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

Algebraic integrability of confluent Neumann system

In this paper we study the Neumann system, which describes the harmonic oscillator (of arbitrary dimension) constrained to the sphere. In particular we will consider the confluent case where two eigenvalues of the potential coincide, which implies that the system has S^{1} symmetry. We will prove complete algebraic integrability of confluent Neumann system and show that its flow can be linearized on the generalized Jacobian torus of some singular algebraic curve. The symplectic reduction of S^{1} action will be described and we will show that the general Rosochatius system is a symplectic quotient of the confluent Neumann system, where all the eigenvalues of the potential are double. This will give a new mechanical interpretation of the Rosochatius system.Comment: 17 pages, 1 figur

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 orexigenic hormone acyl-ghrelin increases adult hippocampal neurogenesis and enhances pattern separation.

An important link exists between intact metabolic processes and normal cognitive functioning; however, the underlying mechanisms remain unknown. There is accumulating evidence that the gut hormone ghrelin, an orexigenic peptide that is elevated during calorie restriction (CR) and known primarily for stimulating growth hormone release, has important extra-hypothalamic functions, such as enhancing synaptic plasticity and hippocampal neurogenesis. The present study was designed to evaluate the long-term effects of elevating acyl-ghrelin levels, albeit within the physiological range, on the number of new adult born neurons in the dentate gyrus (DG) and performance on the Spontaneous Location Recognition (SLR) task, previously shown to be DG-dependent and sensitive to manipulations of plasticity mechanisms and cell proliferation. The results revealed that peripheral treatment of rats with acyl-ghrelin enhanced both adult hippocampal neurogenesis and performance on SLR when measured 8-10 days after the end of acyl-ghrelin treatment. Our data show that systemic administration of physiological levels of acyl-ghrelin can produce long-lasting improvements in spatial memory that persist following the end of treatment. As ghrelin is potentially involved in regulating the relationship between metabolic and cognitive dysfunction in ageing and neurodegenerative disease, elucidating the underlying mechanisms holds promise for identifying novel therapeutic targets and modifiable lifestyle factors that may have beneficial effects on the brain.This work was supported by grants from the Medical Research Council (grant G0902250/94306), The Royal Society and the Biotechnology and Biological Sciences Research Council (grant BB/G019002/1).This is the final version. It was first published by Elsevier at http://www.sciencedirect.com/science/article/pii/S030645301400399

Volunteer role mastery and commitment: Can HRM make a difference?

Although the literature on human resource management (HRM) has provided compelling evidence that certain HRM practices can help employees attain the competence and confidence to carry out their role, less is known about the potential impact of HRM practices on volunteers in the context of non-profit organisations. This study addresses this gap by presenting a model that situates role mastery – operationalised as role clarity and self-efficacy – as its centrepiece. Our model suggests that role mastery leads to commitment to the volunteer organisation and that role mastery can be achieved through training and supportive relationships with paid staff. A dual-mediation analysis of survey data from a humanitarian non-profit organisation in the United Kingdom (n=647) supported our theoretical model. We contribute to volunteering theory and practice by identifying tools that non-profit organisations can employ to maximise the role mastery and commitment of volunteers

Perineuronal net digestion with chondroitinase restores memory in mice with tau pathology.

Alzheimer's disease is the most prevalent tauopathy and cause of dementia. We investigate the hypothesis that reactivation of plasticity can restore function in the presence of neuronal damage resulting from tauopathy. We investigated two models with tau hyperphosphorylation, aggregation and neurodegeneration: a transgenic mouse model in which the mutant P301S tau is expressed in neurons (Tg P301S), and a model in which an adeno-associated virus expressing P301S tau (AAV-P301S) was injected in the perirhinal cortex, a region critical for object recognition (OR) memory. Both models show profound loss of OR memory despite only 15% neuronal loss in the Tg P301S and 26% in AAV-P301S-injected mice. Recordings from perirhinal cortex slices of 3month-old P301S transgenic mice showed a diminution in synaptic transmission following temporal stimulation. Chondroitinase ABC (ChABC) can reactivate plasticity and affect memory through actions on perineuronal nets. ChABC was injected into the perirhinal cortex and animals were tested for OR memory 1week later, demonstrating restoration of OR memory to normal levels. Synaptic transmission indicated by fEPSP amplitude was restored to control levels following ChABC treatment. ChABC did not affect the progression of neurodegenerative tauopathy. These findings suggest that increasing plasticity by manipulation of perineuronal nets offers a novel therapeutic approach to the treatment of memory loss in neurodegenerative disorders.This work was supported by the European Union Framework 7 Project Plasticise (S.Y., M.C., M.G.S., J.W.F., P.R., P.A., B.L.S.), the Wellcome Trust (L.M.S., T.J.B.), the Alzheimer's Research UK (M.G.S.), and the UK Medical Research Council (L.M.S., T.J.B.). J.W.F.'s work is supported by the ERC-ECMneuro, the Christopher and Dana Reeve Foundation and the NIHR Cambridge biomedical research center.This article was originally published in Experimental Neurology (S Yang, M Cacqueve, LM Saksida, TJ Bussey, BL Schneider, P Aebischer, R Melani, T Pizzorusso, JW Fawcett, MG Spillantini, Experimental Neurology 2015, 265, 48-58

Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing

Perineuronal nets (PNNs) are chondroitin sulphate proteoglycan-containing structures on the neuronal surface that have been implicated in the control of neuroplasticity and memory. Age-related reduction of chondroitin 6-sulphates (C6S) leads to PNNs becoming more inhibitory. Here, we investigated whether manipulation of the chondroitin sulphate (CS) composition of the PNNs could restore neuroplasticity and alleviate memory deficits in aged mice. We first confirmed that aged mice (20-months) showed memory and plasticity deficits. They were able to retain or regain their cognitive ability when CSs were digested or PNNs were attenuated. We then explored the role of C6S in memory and neuroplasticity. Transgenic deletion of chondroitin 6-sulfotransferase (chst3) led to a reduction of permissive C6S, simulating aged brains. These animals showed very early memory loss at 11 weeks old. Importantly, restoring C6S levels in aged animals rescued the memory deficits and restored cortical long-term potentiation, suggesting a strategy to improve age-related memory impairment

False recognition in a mouse model of Alzheimer's disease: rescue with sensory restriction and memantine.

Alzheimer's disease is commonly regarded as a loss of memory for past events. However, patients with Alzheimer's disease seem not only to forget events but also to express false confidence in remembering events that have never happened. How and why false recognition occurs in such patients is currently unknown, and treatments targeting this specific mnemonic abnormality have not been attempted. Here, we used a modified object recognition paradigm to show that the tgCRND8 mouse-which overexpresses amyloid β and develops amyloid plaques similar to those in the brains of patients with Alzheimer's disease-exhibits false recognition. Furthermore, we found that false recognition did not occur when tgCRND8 mice were kept in a dark, quiet chamber during the delay, paralleling previous findings in patients with mild cognitive impairment, which is often considered to be prodromal Alzheimer's disease. Additionally, false recognition did not occur when mice were treated with the partial N-methyl-d-aspartic acid receptor antagonist memantine. In a subsequent experiment, we found abnormally enhanced N-methyl-d-aspartic acid receptor-dependent long-term depression in these mice, which could be normalized by treatment with memantine. We suggest that Alzheimer's disease typical amyloid β pathology leads to aberrant synaptic plasticity, thereby making memory representations more susceptible to interfering sensory input, thus increasing the likelihood of false recognition. Parallels between these findings and those from the literature on Alzheimer's disease and mild cognitive impairment suggest a mechanism underlying false recognition in these patients. The false recognition phenomenon may provide a novel paradigm for the discovery of potential therapies to treat the mnemonic dysfunction characteristic of this disease

Paradoxical reversal learning enhancement by stress or prefrontal cortical damage: rescue with BDNF.

Stress affects various forms of cognition. We found that moderate stress enhanced late reversal learning in a mouse touchscreen-based choice task. Ventromedial prefrontal cortex (vmPFC) lesions mimicked the effect of stress, whereas orbitofrontal and dorsolateral striatal lesions impaired reversal. Stress facilitation of reversal was prevented by BDNF infusion into the vmPFC. These findings suggest a mechanism by which stress-induced vmPFC dysfunction disinhibits learning by alternate (for example, striatal) systems

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.This is the published version of the manuscript. It is available online from NPG in Cell Death and Differentiaiton here: http://www.nature.com/cdd/journal/vaop/ncurrent/full/cdd2014151a.html