The dentate gyrus (DG) of the mammalian hippocampus is hypothesized to mediate pattern separation--the formation of distinct and orthogonal representations of mnemonic information--and also undergoes ...neurogenesis throughout life. How neurogenesis contributes to hippocampal function is largely unknown. Using adult mice in which hippocampal neurogenesis was ablated, we found specific impairments in spatial discrimination with two behavioral assays: (i) a spatial navigation radial arm maze task and (ii) a spatial, but non-navigable, task in the mouse touch screen. Mice with ablated neurogenesis were impaired when stimuli were presented with little spatial separation, but not when stimuli were more widely separated in space. Thus, newborn neurons may be necessary for normal pattern separation function in the DG of adult mice.
The Mini‐RF radar instrument on the Lunar Reconnaissance Orbiter spacecraft mapped both lunar poles in two different RF wavelengths (complete mapping at 12.6 cm S‐band and partial mapping at 4.2 cm ...X‐band) in two look directions, removing much of the ambiguity of previous Earth‐ and spacecraft‐based radar mapping of the Moon's polar regions. The poles are typical highland terrain, showing expected values of radar cross section (albedo) and circular polarization ratio (CPR). Most fresh craters display high values of CPR in and outside the crater rim; the pattern of these CPR distributions is consistent with high levels of wavelength‐scale surface roughness associated with the presence of block fields, impact melt flows, and fallback breccia. A different class of polar crater exhibits high CPR only in their interiors, interiors that are both permanently dark and very cold (less than 100 K). Application of scattering models developed previously suggests that these anomalously high‐CPR deposits exhibit behavior consistent with the presence of water ice. If this interpretation is correct, then both poles may contain several hundred million tons of water in the form of relatively “clean” ice, all within the upper couple of meters of the lunar surface. The existence of significant water ice deposits enables both long‐term human habitation of the Moon and the creation of a permanent cislunar space transportation system based upon the harvest and use of lunar propellant.
Key Points
The Mini‐RF on LRO mapped the polar regions of the Moon
Dark craters near the lunar poles contain water ice
Mini‐RF radar measures surface properties on the Moon
Rationale
Spontaneous (novel) object recognition (SOR) is one of the most widely used rodent behavioural tests. The opportunity for rapid data collection has made SOR a popular choice in studies that ...explore cognitive impairment in rodent models of schizophrenia, and that test the efficacy of drugs intended to reverse these deficits.
Objectives
We provide an overview of the many recent studies that have used SOR to explore the mnemonic effects of manipulation of the key transmitter systems relevant to schizophrenia—the dopamine, glutamate, GABA, acetylcholine, serotonin and cannabinoid systems—alone or in combination. We also review the use of SOR in studying memory in genetically modified mouse models of schizophrenia, as well as in neurodevelopmental and lesion models. We end by discussing the construct and predictive validity, and translational relevance, of SOR with respect to cognitive impairment in schizophrenia.
Results
Perturbation of the dopamine or glutamate systems can generate robust and reliable impairment in SOR. Impaired performance is also seen following antagonism of the muscarinic acetylcholine system, or exposure to cannabinoid agonists. Cognitive enhancement has been reported using alpha7-nicotinic acetylcholine receptor agonists and 5-HT
6
antagonists. Among non-pharmacological models, neonatal ventral hippocampal lesions and maternal immune activation can impair SOR, while mixed results have been obtained with mice carrying mutations in schizophrenia risk-associated genes, including neuregulin and COMT.
Conclusions
While SOR is not without its limitations, the task represents a useful method for studying manipulations with relevance to cognitive impairment in schizophrenia, as well as the interactions between them.
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.
We describe a touchscreen method that satisfies a proposed ‘wish-list’ of desirables for a cognitive testing method for assessing rodent models of schizophrenia. A number of tests relevant to ...schizophrenia research are described which are currently being developed and validated using this method. These tests can be used to study reward learning, memory, perceptual discrimination, object-place associative learning, attention, impulsivity, compulsivity, extinction, simple Pavlovian conditioning, and other constructs. The tests can be deployed using a ‘flexible battery’ approach to establish a cognitive profile for a particular mouse or rat model. We have found these tests to be capable of detecting not just impairments in function, but enhancements as well, which is essential for testing putative cognitive therapies. New tests are being continuously developed, many of which may prove particularly valuable for schizophrenia research.
This article is part of a Special Issue entitled ‘Schizophrenia’.
► We describe a touchscreen method for assaying cognition in rodent models. ► A number of tests relevant to schizophrenia research are described. ► The tests can be used to study multiple aspects of cognition. ► The tests can be combined in a flexible battery to establish a cognitive profile. ► The tests are capable of detecting both impairments and enhancements in function.
According to the 'mental time travel hypothesis' animals, unlike humans, cannot mentally travel backwards in time to recollect specific past events (episodic memory) or forwards to anticipate future ...needs (future planning). Until recently, there was little evidence in animals for either ability. Experiments on memory in food-caching birds, however, question this assumption by showing that western scrub-jays form integrated, flexible, trial-unique memories of what they hid, where and when. Moreover, these birds can adjust their caching behaviour in anticipation of future needs. We suggest that some animals have elements of both episodic-like memory and future planning.
► TUNL can be used to study spatial working memory or spatial pattern separation. ► TUNL likely has fewer mediating strategies then other DNMTP tasks. ► TUNL is highly sensitive to the ...delay-dependent effects of hippocampal lesions.
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.
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.
•PS may be fundamental to many aspects of cognition including perception.•PS might be thought to happen in many regions, not just the hippocampus.•The DG is unlikely to be a truly domain-general ...pattern separator.•PS may have much wider explanatory power than previously suspected.
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.
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.
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