Stability and variability of place cell activity during behavior: functional implications for dynamic coding of spatial information.

In addition to their discharge strongly related to a rat's location in the environment, hippocampal place cells have recently been discovered to carry other more subtle signals. For instance, place cells exhibit overdispersion, i.e., a tendency to have highly variable firing rates across successive passes in the firing field, which may reflect the processing of different classes of cues. In addition, the place cell population tends to fire synchronously during specific phases of place navigation, presumably signaling the animal's arrival at the goal location, or to be reactivated during either sleep or wakefulness following exposure to a new environment, a process thought to be important for memory consolidation. Although these various phenomena are expressed at different timescales, it is very likely that they can occur at the same time during an animal's exposure to a spatial environment. The advantage of such simultaneous processing is that it permits the organism both to be aware of its own location in the environment, and to attend to other environmental features and to store multiple experiences. However its pitfall is that it may result in noisy signals that are difficult to decipher by output structures. Therefore the question is asked of how the information carried by each process can be disentangled. We provide some examples from recent research work showing that this problem is far from being trivial and we propose an explanatory framework in which place cell activity at different timescales could be viewed as a series of dynamic attractors nested within each other.

A model of grid cells involving extra hippocampal path integration, and the hippocampal loop.

In this paper, we present a model for the generation of grid cells and the emergence of place cells from multimodal input to the entorhinal cortex (EC). In this model, grid cell activity in the dorsocaudal medial entorhinal cortex (dMEC) [28] results from the operation of a long-distance path integration system located outside the hippocampal formation, presumably in retrosplenial and/or parietal cortex. If the connections between these structures and dMEC are organized as a modulo N operator, the resulting activity of dMEC neurons is a grid cell pattern. Furthermore, a robust high-resolution positional code can be built from a small set of different grid cells if the modulo factors are relatively prime. On the other hand, broad visual place cell activity in the MEC can result from the integration of visual information depending on the view-field of the visual input. The merging of entorhinal visual place cell information and grid cell information in the EC and/or in the dentate gyrus (DG) allows the building of precise and robust "place cells" (e.g., whose activity is maintained if light is suppressed for a short duration). Our model supports our previous proposition that hippocampal "place cell" activity code transitions between two successive states ("transition cells") rather than mere current locations. Furthermore, we discuss the possibility that the hippocampal loop participates in the emergence of grid cell activity but is not sufficient by itself. Finally, path integration at a short time scale (which is reset from one place to the next) would be merged in the subiculum with CA3/CA1 "transition cells" [22] to provide a robust feedback about current action to the deep layer of the entorhinal cortex in order to predict the recognition of the new animal location.

Nucleus accumbens dopamine receptors in the consolidation of spatial memory.

Nucleus accumbens dopamine is known to play an important role in motor activity and in behaviours governed by drugs and natural reinforcers, as well as in non-associative forms of learning. At the same time, activation of D1 and D2 dopamine receptors has been suggested to promote intracellular events related to neural plasticity. Therefore, in this study we wished to investigate the role of the two classes of dopamine receptors within the nucleus accumbens on the consolidation of spatial information. On day 1, CD1 male mice were placed in an open field containing five different objects and, immediately after three sessions of habituation, the animals were focally injected within the nucleus accumbens with either the D1 antagonist SCH 23390 (12.5, 25 or 50 ng/side), or the D2 antagonist sulpiride (25, 50, 75 or 100 ng/side). Twenty-four hours later the ability of mice to discriminate an object displacement was assessed. Both the D1 and the D2 antagonists impaired the ability of mice to detect the spatial change. If the highest doses of the two antagonists were injected 2 h after the end of the last of the habituation sessions, no effect was observed in the reactivity to spatial change examined 24 h later. These data demonstrate that activation of both D1 and D2 receptors within the accumbens is necessary in the early stages of the consolidation of spatial information. The data are discussed in terms of involvement of nucleus accumbens dopamine in information processing in the absence of explicit reinforcers.

NMDA and AMPA antagonist infusions into the ventral striatum impair different steps of spatial information processing in a nonassociative task in mice.

Most of the research on ventral striatal functions has been focused on their role in modulating reward and motivation. More recently, a possible role of this structure in cognitive functions has been suggested. However, very little information is available on the involvement of the nucleus accumbens in the different stages of the consolidation process. In this study, the effect of focal injections of AP-5 and DNQX, competitive antagonists at the NMDA and AMPA receptors, respectively, was examined in a nonassociative task designed to estimate the ability of mice to react to spatial changes. The task consists of placing the animals in an open field containing five objects; after three sessions of habituation, their reactivity to object displacement was examined 24 hr later. AP-5 injections administered after training impaired the ability of mice to detect the spatial novelty but did not affect response when injected 120 min after training or before testing. On the contrary, DNQX did not affect response when administered immediately or 120 min after training but did impair spatial discrimination when administered before training or testing. These data demonstrate a double dissociation between glutamate receptor subtypes, such that accumbens NMDA receptors are important for consolidation and not ongoing discrimination of spatial information, whereas AMPA receptors have an opposite role in these processes.

Role of dopaminergic system in reactivity to spatial and non-spatial changes in mice.

RATIONALE: While experimental evidence shows that dopamine (DA) systems have an important role in locomotor function and in motivation, their role in the reactivity to spatial and non-spatial novelty is less well established. OBJECTIVE: In this study, we investigated the effects of dopaminergic pharmacological manipulation on the capability of CD1 mice to encode spatial and non-spatial information in an open field with objects. METHODS: The effects of systemic administration of: (1) selective D1 and D2 antagonists (SCH23390, 0.015 mg/kg or 0.020 mg/kg; sulpiride, 10 mg/kg or 20 mg/kg); (2) direct and indirect DA agonists (apomorphine, 1 mg/kg or 2 mg/kg; amphetamine, 1 mg/kg or 2 mg/kg) were studied. RESULTS: On the one hand, systemic administration of either D1 or D2 antagonists induced a selective impairment in the detection of spatial change but did not affect reaction to non-spatial novelty. On the other hand, amphetamine induced a selective decrease in exploratory activity in the first three sessions. This decrease did not affect the ability of mice to react to spatial change, but a dose-dependent decrease was observed in reactivity to non-spatial novelty. Such an effect does not seem to be due to amphetamine-induced hyperactivity or to non-DA mechanisms, since apomorphine induced a similar neophobic profile, without affecting locomotion. CONCLUSIONS: Taken together, these results demonstrate that manipulations of DA transmission affect reactivity to spatial and non-spatial novelty. In particular, we suggest that these two behavioral responses are modulated in opposite ways by the DA system.

Effects of lesions to the glutamatergic afferents to the nucleus accumbens in the modulation of reactivity to spatial and non-spatial novelty in mice.

The purpose of this study was to compare the effects of selective lesions of the three main sources of limbic afferents to the nucleus accumbens-fornix, prelimbic cortex and amygdala-with those induced by N-methyl-D-aspartate receptor blockage in this structure, in a non-associative task designed to estimate the ability of rodents to encode spatial and non-spatial relationships between discrete stimuli. The task consists of placing mice in an open field containing five objects and, after three sessions of habituation, examining their reactivity to object displacement (spatial novelty) and object substitution (object novelty). Focal administrations of the competitive N-methyl-D-aspartate antagonist DL-2-amino-5-phosphonopentanoic acid (0.1 microg/side) induced a selective impairment in the ability of mice to react to the spatial change. Lesions to the different structures affect the response of mice to spatial and non-spatial novelty in different ways. In particular, while fornix lesions induced a decrease in re-exploration of the displaced objects, prelimbic cortex lesions enhanced the exploration of both displaced and non-displaced objects. Finally, the basolateral amygdala lesions did not induce any impairment in the detection of the displaced objects but decreased the latencies to approach novel objects. It is concluded that N-methyl-D-aspartate receptor blockage in the nucleus accumbens subsumes the effects of the three lesions. Some hypotheses on the role of glutamatergic transmission in the accumbens on information processing are briefly discussed.

N-methyl-D-aspartate and dopamine receptor involvement in the modulation of locomotor activity and memory processes.

In this study we report on the effects of N-methyl-D-aspartate (NMDA)- and dopamine (DA)-receptor manipulation on the modulation of one-trial inhibitory avoidance response and the encoding of spatial information, as assessed with a non-associative task. Further, a comparison with the well-known effects of the manipulation of these two receptor systems on locomotor activity is outlined. It is well assessed that NMDA-receptor blockage induces a stimulatory action on locomotor activity similar to that exerted by DA agonists. There is evidence showing that the nucleus accumbens is involved in the response induced by both NMDA antagonists and DA agonists. We show results indicating a functional interaction between these two neural systems in modulating locomotor activity, with D2 DA-receptor antagonists (sulpiride and haloperidol) being more effective than the D1 antagonist (SCH 23390) in blocking MK-801-induced locomotion. A different profile is shown in the effects of NMDA antagonists and DA agonists in the modulation of memory processes. In one-trial inhibitory avoidance response, NMDA antagonists (MK-801 and CPP) impair the response on test day, while DA agonists exert a facilitatory effect; furthermore, sub-effective doses of both D1 (SKF 23390) and D2 (quinpirole) are able to attenuate the impairing effect in a way similar to that induced by NMDA antagonists. The effects of NMDA- and DA-acting drugs on the response to spatial novelty, as assessed with a task designed to study the ability of animals to react to discrete spatial changes, are in good accord with the effects observed on passive avoidance. The results show that NMDA as well as DA antagonists, at low doses, selectively impair the reactivity of mice to spatial changes. In a last series of experiments, the possible role of NMDA receptors located in the nucleus accumbens was investigated regarding reactivity to spatial novelty. The experiments gave apparently contrasting results: while showing an impairing effect of focal administrations of NMDA antagonists in the nucleus accumbens on reactivity to spatial novelty, no effect of ibotenic acid lesions of the same structure was observed.

N-methyl-D-aspartate receptors in the nucleus accumbens are involved in detection of spatial novelty in mice.

The aim of this study was to investigate the role played by intra-accumbens N-methyl-D-aspartate (NMDA) receptors in spatial information encoding. For this purpose, the effect of local administration of both competitive (AP-5) and non-competitive (MK-801) NMDA antagonists was assessed in a task designed to estimate the ability of rodents to encode spatial relationships between discrete stimuli. The task consists of placing mice in an open field containing five objects and, after three sessions of habituation, examining their reactivity to object displacement (spatial novelty) and object substitution (object novelty). The results show that both doses of MK-801 (0.15 and 0.3 microg/side) induced a selective impairment in the capability of mice to detect spatial novelty. A similar effect was obtained by injecting the low dose of the competitive antagonist AP-5 (0.1 microg/side), whereas the high dose (0.15 microg/side) abolished detection of both spatial and object novelty. Taken together, these results show that intra-accumbens injections of low doses of competitive and non-competitive NMDA antagonists can produce selective deficits in processing spatial information resembling those observed after hippocampal damage. Moreover, the fact that pharmacological treatments spare memory processes involved in habituation suggests that NMDA antagonists may interfere with the formation of spatial representations rather than producing memory deficits per se.