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Funder: Motor Neurone Disease Association (MNDA); doi: https://doi.org/10.13039/501100000406, Funder: the Lady Edith Wolfson Fellowship Fund, the van Geest Foundation, Perseveration and apathy are two of the most common behavioural and psychological symptoms of dementia (BPSDs) in amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Availability of a validated and behaviourally characterised animal model is crucial for translational research into BPSD in the FTD context. We behaviourally evaluated the male TDP-43Q331K mouse, an ALS-FTD model with a human-equivalent mutation (TDP-43Q331K) knocked into the endogenous Tardbp gene. We utilised a panel of behavioural tasks delivered using the rodent touchscreen apparatus, including progressive ratio (PR), extinction and visual discrimination/reversal learning (VDR) assays to examine motivation, response inhibition and cognitive flexibility, respectively. Relative to WT littermates, TDP-43Q331K mice exhibited increased responding under a PR schedule. While elevated PR responding is typically an indication of increased motivation for reward, a trial-by-trial response rate analysis revealed that TDP-43Q331K mice exhibited decreased maximal response rate and slower response decay rate, suggestive of reduced motivation and a perseverative behavioural phenotype, respectively. In the extinction assay, TDP-43Q331K mice displayed increased omissions during the early phase of each session, consistent with a deficit in activational motivation. Finally, the VDR task revealed cognitive inflexibility, manifesting as stimulus-bound perseveration. Together, our data indicate that male TDP-43Q331K mice exhibit a perseverative phenotype with some evidence of apathy-like behaviour, similar to BPSDs observed in human ALS-FTD patients. The TDP-43Q331K knock-in mouse therefore has features that recommend it as a useful platform to facilitate translational research into behavioural symptoms in the context of ALS-FTD.

Memory loss is a usual consequence of ageing. In aged brains, perineuronal nets (PNNs), which limit neuroplasticity and are implicated in memory, become inhibitory due to decreased 6-sulphation of their glycan chains (C6S). Aged mice show progressive deficits in memory tasks, but removal of PNNs or digestion of their glycans rescued age-related memory loss. Reduction of permissive C6S by transgenic deletion of 6-sulfotransferase led to very early memory loss. However, restoring C6S levels in aged animals by AAV delivery or transgenic expression of 6-sulfotransferase restored memory. Low C6S levels caused loss of cortical long-term potentiation, which was restored by AAV-mediated 6-sulfotransferase delivery. The study shows that loss of C6S in the aged brain leads to declining memory and cognition, which can be restored by C6S replacement. One sentence summary Sulphation changes in perineuronal nets lead to age-related memory loss; correction of sulphation restores memory.

Neuroscience is undergoing an open-access revolution. Repositories in areas such as neuroimaging and genomics have provided a paradigm shift in the way we are now able to analyze, share, and re-use vast amounts of data from multiple laboratories. Unfortunately, one area that is far behind in this respect is behavioural evaluation of animal models. Thanks to a new set of automated tests based on touchscreen technology [1], there is potential for standardized outputs in animal behavioral neuroscience that are consistent with open-access sharing. However, there is currently no mechanism to provide quality control for such data or to deposit them in an open access repository for reuse, like approaches used in the imaging and genomics fields. In order to enable cognitive data, obtained using the highly translatable and automated touchscreen technology to join the open-access revolution, we have developed MouseBytes, a web-based repository that enables researchers to store, share, visualize, and analyze cognitive data. We envision that MouseBytes will be the premier platform to allow cognitive data to become open access, searchable and to be reused. Furthermore, MouseBytes will support the innovative integration of standardized behavioural with MRI and RNA-sequencing, allowing comprehensive multi-modal information in mouse models of disease.

Attention is the cognitive processing that facilitates the ability to target and attend to relevant environmental stimuli, while filtering out irrelevant or distracting stimuli. Control over selective attention is theorized to be dependent on organized neural communication that stems from the medial prefrontal cortex (mPFC). To evaluate selective and sustained attention, mice were trained on the novel touchscreen rodent continuous performance task (rCPT), a task designed to emulate the human CPT. In the rodent version, images are continuously presented on a touchscreen, where mice have been trained to selectively respond to one image type while suppressing responses to all others. Following training on the rCPT, bilateral cannulas were implanted into the prelimbic region of the mPFC. Immediately prior to cognitive testing, a mixture of GABA A and B agonists were infused into the prelimbic to temporarily inactivate the structure. Inactivating the prelimbic cortex significantly impaired performance on this task, resulting in a reduced ability to discriminate the target from non-target images, as well as a reduction in speed and overall responding. Currently, mice expressing optogenetic receptors are being used to evaluate how parvalbumin interneuron activity within the prelimbic cortex influences attentional performance on the rCPT. As the parvalbumin interneuron population is heavily implicated in generating coordinated neuronal activity and supporting cognition, it is predicted that inhibiting these interneurons and altering synchronous prelimbic activity will impair rCPT performance.

The translational gap between animal models and clinical trials is a longstanding, yet largely unresolved, limitation in the study of cognition. This discrepancy is largely due to the differences in how cognition is assessed in animal models compared to those in clinical populations. In the stimulus-response (S-R) learning literature, for example, the techniques used to assess the acquisition of habitual behaviour differ greatly across species, leading to poor cross-species translation and often conflicting results. As a result, we set out to optimize a S-R learning task in mice using the touchscreen-based operant technologies. Similar to human studies, this touchscreen technique encourages animals to respond to visual stimuli displayed on a touchscreen according to a specific rule. Allowing for very similar, if not identical, cognitive assays in mice and men, this technique promotes high translational potential and a high degree of standardisation. Originally developed for rats, the Visuomotor Conditional Learning (VMCL) task encourages animals to learn arbitrary associations between visual stimuli and motor responses. In naïve C57BL/6 mice, we sought to optimize VMCL task parameters to promote better and more efficient responding, identifying the length of inter-trial intervals and the limited hold period as two potential candidates. The validation of this task will provide a novel means through which to study the neural correlates of S-R learning, and its use in conjunction with fiber photometry recordings may be provided.

International audience; The 22q11.2 deletion syndrome (22q11.2DS) confers high risk of neurodevelopmental disorders such as schizophrenia and attention-deficit hyperactivity disorder. These disorders are associated with attentional impairment, the remediation of which is important for successful therapeutic intervention. We assessed a 22q11.2DS mouse model (Df(h22q11)/+) on a touchscreen rodent continuous performance test (rCPT) of attention and executive function that is analogous to human CPT procedures. Relative to wild-type littermates, Df(h22q11)/+ male mice showed impaired attentional performance as shown by decreased correct response ratio (hit rate) and a reduced ability to discriminate target stimuli from non-target stimuli (discrimination sensitivity, or d’). The Df(h22q11)/+ model exhibited decreased prefrontal cortical-hippocampal oscillatory synchrony within multiple frequency ranges during quiet wakefulness, which may represent a biomarker of cognitive dysfunction. The stimulant amphetamine (0–1.0 mg/kg, i.p.) dose-dependently improved d’ in Df(h22q11)/+ mice whereas the highest dose of modafinil (40 mg/kg, i.p.) exacerbated their d’ impairment. This is the first report to directly implicate attentional impairment in a 22q11.2DS mouse model, mirroring a key endophenotype of the human disorder. The capacity of the rCPT to detect performance impairments in the 22q11.2DS mouse model, and improvement following psychostimulant-treatment, highlights the utility and translational potential of the Df(h22q11)/+ model and this automated behavioral procedure.

Important tools in the study of prefrontal cortical-dependent executive functions are cross-species behavioural tasks with translational validity. A widely used test of executive function and attention in humans is the continuous performance task (CPT). Optimal performance in variations of this task is associated with activity along the medial wall of the prefrontal cortex, including the anterior cingulate cortex (ACC), for its essential components such as response control, target detection and processing of false alarm errors. We assess the validity of a recently developed rodent touchscreen continuous performance task (rCPT) that is analogous to typical human CPT procedures. Here we evaluate the performance of mice with quinolinic acid-induced lesions centred on the ACC in the rCPT following a range of task parameter manipulations designed to challenge attention and impulse control. Lesioned mice showed a disinhibited response profile expressed as a decreased response criterion and increased false alarm rates. ACC lesions also resulted in a milder increase in inter-trial interval responses ('ITI touches') and hit rate. Lesions did not affect discriminative sensitivity d'. The disinhibited behaviour of ACC lesioned animals was stable and not affected by the manipulation of variable task parameter manipulations designed to increase task difficulty. The results are in general agreement with human studies implicating the ACC in the processing of inappropriate responses. We conclude that the rCPT may be useful for studying prefrontal cortex function in mice and has the capability of providing meaningful links between animal and human cognitive tasks.

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. Fil: Kent, Brianne A.. University of Cambridge; Reino Unido Fil: Beynon, Amy L.. Swansea University; Reino Unido Fil: Hornsby, Amanda K. E.. Swansea University; Reino Unido Fil: Bekinschtein, Pedro Alejandro. University of Cambridge; Reino Unido. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Bussey, Timothy J.. University of Cambridge; Reino Unido Fil: Davies, Jeffrey S.. Swansea University; Reino Unido Fil: Saksida, Lisa M.. University of Cambridge; Reino Unido

The original version of the above article contained a mistake in the equation found in page 3953. Correct equation should be: c = -z(HR)+z(FAR)/2 Responsivityindex(RI) = HR+FAR-1/1-(HR-FAR)2.

Rationale\ud The hippocampus is implicated in many of the cognitive impairments observed in conditions such as Alzheimer’s disease (AD) and schizophrenia (SCZ). Often, mice are the species of choice for models of these diseases and the study of the relationship between brain and behaviour more generally. Thus, automated and efficient hippocampal-sensitive cognitive tests for the mouse are important for developing therapeutic targets for these diseases, and understanding brain-behaviour relationships. One promising option is to adapt the touchscreen-based trial-unique nonmatching-to-location (TUNL) task that has been shown to be sensitive to hippocampal dysfunction in the rat. \ud Objectives\ud This study aims to adapt the TUNL task for use in mice and to test for hippocampus-dependency of the task. \ud Methods\ud TUNL training protocols were altered such that C57BL/6 mice were able to acquire the task. Following acquisition, dysfunction of the dorsal hippocampus (dHp) was induced using a fibre-sparing excitotoxin, and the effects of manipulation of several task parameters were examined. \ud Results\ud Mice could acquire the TUNL task using training optimised for the mouse (experiments 1). TUNL was found to be sensitive to dHp dysfunction in the mouse (experiments 2, 3 and 4). In addition, we observed that performance of dHp dysfunction group was somewhat consistently lower when sample locations were presented in the centre of the screen. \ud Conclusions\ud This study opens up the possibility of testing both mouse and rat models on this flexible and hippocampus-sensitive touchscreen task.

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.

How the rich and diverse set of vertebrate higher cognitive functions and the susceptibility to human mental illness evolved is unknown. The vertebrate cognitive repertoire comprises multiple forms of learning, attention and executive functions, which are selectively disrupted in mental disorders, such as schizophrenia, autism and intellectual disability. Two whole genome duplications at the base of the vertebrate lineage generated gene paralogs that expanded and diversified the molecular complexity of simpler invertebrate synapse proteomes. Here we use computerized touchscreen tests for higher cognitive functions in mice and humans to examine the phenotype of mutations in one such set of paralogs, the Dlg family of synaptic scaffold proteins. Comparing mice carrying mutations in four Dlg paralogs shows simple associative learning required Dlg4 function while Dlg2 and Dlg3 diversified to play specific and opposing roles in complex learning and attentional processes. We compared the selective impairments of the mouse Dlg2 mutation with humans carrying Dlg2 mutations using homologous cognitive test apparatus and found a high degree of similarity in the selective disruption of the cognitive repertoire by Dlg2 mutations in both species. In humans, Dlg2 mutations are associated with schizophrenia and mutations in Dlg3 causes intellectual disability. Our data demonstrate that paralogous gene duplication and diversification initiated over 500 million years (My) ago diversified the regulation of vertebrate higher cognitive functions and that the constraint in structure and function of these genes within the last 100 My conserved the specific cognitive roles of genes underlying human mental illness. The demonstrated conservation in cognitive function using homologous psychological test apparatus also provides a new approach to translating the genetic studies of mental illness into therapeutic benefit.

Several mouse models of Alzheimer's disease (AD) with abundant β-amyloid and/or aberrantly phosphorylated tau develop memory impairments. However, multiple non-mnemonic cognitive domains such as attention and executive control are also compromised early in AD individuals. Currently, it is unclear whether mutations in the β-amyloid precursor protein (APP) and tau are sufficient to cause similar, AD-like attention deficits in mouse models of the disease. To address this question, we tested 3xTgAD mice (which express APPswe, PS1M146V, and tauP301L mutations) and wild-type control mice on a newly developed touchscreen-based 5-choice serial reaction time test of attention and response control. The 3xTgAD mice attended less accurately to short, spatially unpredictable stimuli when the attentional demand of the task was high, and also showed a general tendency to make more perseverative responses than wild-type mice. The attentional impairment of 3xTgAD mice was comparable to that of AD patients in two aspects: first, although 3xTgAD mice initially responded as accurately as wild-type mice, they subsequently failed to sustain their attention over the duration of the task; second, the ability to sustain attention was enhanced by the cholinesterase inhibitor donepezil (Aricept). These findings demonstrate that familial AD mutations not only affect memory, but also cause significant impairments in attention, a cognitive domain supported by the prefrontal cortex and its afferents. Because attention deficits are likely to affect memory encoding and other cognitive abilities, our findings have important consequences for the assessment of disease mechanisms and therapeutics in animal models of AD.

The present experiment tested predictions of a 'perceptual-mnemonic/feature conjunction' (PMFC) model of perirhinal cortex function. The model predicts that lesions of perirhinal cortex should disrupt complex visual discriminations with a high degree of 'feature ambiguity', a property of visual discrimination problems that can emerge when features of an object are rewarded when they are part of one object, but not when part of another. As feature ambiguity is thought to be the critical factor, such effects should be independent of the number of objects to be discriminated. This was tested directly, by assessing performance of control monkeys and monkeys with aspiration lesions of perirhinal cortex on a series of concurrent discriminations in which the number of object pairs was held constant, but the degree of feature ambiguity was varied systematically. Monkeys were tested in three conditions: Maximum Feature Ambiguity, in which all features were explicitly ambiguous (AB+, CD+, BC-, AD-; the biconditional problem); Minimum Feature Ambiguity, in which no features were explicitly ambiguous (AB+, CD+, EF-, GH-); and Intermediate Feature Ambiguity, in which half the features were explicitly ambiguous (AB+, CD+, CE-, AF-). The pattern of results closely matched that predicted by simulations using a connectionist network: monkeys with perirhinal cortex lesions were unimpaired in the Minimum Feature Ambiguity condition, mildly impaired in the Intermediate Feature Ambiguity condition and severely impaired in the Maximum Feature Ambiguity condition. These results confirm the predictions of the PMFC model, and force a reconsideration of prevailing views regarding perirhinal cortex function.

RATIONALE: Continuous performance tests (CPTs) are widely used to assess attentional processes in a variety of disorders including Alzheimer's disease and schizophrenia. Common human CPTs require discrimination of sequentially presented, visually patterned 'target' and 'non-target' stimuli at a single location. OBJECTIVES: The aims of this study were to evaluate the performance of three popular mouse strains on a novel rodent touchscreen test (rCPT) designed to be analogous to common human CPT variants and to investigate the effects of donepezil, a cholinesterase inhibitor and putative cognitive enhancer. METHODS: C57BL/6J, DBA/2J and CD1 mice (n = 15-16/strain) were trained to baseline performance using four rCPT training stages. Then, probe tests assessed the effects of parameter changes on task performance: stimulus size, duration, contrast, probability, inter-trial interval or inclusion of flanker distractors. rCPT performance was also evaluated following acute administration of donepezil (0-3 mg/kg, i.p.). RESULTS: C57BL/6J and DBA/2J mice showed similar acquisition rates and final baseline performance following rCPT training. On probe tests, rCPT performance of both strains was sensitive to alteration of visual and/or attentional demands (stimulus size, duration, contrast, rate, flanker distraction). Relative to C57BL/6J, DBA/2J mice exhibited (1) decreasing sensitivity (d') across the 45-min session, (2) reduced performance on probes where the appearance of stimuli or adjacent areas were changed (size, contrast, flanking distractors) and (3) larger dose- and stimulus duration-dependent changes in performance following donepezil administration. In contrast, CD1 mice failed to acquire rCPT (stage 3) and pairwise visual discrimination tasks. CONCLUSIONS: rCPT is a potentially useful translational tool for assessing attention in mice and for detecting the effects of nootropic drugs.

Rationale\ud 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. \ud Objectives\ud 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. \ud Methods\ud 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. \ud Results\ud 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. \ud Conclusions\ud dPAL and cdPAL performance is hippocampus-dependent in the mouse, but both tasks can be learned in the absence of a functional dHp.

A chromosomal microdeletion at the 22q11.2 locus is associated with extensive cognitive impairments, schizophrenia and other psychopathology in humans. Previous reports indicate that mouse models of the 22q11.2 microdeletion syndrome (22q11.2DS) may model the genetic basis of cognitive deficits relevant for neuropsychiatric disorders such as schizophrenia. To assess the models usefulness for drug discovery, a novel mouse (Df(h22q11)/+) was assessed in an extensive battery of cognitive assays by partners within the NEWMEDS collaboration (Innovative Medicines Initiative Grant Agreement No. 115008). This battery included classic and touchscreen-based paradigms with recognized sensitivity and multiple attempts at reproducing previously published findings in 22q11.2DS mouse models. This work represents one of the most comprehensive reports of cognitive functioning in a transgenic animal model. In accordance with previous reports, there were non-significant trends or marginal impairment in some tasks. However, the Df(h22q11)/+ mouse did not show comprehensive deficits; no robust impairment was observed following more than 17 experiments and 14 behavioral paradigms. Thus - within the current protocols - the 22q11.2DS mouse model fails to mimic the cognitive alterations observed in human 22q11.2 deletion carriers. We suggest that the 22q11.2DS model may induce liability for cognitive dysfunction with additional "hits" being required for phenotypic expression.

Apathy is pervasive across many neuropsychiatric disorders but is poorly characterized mechanistically, so targeted therapeutic interventions remain elusive. A key impediment has been the lack of validated assessment tools to facilitate translation of promising findings between preclinical disease models and patients. Apathy is a common symptom in Huntington's disease. Due to its established genetic basis and the availability of defined animal models, this disease offers a robust translational framework for linking motivated behavior with underlying neurobiology and an ideal context in which to evaluate a quantitative, translational apathy assessment method. In this study we therefore aimed to demonstrate the validity of using touchscreen-delivered progressive ratio tasks to mirror apathy assessment in Huntington's disease patients and a representative mouse model. To do this we evaluated Huntington's disease patients (n = 23) and age-matched healthy controls (n = 20), and male R6/1 mice (n = 23) and wildtype controls (n = 29) for apathy-like behavior using touchscreen-delivered progressive ratio tasks. The primary outcome measure of the assessment was breakpoint, defined as the highest number of touchscreen responses emitted before task engagement ceased. Patients and R6/1 mice were both found to exhibit significantly reduced breakpoints relative to their respective control groups, consistent with apathy-like behavior. This performance was also not associated with motoric differences in either species. These data demonstrate the utility of touchscreen-delivered progressive ratio tasks in detecting clinically relevant motivational deficits in Huntington's disease. This approach may offer a platform from which clinically relevant mechanistic insights concerning motivation symptoms can be derived and provide an effective route for translation of promising preclinical findings into viable therapeutic interventions.

INTRODUCTION: 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. METHODS: 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). RESULTS: Despite using sensitive tasks, there were no apparent changes in executive function, attention, or recognition memory in the transgenic mice from 5 to 17 months of age. CONCLUSIONS: 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.

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 3 month-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 1 week 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., Highlights • Progressive tau pathology in the perirhinal cortex impairs object recognition memory. • ChABC treatment improves plasticity and object recognition memory in mice with tau pathology. • The improvement of object recognition memory by ChABC is temporary and related to ChABC expression.

Perineuronal nets are extracellular matrix structures surrounding cortical neuronal cell bodies and proximal dendrites, and are involved in the control of brain plasticity and the closure of critical periods. Expression of the link protein Crtl1/Hapln1 in neurons has recently been identified as the key event triggering the formation of perineuronal nets. Here we show that the genetic attenuation of perineuronal nets in adult brain Crtl1 knockout mice enhances long term object recognition memory and facilitates long-term depression in the perirhinal cortex, a neural correlate of object recognition memory. Identical prolongation of memory follows localised digestion of perineuronal nets with chondroitinase ABC, an enzyme that degrades the chondroitin sulphate proteoglycans (CSPGs) components of PNNs. The memory-enhancing effect of chondroitinase ABC treatment attenuated over time, suggesting that regeneration of PNNs gradually restored control plasticity levels. Our findings indicate that perineuronal nets regulate both memory and experience-driven synaptic plasticity in adulthood.