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

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-

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

PERFORMANCE OF TRANSGENIC TgTau-P301L MICE IN A 5-CHOICE SERIAL REACTION TIME TASK (5-CSRTT) AS A MODEL OF ALZHEIMER’S DISEASE

Alzheimer’s disease is increasing to epidemic levels with an estimated 36 million people affected worldwide (Wimo 2010). The aetiology of the disease is not known, which is hindering the progression of the treatment. This study is a longitudinal investigation into the performance of TgTauP301L mice as an animal model of Alzheimer’s disease on the computer automated touchscreen 5- choice serial reaction time task (5-CSRTT). TgTauP301L mice have a single tau mutation in the P301L gene and develop the tau pathology that represents the observed tauopathy in patients with Alzheimer’s disease. The aim of the investigation is to observe if tau pathology in the TgTauP301L mice causes a cognitive impairment in attention and executive function and at what stage this can be identified by the 5-CSRTT task. This will establish if the animals can be used as a therapeutic model for pre-clinical drug trials and help to identify an early indicator and intervention point in patients with Alzheimer’s disease. The animals have previously been studied at 5-months and no differences between performances of the TgTauP301L mice and wild type mice were found (unpublished data). This study measured the performance of the animals at 7- months which is when the tauopathy begins to develop in TgTauP301L mice (Murakami 2005). The results of this study showed that there was no deficit in the performance of the TgTauP301L compared to the wild type mice and there had been no change in the animals’ performance compared to at 5-months. The animals will be retested at 12-months once the pathology has extensively spread to see if the tauopathy causes a deficit in performance

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

Impaired object-location learning and recognition memory but enhanced sustained attention in M2 muscarinic receptor-deficient mice

© 2018, The Author(s). Rationale: Muscarinic acetylcholine receptors are known to play key roles in mediating cognitive processes, and impaired muscarinic cholinergic neurotransmission is associated with normal ageing processes and Alzheimer’s disease. However, the specific contributions of the individual muscarinic receptor subtypes (M1–M5) to cognition are presently not well understood. Objectives: The aim of this study was to investigate the contribution of M2-type muscarinic receptor signalling to sustained attention, executive control and learning and memory. Methods: M2 receptor-deficient (M2−/−) mice were tested on a touchscreen-operated task battery testing visual discrimination, behavioural flexibility, object-location associative learning, attention and response control. Spontaneous recognition memory for real-world objects was also assessed. Results: We found that M2−/− mice showed an enhancement of attentional performance, but significant deficits on some tests of learning and memory. Executive control and visual discrimination were unaffected by M2-depletion. Conclusions: These findings suggest that M2 activation has heterogeneous effects across cognitive domains, and provide insights into how acetylcholine may support multiple specific cognitive processes through functionally distinct cholinergic receptor subtypes. They also suggest that therapeutics involving M2 receptor-active compounds should be assessed across a broad range of cognitive domains, as they may enhance some cognitive functions, but impair others

Adult hippocampal neurogenesis and its role in cognition.

UNLABELLED: Adult hippocampal neurogenesis (AHN) has intrigued neuroscientists for decades. Several lines of evidence show that adult-born neurons in the hippocampus are functionally integrated and contribute to cognitive function, in particular learning and memory processes. Biological properties of immature hippocampal neurons indicate that these cells are more easily excitable compared with mature neurons, and demonstrate enhanced structural plasticity. The structure in which adult-born hippocampal neurons are situated-the dentate gyrus-is thought to contribute to hippocampus function by disambiguating similar input patterns, a process referred to as pattern separation. Several ideas about AHN function have been put forward; currently there is good evidence in favor of a role for AHN in pattern separation. This function of AHN may be understood within a 'representational-hierarchical' view of brain organization. WIREs Cogn Sci 2014, 5:573-587. doi: 10.1002/wcs.1304 For further resources related to this article, please visit the WIREs website. CONFLICT OF INTEREST: The authors have declared no conflicts of interest for this article.The discovery of neurogenesis in the brain of adult mammals1-3 , including humans4 , received considerable attention as it challenged the prevailing dogma that the brain is ‘post-mitotic’ and as such is endowed with limited regenerative capacity. In the mammalian brain, adult neurogenesis is restricted to two regions: 1. the DG, at the border of the granule cell layer and hilus (the subgranular zone) where adult neurogenesis gives rise to the primary granule cells (GCs), and 2. the subventricular zone of the lateral ventricles; cells born here subsequently migrate to the olfactory bulb5-7 . Given the well-established role of the hippocampus in learning and memory8 , it was soon suggested that AHN may contribute to these functions in some way. This idea was supported by the finding that memory demand correlated with AHN in birds9 and that in rats AHN could be stimulated by learning a spatial task10. In this manuscript, we will review some of the biological properties of adult-born hippocampal neurons and provide an overview of the structure in which adult-born hippocampal neurons are situated, the dentate gyrus. This is followed by an overview of studies that have addressed a putative role of AHN in learning and memory function and a discussion of the ideas on how adult-born hippocampal neurons may contribute to hippocampus function.This is the author accepted manuscript. The final version is available from Wiley at http://onlinelibrary.wiley.com/doi/10.1002/wcs.1304/abstract

The role of the dorsal hippocampus in two versions of the touchscreen automated paired associates learning (PAL) task for mice.

RATIONALE: The CANTAB object-location paired-associate learning (PAL) test can detect cognitive deficits in schizophrenia and Alzheimer's disease. A rodent version of touch screen PAL (dPAL) has been developed, but the underlying neural mechanisms are not fully understood. Although there is evidence that inactivation of the hippocampus following training leads to impairments in rats, this has not been tested in mice. Furthermore, it is not known whether acquisition, as opposed to performance, of the rodent version depends on the hippocampus. This is critical as many mouse models may have hippocampal dysfunction prior to the onset of task training. OBJECTIVES: The objectives of this study are to examine the effects of dorsal hippocampal (dHp) dysfunction on both performance and acquisition of mouse dPAL and to determine if hippocampal task sensitivity could be increased using a newly developed context-disambiguated PAL (cdPAL) paradigm. METHODS: In experiment 1, C57Bl/6 mice received post-acquisition dHp infusions of the GABA agonist muscimol. In experiment 2, C57Bl/6 mice received excitotoxic dHp lesions prior to dPAL/cdPAL acquisition. RESULTS: Post-acquisition muscimol dose-dependently impaired dPAL and cdPAL performance. Pre-acquisition dHp lesions had only mild effects on both PAL tasks. Behavioural challenges including addition of objects and degradation of the visual stimuli with noise did not reveal any further impairments. CONCLUSIONS: dPAL and cdPAL performance is hippocampus-dependent in the mouse, but both tasks can be learned in the absence of a functional dHp.CHK received funding from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI11C1183). CJH, LMS and TJB were funded by Medical Research Council/Wellcome Trust grant 089703/Z/09/Z. BAK was funded by a Gates-Cambridge Fellowship. LMS and TJB also received funding from the Innovative Medicine Initiative Joint Undertaking under grant agreement no 115008 of which resources are composed of EFPIA inkind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013).This is the final published version. It first appeared from Springer at http://dx.doi.org/10.1007/s00213-015-3949-

Double dissociation between the effects of peri-postrhinal cortex and hippocampal lesions on tests of object recognition and spatial memory: heterogeneity of function within the temporal lobe.

It is widely believed that declarative memory is mediated by a medial temporal lobe memory system consisting of several distinct structures, including the hippocampus and perirhinal cortex. The strong version of this view assumes a high degree of functional homogeneity and serial organization within the medial temporal lobe, such that double dissociations between individual structures should not be possible. In the present study, we tested for a functional double dissociation between the hippocampus and peri-postrhinal cortex in a single experiment. Rats with bilateral excitotoxic lesions of either the hippocampus or peri-postrhinal cortex were assessed in tests of spatial memory (radial maze) and object recognition memory. For the latter, the spontaneous object recognition task was conducted in a modified apparatus designed to minimize the potentially confounding influence of spatial and contextual factors. A clear functional double dissociation was observed: rats with hippocampal lesions were impaired relative to controls and those with peripostrhinal cortex lesions on the spatial memory task, whereas rats with peri-postrhinal lesions were impaired relative to the hippocampal and control groups in object recognition. These results provide strong evidence in favor of heterogeneity and independence of function within the temporal lobe