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Spatial working memory can be assessed in mice through the spontaneous alternation T-maze test. The T-maze is a T-shaped apparatus featuring a stem (start arm) and two lateral goal arms (left and right arms). The procedure is based on the natural tendency of rodents to prefer exploring a novel arm over a familiar one, which induces them to alternate the choice of the goal arm across repeated trials. During the task, in order to successfully alternate choices across trials, an animal has to remember which arm had been visited in the previous trial, which makes spontaneous alternation T-maze an optimal test for spatial working memory. As this test relies on a spontaneous behaviour and does not require rewards, punishments or pre-training, it represents a particularly useful tool for cognitive evaluation, both time-saving and animal-friendly. We describe here in detail the apparatus and the protocol, providing representative results on wild-type healthy mice.

Background Maraviroc is an antiretroviral agent and C-C chemokine coreceptor 5 (CCR5) antagonist that is currently used to treat human immunodeficiency virus. CCR5/μ-opioid receptor heterodimerization suggests that maraviroc could be a treatment for oxycodone abuse. We treated rats with maraviroc to explore its effect on oxycodone-seeking and its interference with the analgesic effects of oxycodone. We used resting-state blood-oxygen-level-dependent functional connectivity to assess the effect of maraviroc on oxycodone-enhanced coupling in the reward circuitry and performed behavioural tests to evaluate the effect of maraviroc on oxycodone rewarding properties and on oxycodone-seeking after prolonged abstinence. Methods Two groups of rats were exposed to 8 consecutive days of oxycodone-conditioned place preference training and treatment with maraviroc or vehicle. Two additional groups were trained to self-administer oxycodone for 10 days and then tested for drug seeking after 14 days of abstinence with or without daily maraviroc treatment. We tested the effects of maraviroc on oxycodone analgesia using a tail-flick assay. We analyzed resting-state functional connectivity data using a rat 3-dimensional MRI atlas of 171 brain areas. Results Maraviroc significantly decreased conditioned place preference and attenuated oxycodone-seeking behaviour after prolonged abstinence. The analgesic effect of oxycodone was maintained after maraviroc treatment. Oxycodone increased functional coupling with the accumbens, ventral pallidum and olfactory tubercles, but this was reduced with maraviroc treatment. Limitations All experiments were performed in male rats only. Conclusion Maraviroc treatment attenuated oxycodone-seeking in abstinent rats and reduced functional coupling in the reward circuitry. The analgesic effects of oxycodone were not affected by maraviroc.

Background The newborn hearing screening programme (NHSP) in England was impacted by the COVID-19 pandemic as screening and audiology services initially stopped outpatients, some parents declined or delayed screening and services struggled to manage capacity with reduced staffing. To monitor the impact Public Health England (PHE) produced weekly data reports. A modelling tool was developed for providers to identify babies still awaiting screening or audiological assessment using the national IT system, SMaRT4Hearing (S4H) and audiology data. This information was used to track screening completion and to support restoration of hearing screening prioritising babies with the greatest chance of permanent childhood hearing impairment (PCHI). Objectives Development of a modelling tool to provide assurance of screening pathway completion, map additional audiology capacity required for babies deferred from screening and prioritise babies that need to be seen first on the basis of risk to minimise delays in the diagnosis of PCHI Methods Weekly data reports extracted from S4H highlighting services with less than 90% coverage and more than 40% of screen referrals awaiting audiology to support commissioner assurance of screening and audiological capacity. Development of a modelling tool for use by screening providers and audiology services Results The programme saw a significant reduction in the number of babies with a completed screen outcome, a slight rise in the number referred to audiology and an increasing number of babies awaiting diagnostic assessment. 1. Coverage Week on week coverage for April 2020 – end of March 2021 compared to April 2019 – March 2020 These data describe an initial drop in coverage at the start of the pandemic from 98.8% to 76.1% with return to near expected levels of coverage over time. There remain more babies that did not have hearing screening compared to the year before. 2. Providers with 40% screening referrals awaiting audiology Tracking of progress by highlighting services meeting these criteria in a national summary report for screening commissioners supported by detailed metrics for each provider. 3. Comparison of diagnosis of permanent childhood hearing impairment The number of unilateral and bilateral cases of permanent childhood hearing impairment diagnosed within the screening programme in 2020/21 is compared to 2019/20 tracking babies deferred for behavioural testing in audiology at the age 7–9 months. Conclusions The COVID-19 pandemic initially impacted the coverage for the newborn screening programme. Coverage has improved over time but there remains a proportion of babies that were not offered initial screening or deferred screening until audiological assessment at 7–9 months of age. These babies are now reaching the age to be seen in audiology. Weekly reporting and use of the modelling tool to support screening and audiology capacity mapping has provided assurance to screening commissioners that the babies at greatest risk have been prioritised. Final full year figures will estimate the potential number of delayed diagnoses of permanent childhood hearing impairment in 2020/21. Paediatric services need to be aware of the impact of COVID-19 on newborn hearing screening and should check if screening has been completed or that babies are referred for audiological assessment.

Graphical abstract, The elevated plus maze is a commonly used and well-validated test of anxiety-related behaviour in rodents. The use of fish in behavioural neuroscience paradigms is increasing, necessitating an equivalent test for studying anxiety-like behaviour in fish. Because behaviour in the elevated plus maze is driven by aversion to open space, the submerged plus maze described here uses transparent walls to elicit similar behaviour in fish. The tendency of fish to explore or avoid the sections of the maze containing transparent walls is used as proxy for anxiety level. This submerged plus maze was designed and validated for convict cichlid (Amatitlania nigrofasciata) fish.

Mistranslated numbers have the potential to cause serious effects, such as financial loss or medical misinformation. In this work we develop comprehensive assessments of the robustness of neural machine translation systems to numerical text via behavioural testing. We explore a variety of numerical translation capabilities a system is expected to exhibit and design effective test examples to expose system underperformance. We find that numerical mistranslation is a general issue: major commercial systems and state-of-the-art research models fail on many of our test examples, for high- and low-resource languages. Our tests reveal novel errors that have not previously been reported in NMT systems, to the best of our knowledge. Lastly, we discuss strategies to mitigate numerical mistranslation., Comment: Findings of ACL, to appear

Despite the rise of Alzheimer's disease (AD) in an ageing population, no cure is currently available for this disorder. This study assessed the role of a natural compound, Antroquinonol, in modifying the progression of AD when administered at the start and/or before appearance of symptoms and when the disease was well established, in a transgenic animal model. Antroquinonol was administered daily for 8 weeks, in 11 week (early stage) and 9 month (late stage) male transgenic mice (3 times Transgenic mice PS1M146V, APPSwe, and tauP301L, 3 ​Tg XAD) and their respective aged controls. Behavioural testing (including Elevated Plus Maze Watermaze, Recognition object testing and Y maze) was performed at the end of the drug administration. In addition AD biomarkers (Amyloid beta 42 (Aβ42), tau and phospho-tau levels), oxidative stress and inflammatory markers, were assessed in tested mice brains after their sacrifice at the end of the treatment. When administered before the start of symptoms at 11 weeks, Antroquinonol treatment at 34 ​mg/kg (D2) and more consistently at 75 ​mg/kg (D3), had a significant effect on reducing systemic inflammatory markers (Interleukin 1, IL-1β and TNF-α) and AD biomarker (Amyloid Beta 42, Aβ42 and tau) levels in the brain. The reduction of behavioural impairment reported for 3TgXAD mice was observed significantly for the D3 drug dose only and for all behavioural tests, when administered at 11 weeks. Similarly, beneficial effects of Antroquinonol (at higher dose D3) were noted in the transgenic mice in terms of AD biomarkers (tau and phosphorylated-tau), systemic inflammatory (IL-1β), brain anti-inflammatory (Nrf2) and oxidative (3-Nitrotyrosine, 3NT) markers. Improvement of memory impairment was also reported when Antroquinonol (D3) was administered at late stage (9 months). Since Antroquinonol has been used without adverse effects in previous successful clinical trials, this drug may offer a new avenue of treatment to modify AD development and progression.

This study tested the idea that stuttering is caused by over-reliance on auditory feedback. The theory is motivated by the observation that many fluency-inducing situations, such as synchronised speech and masked speech, alter or obscure the talker’s feedback. Typical speakers show ‘speaking-induced suppression’ of neural activation in superior temporal gyrus (STG) during self-produced vocalisation, compared to listening to recorded speech. If people who stutter over-attend to auditory feedback, they may lack this suppression response. In a 1.5T fMRI scanner, people who stutter spoke in synchrony with an experimenter, in synchrony with a recording, on their own, in noise, listened to the experimenter speaking and read silently. Behavioural testing outside the scanner demonstrated that synchronising with another talker resulted in a marked increase in fluency regardless of baseline stuttering severity. In the scanner, participants stuttered most when they spoke alone, and least when they synchronised with a live talker. There was no reduction in STG activity in the Speak Alone condition, when participants stuttered most. There was also strong activity in STG in response to the two synchronised speech conditions, when participants stuttered least, suggesting that either stuttering does not result from over-reliance on feedback, or that the STG activation seen here does not reflect speech feedback monitoring. We discuss this result with reference to neural responses seen in the typical population.

Neuroimaging has advanced our understanding of human psychology using reductionist stimuli that often do not resemble information the brain naturally encounters. It has improved our understanding of the network organization of the brain mostly through analyses of ‘resting-state’ data for which the functions of networks cannot be verifiably labelled. We make a ‘Naturalistic Neuroimaging Database’ (NNDb v1.0) publically available to allow for a more complete understanding of the brain under more ecological conditions during which networks can be labelled. Eighty-six participants underwent behavioural testing and watched one of 10 full-length movies while functional magnetic resonance imaging was acquired. Resulting timeseries data are shown to be of high quality, with good signal-to-noise ratio, few outliers and low movement. Data-driven functional analyses provide further evidence of data quality. They also demonstrate accurate timeseries/movie alignment and how movie annotations might be used to label networks. The NNDb can be used to answer questions previously unaddressed with standard neuroimaging approaches, progressing our knowledge of how the brain works in the real world., Measurement(s) functional brain measurement • Behavioral Assessment Technology Type(s) functional magnetic resonance imaging • NIH Toolbox Factor Type(s) movie Sample Characteristic - Organism Homo sapiens Sample Characteristic - Environment laboratory facility Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.12869855

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders that are caused by genetic and/or environmental impacts, often probably by the interaction of both. They are characterised by deficits in social communication and interaction and by restricted and repetitive behaviours and interests from early childhood on, causing significant impairment. While it is clear that no animal model captures the full complexity of ASD in humans, genetic models are extremely useful for studying specific symptoms associated with ASD and the underlying cellular and molecular mechanisms. In this review we summarize the behavioral paradigms used in rodents to model ASD symptoms as they are listed in the DSM-5. We then review existing genetic rodent models with disruptions in ASD candidate genes, and we map their phenotypes onto these behavioural paradigms. The goal of this review is to give a comprehensive overview on how ASD symptoms can be studied in animal models and to give guidance for which animal models are appropriate to study specific symptom clusters.

Environmental contaminants such as metal ions can have detrimental effects on aquatic organisms at the molecular, organismal and population levels. In the present work, we examined the interactive effect of Cu(II) and conspecific alarm substance on zebrafish behavioural responses utilizing the novel tank diving assay. To this end, 3 novel tank diving tests (on day 0, 3 and 10 of the experimental phase) were conducted on zebrafish in 4 experimental groups: (1) control: no Cu(II) and no alarm substance, (2) Cu(II) only: exposed to 0.78 μM Cu(II) (25 % of the 240 h LC50) in the home tank for 10 days, (3) alarm substance only: exposed to alarm substance for 6 min concomitant with behavioural testing, and (4) Cu(II) + alarm substance: exposed to 0.78 μM Cu(II) in the home tank for 10 days and treated with alarm substance for 6 min during the behavioural testing. Results showed robust habituation response of zebrafish. Exposure to Cu(II) did not affect the behavioural phenotypes of zebrafish in the novel tank diving test or habituation responses. Alarm substance treatment evoked strong anxiety-like behaviour. Finally, zebrafish in the Cu(II) + alarm substance group lost their sensitivity to alarm substance in repeated novel tank assays throughout the concomitant Cu(II) exposure; this observation is tentatively ascribed to Cu(II)-induced olfactory impairment.

Ferrets (Mustela putorius furo) are a valuable animal model used in biomedical research. Like many animals, ferrets undergo significant variation in body weight seasonally, affected by photoperiod, and these variations complicate the use weight as an indicator of health status. To overcome this requires a better understanding of these seasonal weight changes. We provide a normative weight data set for the female ferret accounting for seasonal changes, and also investigate the effect of fluid regulation on weight change. Female ferrets (n = 39) underwent behavioural testing from May 2017 to August 2019 and were weighed daily, while housed in an animal care facility with controlled light exposure. In the winter (October to March), animals experienced 10 hours of light and 14 hours of dark, while in summer (March to October), this contingency was reversed. Individual animals varied in their body weight from approximately 700 to 1200 g. However, weights fluctuated with light cycle, with animals losing weight in summer, and gaining weight in winter such that they fluctuated between approximately 80% and 120% of their long-term average. Ferrets were weighed as part of their health assessment while experiencing water regulation for behavioural training. Water regulation superimposed additional weight changes on these seasonal fluctuations, with weight loss during the 5-day water regulation period being greater in summer than winter. Analysing the data with a Generalised Linear Model confirmed that the percentage decrease in weight per week was relatively constant throughout the summer months, while the percentage increase in body weight per week in winter decreased through the season. Finally, we noted that the timing of oestrus was reliably triggered by the increase in day length in spring. These data establish a normative benchmark for seasonal weight variation in female ferrets that can be incorporated into the health assessment of an animal's condition.

In recent years our understanding of Parkinson's disease has expanded both in terms of pathological hallmarks as well as relevant genetic influences. In parallel with the aetiological discoveries a multitude of PD animal models have been established. The vast majority of these are rodent models based on environmental, genetic and mechanistic insight. A major challenge in many of these models is their ability to only recapitulate some of the complex disease features seen in humans. Although symptom alleviation and clinical signs are of utmost importance in therapeutic research many of these models lack comprehensive behavioural testing. While non-motor symptoms become increasingly important as early diagnostic markers in PD, they are poorly characterized in rodents. In this review we look at well-established and more recent animal models of PD in terms of behavioural characterization and discuss how they can best contribute to progression in Parkinson's research.

A reliable self-report measure to assess the broad spectrum of face recognition ability (FRA) from developmental prosopagnosia (DP) to super-recognition would make a valuable contribution to initial screening of large populations. We examined the performance of 96 naive participants and seven super-recognisers (SRs) using a range of face and object processing tasks and a newly developed 20-item questionnaire, the Stirling Face Recognition Scale (SFRS). Overall, our findings suggest that young adults have only moderate insight into their FRA, but those who have been previously informed of their (exceptional) performance, the SRs, estimate their FRA accurately. Principal component analysis of SFRS yielded two components. One loads on questions about low ability and correlates with perceptual tasks, and one loads on questions about high FRA and correlates with memory for faces. We recommend that self-report measures of FRA should be used in addition to behavioural testing, to allow for cross-study comparisons, until new, more reliable instruments of self-report are developed. However, self-report measures should not be solely relied upon to identify highly skilled individuals. Implications of these results for theory and applied practice are discussed.

The spatial auditory change complex (ACC) is a cortical response elicited by a change in place of stimulation. There is growing evidence that it provides a useful objective measure of electrode discrimination in cochlear implant (CI) users. To date, the spatial ACC has only been measured in relatively experienced CI users with one type of device. Early assessment of electrode discrimination could allow auditory stimulation to be optimized during a potentially sensitive period of auditory rehabilitation. In this study we used a direct stimulation paradigm to measure the spatial ACC in both pre- and post-lingually deafened adults. We show that it is feasible to measure the spatial ACC in different CI devices and as early as 1 week after CI switch-on. The spatial ACC has a strong relationship with performance on a behavioural discrimination task and in some cases provides information over and above behavioural testing. We suggest that it may be useful to measure the spatial ACC to guide auditory rehabilitation and improve hearing performance in CI users.

Purpose of Review Individuals with autism spectrum disorders (ASD) commonly also suffer from gastrointestinal (GI) dysfunction; however, few animal model studies have systematically examined both ASD and GI dysfunction. In this review, we highlight studies investigating GI dysfunction and alterations in gut microbiota in animal models of ASD with the aim of determining if routinely used microbiology and enteric neurophysiology assays could expand our understanding of the link between the two. Recent Findings Gut–brain axis research is expanding, and several ASD models demonstrate GI dysfunction. The integration of well-established assays for detecting GI dysfunction into standard behavioural testing batteries is needed. Summary Advances in understanding the role of the gut–brain axis in ASD are emerging; however, we outline standard assays for investigating gut–brain axis function in rodents to strengthen future phenotyping studies. Integrating these findings to the field of animal behaviour is one of the next major challenges in autism research.

Fluoxetine (Prozac™) is designed to alter human behaviour; however, because many physiological pathways are conserved across vertebrates, this drug may affect the behaviour of fish living in fluoxetine-polluted environments. Although a number of studies have used behaviour to document the sub-lethal effects of fluoxetine, the repeatability of these effects across experiments, across behavioural contexts, and over different exposure durations are rarely considered. Here, we conducted two experiments and assessed how fluoxetine exposure affected a range of fitness-related behaviours in wild round goby (Neogobius melanostomus). We found that fluoxetine impacts round goby behaviour at high (40 μg/l) doses, but not at environmentally relevant low doses (1 μg/l). In both experiments, an acute 3-day exposure to fluoxetine reduced round goby aggression in multiple behavioural contexts, but had no detectable effect on overall activity or social affiliative behaviour. While a chronic 28-day exposure to fluoxetine exposure still reduced aggression, this reduction was only detectable in one behavioural context. Our findings demonstrate the importance of repeated behavioural testing (both between and within experiments) and contribute to a growing body of literature evaluating the effects of fluoxetine and other pharmaceuticals on animal behaviour.

Aquatic organisms in pharmacology and toxicology research are often exposed to compounds in isolation prior to physiological or behavioural testing. Recent evidence suggests that the presence of conspecifics during a stressful event can modulate behavioural outcomes (called ‘social buffering’) when testing occurs within the same context. It is unknown, however, whether the social environment during exposure interacts with the efficacy of anxiety-altering substances when subsequently tested in the absence of conspecifics. In this study, zebrafish were individually exposed to habitat water or ethanol (1.0% vol/vol) while untreated conspecifics were visually present or absent during dosing. Using the novel object approach test, a validated test of boldness and anxiety-like behaviour, we observed significantly greater effects of ethanol in isolated fish, compared to fish with a view of conspecifics during dosing. These results were not explained by altered locomotion during exposure, which might otherwise increase drug uptake. This highlights the need to consider the social environment during exposure when conducting and interpreting behavioural research involving drug or toxicant exposure.

Background For reasons of cost and ethical concerns, models of neurodegenerative disorders such as Huntington disease (HD) are currently being developed in farm animals, as an alternative to non-human primates. Developing reliable methods of testing cognitive function is essential to determining the usefulness of such models. Nevertheless, cognitive testing of farm animal species presents a unique set of challenges. The primary aims of this study were to develop and validate a mobile operant system suitable for high throughput cognitive testing of sheep. New method We designed a semi-automated testing system with the capability of presenting stimuli (visual, auditory) and reward at six spatial locations. Fourteen normal sheep were used to validate the system using a two-choice visual discrimination task. Four stages of training devised to acclimatise animals to the system are also presented. Results All sheep progressed rapidly through the training stages, over eight sessions. All sheep learned the 2CVDT and performed at least one reversal stage. The mean number of trials the sheep took to reach criterion in the first acquisition learning was 13.9 ± 1.5 and for the reversal learning was 19.1 ± 1.8. Comparison with existing method(s) This is the first mobile semi-automated operant system developed for testing cognitive function in sheep. Conclusions We have designed and validated an automated operant behavioural testing system suitable for high throughput cognitive testing in sheep and other medium-sized quadrupeds, such as pigs and dogs. Sheep performance in the two-choice visual discrimination task was very similar to that reported for non-human primates and strongly supports the use of farm animals as pre-clinical models for the study of neurodegenerative diseases.

In this eighteenth (2016) Annual Review Issue of The Journal of Pathology, we present a collection of 19 invited review articles that cover different aspects of cellular and animal models of disease. These include genetically-engineered models, chemically-induced models, naturally-occurring models, and combinations thereof, with the focus on recent methodological and conceptual developments across a wide range of human diseases.

Kognitivna fleksibilnost pomeni zmožnost spremembe določenega, manj optimalnega, vzorca vedenja v spreminjajočih se razmerah. Ta zmožnost je izjemnega pomena za preživetje in je povezana z mnogimi psihiatričnimi motnjami. Za razumevanje in preučevanje kognitivne fleksibilnosti je bilo razvitih več vedenjskih testov. Za enega pomembnejših in bolj uporabljenih se je izkazal test reverznega učenja. Ta uporablja set različnih vizualnih dražljajev, ki so izmenično nagrajeni ali nenagrajeni. S pomočjo testa so že bile ugotovljene nekatere možganske regije, ki so povezane z nadzorom kognitivne fleksibilnosti. To so predvsem podregije prefrontalne skorje – orbitofrontalna skorja in medialna prefrontalna skorja ter tudi striatum in amigdala. V raziskavi smo zato želeli raziskati vlogo teh podregij in lokalno specifičnega serotoninskega delovanja na kognitivno fleksibilnost. Uporabili smo test reverznega učenja, implementiranega v na dotik občutljiv zaslon, ki je bil izveden na živalskih modelih – podganah. Izvedli smo lokalne farmakološke manipulacije določenih možganskih regij s pomočjo intrakranialnih mikroinfuzij GABAergičnih in glutamatergičnih agensov ter antagonistov serotoninskih receptorjev. Ugotovili smo, da obstaja funkcionalna disociacija med medialno in lateralno orbitofrontalno skorjo. Ti regiji nimata samo različne ampak celo nasprotno funkcijo pri reverznem učenju in nadzoru ter inhibiciji vedenjskih odzivov in naučenega vedenja. Medialna prefrontalna skorja je prav tako pomembna pri reverznem učenju. Specifično serotoninsko signaliziranje v prefrontalni skorji pa se v naši raziskavi ni izkazalo za ključno pri reverznem učenju, kar kliče po nadaljnjih raziskavah. Cognitive flexibility, the ability to change the pattern of behaviour in the face of changing environmental conditions, is crucial for survival and is thus associated with many psychiatric disorders. To asses and study cognitive flexibility in different species many tasks have been developed including reversal learning paradigms. Reversal learning paradigms use a set of different stimuli which are in turn rewarded or not rewarded. They have pointed out important brain regions for the control of cognitive flexibility. Prefrontal cortex and its subregions – orbitofrontal cortex and medial prefrontal cortex with connections to the striatum and amygdala are implicated in cognitive flexibility. Therefore, we wanted to explore the role of prefrontal cortex subregions and site-specific serotonin signalling in cognitive flexibility using touchscreen-based serial reversal behavioural paradigm in rat models. We performed local pharmacological manipulations using intracranial microinfusions of GABAergic and glutamatergic agents as well as serotonin receptor antagonists. The behavioural testing provided us with some important insights. We showed that there is a functional dissociation between medial and lateral orbitofrontal cortex, which not only seems to have separate, but also opposite functions and is important for the inhibition of responses and previously learned behaviour. The medial prefrontal cortex is also implicated in cognitive flexibility. However, specific serotonin signalling modulation failed to produce any significant results and thus needs some further investigation.

Highlights • History of behavioural testing for recognition memory in primates. • Behavioural testing for recognition memory in rodents using spontaneous recognition. • The functional imaging of rodent recognition memory using immediate-early genes. • Network analyses based on structural equation modelling of immediate-early gene data., Research into object recognition memory has been galvanised by the introduction of spontaneous preference tests for rodents. The standard task, however, contains a number of inherent shortcomings that reduce its power. Particular issues include the problem that individual trials are time consuming, so limiting the total number of trials in any condition. In addition, the spontaneous nature of the behaviour and the variability between test objects add unwanted noise. To combat these issues, the ‘bow-tie maze’ was introduced. Although still based on the spontaneous preference of novel over familiar stimuli, the ability to give multiple trials within a session without handling the rodents, as well as using the same objects as both novel and familiar samples on different trials, overcomes key limitations in the standard task. Giving multiple trials within a single session also creates new opportunities for functional imaging of object recognition memory. A series of studies are described that examine the expression of the immediate-early gene, c-fos. Object recognition memory is associated with increases in perirhinal cortex and area Te2 c-fos activity. When rats explore novel objects the pathway from the perirhinal cortex to lateral entorhinal cortex, and then to the dentate gyrus and CA3, is engaged. In contrast, when familiar objects are explored the pathway from the perirhinal cortex to lateral entorhinal cortex, and then to CA1, takes precedence. The switch to the perforant pathway (novel stimuli) from the temporoammonic pathway (familiar stimuli) may assist the enhanced associative learning promoted by novel stimuli.

Key points To shed light on the controversial issue of how chronic immobilization affects cortical output, adult rats were subjected to intracortical microstimulation at different time-points during and after unilateral forelimb casting. After cast application, cortical hypoexcitability appeared bilateral, specific for forelimb area, but stronger in the contralateral-to-cast hemisphere. Cortical excitability progressively decreased over 30 days of immobilization and, after cast removal, steadily increased, but remained partial at 15 days. Cortical application of the GABAA-receptor antagonist bicuculline revealed an impairment of intracortical synaptic connectivity in the forelimb area during the cast period and for up to 15 days after cast removal. Rehabilitation using a rotarod performance protocol did not advance the normalization of normal forelimb map extension and enabled cortical output towards the distal forelimb only in sites that had maintained their excitability. Cortical hypoexcitability following immobilization is caused by reversible impairment of intracortical synaptic connectivity. This may suggest new approaches in conditions that require longterm limb immobilization. Abstract Experimental and clinical studies have attempted to evaluate the changes in cortical activity seen after immobilization-induced longterm sensorimotor restriction, although results remain controversial. We used intracortical microstimulation (ICMS), which provides topographic movement representations of the motor areas in both hemispheres with optimal spatial characterization, combined with behavioural testing to unravel the effects of limb immobilization on movement representations in the rat primary motor cortex (M1). Unilateral forelimb immobilization in rats was achieved by casting the entire limb and leaving the cast in place for 15 or 30 days. Changes in M1 were bilateral and specific for the forelimb area, but were stronger in the contralateral-to-cast hemisphere. The threshold current required to evoke forelimb movement increased progressively over the period in cast, whereas the forelimb area size decreased and the non-excitable area size increased. Casting resulted in a redistribution of proximal/distal movement representations: proximal forelimb representation increased, whereas distal representation decreased in size. ICMS after cast removal showed a reversal of changes, which remained partial at 15 days. Local application of the GABAA-antagonist bicuculline revealed the impairment of cortical synaptic connectivity in the forelimb area during the period of cast and for up to 15 days after cast removal. Six days of rehabilitation using a rotarod performance protocol after cast removal did not advance map size normalization in the contralateral-to-cast M1 and enabled the cortical output towards the distal forelimb only in sites that had maintained their excitability. These results are relevant to our understanding of adult M1 plasticity during and after sensorimotor deprivation, and to new approaches to conditions that require longterm limb immobilization.

In mammals, weaning constitutes an important phase in the progression to adulthood. It comprises the termination of suckling and is characterized by several changes in the behaviour of both mother and offspring. Furthermore, numerous studies in rodents have shown that the time point of weaning shapes the behavioural profile of the young. Most of these studies, however, have focused on 'early weaning', while relatively little work has been done to study 'late weaning' effects. The aim of the present study was therefore to explore behavioural effects of 'late weaning', and furthermore to gain insights into modulating effects of weaning age on the consistency of behavioural expressions over time. In total, 25 male and 20 female C57BL/6J mice, weaned after three (W3) or four (W4) weeks of age, were subjected to a series of behavioural paradigms widely used to assess anxiety-like behaviour, exploratory locomotion, and nest building performance. Behavioural testing took place with the mice reaching an age of 20 weeks and was repeated eight weeks later to investigate the stability of behavioural expressions over time. At the group level, W4 mice behaved less anxious and more explorative than W3 animals in the Open Field and Novel Cage, while anxiety-like behaviour on the Elevated Plus Maze was modulated by a weaning-age-by-sex interaction. Furthermore, weaning age shaped the degree of behavioural stability over time in a sex-specific way. While W3 females and W4 males displayed a remarkable degree of behavioural stability over time, no such patterns were observed in W3 males and W4 females. Adding to the existing literature, we could thus confirm that effects of weaning age do indeed exist when prolonging this phase, and were furthermore able to provide first evidence for the impact of weaning age and sex on the consistency of behavioural expressions over time.

Contains fulltext : 167237.pdf (Publisher’s version ) (Closed access) 'Big Data' and 'Population Imaging' are becoming integral parts of inspiring research aimed at delineating the biological underpinnings of psychiatric disorders. The scientific strategies currently associated with big data and population imaging are typically embedded in so-called discovery science, thereby pointing to the hypothesis-generating rather than hypothesis-testing nature of discovery science. In this issue, Yihong Zhao and F. Xavier Castellanos provide a compelling overview of strategies for discovery science aimed at progressing our understanding of neuropsychiatric disorders. In particular, they focus on efforts in genetic and neuroimaging research, which, together with extended behavioural testing, form the main pillars of psychopathology research.

Purpose: Grating acuity values obtained with preferential looking techniques do not correspond to test results obtained with letter charts. The aim of the study was to investigate the agreement between grating acuity and other acuity tests. Methodc Twenty-eight adult patients with strabismic amblyopia were assessed with the preferential looking-method and other linear and single letter and symbol tests. Results: Assessment with preferential looking regularly led to an overestimation of the acuity values, but between preferential looking and single optotypes there was a much better agreement. This is most likely due to ‘crowding’ in strabismic amblyopia. A crowding ratio was calculated in the amblyopic eye, and crowding was found to be more prominent for comparisons of preferential looking with optotypes in rows, than for preferential looking and single optotypes. Conclusions: Strabismic amblyopia cannot be reliably identified with grating acuity. Preferential looking-testing is therefore of limited use as a screening method for the detection of amblyopia, but preferential looking could still be useful in the assessment and treatment.

Objectives: We sought to determine whether rotenone, a commonly used pesticide, exhibits neurotoxicity in zebrafish by causing dopamine neuron loss through rotenone-induced oxidative damage. Methods: We exposed transgenic zebrafish embryos expressing green fluorescent protein under the control of the cis-regulatory elements of dopamine transporter (dat) to rotenone to determine the neurotoxic effects of rotenone on dopamine neuron abundance and pattern distribution, as well as the presence of apoptotic markers. The oxidative stress potential of rotenone on embryos was assessed using a live MitoSOX Red assay, and behavioural testing on adult zebrafish was assessed using video recordings of midline crossing events. Results: Zebrafish embryos treated with rotenone displayed a 50% reduction in dopamine neurons in the ventral diencephalon when exposed to 30µM rotenone (n=6, p

A functional MRI-naming paradigm was employed to investigate the neural correlates of successful phonological treatment in an individual with impaired word-retrieval poststroke. Items to be treated were selected in a pretest. A subsequent pretreatment fMRI scan measured brain activity during unsuccessful naming of objects to be treated and during successful naming of a comparison set of items. A phonological naming treatment was delivered 2 to 3 times weekly over 3 weeks with posttreatment behavioural testing indicating 100% accuracy on treated items. A posttreatment fMRI scan indicated that compared to the pretreatment scan, successful naming of treated items was associated with significantly increased brain activity in a number of left and right hemisphere regions including the left inferior parietal cortex which has been associated with phonological processing in healthy individuals, suggesting a candidate neural mechanism for sound-based treatments of naming.

ATP released from damaged or inflamed tissues can act at P2X receptors expressed on primary afferent neurones. The resulting depolarization can initiate action potentials that are interpreted centrally as pain. P2X3 subunits are found in a subset of small-diameter, primary afferent neurones, some of which are also sensitive to capsaicin. They can form homo-oligomeric channels, or they can assemble with P2X2 subunits into hetero-oligomers. Studies with antagonists selective for P2X3-containing receptors, experiments with antisense oligonucleotides to reduce P2X3 subunit levels, and behavioural testing of P2X3 knock-out mice, all suggest a role for the P2X2/3 receptor in the signalling of chronic inflammatory pain and some features of neuropathic pain. The availability of such tools and experimental approaches promises to accelerate our understanding of the other physiological roles for P2X receptors on primary afferent neurones.

Birth is a particularly vulnerable time for acquiring brain injury. Unfortunately, very few treatments are available for those affected. Here we explore the effectiveness of prenatal intervention in an animal model of early brain damage. We used a complex housing paradigm as a form of prenatal enrichment. Six nulliparous dams and one male rat were placed in complex housing (condomom group) for 12 hours per day until the dams' delivered their pups. At parturition the dams were left in their home (standard) cages with their pups. Four dams were housed in standard cages (cagemom group) throughout pregnancy and with their pups until weaning. At postnatal day 3 (P3) infants of both groups received frontal cortex removals or sham surgery. Behavioural testing began on P60 and included the Morris water task and a skilled reaching task. Brains were processed for Golgi analyses. Complex housing of the mother had a significant effect on the behaviour of their pups. Control animals from the condomom group outperformed those of the cagemom group in the water task. Condomom animals with lesions performed better than their cagemom cohorts in both the water task and in skilled reaching. Condomom animals showed an increase in cortical thickness at anterior planes and thalamic area at both anterior and posterior regions. Golgi analyses revealed an increase in spine density. These results suggest that prenatal enrichment alters brain organization in manner that is prophylactic for perinatal brain injury. This result could have significant implications for the prenatal management of infants expected to be at risk for difficult birth.

Item does not contain fulltext The establishment of robust and replicable behavioural testing paradigms with translational value for psychiatric diseases is a major step forward in developing and testing etiology-directed treatment for these complex disorders. Based on the existing literature, we have generated an inventory of applied rodent behavioural testing paradigms relevant to autism spectrum disorders (ASD). This inventory focused on previously used paradigms that assess behavioural domains that are affected in ASD, such as social interaction, social communication, repetitive behaviours and behavioural inflexibility, cognition as well as anxiety behaviour. A wide range of behavioural testing paradigms for rodents were identified. However, the level of face and construct validity is highly variable. The predictive validity of these paradigms is unknown, as etiology-directed treatments for ASD are currently not on the market. To optimise these studies, future efforts should address aspects of reproducibility and take into account data about the neurodevelopmental underpinnings and trajectory of ASD. In addition, with the increasing knowledge of processes underlying ASD, such as sensory information processes and synaptic plasticity, phenotyping efforts should include multi-level automated analysis of, for example, representative task-related behavioural and electrophysiological read-outs.

In 1968, Melzack and Casey published a pivotal paper in which they described a model of the sensory, motivational and cognitive determinants of pain. Much of Ronald Melzack's career has been dedicated to exploring this complex relationship. Of primary importance is the influence that Ron has had on the development of some of the current research interests of the present author. For instance, Ron's theoretical approach provided the underpinnings for the development of an additional behavioural testing technique in rat models of nociception that has been recently developed in the author's laboratory. The test is based on the assumption that escape and avoidance of a stimulus are clear indications that the stimulus is aversive. It is proposed that behavioural test paradigms based on this approach provide additional information beyond the traditional measures of stimulus-evoked reflexive responses. With these tests, the underlying assumption that different aspects of pain are processed by different neural substrates can be tested.

Background: Disruption of circadian rhythms is associated with several deleterious health consequences and cognitive impairment. It is estimated that as many as one in five workers are exposed to this risk factor due to experiencing some degree of chronodisruption by way of recurring patterns of shift work. It is not presently clear therefore how efficiently the mammalian circadian system entrains to alternative light/dark cycles such as those found in shift work schedules. Methods: The present study examines male CD-1 mice exposed to three different paradigms of rapidly rotating shift work-like light/dark manipulations compared to control animals maintained on a standard 12:12 h light/dark cycle. Results: Analysis of circadian patterns of behaviour under such conditions reveals that for fast rotating schedules of light/dark there is minimal circadian entrainment. Further, when placed in constant conditions after a period under the “shift work” lighting conditions there were changes to circadian period associated with the shift work schedules. In contrast to previous studies the shift work-like conditions did not produce changes in animal bodyweight. Behavioural testing suggests possible anxiogenic and hyperactive outcomes dependent on rotation speed as animals displayed open field thigmotaxis and hyperlocomotion. Conclusion: These results indicate that exposure to alternating patterns of light and dark as experienced by millions of shift workers may produce long-lasting changes in both mammalian circadian and neurobehavioural systems.

BackgroundTo date, experimental and preclinical studies on neuropsychiatric conditions have almost exclusively been performed in experimentally-induced animal models and have only rarely relied upon an ethological approach where animals have been observed in more naturalistic settings. The laboratory species of choice has been the rodent while the potential of more closely-related non-human primates have remained largely underexplored.MethodsThe present study, therefore, aimed at investigating the possible existence of spontaneous atypical/abnormal behaviours displayed by 40 cynomolgus macaques in captive conditions using an unbiased ethological scan-sampling analysis followed by multifactorial correspondence analysis and a hierarchical clustering.ResultsThe study identified five distinct profiles (groups A to E) that significantly differed on several behaviours, body postures, body orientations, gaze directions and locations in the cage environment. We suggest that animals from the low n groups (D and E) present depressive-like and anxious-like symptoms, reminiscent of depressive and generalized anxiety disorders. Inter-individual differences were highlighted through unbiased ethological observations of spontaneous behaviours and associated parameters, although these were not associated with differences in plasma or cerebrospinal fluid levels of either stress-related hormones or monoamines, i.e. in accordance with the human situation.ConclusionsNo interventional behavioural testing was required to discriminate between 3 typical and 2 atypical ethologically-defined behavioural profiles, reminiscent of certain depressive-like and anxiety-like symptoms. The use of unbiased behavioural observations might, thus, allow the identification of animal models of human mental/behavioural disorders and their most appropriate control groups.

Depression is a heterogeneous disorder displaying a range of symptoms including feelings of despair and social withdrawal. Social isolation may complicate the progression of depression and have effects on both behaviour and physiology. The aim of this study was to investigate the effects of social isolation on behavioural and metabolic parameters in a genetic rat model of depression, the Flinders Sensitive and Resistant Line (FSL/FRL) rats. Rats were housed either individually (social isolation) or pair-housed for 5 weeks, and subjected to behavioural testing and metabolic evaluation. We found that social isolation erased the characteristic difference in depressive-like behaviour, measured as immobility in the forced swim test, between the FSL and FRL rats. Social isolation affected both strains equally in impairing object recognition memory, while leading to an increased explorative behaviour in the elevated plus maze test. Surprisingly, single-housed FRL rats showed an increased food intake compared to pair-housed FRL rats, whereas no difference in food intake or body weight was evident in FSL rats. Our results indicate that social isolation for 5 weeks causes behavioural alterations, independent of strain. As the changes in appetite were only observed in the FRL rats, this may suggest that this strain responds to the stress of isolation by a change in feeding behaviour. http://dx.doi.org/10.1016/j.bbr.2012.01.050

Alan Cowey, who died in December, was a leading figure in the field of physiological psychology for four decades and a pioneer in cognitive neuroscience long before the term was coined. He published over 300 papers, but the large number is less important than the fact that many of them report discoveries. The number and weight of his firsts created enduring fields of research in laboratories around the world. His early work established new standards for behavioural testing of the non-human primate visual system.

To date, the reliability of induction of a depressive-like state using chronic stress models is confronted by many methodological limitations. We believe that the modifications to the stress paradigm in mice proposed herein allow some of these limitations to be overcome. Here, we discuss a variant of the standard stress paradigm, which results in anhedonia. This anhedonic state was defined by a decrease in sucrose preference that was not exhibited by all animals. As such, we propose the use of non-anhedonic, stressed mice as an internal control in experimental mouse models of depression. The application of an internal control for the effects of stress, along with optimized behavioural testing, can enable the analysis of biological correlates of stress-induced anhedonia versus the consequences of stress alone in a chronic-stress depression model. This is illustrated, for instance, by distinct physiological and molecular profiles in anhedonic and non-anhedonic groups subjected to stress. These results argue for the use of a subgroup of individuals who are negative for the induction of a depressive phenotype during experimental paradigms of depression as an internal control, for more refined modeling of this disorder in animals.

Depression affects around 320 million people worldwide. Growing evidence proposes the immune system to be the core interface between psychosocial stress and the neurobiological and behavioural features of depression. Many studies have identified purinergic signalling via the P2X7 receptor (P2X7R) to be of great importance in depression genesis yet only a few have evaluated P2X7R antagonists in chronic stress-based depression models. This review summarizes their findings and analyses their methodology. The four available studies used three to nine weeks of unpredictable, chronic mild stress or unpredictable, chronic stress in male mice or rats. Stress paradigm composition varied moderately, with stimuli being primarily psychophysical rather than psychosocial. Behavioural testing was performed during or after the last week of stress application and resulted in depressive-like behaviours, immune changes (NLRP3 assembly, interleukin-1β level increase, microglia activation) and neuroplasticity impairment. During the second half of each stress paradigm, a P2X7R antagonist (Brilliant Blue G, A-438079, A-804598) was applied. Studies differed with regard to antagonist dosage and application timing. Nonetheless, all treatments attenuated the stress-induced neurobiological changes and depressive-like behaviours. The evidence at hand underpins the importance of P2X7R signalling in chronic stress and depression. However, improvements in study planning and reporting are necessary to minimize experimental bias and increase data purview. To achieve this, we propose adherence to the Research Domain Criteria and the STRANGE framework.

Rats were given sham operations, vehicle injections, or injections of the axon-sparing excitotoxin ibotenic acid into the septum. In Experiment 1, behavioural testing commenced 16 days after the operation; in Experiment 2 behavioural testing commenced following testing on another task, 31 days after the operation. The rats were trained to run in an alley for food reward given on every trial (Continuous Reinforcement, CR) or on a random fifty percent of trials (Partial Reinforcement, PR) and then the running response was extinguished. All the experimental groups showed the normal partial reinforcement extinction effect (PREE) in that PR-trained animals were significantly more resistant to extinction than CR-trained animals. However the rats with ibotenic acid lesions also showed a significant decrease in resistance to extinction regardless of training condition. The same pattern of results was seen at each of the two post-operative testing times. The results were thus readily replicable, and entirely unlike previous reports of the behavioural effects on this task of conventional septal lesions of equivalent size. In Experiment 3, neurochemical analysis of the hippocampus in rats with ibotenic acid-induced lesions demonstrated that choline acetyl-transferase levels were reduced to the same extent as in rats with comparable conventional lesions.

1. Three kittens were reared in visual environments that consisted of stripes at one of three orientations - horizontal, right oblique, or left oblique. Two additional cats were reared as controls. One of these matured viewing right and left oblique stripes on alternate days. The other experienced a normal visual environment. 2. Following the completion of rearing, and after several weeks of normal visual experience, behavioural testing of the stripe-reared animals demonstrated a deficit in visual acuity for orientations which were not present in the early visual environment. No comparable deficit emerged for either of the control cats. 3. Following 1-3 years of further, normal, visual experience, each of the cats was shipped separately to California where single units were recorded from area 17 of the visual cortex and an effort made to guess the early visual history of each animal which was unknown to the experimenters. Cell samples from each experimental cat and the normal control cat allowed the physiologist to guess their early visual experience correctly. The control cat which matured viewing orthogonal sets of oblique stripes on alternate days demonstrated a bias for horizontal contours in his cell sample. In contrast to units recorded from normal cats, about 80% of which are binocular, only about 30% of the cells recorded from the stripe-reared animals could be influenced by both eyes.

In order to test therapeutics, functional assessments are required. In pre-clinical stroke research, there is little consensus regarding the most appropriate behavioural tasks to assess deficits, especially when testing over extended times in milder models with short occlusion times and small lesion volumes. In this study, we comprehensively assessed 16 different behavioural tests, with the aim of identifying those that show robust, reliable and stable deficits for up to two months. These tasks are regularly used in stroke research, as well as being useful for examining striatal dysfunction in models of Huntington’s and Parkinson’s disease. Two cohorts of male Wistar rats underwent the intraluminal filament model of middle cerebral artery occlusion (30 min) and were imaged 24 h later. This resulted in primarily subcortical infarcts, with a small amount of cortical damage. Animals were tested, along with sham and naïve groups at 24 h, seven days, and one and two months. Following behavioural testing, brains were processed and striatal neuronal counts were performed alongside measurements of total brain and white matter atrophy. The staircase, adjusting steps, rotarod and apomorphine-induced rotations were the most reliable for assessing long-term deficits in the 30 min transient middle cerebral artery occlusion model of stroke.

Handling laboratory animals during test procedures is an important source of stress that may impair reliability of test responses. Picking up mice by the tail is aversive, stimulating stress and anxiety. Responses among anxious animals can be confounded further by neophobia towards novel test environments and avoidance of test stimuli in open areas. However, handling stress can be reduced substantially by using a handling tunnel, or cupping mice without restraint on the open hand. Here we establish whether non-aversive handling, brief prior familiarisation with the test arena and alternative stimulus placement could significantly improve performance of mice in behavioural tests. We use a simple habituation-dishabituation paradigm in which animals must discriminate between two urine stimuli in successive trials, a task that mice can easily perform. Tail handled mice showed little willingness to explore and investigate test stimuli, leading to poor test performance that was only slightly improved by prior familiarisation. By contrast, those handled by tunnel explored readily and showed robust responses to test stimuli regardless of prior familiarisation or stimulus location, though responses were more variable for cup handling. Our study shows that non-aversive tunnel handling can substantially improve mouse performance in behavioural tests compared to traditional tail handling.