Temporal dissociation of phencyclidine: Induced locomotor and social alterations in rats using an automated homecage monitoring system – implications for the 3Rs and preclinical drug discovery

Background: Rodent behavioural assays are widely used to delineate the mechanisms of psychiatric disorders and predict the efficacy of drug candidates. Conventional behavioural paradigms are restricted to short time windows and involve transferring animals from the homecage to unfamiliar apparatus which induces stress. Additionally, factors including environmental perturbations, handling and the presence of an experimenter can impact behaviour and confound data interpretation. To improve welfare and reproducibility these issues must be resolved. Automated homecage monitoring offers a more ethologically relevant approach with reduced experimenter bias. Aim: To evaluate the effectiveness of an automated homecage system at detecting locomotor and social alterations induced by phencyclidine (PCP) in group-housed rats. PCP is an NMDA receptor antagonist commonly utilised to model aspects of schizophrenia. Methods: Rats housed in groups of 3 were implanted with radio frequency identification (RFID) tags. Each homecage was placed over a RFID reader baseplate for the automated monitoring of the social and locomotor activity of each individual rat. For all rats, we acquired homecage data for 24 h following administration of both saline and PCP (2.5 mg/kg). Results: PCP resulted in significantly increased distance travelled from 15 to 60 min post injection. Furthermore, PCP significantly enhanced time spent isolated from cage-mates and this asociality lasted from 60 to 105 min post treatment. Conclusions: Unlike conventional assays, in-cage monitoring captures the temporal duration of drug effects on multiple behaviours in the same group of animals. This approach could benefit psychiatric preclinical drug discovery though improved welfare and increased between-laboratory replicability

Locating bugs without looking back

Bug localisation is a core program comprehension task in software maintenance: given the observation of a bug, e.g. via a bug report, where is it located in the source code? Information retrieval (IR) approaches see the bug report as the query, and the source code files as the documents to be retrieved, ranked by relevance. Such approaches have the advantage of not requiring expensive static or dynamic analysis of the code. However, current state-of-the-art IR approaches rely on project history, in particular previously fixed bugs or previous versions of the source code. We present a novel approach that directly scores each current file against the given report, thus not requiring past code and reports. The scoring method is based on heuristics identified through manual inspection of a small sample of bug reports. We compare our approach to eight others, using their own five metrics on their own six open source projects. Out of 30 performance indicators, we improve 27 and equal 2. Over the projects analysed, on average we find one or more affected files in the top 10 ranked files for 76% of the bug reports. These results show the applicability of our approach to software projects without history

Responses of primate LGN cells to moving stimuli involve a constant background modulation by feedback from area MT

The feedback connections from the cortical motion area middle temporal (MT), to layer 6 of the primary visual cortex (V1), have the capacity to drive a cascaded feedback influence from the layer 6 cortico-geniculate cells back to the lateral geniculate nucleus (LGN) relay cells. This introduces the possibility of a re-entrant motion signal affecting the relay of the retinal input through the LGN to the visual cortex. The question is whether the response of LGN cells to moving stimuli involves a component derived from this feedback. By producing a reversible focal pharmacological block of the activity of an MT direction column we show the presence of such an influence from MT on the responses of magno, parvo and koniocellular cells in the macaque LGN. The pattern of effect in the LGN reflects the direction bias of the MT location inactivated. This suggests a moving stimulus is captured by iterative interactions in the circuit formed by visual cortical areas and visual thalamus

Stimulus Motion Propels Traveling Waves in Binocular Rivalry

State transitions in the nervous system often take shape as traveling waves, whereby one neural state is replaced by another across space in a wave-like manner. In visual perception, transitions between the two mutually exclusive percepts that alternate when the two eyes view conflicting stimuli (binocular rivalry) may also take shape as traveling waves. The properties of these waves point to a neural substrate of binocular rivalry alternations that have the hallmark signs of lower cortical areas. In a series of experiments, we show a potent interaction between traveling waves in binocular rivalry and stimulus motion. The course of the traveling wave is biased in the motion direction of the suppressed stimulus that gains dominance by means of the wave-like transition. Thus, stimulus motion may propel the traveling wave across the stimulus to the extent that the stimulus motion dictates the traveling wave's direction completely. Using a computational model, we show that a speed-dependent asymmetry in lateral inhibitory connections between retinotopically organized and motion-sensitive neurons can explain our results. We argue that such a change in suppressive connections may play a vital role in the resolution of dynamic occlusion situations

Identification of Altered Evoked and Non-Evoked Responses in a Heterologous Mouse Model of Endometriosis-Associated Pain

The aim of this study was to develop and refine a heterologous mouse model of endometriosis-associated pain in which non-evoked responses, more relevant to the patient experience, were evaluated. Immunodeficient female mice (N = 24) were each implanted with four endometriotic human lesions (N = 12) or control tissue fat (N = 12) on the abdominal wall using tissue glue. Evoked pain responses were measured biweekly using von Frey filaments. Non-evoked responses were recorded weekly for 8 weeks using a home cage analysis (HCA). Endpoints were distance traveled, social proximity, time spent in the center vs. outer areas of the cage, drinking, and climbing. Significant differences between groups for von Frey response, climbing, and drinking were detected on days 14, 21, and 35 post implanting surgery, respectively, and sustained for the duration of the experiment. In conclusion, a heterologous mouse model of endometriosis-associated evoked a non-evoked pain was developed to improve the relevance of preclinical models to patient experience as a platform for drug testing

A Multi-Stage Model for Fundamental Functional Properties in Primary Visual Cortex

Many neurons in mammalian primary visual cortex have properties such as sharp tuning for contour orientation, strong selectivity for motion direction, and insensitivity to stimulus polarity, that are not shared with their sub-cortical counterparts. Successful models have been developed for a number of these properties but in one case, direction selectivity, there is no consensus about underlying mechanisms. We here define a model that accounts for many of the empirical observations concerning direction selectivity. The model describes a single column of cat primary visual cortex and comprises a series of processing stages. Each neuron in the first cortical stage receives input from a small number of on-centre and off-centre relay cells in the lateral geniculate nucleus. Consistent with recent physiological evidence, the off-centre inputs to cortex precede the on-centre inputs by a small (∼4 ms) interval, and it is this difference that confers direction selectivity on model neurons. We show that the resulting model successfully matches the following empirical data: the proportion of cells that are direction selective; tilted spatiotemporal receptive fields; phase advance in the response to a stationary contrast-reversing grating stepped across the receptive field. The model also accounts for several other fundamental properties. Receptive fields have elongated subregions, orientation selectivity is strong, and the distribution of orientation tuning bandwidth across neurons is similar to that seen in the laboratory. Finally, neurons in the first stage have properties corresponding to simple cells, and more complex-like cells emerge in later stages. The results therefore show that a simple feed-forward model can account for a number of the fundamental properties of primary visual cortex

Analysis of individual mouse activity in group housed animals of different inbred strains using a novel automated home cage analysis system.

Central nervous system disorders such as autism as well as the range of neurodegenerative diseases such as Huntington's disease are commonly investigated using genetically altered mouse models. The current system for characterizing these mice usually involves removing the animals from their home-cage environment and placing them into novel environments where they undergo a battery of tests measuring a range of behavioral and physical phenotypes. These tests are often only conducted for short periods of times in social isolation. However, human manifestations of such disorders are often characterized by multiple phenotypes, presented over long periods of time and leading to significant social impacts. Here, we have developed a system which will allow the automated monitoring of individual mice housed socially in the cage they are reared and housed in, within established social groups and over long periods of time. We demonstrate that the system accurately reports individual locomotor behavior within the group and that the measurements taken can provide unique insights into the effects of genetic background on individual and group behavior not previously recognized