Effects of Subchronic Phencyclidine (PCP) Treatment on Social Behaviors, and Operant Discrimination and Reversal Learning in C57BL/6J Mice

Subchronic treatment with the psychotomimetic phencyclidine (PCP) has been proposed as a rodent model of the negative and cognitive/executive symptoms of schizophrenia. There has, however, been a paucity of studies on this model in mice, despite the growing use of the mouse as a subject in genetic and molecular studies of schizophrenia. In the present study, we evaluated the effects of subchronic PCP treatment (5 mg/kg twice daily × 7 days, followed by 7 days withdrawal) in C57BL/6J mice on (1) social behaviors using a sociability/social novelty-preference paradigm, and (2) pairwise visual discrimination and reversal learning using a touchscreen-based operant system. Results showed that mice subchronically treated with PCP made more visits to (but did not spend more time with) a social stimulus relative to an inanimate one, and made more visits and spent more time investigating a novel social stimulus over a familiar one. Subchronic PCP treatment did not significantly affect behavior in either the discrimination or reversal learning tasks. These data encourage further analysis of the potential utility of mouse subchronic PCP treatment for modeling the social withdrawal component of schizophrenia. They also indicate that the treatment regimen employed was insufficient to impair our measures of discrimination and reversal learning in the C57BL/6J strain. Further work will be needed to identify alternative methods (e.g., repeated cycles of subchronic PCP treatment, use of different mouse strains) that reliably produce discrimination and/or reversal impairment, as well as other cognitive/executive measures that are sensitive to chronic PCP treatment in mice

QCD Physics with ZEUS and H1 at HERA

A review is presented of recent results in QCD from the H1 and ZEUS experiments at HERA, emphasizing the use of higher order calculations to describe the data.Comment: 12 pages, 15 figures, invited review paper for Mod. Phys. Lett

Motivational assessment of mice using the touchscreen operant testing system: effects of dopaminergic drugs.

RATIONALE: Touchscreens are widely used to examine rodent cognition. Current paradigms require animals to view stimuli and nose poke at an appropriate touchscreen location. After responding, there is little screen interaction and, as infra-red touchscreens eliminate the need for physical contact, minimal somatosensory feedback. It is therefore unclear if touchscreens can support the vigorous, repetitive responding required in paradigms like progressive ratio (PR) for assessing motivation and effort-related choice (ERC) for assessing decision-making. OBJECTIVES: This study aims to adapt and validate PR and ERC for the rodent touchscreen. METHODS: Male C57Bl/6 mice were trained until responding on PR stabilised. Amphetamine, sulpiride and raclopride were administered via the intraperitoneal route to modify performance. Mice were transferred to ERC and paradigm parameters adjusted to demonstrate behavioural modification. ERC reward preference was assessed by home cage choice analysis. RESULTS: PR performance stabilised within seven sessions. Amphetamine (1 mg/kg) increased and raclopride (0.3 mg/kg) decreased performance by 63 and 28 %, respectively, with a 20-min injection-test interval. Sulpiride (50 mg/kg) decreased performance by 19 % following a 40-min injection-test interval. Increasing ERC operant requirements shifted responding from the operant response-dependent preferred reward towards the freely available alternative. CONCLUSIONS: Vigorous, repetitive responding is sustainable in touchscreen PR and ERC and task validation mirrors non-touchscreen versions. Thus, motivation and reward-related decision-making can be measured directly with touchscreens and can be evaluated prior to cognitive testing in the same apparatus to avoid confounding by motivational factors.CJH, TJB and LMS were funded by Wellcome Trust grant 089703/Z/09/Z. TJB and LMS also received funding from the Innovative Medicine Initiative Joint Undertaking under grant agreement no 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013).This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s00213-015-4009-

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.LMS and TJB were funded by Medical Research Council/Wellcome Trust grant 089703/Z/09/Z.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.nlm.2016.01.00

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

Paradoxical facilitation of object recognition memory after infusion of scopolamine into perirhinal cortex: implications for cholinergic system function.

The cholinergic system has long been implicated in learning and memory, yet its specific function remains unclear. In the present study, we investigated the role of cortical acetylcholine in a rodent model of declarative memory by infusing the cholinergic muscarinic receptor antagonist scopolamine into the rat perirhinal cortex during different stages (encoding, storage/consolidation, and retrieval) of the spontaneous object recognition task. Presample infusions of scopolamine significantly impaired object recognition compared with performance of the same group of rats on saline trials; this result is consistent with previous reports supporting a role for perirhinal acetylcholine in object information acquisition. Scopolamine infusions directly before the retrieval stage had no discernible effect on object recognition. However, postsample infusions of scopolamine with sample-to-infusion delays of up to 20 h significantly facilitated performance relative to postsample saline infusion trials. Additional analysis suggested that the infusion episode could cause retroactive or proactive interference with the sample object trace and that scopolamine blocked the acquisition of this interfering information, thereby facilitating recognition memory. This is, to our knowledge, the first example of improved recognition memory after administration of scopolamine. The overall pattern of results is inconsistent with a direct role for cortical acetylcholine in declarative memory consolidation or retrieval. Rather, the cholinergic input to the perirhinal cortex may facilitate acquisition by enhancing the cortical processing of incoming stimulus information

Measuring Motivation and Reward-Related Decision Making in the Rodent Operant Touchscreen System.

This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1002/0471142301.ns0834s74This unit is designed to facilitate implementation of the fixed and progressive ratio paradigms and the effort-related choice task in the rodent touchscreen apparatus to permit direct measurement of motivation and reward-related decision making in this equipment. These protocols have been optimized for use in the mouse and reliably yield stable performance levels that can be enhanced or suppressed by systemic pharmacological manipulation. Instructions are also provided for the adjustment of task parameters to permit use in mouse models of neurodegenerative disease. These tasks expand the utility of the rodent touchscreen apparatus beyond the currently available battery of cognitive assessment paradigms.The protocols presented in this Unit were developed and optimized as part of a research program funded by Wellcome Trust grant 089703/Z/09/Z awarded to TJB and LMS. TJB and LMS also received funding from the Innovative Medicine Initiative Joint Undertaking under grant agreement n° 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007- 2013). TJB and LMS consult for Campden Instruments Ltd

Decision Making in Mice During an Optimized Touchscreen Spatial Working Memory Task Sensitive to Medial Prefrontal Cortex Inactivation and NMDA Receptor Hypofunction

Working memory is a fundamental cognitive process for decision-making and is a hallmark impairment in a variety of neuropsychiatric and neurodegenerative diseases. Spatial working memory paradigms are a valuable tool to assess these processes in rodents and dissect the neurobiology underlying working memory. The trial unique non-match to location (TUNL) task is an automated touchscreen paradigm used to study spatial working memory and pattern separation processes in rodents. Here, animals must remember the spatial location of a stimulus presented on the screen over a delay period; and use this representation to respond to the novel location when the two are presented together. Because stimuli can be presented in a variety of spatial configurations, TUNL offers a trial-unique paradigm, which can aid in combating the development of unwanted mediating strategies. Here, we have optimized the TUNL protocol for mice to reduce training time and further reduce the potential development of mediating strategies. As a result, mice are able to accurately perform an enhanced trial-unique paradigm, where the locations of the sample and choice stimuli can be presented in any configuration on the screen during a single session. We also aimed to pharmacologically characterize this updated protocol, by assessing the roles of the medial prefrontal cortex (mPFC) and N-methyl-D-aspartate (NMDA) receptor (NMDAr) functioning during TUNL. Temporary inactivation of the medial prefrontal cortex (mPFC) was accomplished by directly infusing a mixture of GABA agonists muscimol and baclofen into the mPFC. We found that mPFC inactivation significantly impaired TUNL performance in a delay-dependent manner. In addition, mPFC inactivation significantly increased the susceptibility of mice to proactive interference. Mice were then challenged with acute systemic injections of the NMDAr antagonist ketamine, which resulted in a dose-dependent, delay-dependent working memory impairment. Together, we describe an optimized automated touchscreen task of working memory, which is dependent on the intact functioning of the mPFC and sensitive to acute NMDAr hypofunction. With the vast genetic toolbox available for modeling disease and probing neural circuit functioning in mice, the TUNL task offers a valuable paradigm to pair with these technologies to further investigate the processes underlying spatial working memory