30 research outputs found

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

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    Funder: Alzheimers research UKPerineuronal 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.Alzherimers research UK European research counci

    Basal Forebrain and Brainstem Cholinergic Neurons Differentially Impact Amygdala Circuits and Learning-Related Behavior

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    The central cholinergic system and the amygdala are well-known to be important for motivation and mnemonic processes. Different cholinergic populations innervate the amygdala but it is unclear how these projections impact amygdala activity and behavior. Using optogenetic circuit-mapping strategies in ChAT-cre mice we demonstrate that amygdala-projecting basal forebrain and brainstem ChAT-containing neurons can differentially affect amygdala circuits and behavior. Photoactivating ChAT terminals in vitro revealed the underlying synaptic impact of brainstem inputs to the central lateral division to be excitatory, mediated via the synergistic glutamatergic activation of AMPA and NMDA receptors. In contrast, stimulating NBm-ChAT inputs to the basal nucleus resulted in endogenous ACh release resulting in muscarinic receptor dependent biphasic inhibition-excitation responses onto principal neurons. Such a biphasic inhibitory-excitatory response profile is a physiological hallmark of neural oscillations and could thus form the basis of acetylcholine-mediated rhythmicity in amygdala networks. Consistent with this, in vivo NBm activation strengthened amygdala basal nucleus theta and gamma frequency rhythmicity, both of which continued for seconds after stimulation. Stimulation-evoked and ongoing increases in gamma and theta power were dependent on local nicotinic or muscarinic receptor activation, respectively. Activation of brainstem ChAT-containing neurons however resulted in a transient increase in central lateral amygdala network synchrony that was independent of cholinergic receptors. In addition, driving these respective inputs in behaving animals induced opposing appetitive and defensive learning-related behavioral changes. Since learning and memory is supported by both cellular and network-level processes in central cholinergic and amygdala networks, these results provide a route by which distinct cholinergic inputs can convey salient information to the amygdala and promote associative biophysical changes that underlie amygdala-dependent memories.This work was supported by the Royal Society, The Wellcome Trust (JAS), the Sigrid Juselius Foundation (TA), and by a Herchel Smith Fellowship (YAH)

    Cite Share Publisher Correction: TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD

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    In the version of this article initially published, the footnote number 17 was missing from the author list for the two authors who contributed equally. Also, the authors have added a middle initial for author Justin R. Fallon and an acknowledgement to the Babraham Institute Imaging Facility and Sequencing Core Facility. The errors have been corrected in the HTML and PDF versions of the articl

    Longitudinal evaluation of Tau‐P301L transgenic mice reveals no cognitive impairments at 17 months of age

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    Tau is a microtubule-associated binding protein implicated in neurodegenerative tauopathies, including frontotemporal dementia (FTD) and Alzheimer’s disease (AD). These diseases result in the intracellular accumulation of hyperphosphorylated tau in the form of neurofibrillary tangles, the presence of which is associated with cognitive deficits. We conducted a longitudinal behavioral study to provide a profile of the TgTau(P301L)23027 transgenic mouse in multiple cognitive domains across multiple ages. P301L is the tau mutation most frequently observed in patients with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and this mouse model recapitulates the progressive development of glial and neurofibrillary tangles, and associated cerebral atrophy observed in patients. We examined frontal cortex-dependent executive function and attention with the touchscreen 5-choice serial reaction time test (5-CSRTT) and assessed the function of temporal cortical structures using novel object recognition (OR). Despite using sensitive tasks, there were no apparent changes in executive function, attention, or recognition memory in the transgenic mice from 5 – 17 months of age. This study represents the first comprehensive longitudinal analysis of cognition in the TgTauP301L mouse model, and suggests that this model is not ideal for studying early attention and recognition memory impairments associated with tauopathy. However, spatial and object recognition memory impairments were observed during follow-up assessments when the mice were 18 and 21 months, respectively. These impairments are consistent with previous publications, and with a dementia-like phenotype in these mice when aged

    Optimisation of cognitive performance in rodent operant (touchscreen) testing: Evaluation and effects of reinforcer strength

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    Operant testing is a widely used and highly effective method of studying cognition in rodents. Performance on such tasks is sensitive to reinforcer strength. It is therefore advantageous to select effective reinforcers to minimize training times and maximize experimental throughput. To quantitatively investigate the control of behavior by different reinforcers, performance of mice was tested with either strawberry milkshake or a known powerful reinforcer, super saccharin (1.5% or 2% (w/v) saccharin/1.5% (w/v) glucose/water mixture). Mice were tested on fixed (FR)- and progressive-ratio (PR) schedules in the touchscreen-operant testing system. Under an FR schedule, both the rate of responding and number of trials completed were higher in animals responding for strawberry milkshake versus super saccharin. Under a PR schedule, mice were willing to emit similar numbers of responses for strawberry milkshake and super saccharin; however, analysis of the rate of responding revealed a significantly higher rate of responding by animals reinforced with milkshake versus super saccharin. To determine the impact of reinforcer strength on cognitive performance, strawberry milkshake and super saccharin-reinforced animals were compared on a touchscreen visual discrimination task. Animals reinforced by strawberry milkshake were significantly faster to acquire the discrimination than animals reinforced by super saccharin. Taken together, these results suggest that strawberry milkshake is superior to super saccharin for operant behavioral testing and further confirms that the application of response rate analysis to multiple ratio tasks is a highly sensitive method for the detection of behavioral differences relevant to learning and motivation.The present research was supported by a National Centre for the Replacement, Refinement and Reduction of Animals in Research project grant awarded to TJB, LMS and CJH. BUP is supported by a Medical Research Council PhD studentship

    MAM-E17 rat model impairments on a novel continuous performance task: effects of potential cognitive enhancing drugs

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    Rationale\textit{Rationale} Impairments in attention and inhibitory control are endophenotypic markers of neuropsychiatric disorders such as schizophrenia and represent key targets for therapeutic management. Robust preclinical models and assays sensitive to clinically relevant treatments are crucial for improving cognitive enhancement strategies. Objectives\textit{Objectives} We assessed a rodent model with neural and behavioral features relevant to schizophrenia (gestational day 17 methylazoxymethanol acetate treatment (MAM-E17)) on a novel test of attention and executive function, and examined the impact of putative nootropic drugs. Methods\textit{Methods} MAM-E17 and sham control rats were trained on a novel touchscreen-based rodent continuous performance test (rCPT) designed to closely mimic the human CPT paradigm. Performance following acute, systemic treatment with an array of pharmacological compounds was investigated. Results\textit{Results} Two cohorts of MAM-E17 rats were impaired on rCPT performance including deficits in sensitivity (d′) and increased false alarm rates (FARs). Sulpiride (0–30 mg/kg) dose-dependently reduced elevated FAR in MAM-E17 rats whereas low-dose modafinil (8 mg/kg) only improved d′ in sham controls. ABT-594 (5.9–19.4 μg/kg) and modafinil (64 mg/kg) showed expected stimulant-like effects, while LSN2463359 (5 mg/kg), RO493858 (10 mg/kg), atomoxetine (0.3–1 mg/kg), and sulpiride (30 mg/kg) showed expected suppressant effects on performance across all animals. Donepezil (0.1–1 mg/kg) showed near-significant enhancements in d′, and EVP-6124 (0.3–3 mg/kg) exerted no effects in the rCPT paradigm. Conclusion\textit{Conclusion} The MAM-E17 model exhibits robust and replicable impairments in rCPT performance that resemble attention and inhibitory control deficits seen in schizophrenia. Pharmacological profiles were highly consistent with known drug effects on cognition in preclinical and clinical studies. The rCPT is a sensitive and reliable tool with high translational potential for understanding the etiology and treatment of disorders affecting attention and executive dysfunction.The research leading to these results has received support 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). The Behavioural and Clinical Neuroscience Institute is co-funded by the Medical Research Council and the Wellcome Trust. BGL received funding support from the "La Caixa" Fellowship Postgraduate Programme. ML was supported by the Chinese Scholarship Council Joint PhD Program. JA received funding support from the Swedish Pharmaceutical Society and the Swedish Research Council (no. 350- 2012-230)

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

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    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

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

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    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.This work was supported by 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). CJH was funded by Wellcome Trust grant 089703/Z/09/Z.This is the final version of the article. It first appeared from Springer via http://link.springer.com/article/10.1007/s00213-015-4038-

    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.

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    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.This work was supported by 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). As part of this project, CAO was funded by Janssen Pharmaceuticals, Inc., of Johnson & Johnson.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00213-015-4019-
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