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Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102
Submitted 11 December 2003; accepted in final form 6 January 2004
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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), it relays most neocortical sensory inputs to the entorhinal–hippocampal system. Moreover, it represents the main return path for hippocampo-entorhinal efferents to the neocortex (reviewed in Witter et al. 2000).
In particular, tract-tracing studies have revealed that information transfer between the neocortex and hippocampus depends on the sequential, stepwise activation of the perirhinal and entorhinal cortices (neocortex to area 36 to area 35 to entorhinal cortex to hippocampus and conversely). However, the progression of impulse traffic into discrete steps is not perfect, given that some deep neocortical neurons project beyond area 36 into area 35 and the lateral entorhinal cortex (Burwell and Amaral 1998a,b; Insausti et al. 1987; McIntyre et al. 1996; Saleem and Tanaka 1996; Suzuki and Amaral 1994; VanHoesen and Pandya 1975; reviewed in Burwell and Witter 2002). Similarly, some entorhinal axons extend to area 36 and the temporal neocortex (Burwell and Amaral 1998b; Deacon et al. 1983; Insausti et al. 1997; Suzuki and Amaral 1994; Swanson and Köhler 1986; reviewed in Burwell and Witter 2002).
Although little physiological work has been performed on this issue, it is typically assumed that the rhinal cortices (here defined to include the perirhinal, postrhinal, and entorhinal cortices) faithfully transmit neocortical inputs to the hippocampus and reciprocally. In fact, some models of episodic memory rest on this assumption. In the two-stage model of episodic memory, for instance, it is hypothesized that during waking, information of neocortical origin is initially stored in the hippocampus by changes in the strength of connections between pyramidal neurons. Later on during slow-wave sleep (SWS), the synchronized discharges of CA3 neurons in relation to sharp waves would "replay" representations stored in CA3 and, by activation of the rhinal cortices, reactivate neocortical neurons representing the event of interest (Buzsáki 1989). Ultimately, such SWS replay of waking activities would lead to long-term synaptic changes in the associative cortical networks that store memories (Buzsáki 1989; Pennartz et al. 2002).
Although evidence of replay was obtained in the hippocampus (Nadasdy et al. 1999; Skaggs and McNaughton 1996; Wilson and McNaughton 1994; reviewed in Sutherland and McNaughton 2000), whether hippocampal-driven activity is relayed by the perirhinal cortex back to neocortical storage sites has never been investigated before.
Thus determining the reliability of impulse transmission through the perirhinal cortex is an issue of crucial importance. Lesion and physiological studies already indicate that the perirhinal cortex plays a critical role in higher-order perceptual and/or mnemonic functions (Murray and Richmond 2001; Suzuki 1996), but its precise contribution, compared with that of the hippocampus, remains debated (Brown and Aggleton 2001).
The present study was undertaken to examine directly the transfer properties of the perirhinal cortex using multisite extracellular recordings as well as electrical stimulation of the temporal neocortex and entorhinal cortex. Our results suggest that the perirhinal cortex is not a passive relay station, but rather a gating or filtering network.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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All procedures for acute experiments were approved by the Institutional Animal Care and Use Committee of Rutgers University, in compliance with the Guide for the Care and Use of Laboratory Animals (Department of Health and Human Services publication 86-23). Ten adult cats (2.5–3.5 kg) were preanesthetized with a mixture of ketamine and xylazine [15 and 2 mg/kg, intramuscularly (im)] and artificially ventilated with a mixture of ambient air, oxygen, and isoflurane. Atropine (0.05 mg/kg, im) was administered to prevent secretions. The end-tidal concentration in CO2 was kept at 3.7 ± 0.2% and the body temperature was maintained at 37° C with a heating pad. The level of anesthesia was assessed by continuously monitoring the electroencephalogram and electrocardiogram. The bone overlying the rhinal region was removed and the dura mater opened.
To activate perirhinal and entorhinal neurons synaptically, an array of concentric stimulating electrodes was positioned in the band of neocortex that borders the perirhinal area laterally (Fig. 1A, top row of concentric circles). Similarly, concentric stimulating electrodes were positioned in the entorhinal cortex (Fig. 1A, bottom row of concentric circles). Evoked unit and field responses were recorded in between these 2 groups of stimulation sites by arrays of high-impedance microelectrodes (Fig. 1A, dots; 2-mm spacing; 2–6 M
at 1 kHz; OD = 80 µm; FHC, Brunswick, ME). These arrays were constructed by drilling small holes in a Teflon block and inserting the electrodes into them so that recordings could be obtained simultaneously from the perirhinal and entorhinal cortices. The block was attached to a micromanipulator and microelectrodes were lowered as a group in steps of 5 µm. See below for recording methods.
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These experiments were carried out at Université Laval (Québec, Canada) in agreement with the guidelines of the Canadian Council for Animal Care. Adult cats were chronically implanted in a stereotaxic position under deep anesthesia in sterile conditions. The anesthesia was induced with ketamine (15 mg/kg, im), and atropine sulfate (0.05 mg/kg, im) was administered to prevent secretions. Then, sodium pentobarbital was injected gradually [Somnotol, 
15 mg/kg, intravenously (iv)]. To record eye movements [electrooculogram (EOG)], two silver-ball electrodes were fixed into the supraorbital cavity with dental cement. Two Teflon-insulated wires were inserted in the neck muscles to monitor electromyographic activity (EMG), and stainless steel screws were anchored to the bone overlying the pericruciate area to monitor the electroencephalogram (EEG).
Then, arrays of tungsten electrodes were lowered until the electrodes reached the deep layers of the rhinal cortices (for details see Collins and Paré 1999). The array was constructed as above with the exception that the Teflon block was inserted in a tightly fitting Delrin sleeve, which was cemented to the bone. During the recording sessions, the electrodes could be lowered as a group by means of a micrometric screw. The lengths of electrodes were adjusted so that unit recordings could be obtained simultaneously from the temporal neocortex and both perirhinal and entorhinal cortices.
Finally, four screws were cemented to the skull. These screws were later used to fix the cat's head in a stereotaxic position without pain or pressure. Penicillin (20,000 IU/kg, im) and buprenorphine (0.03 mg/kg, im every 12 h for 24 h) were administered postoperatively. Recording sessions began 6 to 8 days after the surgery. In between experimental sessions, the animals slept, ate, and drank without restriction. During the recording sessions, behavioral states of vigilance were distinguished on the basis of previously described electrographic criteria (Steriade and Hobson 1976).
Recording methods
During the experiments, electrodes were lowered as a group. Neuronal activity was sampled at 
100-µm intervals. Each time the electrodes were moved to a new recording site, 15–30 min elapsed before data were acquired, to ensure mechanical stability. The signals picked up by the electrodes (0.1 Hz to 20 kHz) as well as EEG, EMG, and EOG activity (in the case of chronic experiments) were observed on an oscilloscope, digitized, and stored on a hard disk. When evoked activity was studied, 30 to 300 shocks were delivered at each stimulation site, depending on the reliability of unit responses (the less reliable the response, the greater the number of shocks).
Histological identification of recording and stimulating sites
At the end of the experiments, recording sites were marked with electrolytic lesions (0.5 mA for 5 s). After this, the animals were given an overdose of sodium pentobarbital (50 mg/kg, iv) and perfused with a cold saline solution (0.9%) followed by a solution containing 2% paraformaldehyde and 1% glutaraldehyde in 0.1 M phosphate buffer saline (pH 7.4). The brains were later sectioned on a vibrating microtome (at 100 µm) and stained with thionin or neutral red to verify the position of the recording electrodes. The microelectrode tracks were reconstructed by combining micrometer readings with the histology.
Analysis
Analyses were performed off-line with commercial software (IGOR, Wavemetrics, Lake Oswego, Oregon) and homemade software running on Macintosh computers. Spikes were detected using a window discriminator after digital filtering (0.3–20 kHz) of the raw waves. We considered only easily distinguishable neurons with a signal to noise ratio 3. Perievent histograms (PEHs) of unit discharges were computed. All values are expressed as means ± SE.
In the chronic experiments, crosscorrelograms of unit discharges were computed for all simultaneously recorded cell pairs (bins of 1 or 10 ms; range of ±200 ms and ±1 s, respectively) in waking and SWS. To be included in the analysis, neurons had to fire at 0.1 Hz in the particular behavioral state under consideration. Crosscorrelograms were then normalized to an average count of 1 and pooled in separate population histograms, depending on the position of the reference neurons and the distance between recorded cells.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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RESPONSIVENESS OF PERI- AND ENTORHINAL NEURONS TO NEOCORTICAL STIMULI. The effect of neocortical stimuli was tested in 584 perirhinal and 586 entorhinal neurons. Examples of histologically identified recording sites are provided in Fig. 1, B and C. Neocortical stimuli were much more efficient in orthodromically activating perirhinal (Fig. 2) than entorhinal (Fig. 3) neurons. Indeed, 39% of perirhinal cells (or 228 cells) could be synaptically activated from one or more neocortical stimulation sites (average latency of 12.9 ± 0.87 ms, Fig. 2B), compared with only 1.4% (or 8 cells) in the entorhinal cortex (average latency of 29.3 ± 4.4 ms). The difference in the proportion of responsive neurons was statistically significant (
2 = 254.8, P < 0.05).
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2 = 0.043, P > 0.05). Similarly, no difference in the laminar distribution of cells responsive to neocortical stimuli was found in the entorhinal cortex (deep, 4 of 321; superficial, 4 of 265; 2 = 0.073, P > 0.05). The limited responsiveness of entorhinal neurons to neocortical stimuli was observed despite the fact that we routinely tested a large range of neocortical stimulation intensities (0.1–1.5 mA) and frequencies (0.01–300 Hz). Moreover, in an attempt to increase the likelihood of finding responsive entorhinal neurons, we stimulated a variety of neocortical sites (see Fig. 1A) one at a time or in pairs separated by various rostrocaudal distances (4, 8, or 12 mm in the rostrocaudal axis; see Fig. 1A), but without success.
Examples of orthodromically activated perirhinal neurons are provided in Fig. 2, A and C. Most perirhinal neurons responded to neocortical stimuli with a relatively fixed latency (Fig. 2A). In fact, Fig. 2C illustrates the only example of perirhinal cell in which a multimodal peristimulus histogram (PSH) was observed. In contrast, half of responsive entorhinal neurons showed such multimodal poststimulus discharges (Fig. 3A; 4 out of 8 responsive cells). In these entorhinal cells, the interval between successive peaks averaged 10.8 ± 2.0 ms.
In spontaneously firing neurons (perirhinal, n = 21; entorhinal, n = 32), neocortical stimuli often produced long-lasting reductions in firing rate. In the perirhinal cortex, neocortical stimuli produced such inhibitions in all spontaneously active cells. The duration and amplitude of this inhibition increased with the stimulation intensity. Using stimuli of intermediate intensities (100 µs; 0.3 mA), the inhibition lasted 373 ± 21 ms and, at its peak, could transiently silence all cells (peak firing rate reduction of 100%). When neocortical stimuli evoked short-latency excitations (71% or 15 of 21 spontaneously firing cells), the inhibition developed immediately after the short-latency response (Fig. 2D). Neocortical stimuli also evoked an inhibition in the entorhinal cortex, albeit in a lower proportion of cells (59% or 19 of 32 spontaneously active cells). Otherwise, no differences in the duration (328 ± 18 ms) or magnitude (98 ± 1% decrease in instantaneous firing rate) of the inhibition was observed (t-test, P > 0.05).
RESPONSIVENESS OF ENTORHINAL AND PERIRHINAL NEURONS TO ENTORHINAL STIMULI. The results obtained with entorhinal stimuli were the mirror image of those seen with neocortical shocks. Indeed, no orthodromic activations were seen in as many as 271 tested perirhinal neurons compared with 19% of cells in the entorhinal cortex (n = 201; 2 = 55.72, P < 0.05; average latency of 15.5 ± 1.1 ms; Fig. 3C). As was seen with neocortical stimuli, entorhinal shocks elicited a long-lasting inhibition of spontaneous firing. In subsets of spontaneously active entorhinal (n = 41) and perirhinal (n = 22) neurons, the proportion of cells showing a suppression of spontaneous activity after entorhinal stimuli was 68 and 14%, respectively.
Analysis of spontaneous discharges in unanesthetized animals
In the preceding experiments, it is possible that perirhinal and entorhinal responsiveness was affected by the anesthesia or the artificial nature of electrical stimuli. Thus we used a different approach to examine perirhinal transfer of neocortical and entorhinal impulses: we analyzed spontaneous neuronal activity in unanesthetized, head-restrained animals by means of an array of closely spaced microelectrodes in the temporal neocortex as well as the perirhinal and entorhinal cortices (Fig. 4A, scheme). This experiment was repeated 3 times and identical results were obtained.
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SPATIAL EXTENT OF CORRELATED ACTIVITY IN WAKING AND SWS. If the stepwise connectivity that links the temporal neocortex and both peri- and entorhinal cortices allows propagation of signals to and from the hippocampus, one would expect crosscorrelograms of spontaneous firing to exhibit central peaks that decay as the distance between the recorded cells increases. Also, if the prevalent direction of propagation varies depending on the behavioral state, the peaks should gradually shift to the left or right as the distance between recorded cells increases. These ideas are tested below.
Figure 4 illustrates matrices of pooled crosscorrelograms for all simultaneously recorded cell pairs in the states of waking (Fig. 4A) and SWS (Fig. 4B). The numbers in the upper left-hand corner of the histograms indicate electrode positions used to record each cell pair (Fig. 4A, scheme). Asterisks indicate histograms with peaks (within ±50 ms of the origin) that reached statistical significance (paired t-test) at the 0.05 level after correction with the Bonferroni method for multiple comparisons.
In both waking (Fig. 4A) and SWS (Fig. 4B), evidence of synchronized firing was obtained in histograms correlating the activity of cells recorded from the same electrode. Such histograms had obvious peaks centered at around 0 ms (t-test, P < 0.05; Fig. 4, A and B). However, the peak amplitude of crosscorrelograms decreased sharply as the distance between the recorded cells increased. Indeed, at distances 1 mm, the differences between the histogram peaks and flanks generally did not reach significance. Identical results were obtained with bin widths of 1 and 10 ms.
Consistent with previous work in the neocortex (Steriade 1997) and hippocampus (Buzsáki et al. 1983), crosscorrelation of unit activity during SWS revealed a significant increase in synchrony relative to waking (t-test, P < 0.05). However, with the exception of entorhinal neurons (5–6 in Fig. 4, A and B), this increase in correlated activity was seen only for cells recorded at the same site.
In the preceding analysis, it is possible that some pairs of neurons had negatively or positively correlated activity but that averaging crosscorrelograms masked these relations. Also, variations in peak position might have led us to underestimate the amount of correlated activity. To examine these possibilities, individual crosscorrelograms were searched for bins (±50 ms from the origin) that deviated from the average bin value by ±2.8 SDs or more. This corresponds to the z-value required to reach significance in a 2-tailed t-test with P < 0.05 when performing 10 comparisons.
Figure 4C illustrates the result of this analysis for SWS data. This graph plots the proportion of crosscorrelograms with significant positive (y-axis) deviations from average bin values. Depending on the position of the reference cells, separate curves with different thickness are provided (see caption to the right of Fig. 4C). The various symbols indicate the distance between the recorded cells (see caption to the right of Fig. 4C). The dashed line indicates the proportion of significant correlograms expected by chance (2.5%). This analysis yielded results consistent with the population analysis.
The proportion of histograms with significant negative correlations remained below chance level and is not depicted in Fig. 4C. Thus the absence of positive correlations between distant cells in population crosscorrelograms did not result from cancellations between positive and negative correlations.
With respect to positive correlations (Fig. 4C), the proportion of significant crosscorrelograms was highest for cells recorded by the same electrode (empty circles), irrespective of the position of the reference cell. With the exception of entorhinal neurons (thickest line, triangle), the proportion of significant histograms decreased below 20% with 1-mm separation (empty triangles). With longer distances, the proportion of significant correlograms varied with the position of reference neurons and target neurons. For neocortical and area 36 references, the proportion of significant correlograms decayed below chance level with 2-mm spacings and increased slightly to 4–5% with further interelectrode separations. However, with reference cells located in area 35, the proportion of significant correlograms remained as high as 11% with 2-mm spacings.
Thus the probability of correlated activity between neocortical and rhinal neurons is low but higher than expected by chance. Interhistogram variations in the position of the peak prevented detection of these correlations in population crosscorrelograms. Furthermore, for all spacings and reference sites, peaks of individual histograms occurred as frequently in the positive as in the negative direction. This result suggests that there is no prevalent direction of information flow between the neocortex and rhinal cortices.
It may be argued that the low incidence of correlated activity between distant neurons is a necessary consequence of signal attenuation along multisynaptic pathways (Shalden and Newsome 1998; Stevens and Zador 1998). However, the high proportion of significantly correlated activity among entorhinal neurons (Fig. 4C, thick line) led us to suspect that this might not be a general rule. Consistent with this, control experiments (Fig. 5A) revealed that a high proportion of entorhinal neurons separated by 
3 mm display significantly correlated activity in waking and SWS. Figure 5B plots the proportion of entorhinal cell pairs with crosscorrelograms having bins (±50 ms from the origin) that deviated from the average bin value by ±2.8 SDs or more during SWS. Note that in contrast with neocortical and perirhinal cells (Fig. 4), a high proportion of significant crosscorrelograms was seen (25 times chance level). Moreover, evidence of this correlated activity was also present in population histograms (Fig. 5C).
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). To eliminate this possible confound, cells were separated according to their depth using histological controls. Entorhinal cells were grouped as either deep or superficial to the lamina dessicans, whereas perirhinal and neocortical neurons in layers II–III were pooled separately from those in layers IV–VI. In doing so, neurons located close to the border between deep and superficial layers were not considered to minimize the risk of errors. However, the depth of recorded neurons did not change the overall pattern of correlation in both waking and SWS. Whether the reference cells were located in the neocortex, perirhinal cortex, or entorhinal cortex, results were indistinguishable from those obtained in Fig. 4.
NETWORK ACTIVITY DURING ENTORHINAL SHARP WAVES. In the preceding analysis, it could be argued that we underestimated the ability of the perirhinal cortex to transfer neocortical and entorhinal inputs because we considered all spontaneous activity. Indeed, it is possible that the perirhinal cortex only transfers inputs arising from large groups of neurons activated within a narrow time window. To examine this possibility, we computed PEHs of neuronal discharges around large negative EEG events that occurred spontaneously in the entorhinal cortex during SWS: sharp waves (Chrobak and Buzsáki 1994, 1996). These entorhinal EEG events had to meet the following criteria to be included in the analysis. First, they had to be 1.5 mV in amplitude, last 250 ms at half-amplitude, and be associated with visually obvious increases in firing rate (Fig. 6). During selection of entorhinal sharp waves, the observer was blind to the neuronal activity taking place at other recording sites.
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To determine whether the failure of entorhinal sharp wave–related activity to propagate beyond the rhinal sulcus resulted only from distance, by opposition to an active gating mechanism, we performed an analogous analysis using synchronized EEG events recorded in area 36 as a temporal reference. As was the case for the above analysis, we detected large-amplitude (1.5 mV) negative EEG events lasting 250 ms at half-amplitude, and associated with visually obvious increases in firing rate. The procedure used to compute and normalize population PEHs was the same as in the previous case (Fig. 7A).
Figure 7B shows the result of this analysis. Population PEHs look more noisy than in Fig. 7A because a lower number of EEG events met our selection criteria. Nevertheless, in the perirhinal site used for detection of the sharp EEG events (Fig. 7B3), a large increase in average firing rate was apparent around the origin (peak increase of 3.91 over baseline; t-test, P < 0.05). Some evidence of this could be seen in adjacent neocortical recording sites (Fig. 7, B1–B2), albeit more subtle. In contrast, in more medial recording sites (in area 35 and the entorhinal cortex), no increase in firing rate could be detected around the origin (Fig. 7, B4–B6).
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DISCUSSION |
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Low-probability perirhinal transmission of neocortical and entorhinal inputs
There is physiological evidence, albeit controversial, that the perirhinal cortex projects, by way of the entorhinal cortex, to the dentate gyrus (for an overview of the debate see Canning and Leung 1997, 1999; Liu and Bilkey 1998; Naber et al. 1999; Witter et al. 1999). Although we did not test this question directly, our results do not support this possibility, given that neocortical stimulation rarely activated entorhinal neurons.
Nevertheless, our conclusions are in agreement with a series of previous in vitro findings. For instance, in the whole guinea pig brain kept in vitro, electrical stimulation of the lateral olfactory tract was reported to evoke massive neuronal excitation in the entorhinal cortex but no local field response in area 36 (Biella et al. 2003). Similarly, stimulation of the temporal neocortex or area 36 evoked no local field responses in the entorhinal cortex, whereas stimulation of area 35 elicited postsynaptic potentials (PSPs) in a low proportion of intracellularly recorded entorhinal cells (Biella et al. 2002).
Moreover, imaging studies of intrinsic (Frederico et al. 1994) and voltage-sensitive signals (Biella et al. 2003; de Curtis et al. 1999) yielded results identical to those obtained with field potential recordings. Indeed, entorhinal optical signals generated by stimulation of the lateral olfactory tract or hippocampus never propagated lateral to the rhinal fissure. However, intracellular recordings revealed that a few entorhinal cells display excitatory postsynaptic potentials (EPSPs) in response to stimuli applied in area 36 or area 35 (Biella et al. 2003).
Thus there appears to be a discrepancy between anatomical findings, showing strong reciprocal connections between the perirhinal and entorhinal cortices, and physiological data about this pathway. In light of these data, it appears unlikely that correlations seen between electroencephalographic events of the somatosensory cortex and hippocampus (Siapas and Wilson 1998; Sirota et al. 2003) depend on a stepwise progression of impulses through the rhinal cortices. Other routes, such as the midline thalamus (Dolleman-Van der Weel et al. 1996, 1997; Wouterlood et al. 1990) and medial prefrontal cortex (Condé et al. 1995; Hurley et al. 1991), are probably involved. The amygdala is an unlikely candidate because it does not display sleep spindles (reviewed in Paré et al. 2002).
Below, we consider some of the factors that might explain transmission failure across the rhinal fissure.
Factors limiting impulse traffic across the perirhinal cortex
LOCAL INHIBITION. Although synaptic inhibition is ubiquitous in the cerebral cortex, our findings suggest that it plays a particularly important role in the perirhinal cortex. As was reported in other cortical regions (Dutar and Nicoll 1988; McCormick 1989; Scanziani et al. 1991), principal perirhinal neurons display GABAA and GABAB responses (Biella et al. 2001; Garden et al. 2002; Martina et al. 2001).
We submit that the solution to the low-probability perirhinal transfer of impulses resides in the way GABAergic cells of the perirhinal cortex are recruited by neocortical and entorhinal inputs. As mentioned in the INTRODUCTION, the progression of impulses through discrete steps (neocortex to area 36 to area 35 to entorhinal cortex and conversely) is not perfect because some deep neocortical neurons project beyond area 36 into area 35 and the lateral EC (Burwell and Amaral 1998a,b; Insausti et al. 1987; McIntyre et al. 1996; Saleem and Tanaka 1996; Suzuki and Amaral 1994; VanHoesen and Pandya 1975). Moreover, some entorhinal axons extend to area 35 and the temporal neocortex (Burwell and Amaral 1998b; Deacon et al. 1983; Insausti et al. 1997; Suzuki and Amaral 1994; Swanson and Köhler 1986).
Thus progression of impulses through the rhinal cortices occurs in 2 ways: most of the connections involve a relatively slow stepwise progression through a sequence of cortical areas, but a minor proportion of axons "jump ahead." We hypothesize that the latter either originate in 1) GABAergic cells that contact principal neurons or 2) in glutamatergic cells that mainly contact GABAergic interneurons. Because the direct mode of communication is faster than the more prevalent stepwise mode, GABAergic inhibitory PSPs generated by the fast route will precede EPSPs generated by the slow path. As a result, the probability of transfer through the slow path will be severely reduced. Although these predictions await testing with tract tracing coupled to GABA immunocytochemistry at the electron microscopic level, preliminary intracellular recordings of entorhinal neurons in vivo support this hypothesis (unpublished observations).
It is also possible that entorhinal neurons contribute to gate impulse traffic between the neocortex and hippocampus. Consistent with this, physiological studies have disclosed the existence of powerful inhibitory pressures in the entorhinal cortex (Finch et al. 1986, 1988; Funahashi and Stewart 1998; Heinemann et al. 2000; Jones 1990; Jones and Buhl 1992).
INTRINSIC MEMBRANE PROPERTIES OF PERIRHINAL NEURONS. Another factor that may exert an impact on the transfer properties of the perirhinal cortex is the presence of "late-firing" neurons (Faulkner and Brown 1999). In these cells, there is a conspicuous delay between the onset of depolarizing current pulses and spike discharges. This behavior results from a slowly inactivating K+ conductance that activates around –65 mV (Bargas et al. 1989; Hammond and Crépel 1992; Martina et al. 1999; Nisenbaum et al. 1994; Storm 1988). This current attenuates and delays depolarizing voltage transients caused by excitatory synaptic inputs. Because late-firing cells are particularly abundant in layer VI (86% of the cells according to McGann et al. 2001), and deep neurons contribute most perirhinal projections to the neocortex, this property may be detrimental to the transfer of entorhinal inputs to the neocortex. The presence of late-firing cells in perirhinal layer III (Beggs et al. 2000) suggests that this property might interfere with propagation of neocortical inputs toward the entorhinal cortex.
Gating of impulse traffic through the rhinal cortices
Our results suggest that, in the behavioral states investigated here, there is little communication between the temporal neocortex and hippocampus through the rhinal cortices. Our findings suggest that the rhinal cortices are more than a relay between neocortex and hippocampus, but rather a gating or filtering network whose properties remain to be identified. Moreover, the fact that sharp wave–related entorhinal activity failed to propagate through the perirhinal cortex suggests that the hippocampal replay of waking memories in SWS (Buzsáki 1989; Pennartz et al. 2002) is a local phenomenon, or at least, that it does not affect the neocortex through the rhinal cortices. Alternatively, it is possible that transfer of replayed sequences involves such a small and spatially distributed group of rhinal neurons, that it could not be detected with the methods used here. At the very least, our results imply that communication between hippocampus and neocortex does not involve large populations of rhinal cells.
However, the critical question is whether the inhibitory control of perirhino-entorhinal communication is ever lifted and, if so, how. Recently, it was reported that amygdala inputs could promote the spread of perirhinal activity to the entorhinal cortex and hippocampus in conditions of partial GABAA block (Kajiwara et al. 2003). Thus it is conceivable that afferents to the rhinal cortices, by reducing inhibition, might facilitate impulse traffic in this circuit. Although the identity of these afferents remains unknown, likely possibilities include the basolateral amygdala and the medial prefrontal cortex. Indeed, the basolateral amygdala sends a glutamatergic projection to the perirhinal and entorhinal cortices (Krettek and Price 1977a,b; Room and Groenewegen 1986; Smith and Paré, 1994; reviewed in Pitkanen et al. 2000). As for the medial prefrontal cortex, it sends robust projections to the rhinal cortices (Room et al. 1985; Sesack et al. 1989; Takagishi and Chiba 1991).
In conclusion, our findings imply that, in some circumstances at least, the perirhinal cortex operates independently of the entorhinal–hippocampal system and is thus in a position to perform distinct computations.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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This work was supported by National Institute of Mental Health Grant RO1MH-066856-01 to D. Paré and a Fonds de la Recherche en Santé du Québec fellowship to J. Guillaume Pelletier.
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. Paré, CMBN, Aidekman Research Center, Rutgers, The State University of New Jersey, 197 University Ave., Newark, NJ 07102 (E-mail: pare{at}axon.rutgers.edu).
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