Measuring vision using innate behaviours in mice with intact and impaired retina function.

Measuring vision in rodents is a critical step for understanding vision, improving models of human disease, and developing therapies. Established behavioural tests for perceptual vision, such as the visual water task, rely on learning. The learning process, while effective for sighted animals, can be laborious and stressful in animals with impaired vision, requiring long periods of training. Current tests that that do not require training are based on sub-conscious, reflex responses (e.g. optokinetic nystagmus) that don't require involvement of visual cortex and higher order thalamic nuclei. A potential alternative for measuring vision relies on using visually guided innate defensive responses, such as escape or freeze, that involve cortical and thalamic circuits. In this study we address this possibility in mice with intact and degenerate retinas. We first develop automatic methods to detect behavioural responses based on high dimensional tracking and changepoint detection of behavioural time series. Using those methods, we show that visually guided innate responses can be elicited using parametisable stimuli, and applied to describing the limits of visual acuity in healthy animals and discriminating degrees of visual dysfunction in mouse models of retinal degeneration.

Subluxation-related ulnar neuropathy (SUN) syndrome related to distal radioulnar joint instability.

Ulnar neuropathy coexistent with distal radioulnar joint (DRUJ) instability has previously been observed in our practice. The aim of this study was to define this phenomenon and investigate the hypothesis that the cause of this intermittent, positional ulnar neuropathy is related to kinking of the ulnar nerve about the DRUJ. Ulna neuropathy was present in 10/51 (19.6%) of a historical cohort of patients who presented with DRUJ instability. Nine subsequent patients with DRUJ instability and coexistent ulnar neuropathy underwent 3-T magnetic resonance imaging to better understand the mechanism of the observed syndrome. Both 3D qualitative and quantitative analyses were used to assess the presence of nerve 'kinking', displacing the nerve from its normal course and causing nerve compression/distraction in the distal forearm and Guyon's canal. Results of the quantitative analysis were statistically significant (p < 0.05). The clinical features of the condition have been delineated and termed subluxation-related ulnar neuropathy or SUN syndrome. The imaging study was a level II diagnostic study.

3D brain segmentation using active appearance models and local regressors.

We describe an efficient and accurate method for segmenting sets of subcortical structures in 3D MR images of the brain. We first find the approximate position of all the structures using a global Active Appearance Model (AAM). We then refine the shape and position of each structure using a set of individual AAMs trained for each. Finally we produce a detailed segmentation by computing the probability that each voxel belongs to the structure, using regression functions trained for each individual voxel. The models are trained using a large set of labelled images, using a novel variant of 'groupwise' registration to obtain the necessary image correspondences. We evaluate the method on a large dataset, and demonstrate that it achieves results comparable with some of the best published.

Stress potentiation of morphine-induced dopamine efflux in the nucleus accumbens shell is dependent upon stressor uncontrollability and is mediated by the dorsal raphe nucleus.

A single session of uncontrollable (inescapable tailshock, IS), but not controllable (escapable tailshock, ES), stress is known to selectively potentiate subsequent morphine-conditioned place preference in a dorsal raphe nucleus (DRN) serotonin (5-HT) dependent manner. Here, in vivo microdialysis is used to test the hypothesis that prior IS, but not ES, will potentiate morphine-induced dopamine (DA) efflux in the nucleus accumbens (NAc) shell and that this will occur by a pathway involving DRN 5-HT neurons. Male Sprague-Dawley rats were exposed to yoked IS, ES, or no stress. Twenty-four hours later, morphine (3 mg/kg s.c.) or saline was administered during microdialysis. As predicted, prior IS selectively potentiated morphine-induced DA, but not 5-HT, efflux in the NAc. This potentiation was due to morphine's action in the DRN because it was blocked by intra-DRN microinjection of the opioid antagonist naltrexone (10 microg). IS potentiation of morphine-induced DA efflux in the NAc was also dependent upon activation of 5-HT neurons in the DRN because it was blocked by intra-DRN microinjection of the 5-HT1A autoreceptor agonist 8-hydroxy-2-di-n-(propylamino)-tetralin (1 microg). No effect of IS was found on morphine-induced 5-HT or DA efflux in the ventral tegmental area. These results suggest a neural substrate for stress potentiation of morphine reward involving 5-HT neurotransmission in the DRN.

Robust tracking and posture description for laboratory rodents using active shape models.

We are in the process of developing an automated image analysis system, which uses deformable models of shape, learned from image examples, to interpret video images of rodents. Active shape models provide a compact description of the shape of the animal in a way that enables the postures the differentiate various behaviors to be distinguished. They also model the image profile across the shape boundary. We show how these features allow automatic, robust segmentation of the explicit object of interest. Rather than just detecting movement or changes from background in the image, the system can focus on objects that are of the correct shape and appearance. The modeling of the image profiles also allows the system to distinguish between the actual animal and image artifacts. We show how these techniques are being extended to extract postural information, which can then be integrated with positional data to produce a model of behavior.

Intrathecal HIV-1 envelope glycoprotein gp120 induces enhanced pain states mediated by spinal cord proinflammatory cytokines.

Perispinal (intrathecal) injection of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein gp120 creates exaggerated pain states. Decreases in response thresholds to both heat stimuli (thermal hyperalgesia) and light tactile stimuli (mechanical allodynia) are rapidly induced after gp120 administration. gp120 is the portion of HIV-1 that binds to and activates microglia and astrocytes. These glial cells have been proposed to be key mediators of gp120-induced hyperalgesia and allodynia because these pain changes are blocked by drugs thought to affect glial function preferentially. The aim of the present series of studies was to determine whether gp120-induced pain changes involve proinflammatory cytokines [interleukin-1beta (IL-1) and tumor necrosis factor-alpha (TNF-alpha)], substances released from activated glia. IL-1 and TNF antagonists each prevented gp120-induced pain changes. Intrathecal gp120 produced time-dependent, site-specific increases in TNF and IL-1 protein release into lumbosacral CSF; parallel cytokine increases in lumbar dorsal spinal cord were also observed. Intrathecal administration of fluorocitrate (a glial metabolic inhibitor), TNF antagonist, and IL-1 antagonist each blocked gp120-induced increases in spinal IL-1 protein. These results support the concept that activated glia in dorsal spinal cord can create exaggerated pain states via the release of proinflammatory cytokines.

Sciatic inflammatory neuritis (SIN): behavioral allodynia is paralleled by peri-sciatic proinflammatory cytokine and superoxide production.

We have recently developed a model of sciatic inflammatory neuritis (SIN) to assess how immune activation near peripheral nerves influences somatosensory processing. Administration of zymosan (yeast cell walls) around a single sciatic nerve produces dose-dependent low-threshold mechanical allodynia without thermal hyperalgesia. Low (4 microg) doses produce both territorial and extraterritorial allodynia restricted to the injected hindleg. In contrast, higher (40 microg) doses produce territorial and extraterritorial allodynias of both hindlegs, an effect not accounted for by systemic spread of the zymosan. The aim of these experiments was to determine whether these behavioral allodynias were correlated with immunological and/or anatomical changes in or around the sciatic nerve. These experiments reveal that zymosan-induced bilateral allodynia was associated with the following: (a) increased release of both interleukin-1beta and tumor necrosis factor-alpha from peri-sciatic immune cells; (b) increased release of reactive oxygen species from perisciatic immune cells; (c) no change in circulating levels of proinflammatory cytokine; (d) no apparent zymosan-induced influx of immune cells into the sciatic nerve from the endoneurial blood vessels; (e) mild edema of the sciatic, which was predominantly restricted to superficial regions closest to the peri-sciatic immune cells; and (f) no anatomic evidence of changes in either the ipsilateral saphenous nerve or contralateral sciatic nerve that could account for the appearance of extraterritorial or contralateral ("mirror") allodynia, respectively. No reliable differences were found when the low-dose zymosan was compared with vehicle controls. Taken together, these data suggest that substances released by peri-sciatic immune cells may induce changes in the sciatic nerve, leading to the appearance of bilateral allodynia.

The memory clinic. A new approach to the detection of early dementia.

Dementia is commonly diagnosed at a time of major domestic breakdown, when symptoms are severe and family and community patience has been eroded. In order to encourage early referral and identification of patients with treatable conditions, a Memory Clinic is held at the University Hospital in Cardiff. The clinic provides a service for general practitioners, patients and carers, offering a multidisciplinary assessment, early diagnosis, and the planning of an individual 'care package' for each patient. It also has an important educational function and acts as a valuable research resource. A review of 100 consecutive patients recently referred found that 44 had Alzheimer-type dementia and 14 had a probable vascular component to their dementia. This latter group of patients were younger, more likely to be male and had a shorter duration of symptoms. One-third of patients were not dementing, and presenting symptoms in 19 of these dramatically improved with appropriate management, particularly of depression. 43 patients had other previously unrecognised, but treatable, medical conditions. Thus, early diagnosis enables the development of a clear plan for care, existing drug treatment can be rationalised, and appropriate treatment started at a stage when it is potentially of most value.