The representational-hierarchical view of pattern separation: Not just hippocampus, not just space, not just memory?

Pattern separation (PS) has been defined as a process of reducing overlap between similar input patterns to minimize interference amongst stored representations. The present article describes this putative PS process from the "representational-hierarchical" perspective (R-H), which uses a hierarchical continuum instead of a cognitive modular processing framework to describe the organization of the ventral visual perirhinal-hippocampal processing stream. Instead of trying to map psychological constructs onto anatomical modules in the brain, the R-H model suggests that the function of brain regions depends upon what representations they contain. We begin by discussing a main principle of the R-H framework, the resolution of "ambiguity" of lower level representations via the formation of unique conjunctive representations in higher level areas, and how this process is remarkably similar to definitions of PS. Work from several species and experimental approaches suggest that this principle of resolution of ambiguity via conjunctive representations has considerable explanatory power, leads to wide possibilities for experimentation, and also supports some perhaps surprising conclusions.

Trial-unique, delayed nonmatching-to-location (TUNL): a novel, highly hippocampus-dependent automated touchscreen test of location memory and pattern separation.

The hippocampus is known to be important for learning and memory, and is implicated in many neurodegenerative diseases. Accordingly many animal models of learning and memory focus on hippocampus-dependent tests of location learning and memory. These tests often use dry mazes or water mazes; however automated testing in operant chambers confers many advantages over such methods. Some automated tests of location memory, such as delayed nonmatching-to-position (DNMTP) have, however, fallen out of favor following the discovery that such tasks can be solved using mediating behaviors that can bridge the delay and reduce the requirement for memory per se. Furthermore some researchers report that DNMTP performance may not always require the hippocampus. Thus, in an attempt to develop a highly hippocampus-dependent automated test of location memory that elicits fewer mediating behaviors, we have developed a trial-unique nonmatching-to-location (TUNL) task, carried out in a computer-automated touchscreen testing apparatus. To test the efficacy of this assay, rats with lesions to the hippocampus, or a sham lesion control group, were tested under a variety of conditions. Both groups were able to perform well at a delay of 1s, but the lesion group was highly impaired when tested at a 6s delay. Moreover, animals with lesions of the hippocampus showed a greater impairment when the distance between the locations was reduced. This result indicates that TUNL can be used to investigate both memory across a delay, and spatial pattern separation (the ability to disambiguate similar spatial locations). Performance-enhancing mediating behaviors during the task were found to be minimal. Thus, the TUNL task has the potential to serve as a powerful tool for the study of the neurobiology of learning and memory.

Functional dissociations between subregions of the medial prefrontal cortex on the rodent touchscreen continuous performance test (rCPT) of attention.

Converging evidence in humans, monkeys, and rodents suggests a functional dissociation of cognitive function along the dorso-ventral axis of the prefrontal cortex (PFC). Previous studies of attention suggest that the anterior cingulate cortex (ACC) plays a role in target detection, whereas the prelimbic (PL) cortex is important for tests requiring the combined detection and discrimination of signals. We investigated the effect of discrete, quinolinic acid-induced lesions of subregions of the rat medial PFC (mPFC)-ACC, PL cortex, and infralimbic (IL) cortex-on attentional performance on the recently developed rodent touchscreen continuous performance test (rCPT). Rats were tested under a range of behavioral conditions involving stimulus duration (SD), flanker distraction, temporal predictability, and event rate. Rats with lesions of the PL cortex demonstrated the most persistent attentional impairment under conditions of reduced and variable SD and high event rate (lower discrimination sensitivity [d'] and hit rate), and flanker distraction (lower hit rate). Rats with lesions of the ACC exhibited a profound but transient attentional impairment (lower d' and hit rate) in the early stages of behavioral testing, which ameliorated with repeated testing. Rats with lesions of the IL cortex showed no impairments on response control measures. The PL cortex plays a greater role than the ACC in the detection and discrimination of a complex visual stimulus among multiple nontarget stimuli in the rCPT. The findings support evidence for a functional dissociation of attentional performance along the dorso-ventral axis of the mPFC. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Hippocampal lesions in rats impair learning and memory for locations on a touch-sensitive computer screen: the "ASAT" task.

It has been repeatedly demonstrated across species that the hippocampus is critical for spatial learning and memory. Consequently, numerous paradigms have been created to study spatial learning in the rodent. Most of these tasks, such as the Morris water maze, 8-arm radial maze, and T-maze, are non-automated procedures. It was our goal to create an automated task in the rodent that is quickly learned, hippocampal-dependent, and minimizes the confounding variables present in most tests measuring hippocampal-dependent learning and memory. To accomplish this, we created a novel search task using a standard operant box fitted with a touch-sensitive computer monitor. Subjects were required to locate an S+ "hidden" amongst other identical stimuli on the monitor. In two versions of the task the S+ stayed in the same location within a session but shifted location between sessions. In a third version of the task the S+ was moved to a new location after every 10 trials. It was found that the location of the S+ was quickly acquired each day (within 10 trials), and that the hippocampal-lesion group was impaired when compared to their control cohort. With the benefits inherent in automation, these tasks confer significant advantages over traditional tasks used to study spatial learning and memory in the rodent. When combined with previously developed non-spatial cognitive tests that can also be run in the touch-screen apparatus, the result is a powerful cognitive test battery for the rodent.

Cognitive Translation Using the Rodent Touchscreen Testing Approach.

The development of novel therapeutic avenues for the treatment of cognitive deficits in psychiatric and neurodegenerative disease is of high importance, yet progress in this field has been slow. One reason for this lack of success may lie in discrepancies between how cognitive functions are assessed in experimental animals and humans. In an attempt to bridge this translational gap, the rodent touchscreen testing platform is suggested as a translational tool. Specific examples of successful cross-species translation are discussed focusing on paired associate learning (PAL), the 5-choice serial reaction time task (5-CSRTT), the rodent continuous performance task (rCPT) and reversal learning. With ongoing research assessing the neurocognitive validity of tasks, the touchscreen approach is likely to become increasingly prevalent in translational cognitive research.

Comparing the effects of subchronic phencyclidine and medial prefrontal cortex dysfunction on cognitive tests relevant to schizophrenia.

RATIONALE: It is becoming increasingly clear that the development of treatments for cognitive symptoms of schizophrenia requires urgent attention, and that valid animal models of relevant impairments are required. With subchronic psychotomimetic agent phencyclidine (scPCP), a putative model of such impairment, the extent to which changes following scPCP do or do not resemble those following dysfunction of the prefrontal cortex is of importance. OBJECTIVES: The present study carried out a comparison of the most common scPCP dosing regimen with excitotoxin-induced medial prefrontal cortex (mPFC) dysfunction in rats, across several cognitive tests relevant to schizophrenia. METHODS: ScPCP subjects were dosed intraperitoneal with 5 mg/kg PCP or vehicle twice daily for 1 week followed by 1 week washout prior to behavioural testing. mPFC dysfunction was induced via fibre-sparing excitotoxin infused into the pre-limbic and infralimbic cortex. Subjects were tested on spontaneous novel object recognition, touchscreen object-location paired-associates learning and touchscreen reversal learning. RESULTS: A double-dissociation was observed between object-location paired-associates learning and object recognition: mPFC dysfunction impaired acquisition of the object-location task but not spontaneous novel object recognition, while scPCP impaired spontaneous novel object recognition but not object-location associative learning. Both scPCP and mPFC dysfunction resulted in a similar facilitation of reversal learning. CONCLUSIONS: The pattern of impairment following scPCP raises questions around its efficacy as a model of cognitive impairment in schizophrenia, particularly if importance is placed on faithfully replicating the effects of mPFC dysfunction.

Bridging the translational divide: identical cognitive touchscreen testing in mice and humans carrying mutations in a disease-relevant homologous gene.

Development of effective therapies for brain disorders has been hampered by a lack of translational cognitive testing methods. We present the first example of using the identical touchscreen-based cognitive test to assess mice and humans carrying disease-related genetic mutations. This new paradigm has significant implications for improving how we measure and model cognitive dysfunction in human disorders in animals, thus bridging the gap towards effective translation to the clinic.

A novel 2- and 3-choice touchscreen-based continuous trial-unique nonmatching-to-location task (cTUNL) sensitive to functional differences between dentate gyrus and CA3 subregions of the hippocampus.

RATIONALE: The touchscreen continuous trial-unique non-matching-to-location task (cTUNL) has been developed to optimise a battery of tasks under NEWMEDS (Novel Methods leading to New Medication in Depression and Schizophrenia, http://www.newmeds-europe.com ). It offers novel task features of both a practical and a theoretical nature compared to existing touchscreen tasks for spatial working memory. OBJECTIVES: The objective of this study was to determine whether the cTUNL task is sufficiently sensitive to differentiate between dentate gyrus (DG) and CA3 hippocampal subregion contributions to performance. METHODS: The effect of DG and CA3 dysfunction on memory for locations in the cTUNL task was tested. Rats were assessed on versions of the task-two-choice and three-choice-that differed in memory load. Performance was challenged using manipulations of delay and the spatial separation between target and sample locations. RESULTS: Dysfunction of the DG disrupts performance across both delay and spatial separations in two-choice cTUNL when the delay is variable and unpredictable. Increasing the working memory load (three stimuli) increases sensitivity to DG dysfunction, with deficits apparent at fixed, short delays. In contrast, CA3 dysfunction did not disrupt performance. CONCLUSION: Acquisition of cTUNL was rapid, and the task was sensitive to manipulations of delays and separations. A three-choice version of the task was found to be viable. Finally, both the two- and three-choice versions of the task were able to differentiate between limited dysfunction to different areas within the hippocampus. DG dysfunction affected performance when using unpredictable task parameters. CA3 dysfunction did not result in impairment, even at the longest delays tested.

The NEWMEDS rodent touchscreen test battery for cognition relevant to schizophrenia.

RATIONALE: The NEWMEDS initiative (Novel Methods leading to New Medications in Depression and Schizophrenia, http://www.newmeds-europe.com ) is a large industrial-academic collaborative project aimed at developing new methods for drug discovery for schizophrenia. As part of this project, Work package 2 (WP02) has developed and validated a comprehensive battery of novel touchscreen tasks for rats and mice for assessing cognitive domains relevant to schizophrenia. OBJECTIVES: This article provides a review of the touchscreen battery of tasks for rats and mice for assessing cognitive domains relevant to schizophrenia and highlights validation data presented in several primary articles in this issue and elsewhere. METHODS: The battery consists of the five-choice serial reaction time task and a novel rodent continuous performance task for measuring attention, a three-stimulus visual reversal and the serial visual reversal task for measuring cognitive flexibility, novel non-matching to sample-based tasks for measuring spatial working memory and paired-associates learning for measuring long-term memory. RESULTS: The rodent (i.e. both rats and mice) touchscreen operant chamber and battery has high translational value across species due to its emphasis on construct as well as face validity. In addition, it offers cognitive profiling of models of diseases with cognitive symptoms (not limited to schizophrenia) through a battery approach, whereby multiple cognitive constructs can be measured using the same apparatus, enabling comparisons of performance across tasks. CONCLUSION: This battery of tests constitutes an extensive tool package for both model characterisation and pre-clinical drug discovery.

Facilitation of spatial working memory performance following intra-prefrontal cortical administration of the adrenergic alpha1 agonist phenylephrine.

RATIONALE: Spatial working memory is dependent on the appropriate functioning of the prefrontal cortex (PFC). PFC activity can be modulated by noradrenaline (NA) released by afferent projections from the locus coeruleus. The coreuleo-cortical NA system could therefore be a target for cognitive enhancers of spatial working memory. Of the three classes of NA receptor potentially involved, the α2 and α1 classes seem most significant, though agents targeting these receptors have yielded mixed results. This may be partially due to the use of behavioural assays that do not translate effectively from the laboratory to the clinical setting. Use of a paradigm with improved translational potential may be essential to resolve these discrepancies. OBJECTIVES: The objective of this study was to assess the effects of PFC-infused α2 and α1 adrenergic receptor agonists on spatial working memory performance in the touchscreen continuous trial-unique non-matching to location (cTUNL) task in rats. METHODS: Young male rats were trained in the cTUNL paradigm. Cannulation of the mPFC allowed direct administration of GABA agonists for task validation, and phenylephrine and guanfacine to determine the effects of adrenergic agonists on task performance. RESULTS: Infusion of muscimol and baclofen resulted in a delay-dependent impairment. Administration of the α2 agonist guanfacine had no effect, whilst infusion of the α1 agonist phenylephrine significantly improved working memory performance. CONCLUSIONS: Spatial working memory as measured in the rat cTUNL task is dependent on the mPFC. Enhancement of noradrenergic signalling enhanced performance in this paradigm, suggesting a significant role for the α1 receptor in this facilitation.

Calpain inhibition mediates autophagy-dependent protection against polyglutamine toxicity.

Over recent years, accumulated evidence suggests that autophagy induction is protective in animal models of a number of neurodegenerative diseases. Intense research in the field has elucidated different pathways through which autophagy can be upregulated and it is important to establish how modulation of these pathways impacts upon disease progression in vivo and therefore which, if any, may have further therapeutic relevance. In addition, it is important to understand how alterations in these target pathways may affect normal physiology when constitutively modulated over a long time period, as would be required for treatment of neurodegenerative diseases. Here we evaluate the potential protective effect of downregulation of calpains. We demonstrate, in Drosophila, that calpain knockdown protects against the aggregation and toxicity of proteins, like mutant huntingtin, in an autophagy-dependent fashion. Furthermore, we demonstrate that, overexpression of the calpain inhibitor, calpastatin, increases autophagosome levels and is protective in a mouse model of Huntington's disease, improving motor signs and delaying the onset of tremors. Importantly, long-term inhibition of calpains did not result in any overt deleterious phenotypes in mice. Thus, calpain inhibition, or activation of autophagy pathways downstream of calpains, may be suitable therapeutic targets for diseases like Huntington's disease.

Dissociable effects of cingulate and medial frontal cortex lesions on stimulus-reward learning using a novel Pavlovian autoshaping procedure for the rat: implications for the neurobiology of emotion.

The effects of quinolinic acid-induced lesions of the anterior cingulate, posterior cingulate, and medial frontal cortices on stimulus-reward learning were investigated with a novel Pavlovian autoshaping procedure in an apparatus allowing the automated presentation of computer-graphic stimuli to rats (T. J. Bussey, J. L. Muir, & T. W. Robbins, 1994). White vertical rectangles were presented on the left or the right of a computer screen. One of these conditioned stimuli (the CS+) was always followed by the presentation of a sucrose pellet; the other, the CS-, was never followed by reward. With training, rats came to approach the CS+ more often than the CS-. Anterior cingulate cortex-lesioned rats failed to demonstrate normal discriminated approach, making significantly more approaches to the CS- than did sham-operated controls. Medial frontal cortex-lesioned rats acquired the task normally but had longer overall approach latencies. Posterior cingulate cortex lesions did not affect acquisition.

Discrimination of computer-graphic stimuli by mice: a method for the behavioral characterization of transgenic and gene-knockout models.

An automated method is described for the behavioral testing of mice in an apparatus that allows computer-graphic stimulus material to be presented. Mice responded to these stimuli by making a nose-poke toward a computer monitor that was equipped with a touchscreen attachment for detecting responses. It was found that C57BL/6 mice were able to solve single-pair visual discriminations as well as 3-pair concurrent visual discriminations. The finding that mice are capable of complex visual discriminations introduces the possibility of testing mice on nonspatial tasks that are similar to those used with rats, monkeys, and humans. Furthermore, the method seems particularly well suited to the comprehensive behavioral assessment of transgenic and gene-knockout models.

The role of ventral and orbital prefrontal cortex in conditional visuomotor learning and strategy use in rhesus monkeys (Macaca mulatta).

Four rhesus monkeys (Macaca mulatta) were trained to learn novel sets of visuomotor associations in 50 trials or less, within single test sessions. After bilateral ablation of the orbital and ventral prefrontal cortex, the monkeys lost the ability to learn these associations within a session, although they could learn them when given several daily sessions. Thus, relatively slow, across-session visuomotor learning depends on neither the ventral nor orbital prefrontal cortex, but rapid, within-session learning does. The ablations also eliminated at least 2 response strategies, repeat-stay and lose-shift, which might account, in part, for the deficit in rapid learning. The deficit is unlikely to result from a failure of visual discriminative ability or working memory: The monkeys could discriminate similar stimulus material within a session, and reducing the working memory load did not improve within-session learning.

Triple dissociation of anterior cingulate, posterior cingulate, and medial frontal cortices on visual discrimination tasks using a touchscreen testing procedure for the rat.

Four experiments examined effects of quinolinic acid-induced lesions of the anterior cingulate, posterior cingulate, and medial frontal cortices on tests of visual discrimination learning, using a new "touchscreen" testing method for rats. Anterior cingulate cortex lesions impaired acquisition of an 8-pair concurrent discrimination task, whereas posterior cingulate cortex lesions facilitated learning but selectively impaired the late stages of acquisition of a visuospatial conditional discrimination. Medial frontal cortex lesions selectively impaired reversal learning when stimuli were difficult to discriminate; lesions of anterior and posterior cingulate cortex had no effect. These results suggest roles for the anterior cingulate, posterior cingulate, and medial frontal cortex in stimulus-reward learning, stimulus-response learning or response generation, and attention during learning, respectively.

Perirhinal cortex and place-object conditional learning in the rat.

The present study examined whether excitotoxic lesions of the perirhinal cortex can affect acquisition of a place-object conditional task in which object and spatial information must be integrated. Testing was carried out in a double Y-maze apparatus, in which rats learned a conditional rule of the type, "In Place X, choose Object A, not Object B (A+ vs. B-); in Place Y, choose Object B, not Object A (A- vs. B+)." Perirhinal cortex lesions significantly impaired acquisition of this task while sparing performance of an allocentric spatial memory task performed in a radial arm maze. Perirhinal cortex lesions also had no apparent effect on a 1-pair object discrimination task performed in the double Y maze or on retention and acquisition of 4-pair concurrent discrimination problems performed in a computer-automated touch screen testing apparatus. The results suggest that, although the perirhinal cortex and hippocampus can be functionally dissociated, their normal mode of operation includes the integration of object and spatial information.

The parahippocampal region and object identification.

The hippocampus has long been thought to be critical for memory, including memory for objects. However, recent neuropsychological studies in nonhuman primates have indicated that other regions within the medial temporal lobe, specifically, structures in the parahippocampal region, are primarily responsible for object recognition and object identification. This article reviews the behavioral effects of removal of structures within the parahippocampal region in monkeys, and cites relevant work in rodents as well. It is argued that the perirhinal cortex, in particular, contributes to object identification in at least two ways: (i) by serving as the final stage in the ventral visual cortical pathway that represents stimulus features, and (ii) by operating as part of a network for associating together sensory inputs within and across sensory modalities.

A glycine antagonist 7-chlorokynurenic acid attenuates ischemia-induced learning deficits.

Transient global ischemia can result in permanent neuronal damage and impairments in learning and memory. We investigated the therapeutic potential of 7-Chlorokynurenic acid, a potent antagonist at the glycine-modulatory site on the NMDA receptor, in terms of both neuroprotection and behavioral outcome in rats following transient forebrain ischemia. Intraventricular administration of the drug immediately before ischemia significantly attenuated ischemia-induced CA1 pyramidal cell loss. Moreover, ischemic rats treated with 7-Chlorokynurenic acid showed unimpaired acquisition of a delayed nonmatching to sample task 8 weeks following surgery, whereas saline-treated ischemic rats were significantly impaired. These data provide preliminary evidence that the glycine site may be an appropriate target for therapeutic agents in ischemia.

Distinct patterns of behavioural impairments resulting from fornix transection or neurotoxic lesions of the perirhinal and postrhinal cortices in the rat.

The present study provides evidence that lesions of the fornix (FNX) and of the perirhinal/postrhinal cortex (PPRH), which both disconnect the hippocampus from other brain regions, can lead to distinct patterns of behavioural impairments on tests of spatial memory and spontaneous object recognition. For example, whereas FNX lesions impaired allocentric spatial delayed alternation in a T-maze but generally spared a test of spontaneous object recognition, PPRH lesions produced the opposite pattern of results. Indeed, on the T-maze task PPRH animals significantly outperformed controls when the retention delay was increased to 60 s. In addition, some evidence was found that contributions from both the fornix and perirhinal/postrhinal cortex may be required when object and spatial information must be integrated. In an object-in-place test, for example, PPRH animals failed according to two measures, and FNX animals failed according to one measure, to discriminate objects that had remained in fixed locations from those that had exchanged locations with other objects. Neither lesion, however, affected performance of a visuospatial conditional task, a Pavlovian autoshaping task, or a one-pair pattern discrimination task. It is suggested that the perirhinal/postrhinal cortex, rather than being specialised for a particular type of associative learning, is important for processing complex visual stimuli.

Dissociable effects of anterior and posterior cingulate cortex lesions on the acquisition of a conditional visual discrimination: facilitation of early learning vs. impairment of late learning.

Two experiments investigated the effects of quinolinic acid induced lesions of the anterior and posterior cingulate cortices on the acquisition and performance of a conditional visual discrimination (CVD) task, in which rats were required to learn a rule of the type: "If lights are flashing FAST, press the right lever; if SLOW press left". In Experiment 1, animals with lesions of the anterior cingulate cortex (ANT group) demonstrated a significant enhancement in learning during the early stages of task acquisition. Conversely, animals with lesions of the posterior cingulate cortex (POS group) were impaired in learning during the later stages of acquisition. There were no significant differences between the ANT and POS groups on the performance of the task when either variable inter-trial intervals or reduced stimulus durations were imposed. In Experiment 2, the specificity of the lesion effects for processes operative during the early and late stages of learning was tested. Animals were trained to a criterion of 70% correct choices on two consecutive sessions prior to lesioning, and subsequently allowed to continue to acquire the task to the mean asymptotic performance level of 85% correct choices on two consecutive sessions. Animals of the POS group were impaired in learning during this later stage of task acquisition, thus replicating the pattern of results obtained in Experiment 1. The animals in Experiment 2 were then tested following a 30-day retention interval and during extinction (removal of sucrose from the magazine). The extinction test revealed an impairment in the ability of animals in the ANT group to omit lever responses in the absence of reinforcement. These results indicate that the anterior and posterior cingulate cortices are functionally dissociable, and suggest that they may form part of complementary, but competing, learning and memory systems.