Local origin of excitatory-inhibitory tuning equivalence in a cortical network.

The interplay between excitation and inhibition determines the fidelity of cortical representations. The receptive fields of excitatory neurons are often finely tuned to encoded features, but the principles governing the tuning of inhibitory neurons remain elusive. In this study, we recorded populations of neurons in the mouse postsubiculum (PoSub), where the majority of excitatory neurons are head-direction (HD) cells. We show that the tuning of fast-spiking (FS) cells, the largest class of cortical inhibitory neurons, was broad and frequently radially symmetrical. By decomposing tuning curves using the Fourier transform, we identified an equivalence in tuning between PoSub-FS and PoSub-HD cell populations. Furthermore, recordings, optogenetic manipulations of upstream thalamic populations and computational modeling provide evidence that the tuning of PoSub-FS cells has a local origin. These findings support the notion that the equivalence of neuronal tuning between excitatory and inhibitory cell populations is an intrinsic property of local cortical networks.

The medial entorhinal cortex is necessary for the stimulus control over hippocampal place fields by distal, but not proximal, landmarks.

A fundamental property of place cells in the hippocampus is the anchoring of their firing fields to salient landmarks within the environment. However, it is unclear how such information reaches the hippocampus. In the current experiment, we tested the hypothesis that the stimulus control exerted by distal visual landmarks requires input from the medial entorhinal cortex (MEC). Place cells were recorded from mice with ibotenic acid lesions of the MEC (n = 7) and from sham-lesioned mice (n = 6) following 90° rotations of either distal landmarks or proximal cues in a cue- controlled environment. We found that lesions of the MEC impaired the anchoring of place fields to distal landmarks, but not proximal cues. We also observed that, relative to sham-lesioned mice, place cells in animals with MEC lesions exhibited significantly reduced spatial information and increased sparsity. These results support the view that distal landmark information reaches the hippocampus via the MEC, but that proximal cue information can do so via an alternative neural pathway.

Developmental trajectory of episodic-like memory in rats.

Introduction: Episodic memory formation requires the binding of multiple associations to a coherent episodic representation, with rich detail of times, places, and contextual information. During postnatal development, the ability to recall episodic memories emerges later than other types of memory such as object recognition. However, the precise developmental trajectory of episodic memory, from weaning to adulthood has not yet been established in rats. Spontaneous object exploration tasks do not require training, and allow repeated testing of subjects, provided novel objects are used on each trial. Therefore, these tasks are ideally suited for the study of the ontogeny of episodic memory and its constituents (e.g., object, spatial, and contextual memory). Methods: In the present study, we used four spontaneous short-term object exploration tasks over two days: object (OR), object-context (OCR), object-place (OPR), and object-place-context (OPCR) recognition to characterise the ontogeny of episodic-like memory and its components in three commonly used outbred rat strains (Lister Hooded, Long Evans Hooded, and Sprague Dawley). Results: In longitudinal studies starting at 3-4 weeks of age, we observed that short term memory for objects was already present at the earliest time point we tested, indicating that it is established before the end of the third week of life (consistent with several other reports). Object-context memory developed during the fifth week of life, while both object-in-place and the episodic-like object-place-context memory developed around the seventh postnatal week. To control for the effects of previous experience in the development of associative memory, we confirmed these developmental trajectories using a cross-sectional protocol. Discussion: Our work provides robust evidence for different developmental trajectories of recognition memory in rats depending on the content and/or complexity of the associations and emphasises the utility of spontaneous object exploration tasks to assess the ontogeny of memory systems with high temporal resolution.

Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome.

BACKGROUND: Fragile X syndrome (FXS) is a common single gene cause of intellectual disability and autism spectrum disorder. Cognitive inflexibility is one of the hallmarks of FXS with affected individuals showing extreme difficulty adapting to novel or complex situations. To explore the neural correlates of this cognitive inflexibility, we used a rat model of FXS (Fmr1-/y). METHODS: We recorded from the CA1 in Fmr1-/y and WT littermates over six 10-min exploration sessions in a novel environment-three sessions per day (ITI 10 min). Our recordings yielded 288 and 246 putative pyramidal cells from 7 WT and 7 Fmr1-/y rats, respectively. RESULTS: On the first day of exploration of a novel environment, the firing rate and spatial tuning of CA1 pyramidal neurons was similar between wild-type (WT) and Fmr1-/y rats. However, while CA1 pyramidal neurons from WT rats showed experience-dependent changes in firing and spatial tuning between the first and second day of exposure to the environment, these changes were decreased or absent in CA1 neurons of Fmr1-/y rats. These findings were consistent with increased excitability of Fmr1-/y CA1 neurons in ex vivo hippocampal slices, which correlated with reduced synaptic inputs from the medial entorhinal cortex. Lastly, activity patterns of CA1 pyramidal neurons were dis-coordinated with respect to hippocampal oscillatory activity in Fmr1-/y rats. LIMITATIONS: It is still unclear how the observed circuit function abnormalities give rise to behavioural deficits in Fmr1-/y rats. Future experiments will focus on this connection as well as the contribution of other neuronal cell types in the hippocampal circuit pathophysiology associated with the loss of FMRP. It would also be interesting to see if hippocampal circuit deficits converge with those seen in other rodent models of intellectual disability. CONCLUSIONS: In conclusion, we found that hippocampal place cells from Fmr1-/y rats show similar spatial firing properties as those from WT rats but do not show the same experience-dependent increase in spatial specificity or the experience-dependent changes in network coordination. Our findings offer support to a network-level origin of cognitive deficits in FXS.

Abnormal brain state distribution and network connectivity in a SYNGAP1 rat model.

Mutations in the SYNGAP1 gene are one of the common predictors of neurodevelopmental disorders, commonly resulting in individuals developing autism, intellectual disability, epilepsy, and sleep deficits. EEG recordings in neurodevelopmental disorders show potential to identify clinically translatable biomarkers to both diagnose and track the progress of novel therapeutic strategies, as well as providing insight into underlying pathological mechanisms. In a rat model of SYNGAP1 haploinsufficiency in which the exons encoding the calcium/lipid binding and GTPase-activating protein domains have been deleted (Syngap+/Δ-GAP ), we analysed the duration and occurrence of wake, non-rapid eye movement and rapid eye movement brain states during 6 h multi-electrode EEG recordings. We find that although Syngap+/Δ-GAP animals spend an equivalent percent time in wake and sleep states, they have an abnormal brain state distribution as the number of wake and non-rapid eye movement bouts are reduced and there is an increase in the average duration of both wake and non-rapid eye movement epochs. We perform connectivity analysis by calculating the average imaginary coherence between electrode pairs at varying distance thresholds during these states. In group averages from pairs of electrodes at short distances from each other, a clear reduction in connectivity during non-rapid eye movement is present between 11.5 Hz and 29.5 Hz, a frequency range that overlaps with sleep spindles, oscillatory phenomena thought to be important for normal brain function and memory consolidation. Sleep abnormalities were mostly uncorrelated to the electrophysiological signature of absence seizures, spike and wave discharges, as was the imaginary coherence deficit. Sleep spindles occurrence, amplitude, power and spread across multiple electrodes were not reduced in Syngap+/Δ-GAP rats, with only a small decrease in duration detected. Nonetheless, by analysing the dynamic imaginary coherence during sleep spindles, we found a reduction in high-connectivity instances between short-distance electrode pairs. Finally comparing the dynamic imaginary coherence during sleep spindles between individual electrode pairs, we identified a group of channels over the right somatosensory, association and visual cortices that have a significant reduction in connectivity during sleep spindles in mutant animals. This matched a significant reduction in connectivity during spindles when averaged regional comparisons were made. These data suggest that Syngap+/Δ-GAP rats have altered brain state dynamics and EEG connectivity, which may have clinical relevance for SYNGAP1 haploinsufficiency in humans.

Spatial representation by ramping activity of neurons in the retrohippocampal cortex.

Neurons in the retrohippocampal cortices play crucial roles in spatial memory. Many retrohippocampal neurons have firing fields that are selectively active at specific locations, with memory for rewarded locations associated with reorganization of these firing fields. Whether this is the sole strategy for representing spatial memories is unclear. Here, we demonstrate that during a spatial memory task retrohippocampal neurons encode location through ramping activity that extends across segments of a linear track approaching and following a reward, with the rewarded location represented by offsets or switches in the slope of the ramping activity. Ramping representations could be maintained independently of trial outcome and cues marking the reward location, indicating that they result from recall of the track structure. When recorded in an open arena, neurons that generated ramping activity during the spatial memory task were more numerous than grid or border cells, with a majority showing spatial firing that did not meet criteria for classification as grid or border representations. Encoding of rewarded locations through offsets and switches in the slope of ramping activity also emerged in recurrent neural network models trained to solve a similar spatial memory task. Impaired performance of model networks following disruption of outputs from ramping neurons is consistent with this coding strategy supporting navigation to recalled locations of behavioral significance. Our results suggest that encoding of learned spaces by retrohippocampal networks employs both discrete firing fields and continuous ramping representations. We hypothesize that retrohippocampal ramping activity mediates readout of learned models for goal-directed navigation.

Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3-/y rat model of autism.

BACKGROUND: Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cellular underpinnings in a rat model of ASD/ID lacking Nlgn3. METHODS: This study uses a range of behavioural tests to understand differences in fear response behaviour in Nlgn3-/y rats. Following this, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. We used whole-cell patch-clamp recordings from ex vivo PAG slices, in addition to in vivo local-field potential recordings and electrical stimulation of the PAG in wildtype and Nlgn3-/y rats. We analysed behavioural data with two- and three-way ANOVAS and electrophysiological data with generalised linear mixed modelling (GLMM). RESULTS: We observed that, unlike the wildtype, Nlgn3-/y rats are more likely to response with flight rather than freezing in threatening situations. Electrophysiological findings were in agreement with these behavioural outcomes. We found in ex vivo slices from Nlgn3-/y rats that neurons in dorsal PAG (dPAG) showed intrinsic hyperexcitability compared to wildtype. Similarly, stimulating dPAG in vivo revealed that lower magnitudes sufficed to evoke flight behaviour in Nlgn3-/y than wildtype rats, indicating the functional impact of the increased cellular excitability. LIMITATIONS: Our findings do not examine what specific cell type in the PAG is likely responsible for these phenotypes. Furthermore, we have focussed on phenotypes in young adult animals, whilst the human condition associated with NLGN3 mutations appears during the first few years of life. CONCLUSIONS: We describe altered fear responses in Nlgn3-/y rats and provide evidence that this is the result of a circuit bias that predisposes flight over freeze responses. Additionally, we demonstrate the first link between PAG dysfunction and ASD/ID. This study provides new insight into potential pathophysiologies leading to anxiety disorders and changes to fear responses in individuals with ASD.

Lateral entorhinal cortex lesions impair odor-context associative memory in male rats.

Lateral entorhinal cortex (LEC) has been hypothesized to process nonspatial, item information that is combined with spatial information from medial entorhinal cortex to form episodic memories within the hippocampus. Recent studies, however, have demonstrated that LEC has a role in integrating features of episodic memory prior to the hippocampus. While the precise role of LEC is still unclear, anatomical studies show that LEC is ideally placed to be a hub integrating multisensory information. The current study tests whether the role of LEC in integrating information extends to long-term multimodal item-context associations. In Experiment 1, male rats were trained on a context-dependent odor discrimination task, where two different contexts served as the cue to the correct odor. Rats were pretrained on the task and then received either bilateral excitotoxic LEC or sham lesions. Following surgery, rats were tested on the previously learned odor-context associations. Control rats showed good memory for the previously learned association but rats with LEC lesions showed significantly impaired performance relative to both their own presurgery performance and to control rats. Experiment 2 went on to test whether impairments in Experiment 1 were the result of LEC lesions impairing either odor or context memory retention alone. Male rats were trained on simple odor and context discrimination tasks that did not require integration of features to solve. Following surgery, both LEC and control rats showed good memory for previously learned odors and contexts. These data show that LEC is critical for long-term odor-context associative memory.

The Black Box effect: sensory stimulation after learning interferes with the retention of long-term object location memory in rats.

Reducing sensory experiences during the period that immediately follows learning improves long-term memory retention in healthy humans, and even preserves memory in patients with amnesia. To date, it is entirely unclear why this is the case, and identifying the neurobiological mechanisms underpinning this effect requires suitable animal models, which are currently lacking. Here, we describe a straightforward experimental procedure in rats that future studies can use to directly address this issue. Using this method, we replicated the central findings on quiet wakefulness obtained in humans: We show that rats that spent 1 h alone in a familiar dark and quiet chamber (the Black Box) after exploring two objects in an open field expressed long-term memory for the object locations 6 h later, while rats that instead directly went back into their home cage with their cage mates did not. We discovered that both visual stimulation and being together with conspecifics contributed to the memory loss in the home cage, as exposing rats either to light or to a cage mate in the Black Box was sufficient to disrupt memory for object locations. Our results suggest that in both rats and humans, everyday sensory experiences that normally follow learning in natural settings can interfere with processes that promote long-term memory retention, thereby causing forgetting in form of retroactive interference. The processes involved in this effect are not sleep-dependent because we prevented sleep in periods of reduced sensory experience. Our findings, which also have implications for research practices, describe a potentially useful method to study the neurobiological mechanisms that might explain why normal sensory processing after learning impairs memory both in healthy humans and in patients suffering from amnesia.

The stimulus control of local enclosures and barriers over head direction and place cell spatial firing.

OBJECTIVE: Head direction cell and place cell spatially tuned firing is often anchored to salient visual landmarks on the periphery of a recording environment. What is less well understood is whether structural features of an environment, such as orientation of a maze sub-compartment or a polarizing barrier, can likewise control spatial firing. METHOD: We recorded from 54 head direction cells in the medial entorhinal cortex and subicular region of male Lister Hooded rats while they explored an apparatus with four parallel or four radially arranged compartments (Experiment 1). In Experiment 2, we recorded from 130 place cells (in Lister- and Long-Evans Hooded rats) and 30 head direction cells with 90° rotations of a cue card and a barrier in a single environment (Experiment 2). RESULTS: We found that head direction cells maintained a similar preferred firing direction across four separate maze compartments even when these faced different directions (Experiment 1). However, in an environment with a single compartment, we observed that both a barrier and a cue card exerted comparable amounts of stimulus control over head direction cells and place cells (Experiment 2). CONCLUSION: The maintenance of a stable directional orientation across maze compartments suggests that the head direction cell system has the capacity to provide a global directional reference that allows the animal to distinguish otherwise similar maze compartments based on the compartment's orientation. A barrier is, however, capable of controlling spatially tuned firing in an environment in which it is the sole polarizing feature.

Lesions of the head direction cell system impair direction discrimination.

Previous results suggest that directional information from the head direction cell circuit may inform hippocampal place cell firing when an animal is confronted with visually identical environments. To investigate whether such information might also be essential for spatial behavior, we tested adult, male Lister Hooded rats that had received either bilateral lateral mammillary nuclei (LMN) lesions or sham lesions on a four-way, conditional odor-location discrimination in compartments arranged at 60° to one another. We found that significantly fewer rats in the LMN lesion group were able to learn the task compared to the Sham group. We also found that the extent of the behavioral impairment was highly correlated with the degree of tissue loss in the LMN resulting from the lesion. Animals with LMN lesions were also impaired in a nonmatching-to-sample task in a T maze, and the extent of impairment likewise depended on the extent of the lesion. Performance in the odor-location and T-maze tasks was not affected by tissue loss in the medial mammillary nuclei. Together, these results indicate that the LMN, a key node in the head direction circuit, is critical for solving a spatial task that requires a directional discrimination. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

A new perspective on the head direction cell system and spatial behavior.

The head direction cell system is an interconnected set of brain structures containing neurons whose firing is directionally tuned. The robust representation of allocentric direction by head direction cells suggests that they provide a neural compass for the animal. However, evidence linking head direction cells and spatial behavior has been mixed. Whereas damage to the hippocampus yields profound deficits in a range of spatial tasks, lesions to the head direction cell system often yield milder impairments in spatial behavior. In addition, correlational approaches have shown a correspondence between head direction cells and spatial behavior in some tasks, but not others. These mixed effects may be explained in part by a new view of the head direction cell system arising from recent demonstrations of at least two types of head direction cells: 'traditional' cells, and a second class of 'sensory' cells driven by polarising features of an environment. The recognition of different kinds of head direction cells now allows a nuanced assessment of this system's role in guiding navigation.

Sustained correction of associative learning deficits after brief, early treatment in a rat model of Fragile X Syndrome.

Fragile X Syndrome (FXS) is one of the most common monogenic forms of autism and intellectual disability. Preclinical studies in animal models have highlighted the potential of pharmaceutical intervention strategies for alleviating the symptoms of FXS. However, whether treatment strategies can be tailored to developmental time windows that define the emergence of particular phenotypes is unknown. Similarly, whether a brief, early intervention can have long-lasting beneficial effects, even after treatment cessation, is also unknown. To address these questions, we first examined the developmental profile for the acquisition of associative learning in a rat model of FXS. Associative memory was tested using a range of behavioral paradigms that rely on an animal's innate tendency to explore novelty. Fmr1 knockout (KO) rats showed a developmental delay in their acquisition of object-place recognition and did not demonstrate object-place-context recognition paradigm at any age tested (up to 23 weeks of age). Treatment of Fmr1 KO rats with lovastatin between 5 and 9 weeks of age, during the normal developmental period that this associative memory capability is established, prevents the emergence of deficits but has no effect in wild-type animals. Moreover, we observe no regression of cognitive performance in the FXS rats over several months after treatment. This restoration of the normal developmental trajectory of cognitive function is associated with the sustained rescue of both synaptic plasticity and altered protein synthesis. The findings provide proof of concept that the impaired emergence of the cognitive repertoire in neurodevelopmental disorders may be prevented by brief, early pharmacological intervention.

Stellate Cells in the Medial Entorhinal Cortex Are Required for Spatial Learning.

Spatial learning requires estimates of location that may be obtained by path integration or from positional cues. Grid and other spatial firing patterns of neurons in the superficial medial entorhinal cortex (MEC) suggest roles in behavioral estimation of location. However, distinguishing the contributions of path integration and cue-based signals to spatial behaviors is challenging, and the roles of identified MEC neurons are unclear. We use virtual reality to dissociate linear path integration from other strategies for behavioral estimation of location. We find that mice learn to path integrate using motor-related self-motion signals, with accuracy that decreases steeply as a function of distance. We show that inactivation of stellate cells in superficial MEC impairs spatial learning in virtual reality and in a real world object location recognition task. Our results quantify contributions of path integration to behavior and corroborate key predictions of models in which stellate cells contribute to location estimation.

Lesions of the Head Direction Cell System Increase Hippocampal Place Field Repetition.

A central tenet of systems neuroscience is that the mammalian hippocampus provides a cognitive map of the environment. This view is supported by the finding of place cells, neurons whose firing is tuned to specific locations in an animal's environment, within this brain region. Recent work, however, has shown that these cells repeat their firing fields across visually identical maze compartments [1, 2]. This repetition is not observed if these compartments face different directions, suggesting that place cells use a directional input to differentiate otherwise similar local environments [3, 4]. A clear candidate for this input is the head direction cell system. To test this, we disrupted the head direction cell system by lesioning the lateral mammillary nuclei and then recorded place cells as rats explored multiple, connected compartments, oriented in the same or in different directions. As shown previously, we found that place cells in control animals exhibited repeated fields in compartments arranged in parallel, but not in compartments facing different directions. In contrast, the place cells of animals with lesions of the head direction cell system exhibited repeating fields in both conditions. Thus, directional information provided by the head direction cell system appears essential for the angular disambiguation by place cells of visually identical compartments.

Field repetition and local mapping in the hippocampus and the medial entorhinal cortex.

Hippocampal place cells support spatial cognition and are thought to form the neural substrate of a global "cognitive map." A widely held view is that parts of the hippocampus also underlie the ability to separate patterns or to provide different neural codes for distinct environments. However, a number of studies have shown that in environments composed of multiple, repeating compartments, place cells and other spatially modulated neurons show the same activity in each local area. This repetition of firing fields may reflect pattern completion and may make it difficult for animals to distinguish similar local environments. In this review we 1) highlight some of the navigation difficulties encountered by humans in repetitive environments, 2) summarize literature demonstrating that place and grid cells represent local and not global space, and 3) attempt to explain the origin of these phenomena. We argue that the repetition of firing fields can be a useful tool for understanding the relationship between grid cells in the entorhinal cortex and place cells in the hippocampus, the spatial inputs shared by these cells, and the propagation of spatially related signals through these structures.

Place cells on a maze encode routes rather than destinations.

Hippocampal place cells fire at different rates when a rodent runs through a given location on its way to different destinations. However, it is unclear whether such firing represents the animal's intended destination or the execution of a specific trajectory. To distinguish between these possibilities, Lister Hooded rats (n = 8) were trained to navigate from a start box to three goal locations via four partially overlapping routes. Two of these led to the same goal location. Of the cells that fired on these two routes, 95.8% showed route-dependent firing (firing on only one route), whereas only two cells (4.2%) showed goal-dependent firing (firing similarly on both routes). In addition, route-dependent place cells over-represented the less discriminable routes, and place cells in general over-represented the start location. These results indicate that place cell firing on overlapping routes reflects the animal's route, not its goals, and that this firing may aid spatial discrimination.

How does the brain represent the outside world? One way of answering this question is to study the brains of rats, because the basic plan of a rodent's brain is similar to that of other mammals, such as humans. For example, the brains of rodents and humans both contain a structure called the hippocampus, which plays important roles in navigation and spatial memory. Cells within the hippocampus called place cells support these processes by firing electrical impulses whenever the animal occupies a specific location. When a rat runs along a corridor in a maze, its place cells often fire as it approaches a choice point. A given place cell will typically fire before the rat chooses a path leading towards one particular location, but not before choices that lead to other locations. The firing that occurs prior to the choice point is termed "prospective firing". However, it is not known whether the prospective firing of place cells represents the rat's final destination, or the specific route the animal takes to get there. To address this question, Grieves et al. designed a maze in which two different paths from a starting corridor led to the same goal location. If place cells represent the goal location, they should fire whichever route the rat chooses. However, if they represent the specific path the rat takes to the goal, they should fire on one or the other route, but not both. Grieves et al. found that almost all place cells with prospective activity in the starting corridor fired on a single route, as opposed to firing on both routes to the common goal. This suggests that the prospective firing in the hippocampus reflects the route the animal will take, rather than its intended destination. A future challenge will be to understand how the way the hippocampus codes routes interacts with brain circuits that code for intended goals, and how the activity of these circuits influences the animal's ability to navigate.

Place field repetition and spatial learning in a multicompartment environment.

Recent studies have shown that place cells in the hippocampus possess firing fields that repeat in physically similar, parallel environments. These results imply that it should be difficult for animals to distinguish parallel environments at a behavioral level. To test this, we trained rats on a novel odor-location task in an environment with four parallel compartments which had previously been shown to yield place field repetition. A second group of animals was trained on the same task, but with the compartments arranged in different directions, an arrangement we hypothesised would yield less place field repetition. Learning of the odor-location task in the parallel compartments was significantly impaired relative to learning in the radially arranged compartments. Fewer animals acquired the full discrimination in the parallel compartments compared to those trained in the radial compartments, and the former also required many more sessions to reach criterion compared to the latter. To confirm that the arrangement of compartments yielded differences in place cell repetition, in a separate group of animals we recorded from CA1 place cells in both environments. We found that CA1 place cells exhibited repeated fields across four parallel local compartments, but did not do so when the same compartments were arranged radially. To confirm that the differences in place field repetition across the parallel and radial compartments depended on their angular arrangement, and not incidental differences in access to an extra-maze visual landmark, we repeated the recordings in a second set of rats in the absence of the orientation landmark. We found, once again, that place fields showed repetition in parallel compartments, and did not do so in radially arranged compartments. Thus place field repetition, or lack thereof, in these compartments was not dependent on extra-maze cues. Together, these results imply that place field repetition constrains spatial learning.

The head direction cell system and behavior: The effects of lesions to the lateral mammillary bodies on spatial memory in a novel landmark task and in the water maze.

The head direction system is composed of neurons found in a number of connected brain areas that fire in a sharply tuned, directional way. The function of this system, however, has not been fully established. To assess this, we devised a novel spatial landmark task, comparable to the paradigms in which stimulus control has been assessed for spatially tuned neurons. The task took place in a large cylinder and required rats to dig in a specific sand cup, from among 16 alternatives, to obtain a food reward. The reinforced cup was in a fixed location relative to a salient landmark, and probe sessions confirmed that the landmark exerted stimulus control over the rats' cup choices. To assess the contribution of the head direction cell system to this memory task, half of the animals received ibotenic acid infusions into the lateral mammillary nuclei (LMN), an essential node in the head direction network, while the other received sham lesions. No differences were observed in performance of this task between the 2 groups. Animals with LMN lesions were impaired, however, in reversal learning on a water maze task. These results suggest that the LMN, and potentially the head direction cell system, are not essential for the use of visual landmarks to guide spatial behavior.