The well-worn route revisited: Striatal and hippocampal system contributions to familiar route navigation.

Classic research has shown a division in the neuroanatomical structures that support flexible (e.g., short-cutting) and habitual (e.g., familiar route following) navigational behavior, with hippocampal-caudate systems associated with the former and putamen systems with the latter. There is, however, disagreement about whether the neural structures involved in navigation process particular forms of spatial information, such as associations between constellations of cues forming a cognitive map, versus single landmark-action associations, or alternatively, perform particular reinforcement learning algorithms that allow the use of different spatial strategies, so-called model-based (flexible) or model-free (habitual) forms of learning. We sought to test these theories by asking participants (N = 24) to navigate within a virtual environment through a previously learned, 9-junction route with distinctive landmarks at each junction while undergoing functional magnetic resonance imaging (fMRI). In a series of probe trials, we distinguished knowledge of individual landmark-action associations along the route versus knowledge of the correct sequence of landmark-action associations, either by having absent landmarks, or "out-of-sequence" landmarks. Under a map-based perspective, sequence knowledge would not require hippocampal systems, because there are no constellations of cues available for cognitive map formation. Within a learning-based model, however, responding based on knowledge of sequence would require hippocampal systems because prior context has to be utilized. We found that hippocampal-caudate systems were more active in probes requiring sequence knowledge, supporting the learning-based model. However, we also found greater putamen activation in probes where navigation based purely on sequence memory could be planned, supporting models of putamen function that emphasize its role in action sequencing.

Knockout of NMDARs in CA1 and dentate gyrus fails to impair temporal control of conditioned behavior in mice.

The hippocampus has been implicated in temporal learning. Plasticity within the hippocampus requires NMDA receptor-dependent glutamatergic neurotransmission. We tested the prediction that hippocampal NMDA receptors are required for learning about time by testing mice that lack postembryonal NMDARs in the CA1 and dentate gyrus (DG) hippocampal subfields on three different appetitive temporal learning procedures. The conditional knockout mice (Grin1ΔDCA1 ) showed normal sensitivity to cue duration, responding at a higher level to a short duration cue than compared to a long duration cue. Knockout mice also showed normal precision and accuracy of response timing in the peak procedure in which reinforcement occurred after 10 s delay within a 30 s cue presentation. Mice were tested on the matching of response rates to reinforcement rates on instrumental conditioning with two levers reinforced on a concurrent variable interval schedule. Pressing on one lever was reinforced at a higher rate than the other lever. Grin1ΔDGCA1 mice showed normal sensitivity to the relative reinforcement rates of the levers. In contrast to the lack of effect of hippocampal NMDAR deletion on measures of temporal sensitivity, Grin1ΔDGCA1 mice showed increased baseline measures of magazine activity and lever pressing. Furthermore, reversal learning was enhanced when the reward contingencies were switched in the lever pressing task, but this was true only for mice trained with a large difference between relative reinforcement rates between the levers. The results failed to demonstrate a role for NMDARs in excitatory CA1 and DG neurons in learning about temporal information.

Reinforcement rate and the balance between excitatory and inhibitory learning: Insights from deletion of the GluA1 AMPA receptor subunit.

Conditioned responding is sensitive to reinforcement rate. This rate-sensitivity is impaired in genetically modified mice that lack the GluA1 subunit of the AMPA receptor. A time-dependent application of the Rescorla-Wagner learning rule can be used to derive an account of rate-sensitivity by reflecting the balance of excitatory and inhibitory associative strength over time. By applying this analysis, the impairment in GluA1 knockout mice may be explained by reduced sensitivity to negative prediction error and thus, impaired inhibitory learning, such that excitatory associative strength is not reduced during the nonreinforced periods of a conditioned stimulus. The article describes a test of the role of GluA1 in inhibitory learning that requires summing of the associative strengths of cues presented in compound. Mice were trained on a feature negative discrimination of the form A+/AX-. GluA1 knockout mice acquired the discrimination to a similar extent as controls. The inhibitory properties of cue X were verified in a summation test that included a control for nonassociative, external inhibition. The performance of GluA1 knockout mice was similar to that of controls. However, in line with previous findings, GluA1 deletion impaired the precision of timing of conditioned responding. These results provide further evidence that impaired sensitivity to reinforcement rate is not a consequence of impaired inhibitory learning. The results may more readily fit with accounts of rate sensitivity that propose that it reflects encoding of temporal and numeric information rather than being a consequence of changes in associative strength over time. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Dissociating Representations of Time and Number in Reinforcement-Rate Learning by Deletion of the GluA1 AMPA Receptor Subunit in Mice.

Theories of learning differ in whether they assume that learning reflects the strength of an association between memories or symbolic encoding of the statistical properties of events. We provide novel evidence for symbolic encoding of informational variables by demonstrating that sensitivity to time and number in learning is dissociable. Whereas responding in normal mice was dependent on reinforcement rate, responding in mice that lacked the GluA1 AMPA receptor subunit was insensitive to reinforcement rate and, instead, dependent on the number of times a cue had been paired with reinforcement. This suggests that GluA1 is necessary for weighting numeric information by temporal information in order to calculate reinforcement rate. Sample sizes per genotype varied between seven and 23 across six experiments and consisted of both male and female mice. The results provide evidence for explicit encoding of variables by animals rather than implicit encoding via variations in associative strength.

The GluA1 AMPAR subunit is necessary for hedonic responding but not hedonic value in female mice.

The GluA1 subunit of the AMPA receptor has been implicated in anhedonia. Mice that lack GluA1 (Gria1 knockout mice) show reduced lick cluster size, a measure of palatability in feeding behaviour. This deficit may reflect a role for GluA1 in encoding the hedonic value of palatable substances or instead a role for GluA1 in the behavioural expression of hedonic value. We tested the role of GluA1 in hedonic value by assessing sensitivity to changes in the rewarding property of sucrose as a consequence of negative/positive contrast effects in female mice. During training, on half of the days consumption of a flavour (CS+) mixed with 4% sucrose was preceded by consumption of 1% sucrose (positive contrast). On the other half of days consumption of a different flavour (CS-) mixed with 4% sucrose was preceded by consumption of 16% sucrose (negative contrast). In the test session both wild-type, controls and Gria1 knockout mice consumed more of the CS+ flavour than the CS- flavour. While Gria1 knockout mice showed reduced lick cluster sizes, both genotypes made larger lick clusters for the CS+ flavour than the CS- flavour suggesting that the CS+ was more palatable than the CS-. A follow up experiment in normal mice demonstrated that the negative contrast procedure resulted in a conditioned reduction of palatability of the CS- in comparison to an associatively neutral, novel flavour. The results failed to demonstrate a role for GluA1 in hedonic value suggesting that, instead, GluA1 is necessary for hedonic responding.

Cue duration determines response rate but not rate of acquisition of Pavlovian conditioning in mice.

The duration of a conditioned stimulus (CS) is a key determinant of Pavlovian conditioning. Rate estimation theory (RET) proposes that reinforcement rate is calculated over cumulative exposure to a cue and the reinforcement rate of a cue, relative to the background reinforcement rate, determines the speed of acquisition of conditioned responding. Consequently, RET predicts that shorter-duration cues require fewer trials to acquisition than longer-duration cues due to the difference in reinforcement rates. We tested this prediction by reanalysing the results of a previously published experiment. Mice received appetitive Pavlovian conditioning of magazine approach behaviour with a 10-s CS and a 40-s CS. Cue duration did not affect the rate at which responding emerged or the rate at which it peaked. The 10-s CS did elicit higher levels of responding than the 40-s CS. These results are not consistent with rate estimation theory. Instead, they are consistent with an associative analysis that assumes that asymptotic levels of responding reflect the balance between increments and decrements in associative strength across cumulative exposure to a cue.

Distinct and combined responses to environmental geometry and features in a working-memory reorientation task in rats and chicks.

The original provocative formulation of the 'geometric module' hypothesis was based on a working-memory task in rats which suggested that spontaneous reorientation behavior is based solely on the environmental geometry and is impervious to featural cues. Here, we retested that claim by returning to a spontaneous navigation task with rats and domestic chicks, using a single prominent featural cue (a striped wall) within a rectangular arena. Experiments 1 and 2 tested the influence of geometry and features separately. In Experiment 1, we found that both rats and chicks used environmental geometry to compute locations in a plain rectangular arena. In Experiment 2, while chicks failed to spontaneously use a striped wall in a square arena, rats showed a modest influence of the featural cue as a local marker to the goal. The critical third experiment tested the striped wall inside the rectangular arena. We found that although chicks solely relied on geometry, rats navigated based on both environmental geometry and the featural cue. While our findings with rats are contrary to classic claims of an impervious geometric module, they are consistent with the hypothesis that navigation by boundaries and features may involve distinct underlying cognitive computations. We conclude by discussing the similarities and differences in feature-use across tasks and species.

En route to delineating hippocampal roles in spatial learning.

The precise role played by the hippocampus in spatial learning tasks, such as the Morris Water Maze (MWM), is not fully understood. One theory is that the hippocampus is not required for 'knowing where' but rather is crucial in 'getting there'. To explore this idea in the MWM, we manipulated 'getting there' variables, such as passive transport or active swimming towards the hidden platform, in rats with and without hippocampal lesions. Our results suggested that for intact rats, self-motion cues enroute to the hidden goal were a necessary component for 'place learning' to progress. Specifically, intact rats could not learn the hidden goal location, when passively transported to it, despite extensive training. However, when rats were either given hippocampal lesions, or placed in a light-tight box during transportation to the hidden goal, passive-placement spatial learning was facilitated. In a subsequent experiment, the 'getting there' component of place navigation was simplified, via the placement of two overhead landmarks, one of which served as a beacon. When 'getting there' was made easier in this way, hippocampal lesions did not induce deficits in 'knowing where' the goal was. In fact, similar to the facilitation observed in passive-placement spatial learning, hippocampal lesions improved landmark learning relative to controls. Finally, demonstrating that our lesions were sufficiently deleterious, hippocampal-lesioned rats were impaired, as predicted, in an environmental-boundary based learning task. We interpret these results in terms of competition between multiple memory systems, and the importance of self-generated motion cues in hippocampal spatial mapping.

Delay of reinforcement versus rate of reinforcement in Pavlovian conditioning.

Conditioned stimulus (CS) duration is a determinant of conditioned responding, with increases in duration leading to reductions in response rates. The CS duration effect has been proposed to reflect sensitivity to the reinforcement rate across cumulative exposure to the CS, suggesting that the delay of reinforcement from the onset of the cue is not crucial. Here, we compared the effects of delay and rate of reinforcement on Pavlovian appetitive conditioning in mice. In Experiment 1, the influence of reinforcement delay on the timing of responding was removed by making the duration of cues variable across trials. Mice trained with variable duration cues were sensitive to differences in the rate of reinforcement to a similar extent as mice trained with fixed duration cues. Experiments 2 and 3 tested the independent effects of delay and reinforcement rate. In Experiment 2, food was presented at either the termination of the CS or during the CS. In Experiment 3, food occurred during the CS for all cues. The latter experiment demonstrated an effect of delay, but not reinforcement rate. Experiment 4 ruled out the possibility that the lack of effect of reinforcement rate in Experiment 3 was due to mice failing to learn about the nonreinforced CS exposure after the presentation of food within a trial. These results demonstrate that although the CS duration effect is not simply a consequence of timing of conditioned responses, it is dependent on the delay of reinforcement. The results provide a challenge to current associative and nonassociative, time-accumulation models of learning. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The NMDA receptor antagonist MK-801 fails to impair long-term recognition memory in mice when the state-dependency of memory is controlled.

NMDA receptor-dependent synaptic plasticity has been proposed to be important for encoding of memories. Consistent with this hypothesis, the non-competitive NMDA receptor antagonist, MK-801, has been found to impair performance on tests of memory. Interpretation of some of these findings has, however, been complicated by the fact that the drug-state of animals has differed during encoding and tests of memory. Therefore, it is possible that MK-801 may result in state-dependent retrieval or expression of memory rather than actually impairing encoding itself. We tested this hypothesis in mice using tests of object recognition memory with a 24-hour delay between the encoding and test phase. Mice received injections of either vehicle or MK-801 prior to the encoding phase and the test phase. In Experiment 1, a low dose of MK-801 (0.01 mg/kg) impaired performance when the drug-state (vehicle or MK-801) of mice changed between encoding and test, but there was no significant effect of MK-801 on encoding. In Experiment 2, a higher dose of MK-801 (0.1 mg/kg) failed to impair object recognition memory when mice received the drug prior to both encoding and test compared to mice that received vehicle. MK-801 did not affect object exploration, but it did induce locomotor hyperactivity at the higher dose. These results suggest that some previous demonstrations of MK-801 effects may reflect a failure to express or retrieve memory due to the state-dependency of memory rather than impaired encoding of memory.

A biphasic reduction in a measure of palatability following sucrose consumption in mice.

Consumption of foods results in a transient reduction in hedonic value that influences the extent and nature of feeding behavior. The time course of this effect, however, is poorly specified. In an initial experiment, using an analysis of the microstructure of licking in mice we found that consumption of sucrose led to a rapid reduction in lick cluster size, a measure of palatability, which recovered after 10 min, but reemerged 60min after initial consumption. We then replicated the finding that lick cluster size is reduced after 60min, but not 10min, under conditions in which a number of potential behavioural confounds were removed. In Experiment 2 the effect was replicated using a between-subjects design that ruled out the possibility that the effect was a specific consequence of the within-subjects procedures used in the first experiment, in which mice may have come to expect sucrose at different time points within the feeding session. While Experiments 1 and 2 confounded the time between periods of access to sucrose with time since the start of the feeding session, this confound was removed in Experiment 3, and, similar to the previous experiments, it was found that a second reduction in palatability occurred after 60min. Therefore, the effect was dependent only on the time since the previous exposure to sucrose, demonstrating that sucrose consumption initiates a biphasic reduction in palatability. The reduction in lick cluster size after 60min was not typically accompanied by a reduction in consumption suggesting that the more slowly developing reduction in the palatability measure was not simply a consequence of post-ingestive satiety. The cause of the biphasic change is not yet clear, and may reflect independent processes or the consequence of a single process that initiates multiple changes in palatability over time.

GluA1 AMPAR subunit deletion reduces the hedonic response to sucrose but leaves satiety and conditioned responses intact.

The GluA1 subunit of the AMPA receptor has been implicated in schizophrenia. While GluA1 is important for cognition, it is not clear what the role of GluA1 is in hedonic responses that are relevant to the negative symptoms of disorders such as schizophrenia. Here, we tested mice that lack GluA1 (Gria1 -/- mice) on consumption of sucrose solutions using a licking microstructure analysis. GluA1 deletion drastically reduced palatability (as measured by the mean lick cluster size) across a range of sucrose concentrations. Although initial lick rates were reduced, measures of consumption across long periods of access to sucrose solutions were not affected by GluA1 deletion and Gria1 -/- mice showed normal satiety responses to high sucrose concentrations. GluA1 deletion also failed to impair flavour conditioning, in which increased intake of a flavour occurred as a consequence of prior pairing with a high sucrose concentration. These results demonstrate that GluA1 plays a role in responding on the basis of palatability rather than other properties, such as the automatic and learnt post-ingestive, nutritional consequences of sucrose. Therefore, Gria1 -/- mice provide a potential model of anhedonia, adding converging evidence to the role of glutamatergic dysfunction in various symptoms of schizophrenia and related disorders.

Memory-dependent effects on palatability in mice.

While palatability depends on the properties of particular foods, it is also determined by prior experience, suggesting that memory affects the hedonic value of a substance. Here, we report two procedures that affect palatability in mice: negative contrast and flavour habituation. A microstructure analysis of licking behaviour was employed, with the lick cluster size (the number of licks made in quick succession before a pause) used as a measure of palatability. It was first confirmed that lick cluster size increased monotonically as a function of sucrose concentration, whereas consumption followed an inverted U-shaped function. In a successive negative contrast procedure it was found that when shifted from a high sucrose concentration (32%) to a low sucrose concentration (4%), mice made smaller lick clusters than a group that only received the low concentration. Mice exposed to flavours (cherry or grape Kool Aid) mixed with sucrose (16%) made larger lick clusters for familiar flavours compared to novel flavours. This habituation effect was evident after short (5min) and long (24h) test intervals. Both successive negative contrast and flavour habituation failed to affect levels of consumption. Collectively, the results show that prior experience can have effects on lick cluster size that are equivalent to increasing or decreasing the sweetness of a solution. Thus, palatability is not a fixed property of a substance but is dependent on expectation or familiarity that occurs as a result of memory.

Contexts control negative contrast and restrict the expression of flavor preference conditioning.

Consumption of a high concentration of sucrose can have either a detrimental, negative contrast effect or a facilitatory, preference conditioning effect on subsequent consumption of a low concentration of sucrose, depending on the cues that are present during consumption. The role of context and flavor cues in determining these effects were studied using analysis of the microstructure of licking in mice. Exposure to a high concentration followed by exposure to a low concentration resulted in a transient reduction in mean lick cluster size, which was context dependent (Experiment 1). However, there was no change in the total number of licks or overall consumption. When a flavor that had previously been paired with a high concentration was paired with a low concentration, there was an increase in the total number of licks, and overall consumption, but no change in the mean lick cluster size (Experiment 2). Pairing a high concentration with a flavor in a particular context before pairing the context and flavor compound with a low concentration resulted in abolishing the expression of the flavor preference conditioning effect on the total number of licks and consumption (Experiment 3). These results demonstrate that although context and flavor cues have dissociable effects on licking behavior, their interaction has an antagonistic effect on the behavioral expression of memory.

The effect of the amount of blocking cue training on blocking of appetitive conditioning in mice.

Conditioning of a target cue is blocked when it occurs in compound with another cue (blocking cue) that has already received conditioning. Although blocking of appetitive conditioning is commonly used in rodents as a test of selective learning, it has been demonstrated rarely in mice. In order to investigate the conditions that result in blocking in mice two studies tested the effect of the extent of prior blocking cue training on blocking of appetitive conditioning. Mice received either 80 or 200 trials of blocking cue training prior to compound conditioning. A control group received only compound training. Experiment 1 assessed the ability of a visual cue to block conditioning to an auditory target cue. Exposure to the context and the unconditioned stimulus, sucrose pellets, was equated across groups. Blocking was evident in mice that received 200, but not 80 training trials with the visual blocking cue. Responding to the blocking cue was similar across groups. Experiment 2 assessed the ability of an auditory cue to block conditioning to a visual target cue. Blocking was evident in mice trained with 80 and 200 auditory blocking cue trials. The results demonstrate that the strength of blocking in mice is dependent on the modality and experience of the blocking cue. Furthermore, prolonged training of the blocking cue after asymptotic levels of conditioned responding have been reached is necessary for blocking to occur under certain conditions suggesting that the strength of conditioned responding is a limited measure of learning.