (cf. Delatour & GisquetVerrier, 2000; Dias & Aggleton, 2000; Muir, Everitt, & Robbins, 1996) should reveal this contribution. For example, rats with lesions to the medial prefrontal cortex might exhibit a different pattern of behavior either when a novel visual stimulus is first presented or when an infrequently presented visual stimulus (V2) is introduced into a sequence of presentations of a familiar stimulus, V1. This procedure has the potential, therefore, to provide compelling grounds for supposing that the rat medial prefrontal cortex, like its counterpart in humans (e.g., Daffner et al., 2000; Knight, 1984, 1991; Yamaguchi & Knight, 1990), is involved in the processes that underlie novelty detection and attention.

Converging evidence suggests that the prefrontal cortex plays an important role in processes that subserve novelty detection and attention (see e.g., Goldman-Rakic, 1996; Knight & Grabowecky, 1994). For instance, single-unit recordings from the prefrontal cortex of primates indicate that it contains neurons engaged in the registration and maintenance of sensory information and in determining performance on the basis of that information (Fuster & Alexander, 1971; Goldman-Rakic, Fanuhashi, & Bruce, 1991). Moreover, complementary studies in primates (Dias, Robbins, & Roberts, 1996a, 1996b, 1997) and rats (Birrell & Brown, 2000) show that lesions of the prefrontal cortex result in a deficit in the transfer between visual discrimination learning problems—transfer that has been taken to reflect changes in attention to visual stimuli or stimulus dimensions (Mackintosh, 1974). Evidence that implicates the human prefrontal cortex in novelty detection and attention comes from electrophysiological recordings of scalp and intracranial event-related potentials (ERPs). These studies have used simple procedures in which infrequently presented or novel stimuli are introduced into a stream of frequently presented, familiar stimuli (e.g., Daffner et al., 2000; Knight, 1984, 1991; Yamaguchi & Knight, 1990) and have been mirrored by studies with nonhuman animals (for a review, see Swick, Kutas, & Neville, 1994). In this study, we used a procedure with rats that is formally equivalent to those used in studies of ERPs in humans to investigate the contribution of the medial prefrontal cortex to novelty detection and attention.

Method R. Dias and R. C. Honey, School of Psychology, Cardiff University, Cardiff, United Kingdom. R. Dias is now at Merck Sharp & Dohme Research Laboratories, Harlow, Essex, United Kingdom. This research was funded by the Biotechnology and Biological Sciences Research Council (UK) and was conducted when R. Dias was a Medical Research Council Research Fellow and R. C. Honey was a Royal Society University Research Fellow. We thank A. Morgan for help with the histological analysis. Correspondence concerning this article should be addressed to R. C. Honey, School of Psychology, Cardiff University, Tower Building, Park Place, Cardiff CF10 3YG, United Kingdom. E-mail: [email protected]

Subjects and Surgery Thirty-two naive adult hooded Lister rats served as subjects. Each rat was anesthetized by an intraperitoneal injection of pentobarbitone sodium (Sagatal, Rhone Merieux, Dublin, Ireland), at a dose of 60 mg/kg. The rat was then placed in a stereotaxic frame (David Kopf Instruments, Tujunga, CA), and the scalp was retracted to expose the skull. A craniotomy was then made above the sagittal sinus, and the dura was cut to expose the cortex above the appropriate region. For rats receiving prelimbic– infralimbic lesions (Group PIL, n ⫽ 16), injections of 0.33 ␮l of 0.09 M N-methyl-D-aspartic acid (NMDA; Sigma, Poole, UK) dissolved in phosphate buffer (pH 7.2) were delivered through a 1-␮l Hamilton syringe into

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BRIEF COMMUNICATIONS two sites per hemisphere. The stereotaxic coordinates relative to bregma, with the incisor bar set at ⫹5.0 relative to the horizontal plane, were as follows: AP ⫹2.7, lateral ⫾0.8, with a depth of 4.0 mm below the top of the cortex; and AP ⫹4.0, lateral ⫾0.8, with a depth of 3.5 mm below the top of the cortex. Each injection was made gradually over a 4-min period, and the needle remained in situ for a further 4 min before being withdrawn. After completion of the surgical procedure, the skin was sutured, and sulfanilamide powder was applied. The rats serving as surgical controls (Group Sham, n ⫽ 16) received the same treatment as the PIL rats, but after the dura was cut and retracted, did not receive injections of NMDA. After a 2-week period of postoperative recovery, rats were gradually reduced to 80% of their ad-lib weights (M ⫽ 380 g). The rats were maintained at these weights throughout the study. Rats were housed in pairs and had free access to water when they were in their home cages. The colony room in which the rats were housed was illuminated between the hours of 0800 and 2000; training and testing began at approximately 0900.

Histology After the completion of behavioral testing, the rats were anesthetized with an intraperitoneal injection of pentobarbitone sodium (Euthatal, Rhone-Merieux) and perfused transcardially with saline followed by 10% (wt/vol) formol-saline. The brain was removed and postfixed in formolsaline for a minimum of 2 hr before being transferred into 25% (wt/vol) sucrose in 0.2 M phosphate buffer and left overnight. Coronal sections were then cut at 60 ␮m on a freezing sledge microtome, and every third section was mounted and stained with cresyl violet Nissl stain.

Behavioral Procedures and Apparatus All experimental sessions were conducted in two conventional experimental chambers that were identical to those used by Honey et al. (Honey, Good, & Manser, 1998; Honey, Watt, & Good, 1998). These chambers were housed in a brightly lit experimental room. Rats’ behavior during training was videotaped with a Panasonic VHS video camera (Model NV-M40). On the first 2 days of the study, the rats were simply placed in the apparatus for 30 min. On each of the next 4 days, one set of rats (8 from Group PIL and 8 from Group Sham) received a series of 16 trials with one visual stimulus (V1) that consisted of the illumination of a small 3-W covered lightbulb for 10 s. For all rats, this light source was on the left-hand side of the wall that contained the food well (see Honey, Good, & Manser, 1998; Honey, Watt, & Good, 1998). For half of the rats in each group, the light was constantly illuminated during each 10-s presentation, and for the remaining rats, the light flashed (alternating 25 centiseconds on and off). The final 4 trials in each session consisted of 2 presentations of V1 intermixed with 2 presentations of the remaining visual stimulus, V2 (i.e., V1, V2, V1, V2 for half of the rats in each group and V2, V1, V2, V1 for the remainder). On the 5th day, the rats received the same intermixed sequence of presentations of V1 and V2 at the beginning of the session. In all sessions, the first stimulus was presented 30 s after the rat was placed in the chamber, and the interval between the termination of one stimulus presentation and the onset of the next presentation was 30 s. The remaining set of rats (8 in Group Sham and 8 in Group PIL) received identical training, with the exception that the intermixed series of test trials on each day were replaced with 4 presentations of V1. Comparison of the levels of orienting to V1 in rats that received only presentations of V1 with the level of orienting to V1 in rats that received presentations of V1 and V2 allowed us to assess the impact of the introduction of V2 on the course of habituation. Given that there was no impact of V2 presentations on the levels of orienting to V1 between the two sets of rats (for either Groups Sham or PIL), the scores from corresponding presentations of V1 during training were pooled across the two sets of rats.

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Behavioral Scoring Our scoring procedures were identical to those described in Honey et al. (Honey, Good, & Manser, 1998; Honey, Watt, & Good, 1998). Experimental sessions were videotaped and then scored by observers who were unaware of the group membership of the rats being scored. An OR was defined as the tip of the rat’s snout being located in the left-hand side of the apparatus, the side that contained the light source, and pointing in the direction of the light source. With this scoring procedure, the concordance between two observers was high (approximately 95%). Our primary interests were threefold: the initial levels of orienting to V1 in the two groups (Sham and PIL); changes in the level of orienting, both over the course of successive sessions and within the course of a session, in the two groups; and the OR evoked by presentations of V2 introduced into a sequence of presentations of V1 during either the final four trials on the first 4 days of training or the four trials presented at the start of the 5th day of training. Our analysis of these intermixed presentations of V1 and V2 focuses on the first pair of trials within each sequence on Days 1– 4, because the levels of orienting to V2 during the second pair of trials were low and did not differ between the groups. We also combined the first pair of trials for Days 1 and 2, and Days 3 and 4, to provide a larger sample of behavior. Both pairs of trials on the 5th day of training were included in our analysis.

Results Histological Analysis The cytoarchitectonic borders and nomenclature are taken from the atlas by Paxinos and Watson (1986). After histological analysis, 1 rat from each set of lesioned rats was discarded. In all of the remaining cases, there was considerable bilateral cell loss in the prelimbic area that extended from just behind the rostral pole to the level of the genu at the corpus callosum (see Figure 1). The extent of damage in the infralimbic cortex was less consistent, and in 4 rats, this region was largely spared. There was also restricted cell loss in the most rostral and ventral portions of the dorsal anterior cingulate cortex, which was evident bilaterally in 3 rats and unilaterally in another 3 of the 14 rats. In addition, there was limited unilateral cell loss in the dorsal olfactory bulb of 1 rat.

Behavioral Analysis Panel a of Figure 2 shows the initial level of orienting to V1 on the first four occasions on which it was presented on Day 1, and the change in the OR on each of the 3 subsequent days of training, Days 2– 4, during the first four trials of each day. Examination of this panel reveals that the initial level of orienting on Day 1 and the decline in the level of orienting across the 4 days of training was similar in the two groups, Sham and PIL. Analysis of variance (ANOVA) with day and group as factors confirmed that there was an effect of day, F(3, 84) ⫽ 6.28, p ⬍ .01, but no effect of group and no interaction between these factors (Fs ⬍ 1). Panel b of Figure 2 shows the within-session decline in the OR to V1. The scores are pooled across Days 1– 4 and presented in four 4-trial blocks (i.e., excluding the final four trials of each day when V2 was introduced). Inspection of Panel b reveals that the initial OR to V1 on the first block of training and the decline during the course of a session was similar in the two groups, Sham and PIL. An ANOVA with block and group as factors confirmed this description of the results, revealing a main effect of block, F(3, 84) ⫽ 4.33, p ⬍ .01, but no effect of group and no interaction

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in Group PIL and that this effect was apparent when V2 was presented at the end of the training sessions (on Days 1– 4) and when V2 was presented at the beginning of the session of Day 5. An ANOVA revealed an effect of block, F(2, 26) ⫽ 8.22, p ⬍ .01, and an effect of group, F(1, 13) ⫽ 25.65, p ⬍ .01, but no interaction between these factors (F ⬍ 1).

Discussion

Figure 1. Reconstructions of the lesions, made by projecting the lesions onto a series of standardized coronal sections at various distances, in millimeters anterior to bregma. The minimum and maximum extent of the lesions are shown in black and gray, respectively.

between these factors (Fs ⬍ 1). Panel c of Figure 2 depicts the levels of orienting to V1 during the intermixed sequences of test trials. The scores are pooled across the first and second pairs of days of training (when the test sequences came at the end of each session) and are presented separately for the final, 5th day of training (when the test sequence was at the beginning of the session). Examination of this panel reveals that the level of orienting declined from the first to the second block of training and increased on the final day of training, when the test sequence was presented at the beginning of the session. However, it is clear that during these presentations of V1 (see also Panels a and b) there were no differences between Groups Sham and PIL at any point. An ANOVA confirmed that there was an effect of block, F(2, 26) ⫽ 3.41, p ⬍ .05, but no effect of group and no interaction between these factors (Fs ⬍ 1). Finally, Panel d of Figure 2 shows the levels of orienting during V2. It is apparent from inspection of this panel that the level of orienting to V2 changed over the course of training in a way that parallels the changes observed in the level of orienting to V1 (see Panel c). It is also clear that presentations of V2 evoked a much higher level of orienting in Group Sham than

Novel stimuli enjoy privileged access to the processing resources of most, if not all, animals. In nonhuman animals, the presentation of a novel stimulus often results in a characteristic pattern of overt behavior known as the targeting, or orienting, response. In this study, the OR that rats show to visual stimuli was used as a behavioral index in an investigation of the role of the medial prefrontal cortex in novelty detection and attention. The pattern of results was simple: Rats with discrete lesions of the prelimbic and infralimbic cortices (cf. Butters, 1964; Kolb, 1974) exhibited a normal OR to an entirely novel visual stimulus (V1), and this OR declined over the course of a series of presentations of V1. However, when a (relatively) novel visual stimulus (V2) was introduced into a sequence of by-then familiar V1 presentations, control rats were more likely to orient to V2 than were rats with lesions of the medial prefrontal cortex. It is worth noting that the latter results contrast with those from similar studies in which rats with hippocampal lesions showed a normal OR when the physical properties of a habituated stimulus are altered (Honey, Good, & Manser, 1998; Honey, Watt, & Good, 1998; Oswald et al., in press). The present results do, however, complement evidence suggesting that the prefrontal cortex in humans is involved in the processes that underpin novelty detection (e.g., Daffner et al., 2000; Knight, 1984, 1991; Yamaguchi & Knight, 1990). Thus, electrophysiological recordings of scalp and intracranial ERPs reveal that the introduction of a (relatively) novel stimulus into a stream of familiar stimuli results in activity in the prefrontal cortex. There are, no doubt, several ways in which the prefrontal cortex might contribute to processes involved in novelty detection. However, one way in which the prefrontal cortex might contribute to these processes warrants a detailed consideration for three reasons: (a) It provides an account for the precise pattern of observations that we have reported, (b) it is based on a synthesis of theoretical accounts of habituation and existing analyses of prefrontal function, and (c) it is relatively simple and explicit. Many theoretical treatments of habituation suppose that the neural processes that are responsible for generating the OR to a specific stimulus (e.g., V1) are inhibited when a memory of that stimulus, or a similar stimulus, has recently been activated either directly, by the stimulus itself, or indirectly, by association (see Donegan & Wagner, 1987; Konorski, 1967; Sokolov, 1963; Wagner, 1981). Let us first assume that this inhibitory habituation process operates outside the medial prefrontal cortex, thereby providing a basis for the relatively normal decline in the OR to V1 observed in rats with lesions of the medial prefrontal cortex (see Panels a, b, and c in Figure 2). It has also been common to suggest that, in one way or another, components of the prefrontal cortex exert an inhibitory influence over processes that are executed elsewhere (see, e.g., Dias & Aggleton, 2000; Dias et al., 1996a, 1996b, 1997; Knight, 1984; Mishkin, 1964). Now let us assume

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Figure 2. Mean percentages of trials with an orienting response (OR) in rats that had received either sham operations (SHAM) or excitotoxic lesions of the medial prefrontal cortex (PIL) on the initial four presentations of a novel visual stimulus (V1) on each day (a), during consecutive blocks of presentations of V1 within a session (b), and during presentations of V1 (c) and a second stimulus from the same source (V2; d) at the end of training sessions on Days 1– 4 and at the start of the session on Day 5.

that when any novel (or unexpected) stimulus is detected (i.e., one for which no memory is currently active), the prefrontal cortex becomes active and can exert an inhibitory influence over the habituation process. Application of this analysis to the remaining aspects of our results is straightforward. When an entirely novel stimulus (V1) is presented, the prefrontal cortex would become active but would be without influence because there would be no (currently active) habituation process on which the inhibitory influence of the prefrontal cortex could operate. If one assumes that the (familiar) experimental context is quite different from V1 (see below), then the OR to V1 would be no less marked in rats with lesions of the prefrontal cortex than in control rats (see Day 1 in Panel a of Figure 2). However, when V2 is presented after

habituation training with V1, V2 activates the prefrontal cortex (because it is not identical to V1) and the inhibitory habituation process (to the extent that there is stimulus generalization between V1 and V2). A standard account for this process of stimulus discrimination and generalization relies on the notion that V2 activates a set of representational elements (see Estes, 1950; Wagner, 1981), some of which are uniquely activated by V2, with the remainder commonly activated by V1 and V2 (see Mackintosh, 1974, pp. 486 – 487; Rescorla, 1976). Under these circumstances, when V2 is presented after habituation training with V1, the unique elements of V2 activate the prefrontal cortex, which could then inhibit the habituation process provoked by the familiar, common elements and allow an OR to be initiated. According to

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this account, after habituation training with V1, presentation of V2 would provoke more orienting in control rats than in those with prefrontal lesions because in control rats the habituation process would be under the inhibitory influence of the prefrontal cortex (see Panel d in Figure 2; this state of affairs might also allow neophobic reactions to stimuli, controlled outside the prefrontal cortex, to be more apparent in subjects with prefrontal lesions; compare Panels c and d). One clear prediction that follows from this analysis is that the influence that prefrontal lesions exert on the level of orienting during presentations of V2 would not be evident had V2 been quite different from V1. We have no direct evidence that bears on this prediction, and it would be difficult to assess using the procedures from the current study: In our experience, there tends to be a substantial amount of generalization between localized visual stimuli that elicit an OR (see Honey, 1996). A measure of indirect support for this prediction, however, can be derived from both studies of rats’ spontaneous exploration of different, complex objects (see Ennaceur, Neave, & Aggleton, 1997; Mitchell & Laiacona, 1998) and electrophysiological recordings in humans (Knight, 1997, p. 83). Nevertheless, our analysis does have the advantages (already mentioned) that it is relatively simple and is based on a synthesis of existing conceptual models of habituation and extant views about one function that the prefrontal cortex might serve.

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Received May 8, 2001 Revision received September 20, 2001 Accepted December 14, 2001 䡲