Abstract

It has previously been proposed that the prefrontal cortex has a role in ‘executive processes’ and memory function. These activities presumably require modulation of activity in posterior cortex. On the basis of this hypothesis, it was proposed that prefrontal cortex lesions might alter neural activity in the hippocampus, a region implicated in memory processing. A major feature of hippocampal activity is place-related firing. Single unit recordings of CA1 complex spike cells (‘place cells’; n = 64) were made as rats with prefrontal lesions (n = 6) or sham surgeries (n = 7) foraged freely. The spatial information content provided by spikes in cells of lesion animals was significantly greater than in sham-group animals, although the size of their place fields was not affected. The location of the firing fields of lesion-group rats were less stable across time when either 5 h or 3 min intervals were inserted between successive recordings of the same cell. It was hypothesized that animals with prefrontal lesions may be overly influenced by local, less stable environmental cues than sham rats. This may explain both the spatial information content and stability findings. These findings indicate that prefrontal cortex normally modulates spatial responses in the hippocampus.

Introduction

It has previously been proposed that the prefrontal cortex has a role in ‘executive processes’ (Baddeley, 1986). The role of ‘executive controller’ or ‘supervisor’ entails the administration of cognitive processes, via the manipulation of information at various stages of processing, from sensory perception through to the selection of motor responses (Shimamura, 2000). Shimamura (Shimamura, 2000) described the neural basis of executive control in terms of a ‘dynamic filtering theory’, in which the prefrontal cortex acts as a selective gating or filtering mechanism, coordinating incoming signals by either inhibiting or maintaining their activation. The theory proposes that under conditions of interference, an important function of the system involves the inhibition of extraneous activity or noise.

The dynamic filtering model is able to account for several forms of cognitive dysfunction. For example, it has been shown that patients with frontal lobe damage or ‘dysexecutive syndrome’ (Baddeley, 1986) are unable to control the selection of information in temporal storage. This phenomenon has been demonstrated at a physiological level, where Knight and Grabowsky (Knight and Grabowsky, 1995) reported that auditory evoked potentials are enhanced in subjects with prefrontal cortex lesions, suggesting that in the absence of the prefrontal cortex there is a disinhibition of activity in the posterior cortex. This may result in an intrusion of irrelevant information into posterior cortex processing streams and it implies that in the normal brain, the frontal cortex is capable of selectively inhibiting activity in posterior regions as part of the filtering process. Shimimura (Shimimura, 2000) has suggested that the prefrontal cortex performs a similar neural filtering function throughout its entirety, but that different behavioural outcomes occur as a result of region-specific connectivity to cortical (and subcortical) areas that serve different cognitive functions.

There is considerable evidence that the prefrontal cortex is involved in higher order memory functions, particularly, working memory (Funahashi and Kubota, 1994; Goldman-Rakic, 1995; Shimamura, 1995; Miller et al., 1996). Previous studies have shown that lesions of the prefrontal cortex in non-human primates and rodents result in deficits in working memory tasks (Goldman and Rosvold, 1970; Shaw and Aggleton, 1993; Granon et al., 1994; Petrides, 1994; Shimamura, 1995; Bilkey and Liu, 2000). Furthermore, activity of single neurons in the prefrontal cortex of primates occurs during delayed response tasks, indicating that information can be retained in this region in the absence of sensory input (Fuster, 1990; Goldman-Rakic, 1995; Miller et al., 1996; Funahashi et al., 1997).

Given the evidence for prefrontal involvement in memory processing, it follows that the supervisory role of the prefrontal cortex may also include the manipulation of memorial processes. The temporal cortex is known to be involved in memorial processing, with recent research focusing on the roles of the perirhinal cortex (Brown and Aggleton, 2001; Liu and Bilkey, 2001) and the hippocampus (Murray, 1996; Eichenbaum et al., 1999). In a recent study, Zironi et al. (Zironi et al., 2001) demonstrated that lesions to the rat prefrontal cortex resulted in more discrete location-related firing properties of neurons in perirhinal cortex and the neighbouring TE cortex during a delayed non-match-to-position spatial memory task. As a result of this finding it was proposed that the prefrontal cortex normally selectively inhibits firing activity in the temporal cortex, and that damage to the prefrontal cortex augments the firing activity, due to the subsequent disinhibition. It was suggested that this indicated that the prefrontal cortex normally filters the influence of environmental stimuli during the activation of memorial processes.

On the basis of this previous finding, however, it was unclear whether the lesion-induced changes to temporal cortex neuronal activity were a result of changes in object or cue representations or due to changes in spatial context information, such as information regarding the animal’s position in space. In the latter case, the effect may have been mediated through prefrontal modulation of the neighbouring hippocampus, a region that is connected to the perirhinal cortex (Deacon et al., 1983; Burwell and Amaral, 1998; Witter et al., 2000) which is believed to be involved in spatial memory processing (O’Keefe and Nadel, 1978; Jarrard, 1995) and which receives input from the prefrontal cortex (Groenewegen and Uylings, 2000).

The aim of the current study was to investigate whether the prefrontal cortex could potentially modulate spatially related neural activity in the hippocampus. Specifically, the effect of prefrontal cortex lesions on the firing properties of hippo- campal neurons was tested in freely moving rats. These hippocampal neurons are commonly termed ‘place cells’ (O’Keefe and Dostrovsky, 1971), and are known to fire selectively when the animal is in a particular region of the environment. It has been proposed that one function of the collective activity of ensembles of these neurons is to represent an animal’s location in space.

Materials and Methods

Subjects

Thirteen male Sprague–Dawley rats were housed individually in wire mesh cages and maintained on a 12 h light–dark cycle. Surgical and behavioural procedures were conducted during the light phase of the cycle. The animals weighed between ~320 and 400 g at the time of surgery and food and water were freely available prior to surgery and for the following 2 weeks. The animals were handled and treated with care and the experimental procedures used were in accordance with guidelines specified by the NIH in the US regarding the care and use of laboratory animals. The study was approved by the University of Otago Animal Ethics Committee.

Electrode Implantation and Lesions

Surgery was performed under aseptic conditions. Rats were anaes- thetized with sodium pentobarbitol (60 mg/kg; i.p.) and administered Penicillin (0.15 ml i.m). They were placed in a stereotaxic frame (Kopf) where the head was held in the horizontal plane. An overhead heating lamp was used to maintain body temperature. Co-ordinates for prefrontal cortex lesions and hippocampal electrode implantation were derived from the Rat Brain Atlas of Paxinos and Watson (Paxinos and Watson, 1998).

A midline incision was made to expose the skull which was then scraped clean of connective tissue and dried so that bregma and the midline sagittal suture could clearly be seen. Trephines were drilled on both sides of the skull at the co-ordinates 2.0, 3.0 and 4.5 mm anterior to bregma and 1.6 mm lateral to the midline. A monopolar lesioning electrode constructed from teflon-coated; stainless steel wire (125 μm diam.) was lowered into each trephine at a 16° angle towards the midline at depths of 2.0, 1.3 and 2.1, and 1.0 mm, respectively from the cortical surface. Two mA of direct current was then administered for 10 s. Six rats received lesions to the prefrontal cortex. Seven sham animals were operated in the same manner except that the lesioning electrode was not lowered into the brain.

A miniature, moveable microdrive (Bilkey and Muir, 1999), which contained a bundle of eight recording electrodes was implanted unilaterally (counterbalanced across hemispheres) immediately above the cell layer of the dorsal hippocampus (CA1) at 3.8 mm posterior and 2.5 mm medial to bregma, and 1.8 mm below the dural surface. The recording electrodes consisted of formvar-coated, nichrome wires (25 μm diameter) and the whole bundle was cut at a 45° angle just prior to implantation. The electrode assembly and a ground wire were connected to a headplug (McIntyre miniconnector) and anchored to the skull with dental acrylic and jewellers screws. After surgery the animals were administered analgesia (0.2 ml Temgesic; Reckitt & Colman) and left to recover. Two weeks after surgery the rats were placed on a food deprivation schedule during which their weight was reduced to, and maintained at 85% of their free-feeding weight in readiness for the recording procedure.

Recording Apparatus and Environment

Animals were tested in a square (60 × 60 cm by 40 cm deep) black-painted chamber of which the floor and 3 walls were made of hardboard. The fourth wall was made of Plexiglas and had a 40 cm2 clear (unpainted) area in the centre which served as a local cue. This cue was always in the same location relative to the recording room. The chamber was elevated 80 cm above the floor on a table in the centre of a small, darkened room. A single lamp (60 W bulb) provided light. A video camera was mounted on the ceiling directly above the chamber to record the animals’ position. A flexible cable connected to a commutator hung from the ceiling for unit recording. A speaker positioned above the chamber emitted background masking noise. Other items in the room such as furniture, the recording apparatus, a radio and visual stimuli on the wall served as visual cues and were kept constant.

Unit Recording

Extracellular spike activity was recorded in the hippocampus and impedance-matched via a Field Effect Transistor (FET) source-follower located in a head-stage mounted at the end of the recording cable. A ‘quiet’ electrode was used as an indifferent. The output signals were filtered at 300 Hz and 5 kHz, and amplified 10 000 times (Barc Neuro 8 Amplifier) before being digitized at 25 kHz by a Digidata 1200 series interface (Axon instruments) under the control of Axoscope (Axon instruments). Single unit signals were digitized when a spike on any channel exceeded a pre-determined threshold set above the background noise levels and were stored on a personal computer for off-line analysis.

The position of the rat’s head was simultaneously monitored by a tracking system connected to the video camera located above the recording arena. This tracked the position of three infrared light-emitting diodes (LEDs) mounted on the head stage. The LEDs were positioned in a triangular formation ~1 cm apart and centred on the crown of the head. Head position was sampled at 10 Hz (regardless of whether single unit activity was being recorded or not) and this information was made available to the Digidata acquisition system.

Identification of Place Cells

Putative ‘place cells’ were classified as such if they had a spike width (peak-to-trough) of >450 μs, and a signal-to-noise ratio of ~3–1 or greater. These cells were characterized by ‘complex-bursts’ wherein they often fired two to five spikes with an interspike interval of ~5 ms. Complex bursts were identified with an autocorrelation function (Matlab) that calculated the time between all spike pairs. The autocorrelation functions also allowed the experimenter to identify the post-spike refractory period, indicative of a well-isolated neuron, and to distinguish between place cell and theta cell (putative interneuron) firing patterns. On the basis of this classification data from theta cells were not included in the current analysis.

Data Analysis

Units were discriminated from noise and isolated from other cells with customized template-matching software utilized off-line. When the same unit was recorded twice across a delay interval an identical template was used at each analysis. Unit firing was mapped onto the animal’s position within the experimental chamber. In this procedure maps were constructed by dividing the floor of the experimental chamber into a 20 × 20 pixel grid, where each pixel corresponded to 9 cm2. The number of spikes that were fired within each pixel was divided by the time spent in that pixel (dwell time), to generate the firing rate (FR). When an animal spent less than 500 ms in any pixel during the 10 min recording session, the data in that pixel was regarded as being undersampled. The values in these pixels were replaced with the average value of their neighbouring pixels.

A 3 × 3 normalized weighting matrix was then used to smooth the firing rate maps which resulted in the value for each pixel becoming equal to the sum of the firing rate of each neighbouring pixel including itself, multiplied by 0.1111 (or 1/9). Smoothed FR maps were used to calculate the half-amplitude field size (the ‘infield’ region). Pixels not adjacent to at least two other ‘infield’ pixels were removed from the field. A place field (PF) was thus regarded as a continuous region of the map where the FR of the unit was above half of the peak amplitude.

Once the location of the place field was determined from the smoothed data all further calculations were based on raw data. The overall mean firing rate (mFR), the mean firing rate inside the place field (infield FR); the mean firing rate outside the field (outfield FR) and the mean infield/outfield firing rate (or signal-to-noise ratio) were calculated.

To provide a measure of spatial firing that does not require character- ization of the place field, the data obtained from the single recording sessions were analysed using an information content measure (Skaggs et al., 1996). This is a quantitative measure of the amount of information (in bits) about location provided by each spike that a cell generates. A value of 0 indicates that no spatial information is conveyed. In contrast, a typical place cell will normally generate ~1 or more bits of information per spike. Finally, the first-order moment of the whole firing rate map (firing field) was calculated to determine its centre (analogous to a calculation of centre of mass; COM). This measure was utilized on the basis of findings by Fenton et al. (Fenton et al., 2000), who compared different ways of measuring how fields shift after a manipulation. The COM (described as ‘centroid’ in this article) was determined to be the best measure of this effect.

Habituation and General Testing Procedure

Rats were carried to the experimental room in a high-wall, open-top box. They were connected to the recording apparatus then placed into the square testing chamber for 15 min, after it had been wiped clean with a disinfected cloth. Chocolate hail was scattered evenly over the floor of the chamber at regular intervals to encourage the animals to move constantly over it. This procedure was repeated for 3 days or until the rats had learnt to forage. On completion of habituation the electrodes were tested twice daily for cell activity. When a putative place cell was found, it was recorded for 10 min as the rat foraged freely. Once all cells were recorded (or if no cells were evident) the electrodes were incremented 40 μm and the animal was returned to its home cage until the next recording session.

Five-hour delay procedure

A subset of the cells tested in the prior procedure were recorded for a second 10 min session after a 5 h delay period during which the animal was returned to its home cage. These cells were randomly selected from those recorded towards the end of the single session recording procedure. Recording sessions took place in the morning (pre-delay recordings) and then again in the afternoon (post-delay recordings). All procedures were otherwise identical for the two recording sessions. Electrodes were advanced by 40 μm at the end of the post-delay session.

Three-minute Delay Procedure and Containment Manipulation

A separate group of cells was recorded with a similar protocol to that described above except that the delay period was reduced to three min. In order to determine the effect of the delay-interval holding environment on cell firing properties, animals were either moved back into their homecages (outside of the testing room) for the delay period or placed into the holding box immediately adjacent to the testing chamber. In this latter environment they could see all of the distal cues that were available to them from within the chamber. The pre- and post-delay recording sessions lasted for 10 min each and the three min delay period began from the time that the rat was removed from the chamber to the time it was returned to it. Approximately 4 h later this procedure was repeated with the same cell but the animal was placed in the alternative location during the three min delay period so as to counterbalance for location during delay. As for the previous testing procedures the floor and walls of the chamber were wiped clean prior to each recording session. At the end of the second testing period the electrodes were advanced if there were no other place cells to record.

Histology

Rats were deeply anaesthetized with Sodium Pentobarbitol (i.p.) and a 20 V DC current was administered for 10 s to each electrode to mark the electrode tip positions in the brain. Rats were then transcardially perfused with saline (0.9%), followed by 10% formalin solution in 0.9% saline. The brains were removed and immersed in 10% formalin solution for 1 day then switched to a 30% sucrose–formalin solution. Each brain was sectioned (60 μm) in the horizontal plane on a cryostat, then mounted on slides and stained with thionin. Recording electrode positions were determined as was the location and size of prefrontal cortex lesions.

Results

Histology

All recording electrodes passed through the CA1 layer of the hippocampus in both control and lesioned animals. Rats in the lesion group had extensive bilateral damage to the anterior cingulate region [area Cg1 (Paxinos and Watson, 1998); see Fig. 1]. Lesions generally also extended into a small portion of the frontal association cortex (FrA) and motor cortex (M2) at their most anterior extent, and into the cingulate cortex, area 1 (Cg1) in posterior sections. Two animals had larger lesions that included a large portion of the prelimbic area (PrL). One lesion also extended ventrally into the Medial Orbital cortex (MO). The rat anterior cingulate and prelimbic region is thought to be homologous to the dorsolateral prefrontal cortex (DLPFC) in primates [(Ulyings and van Eden, 1990; Granon and Poucet, 2000); although see Preuss (Preuss, 1995)]. No other damage was evident in the orbital regions. There was no evidence to suggest that lesion size or extent correlated with place cell responses and therefore, all lesion animals were treated as a homogeneous group.

Single Session Recordings

A total of 73 putative place cells were recorded from the dorsal CA1 region in seven sham rats and six lesion rats. Several cells were excluded from the final analysis because they did not exhibit complex burst firing; had poor signal-to-noise ratios; there were excessive waveform artefacts; or the rat failed to move around the entire recording chamber. Consequently, 31/36 (86%) of sham cells and 33/37 (89%) of lesion cells were subjected to further analysis.

Basic Firing Properties

The mean peak-to-trough spike width and spike amplitude of cells from the sham and lesion groups were similar [spike width = 531 μs and 534 μs, sham- and lesion-group cells, respectively, t(59) = –0.14, NS; amplitude = 239 μV and 219 μV, t(59) = 1.43, NS]. The firing rate (FR) of cells recorded in sham animals was generally greater than the FR of cells in lesion animals [see Table 1, overall mean FR, t(62) = 2.34, P < 0.05; mean FR inside the field (infield FR), t(62) = 2.06, P < 0.05; mean FR outside the field (outfield FR), t(62) = 2.6, P < 0.05]. The mean infield/ outfield FR ratio was however, of a similar value [t(62) = –0.95, NS]. The information content (bits/spike) of cells recorded from lesion animals was significantly greater than that of cells of sham animals [t(60) = –2.07, P < 0.05].

Place Field Properties

Place field size was nearly identical for cells recorded from sham and lesion animals. The mean place field area of sham-group cells was 290 cm2 (within a total area of 3600 cm2) and the area of fields of lesion-group cells was 285 cm2 [t(62) = 0.11, NS].

Five-hour Delay

Thirty-nine cells were also recorded for a second time after a 5 h delay which the rats spent in their homecages. There were 15 cells recorded from four sham animals and 24 cells recorded from three lesion animals.

Basic Firing Properties

A two-factor, repeated-measures ANOVA was used to compare the firing rates of cells from sham and lesion animals in pre- and post-delay recording sessions. There was no effect of delay but there was a significant group effect. The overall mean firing rate for cells of sham animals was close to double that of lesions [see Table 2; F(1,38) = 7.62, P < 0.01], the infield FR of sham- group cells was greater also, but not significantly different [F(1,38) = 3.63, P = 0.06], and the outfield FR was significantly greater in sham-group cells being more than twice the FR of cells recorded from lesion animals [F(1,38) = 6.54, P < 0.05]. The infield/outfield FR ratio tended to be greater for cells from lesion animals than cells recorded from shams, although this difference was not significant.

Place Field Properties

As was the case for the single session recordings, a two-factor, repeated-measures ANOVA revealed that there was no significant difference between the two groups in terms of the size of place fields (Fig. 2A). The mean place field size of sham-group cells was 309 cm2 in pre-delay recordings and 345 cm2 post-delay, and in lesion-group cells, 255 cm2 and 291 cm2, respectively [F(1,37) = 0.1, NS]. Place field size did not change significantly after the delay in either group [F(1,38) = 0.98), NS].

When a comparison of the position of the COM of the firing field was made pre- and post-delay it was determined that the COM of the firing fields of lesion-group cells had shifted by a significantly greater distance than those of sham-group cells. Lesion-group fields had a mean shift of 9.92 cm, whereas for the sham group the fields shifted 4.69 cm [t(37) = –4.91, P < 0.0001], see Figure 2B. Examples of between-session place field shifts are provided in Figure 3.

A shift in COM could occur as a result of a rotation or translation of the field or because two fields developed where there was previously one. Our observation of the fields indicated that the latter effect occurred in only a few instances. In order to differentiate between translations and rotations, we compared the distance of the COM from the centre of the apparatus in the pre- and post-delay conditions (lesion animals, 5 h delay, COM shift = mean shift). An analysis revealed a significant reduction in this distance across the delay interval [t(12) = 2.38, P < 0.05], indicating that the shifts could not be accounted for simply by rotation.

A post hoc analysis of these data was performed to compare the stability of firing fields within a single recording session. For each cell the firing field positions were compared across the first and second five min of the 10 min pre-delay recording and COM shifts were calculated. There was no significant difference between the two groups in the amount that the fields shifted [t(37) = –0.24, NS] across this no-delay condition.

Three-minute Delay and Containment Manipulation

A total of 19 cells were recorded during this procedure. Nine cells were recorded from two sham animals and 10 cells were recorded from three lesion animals.

Basic Firing Properties

Three-factor, repeated measures ANOVAs were used to compare the pre- and post-delay firing rate (FR) properties of cells of sham and lesion animals across the two delay environments (holding box and homecage).

There were no main effects of group apparent for any of the firing rate properties. There was, however, a significant environment effect for overall mean FR; infield FR; and outfield FR, which were all significantly greater in the holding box environment compared to the homecage environment [see Table 3; main effects, F(1,17) = 7.38, P < 0.01; F(1,17) = 9.24, P < 0.01; F(1,17) = 9.69, P < 0.01, respectively]. The only significant main effects of delay were for infield FR [main effect F(1,17) = 8.16, P < 0.01], and the infield/outfield FR ratio [main effect F(1,17) = 6.65, P < 0.05] where both were greater in the pre- delay recording sessions. There were no significant interactions.

Place Field Properties

The results of a three-factor, repeated measures ANOVA revealed that there were no significant differences in the size of place fields of sham and lesion animals in either of the two delay environments (holding box or homecage), nor differences between the pre-and post-delay recordings.

There was no effect of delay in the firing fields’ COM shift. Sham-group cells had mean shifts of 3.62 cm (homecage environment) and 2.92 cm (holding box) compared to 5.38 cm and 4.17 cm, respectively for lesion-group cells. There was, however, a significant group effect, as overall the cells of lesion animals had significantly greater firing field shifts compared to those of sham animals [F(1,18) = 5.42, P < 0.05], indicating that the 3 min delay per se resulted in larger field shifts in lesion-group cells (see Fig. 4). There was no significant effect of containment, and there were no interactions.

Discussion

The results of the current study demonstrated that lesions of the prefrontal cortex reduced the mean firing rate of hippocampal place cells. This change in rate did not appear to be specific to firing inside the place field, however, as both the infield and outfield rates were lower in the lesion animals. Furthermore, the finding that the infield/outfield firing rate ratio was similar across the two groups implies that there was a proportional reduction in firing rate across the whole environment. An analysis of the spatial information content (Skaggs et al., 1996), a measure of spatial firing that does not require that a particular region be defined as a place field, revealed significantly higher values in cells recorded in rats with lesions. This measure is minimally affected by proportional changes in the firing rate. It is unlikely therefore, that the between-group difference in information content is an artefact of the lesion-induced reduction in place cell firing rate. This finding indicates that the activity of cells in lesion rats provided more information about spatial location than in sham rats even though no significant change in place field size was observed. The incidence of putative place cells, determined primarily as complex bursting cells, was however, not affected by prefrontal lesions in that an almost identical number of cells was recorded in the two groups of animals.

When firing fields were monitored over several recording sessions separated by delay intervals, it was determined that the centres of the fields of lesion-group cells shifted position to a greater extent from session to session compared to fields in sham-group cells. This effect was apparent when both 5 h as well as three min intervals were inserted between recordings. Although the effects of short versus long delays were not tested in a single counterbalanced experiment, a comparison of the two delay conditions indicates that a delay-dependent process may have been operating, with greater field instability at longer delays. Place field position was further assessed within single session recordings to determine whether the instability occurred over what amounted to a zero delay condition. There was however, no difference between groups in terms of the distance that the fields’ centre of mass shifted between the first and second half of recording sessions. This indicated that the shifts only occurred with a delay interval between sessions or were a result of the between-session removal of the animals from the recording environment.

Previous studies have shown that when normal rats are switched between two or more familiar environments, each environment will evoke a unique representation in the hippocampus that is stable across repeated exposures to that environment despite intervening experiences of other locations (O’Keefe and Dostrovsky, 1971; O’Keefe and Conway, 1978; Thompson and Best, 1990). It was hypothesized that the process of removing the lesion-group animals from the testing environ- ment and placing them into their homecages between recording sessions may have subsequently disrupted the hippocampal place representation when they were replaced into the testing chamber.

This hypothesis was investigated by manipulating the containment environment in which the animals spent the delay interval that occurred between recording sessions. During the three min delay procedure animals were either moved back into their homecages (outside of the testing room) for the delay period, or placed into a holding box located adjacent to the testing chamber. In this latter condition animals had continued access to the distal cues that were available to it from within the chamber. An analysis of these data revealed, however, that although the firing fields of lesion-group cells shifted sig- nificantly more overall than those of sham-group cells, there was no effect of containment condition on this measure. This finding demonstrated that it was not simply the removal of the animal from the testing room during the delay interval that caused firing fields to shift position.

One possible explanation of the instability of lesion-group fields is that the place cells may be more influenced by local, less stable cues in these animals compared to in the sham group. In a normal animal, the positional firing of hippocampal cells tends to be under the control of distal visual cues (O’Keefe and Dostrovsky, 1971; O’Keefe and Conway, 1978). Presumably this reflects the fact that in the natural environment distal landmarks are usually more reliable indicators of allocentric position than are local cues. If prefrontal lesioned animals are less able to suppress responses to local cues, then cells in the hippocampus may be more likely to be activated by stimuli such as olfactory traces on the floor and faecal boli. While these stimuli would be relatively stable within a recording session, they would be unstable over time, particularly since the recording chamber was wiped clean between each session. The between-session change in the local environment may have prompted a ‘remapping’ of the hippocampal representation (Muller and Kubie, 1987; Skaggs and McNaughton, 1998). Conversely however, local cues may provide better information about spatial localization over the short term because of their immediate and discrete nature. This might explain why the spatial information content of the firing of hippocampal cells was increased in lesion animals. One way to test this hypothesis would be to repeat the current experiment without cleaning the environment between sessions. If lesion-group animals are tending to use olfactory traces to localize themselves, then under these circumstances minimal place field shift should be observed.

In terms of process, the changes in spatial firing apparent in lesion-group cells may be explained in terms of Shimamura’s (Shimamura, 2000) filtering theory, which stresses that an important function of the prefrontal cortex is to inhibit extraneous incoming signals, or noise. In this model, prefrontal damage would cause disinhibition of posterior cortex, resulting in a failure of the hippocampus, or regions providing input to the hippocampus, to suppress spurious information such as irrelevant local cues.

The results of several studies are consistent with the idea that the frontal cortex modulates the salience of perceptual signals. Knight and Grabowsky (Knight and Grabowsky, 1995) reported data suggesting that prefrontal cortex lesions disinhibited auditory activity in the posterior cortex. Frith et al. (Frith et al., 1991) demonstrated that PET activity in the dorso-lateral prefrontal cortex was increased in conjunction with a reduction of activity in the posterior cortical region in normal subjects performing cognitive tasks. Evidence for fronto-temporal (para-- hippocampal) interactions was also found in schizophrenic patients performing a working memory task (Meyer-Lindenberg et al., 2001). These individuals had less activation in the dorsolateral prefrontal cortex (DLPFC) and inferior parietal lobe than comparison subjects, and conversely, greater activity in inferior temporal lobe, hippocampus and cerebellum. Zironi et al. (Zironi et al., 2001) recently suggested that lesions of prefrontal cortex in the rat enhanced the influence of either spatial or object information in temporal cortex regions such as perirhinal and TE cortex. The current findings are consistent with these previous data and allow for the possibility that enhanced responses in the hippocampus (e.g. the lesion- induced increase in spatial information content) may have modified activity in temporal cortex areas, such as perirhinal cortex, via the connectivity that exists between these regions (Deacon et al., 1983; Burwell and Amaral, 1998; Witter et al., 2000).

Constantinidis et al. (Constantinidis et al., 2002) have recently provided evidence that inhibition in prefrontal circuits may have a role in shaping the temporal firing profile of cortical neurons. Such temporally extended firing patterns may be involved in the memorial processing of sequential events. Thus damage to prefrontal cortex may disturb the ‘buffering’ operations that are an essential part of working memory and that allow this region to maintain posterior cortical representations in an active state over delay intervals (Levy and Goldman-Rakic, 2000). There is evidence that some of the sequential processing that constitutes working and episodic memory is mediated in hippocampal networks for both non-spatial (Fortin et al., 2002; Kesner et al., 2002) and spatial (Chiba et al., 1994) memory processing. Kesner (Kesner, 1998) has proposed that both the prefrontal cortex, specifically the anterior cingulate, and the hippocampus, mediate temporal attributes of memory and Gilbert et al. (Gilbert et al., 2001) have suggested that the CA1 region of the hippocampus is involved in temporal pattern separation. Therefore, an alternative explanation of the instability of place cell firing across delays is that disruptions of prefrontal-temporal cortex circuitry disturb temporal processing within the hippo- campus through an alteration in working memory processes.

Although there are no direct projections from prefrontal cortex to CA1, there are a number of pathways through which this former region could potentially influence hippocampal activity in the rat. For example, there are strong reciprocal connections between prefrontal cortex and the perirhinal and entorhinal cortices (Groenewegen and Uylings, 2000), regions that in turn have strong connections with the hippocampus (Liu and Bilkey, 1999; Naber et al., 1999; Witter et al., 2000). There is evidence that place cells exist in the entorhinal cortex (Quirk et al., 1992) and that the entorhinal cortex has a major role in the generation of CA1 spatial firing (Miller and Best, 1980; Brun et al., 2002). Similarly, perirhinal cortex neurons have also been shown to exhibit place-related firing (Burwell et al., 1998; Zironi et al., 2001) and lesions of perirhinal cortex have been shown to disrupt CA1 place cell stability (Muir and Bilkey, 2001). Thus, disruption of prefrontal-parahippocampal connections could result in a change of spatial information processing in CA1.

There are also a number of subcortical pathways via which the prefrontal cortex could potentially exert an influence on CA1 neurons. For example, there are projections from the PFC to the ventral tegmental area [VTA (Takagishi and Chiba, 1991; Carr and Sesack, 2000)] which then projects to the hippocampus [including the CA1 cell layer (Gasbarri et al., 1994)]. Prefrontal modulation of hippocampal activity could therefore be produced by an alteration of the dopaminergic projections from VTA, which are thought to have a role in suppressing hippocampal excitability (Gasbarri et al., 1997). Although there is no prior evidence to indicate how these connections might affect place cell firing, inactivation of VTA has been shown to affect rats’ ability to acquire spatial learning and memory for place navigation in the Morris water maze (Gasbarri et al., 1996).

In summary, the results of the present study demonstrate that lesions of prefrontal cortex alter the spatial responsivity of hippocampal place cells. The enhancement of spatial firing observed may be a neural correlate of increased attention to, or failure to suppress activity in, representations of local environ- mental cues. In humans with frontal lobe damage, ‘utilization behaviour’ has been described whereby patients’ behaviour becomes more dependent on environmental cues (Lhermitte, 1983). The lesion-induced changes in activity observed in the current study may be a neural correlate of this type of effect. This phenomenon may result from a loss of inhibitory control of the prefrontal cortex over posterior regions and/or a dysfunction in working memory processes.

Notes

This research was supported by a grant from the Marsden Fund to David K. Bilkey. Thank you to Ping Liu and Noah Russell.

Address correspondence to Dr D.K. Bilkey, Department of Psychology and the Neuroscience Research Centre, University of Otago, PO Box 56, Dunedin, New Zealand. Email: sycodkb@psy.otago.ac.nz

Table 1

Firing properties of hippocampal place cells (mean ± SEM)

 Sham (n = 31) Lesion (n = 33) 
*P < 0.05. 
Firing rate (Hz) 
    Overall 2.05 ± 0.3* 1.18 ± 0.2 
    Infield 7.18 ± 1.0* 4.57 ± 0.8 
    Outfield 1.49 ± 0.2* 0.76 ± 0.1 
Infield firing rate/outfield firing rate 7.17 ± 1.0 8.80 ± 1.4 
Information content (bits/spike) 1.03 ± 0.1* 1.41 ± 0.1 
 Sham (n = 31) Lesion (n = 33) 
*P < 0.05. 
Firing rate (Hz) 
    Overall 2.05 ± 0.3* 1.18 ± 0.2 
    Infield 7.18 ± 1.0* 4.57 ± 0.8 
    Outfield 1.49 ± 0.2* 0.76 ± 0.1 
Infield firing rate/outfield firing rate 7.17 ± 1.0 8.80 ± 1.4 
Information content (bits/spike) 1.03 ± 0.1* 1.41 ± 0.1 
Table 2

Comparison of place cell firing properties across a 5 h delay (mean ± SEM)

 Sham (n = 15) Lesion (n = 24
 Pre-delay Post-delay Pre-delay Post-delay 
*P < 0.05, significant difference in firing rate between sham and lesion groups in corresponding delay conditions. 
Firing rate (Hz) 
    Overall 1.72 ± 0.4* 2.06 ± 0.5* 0.92 ± 0.2 0.92 ± 0.2 
    Infield 5.42 ± 0.9 6.07 ± 1.0 4.08 ± 0.6 3.92 ± 0.6 
    Outfield 1.21 ± 0.3* 1.53 ± 0.4* 0.54 ± 0.1 0.76 ± 0.2 
Infield firing rate/outfield firing rate 6.7 ± 1.4 6.57 ± 1.7 10.14 ± 1.9 12.14 ± 3.8 
 Sham (n = 15) Lesion (n = 24
 Pre-delay Post-delay Pre-delay Post-delay 
*P < 0.05, significant difference in firing rate between sham and lesion groups in corresponding delay conditions. 
Firing rate (Hz) 
    Overall 1.72 ± 0.4* 2.06 ± 0.5* 0.92 ± 0.2 0.92 ± 0.2 
    Infield 5.42 ± 0.9 6.07 ± 1.0 4.08 ± 0.6 3.92 ± 0.6 
    Outfield 1.21 ± 0.3* 1.53 ± 0.4* 0.54 ± 0.1 0.76 ± 0.2 
Infield firing rate/outfield firing rate 6.7 ± 1.4 6.57 ± 1.7 10.14 ± 1.9 12.14 ± 3.8 
Table 3

Comparison of place cell firing properties across 3 min delay for two containment conditions (mean ± SEM)

Condition Firing property Holding box Home cage 
  Pre-delay Post-delay Pre-delay Post-delay 
P < 0.01, significant difference in firing rate between corresponding holding box and homecage conditions 
*P < 0.05, 
**P < 0.01, significant difference in firing rate across the 3 min delay. 
Sham (n = 9) firing rate (Hz)     
     overall 1.61 ± 0.3‡ 1.58 ± 0.4‡ 1.18 ± 0.2 1.25 ± 0.3 
     infield 6.74 ± 1.7‡** 6.19 ± 1.9‡ 5.04 ± 1.6** 4.82 ± 2.0 
     outfield 1.14 ± 0.2‡ 1.21 ± 0.3‡ 0.81 ± 0.1 0.87 ± 0.2 
 infield firing rate/outfield firing rate 6.60 ± 1.7* 5.56 ± 1.6 7.18 ± 2.4* 5.23 ± 1.8 
Lesion (n = 10) firing rate (Hz)     
     overall 1.22 ± 0.3‡ 1.01 ± 0.3‡ 0.80 ± 0.2 0.85 ± 0.2 
     infield 5.40 ± 1.2‡** 3.17 ± 0.8‡ 3.86 ± 1.2‡** 2.79 ± 0.7 
     outfield 0.99 ± 0.2‡ 0.72 ± 0.2‡ 0.60 ± 0.2 0.56 ± 0.1 
 Infield firing rate/outfield firing rate 8.12 ± 1.8* 7.63 ± 1.8 8.63 ± 2.5* 5.99 ± 1.6 
Condition Firing property Holding box Home cage 
  Pre-delay Post-delay Pre-delay Post-delay 
P < 0.01, significant difference in firing rate between corresponding holding box and homecage conditions 
*P < 0.05, 
**P < 0.01, significant difference in firing rate across the 3 min delay. 
Sham (n = 9) firing rate (Hz)     
     overall 1.61 ± 0.3‡ 1.58 ± 0.4‡ 1.18 ± 0.2 1.25 ± 0.3 
     infield 6.74 ± 1.7‡** 6.19 ± 1.9‡ 5.04 ± 1.6** 4.82 ± 2.0 
     outfield 1.14 ± 0.2‡ 1.21 ± 0.3‡ 0.81 ± 0.1 0.87 ± 0.2 
 infield firing rate/outfield firing rate 6.60 ± 1.7* 5.56 ± 1.6 7.18 ± 2.4* 5.23 ± 1.8 
Lesion (n = 10) firing rate (Hz)     
     overall 1.22 ± 0.3‡ 1.01 ± 0.3‡ 0.80 ± 0.2 0.85 ± 0.2 
     infield 5.40 ± 1.2‡** 3.17 ± 0.8‡ 3.86 ± 1.2‡** 2.79 ± 0.7 
     outfield 0.99 ± 0.2‡ 0.72 ± 0.2‡ 0.60 ± 0.2 0.56 ± 0.1 
 Infield firing rate/outfield firing rate 8.12 ± 1.8* 7.63 ± 1.8 8.63 ± 2.5* 5.99 ± 1.6 
Figure 1.

Coronal sections of the rat brain showing the location of prefrontal cortex lesions. Solid black regions represent the extent of the smallest lesions, and shaded regions show the extent of the largest lesions. Numbers indicate the distance (mm) of each section anterior to Bregma.

Figure 1.

Coronal sections of the rat brain showing the location of prefrontal cortex lesions. Solid black regions represent the extent of the smallest lesions, and shaded regions show the extent of the largest lesions. Numbers indicate the distance (mm) of each section anterior to Bregma.

Figure 2.

(A) A comparison of the distribution of the size of sham and lesion place fields. Note the similarity between the two groups. (B) A comparison of the distribution of the shifts in firing field centre of mass across the 5 h delay period. The fields of cells in lesion rats shifted a greater distance than the fields of sham-group cells.

Figure 2.

(A) A comparison of the distribution of the size of sham and lesion place fields. Note the similarity between the two groups. (B) A comparison of the distribution of the shifts in firing field centre of mass across the 5 h delay period. The fields of cells in lesion rats shifted a greater distance than the fields of sham-group cells.

Figure 3.

Firing rate maps of sham- (a and b) and lesion-group cells (c, d and e) showing the position of place fields before and after the 5 h delay. The darker pixels correspond to regions where the cell fired at a higher rate. In sham animals the cells fired in the same location before and after the delay period (e.g. cells a and b). The centre of mass of firing fields of lesion cells however, tended to vary between the two recording sessions (c, d and e). Examples of the spike waveforms for recording a (middle) and e (lower) are shown pre- and post-delay.

Figure 3.

Firing rate maps of sham- (a and b) and lesion-group cells (c, d and e) showing the position of place fields before and after the 5 h delay. The darker pixels correspond to regions where the cell fired at a higher rate. In sham animals the cells fired in the same location before and after the delay period (e.g. cells a and b). The centre of mass of firing fields of lesion cells however, tended to vary between the two recording sessions (c, d and e). Examples of the spike waveforms for recording a (middle) and e (lower) are shown pre- and post-delay.

Figure 4.

Comparison of the mean (± SEM) shift in firing field centre of mass in sham- and lesion-group cells for the 5 h and 3 min delay conditions.

Figure 4.

Comparison of the mean (± SEM) shift in firing field centre of mass in sham- and lesion-group cells for the 5 h and 3 min delay conditions.

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