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P J Coffey

Publications and source records attributed to P J Coffey.

At least 19 recordsLinked to original sources
PubMed2007

Constant illumination causes spatially discrete dopamine depletion in the normal and degenerate retina.

A fully competent retinal dopamine system underpins normal visual function. Although this system is known to be compromised both prior to and during retinal degeneration, the spatial dynamics of dopamine turnover within the degenerate retina are at present unknown. Here, using immunohistochemistry for dopamine in combination with quantitative optical density measurements, we reveal a global decline in retinal dopamine levels in the light adapted RCS dystrophic rat, which is restricted to plexiform layers in the dark. Pharmacological blockade of dopamine production with the drug alpha-methyl-p-tyrosine (AMPT) allows the direct visualisation of dopamine depletion in normal and degenerate retina in response to constant illumination. In normal retinae this effect is spatially discrete, being undetectable in perikarya and specific to amacrine cell fibres in sublamina 1 of the inner plexiform layer. A similar response was observed in the retinae of dystrophic rats but with a reduction in amplitude of approximately 50%. It is suggested that the pattern of dopamine depletion observed in rat retina may reflect an AMPT-resistant pool of perikaryal dopamine and/or a reduction in extrasynaptic release of this neurotransmitter in response to illumination in vivo. We conclude that the visualisation of dopamine depletion reported here represents a release of this neurotransmitter in the response to light. Turnover of dopamine in the dystrophic retina is discussed in the context of surviving photoreceptors, including the intrinsically photosensitive melanopsin ganglion cells of the inner retina.

Animals↗
PubMed2005

Retinotopy within rat primary visual cortex using optical imaging.

The purpose of this study was to determine the retinotopic organization of rat primary visual cortex (area 17) using optical imaging technology. Stimulating discrete regions of visual space resulted in localised changes in the remitted light during optical imaging of visual cortex in rat. From these localised changes, our results confirm previous electrophysiological studies on the location, size and organization of rat primary visual cortex. Small differences in the cortical magnification factor (CMF) were found between visual field areas with the highest CMF confined to the upper nasal region. No significant CMF differences were found within the horizontal and vertical visual field axes. No secondary visual areas were activated either anterior or medial to area 17 with the pattern stimuli used in the current study. However, there was evidence of activity to upper nasal stimulation on the posterior lateral extrastriate area. The location of area 17 from optical imaging activity was confirmed anatomically using conventional immunohistochemical techniques. This study shows the retinotopic organization of rat primary visual cortex and serves as a precursor before examining animal models of retinal degeneration and the effectiveness of potential therapies to stem retinal disease.

Animals↗
PubMed2002

Long-term preservation of cortically dependent visual function in RCS rats by transplantation.

Cell transplantation is one way of limiting the progress of retinal degeneration in animal models of blinding diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Here we transplanted a human retinal pigment epithelial (RPE) cell line into the subretinal space of one such model, the Royal College of Surgeons (RCS) rat, and showed, using head tracking to moving stripes and pattern discrimination in conjunction with single-unit cortical physiology, that cortically mediated vision can be preserved with this treatment.

Animals↗
PubMed2001

Photoreceptor rescue after low-dose intravitreal IL-1beta injection in the RCS rat.

Photoreceptor survival in the dystrophic rat was evaluated following administration of IL-1beta at dosages much lower than those used previously for this purpose. Royal College of Surgeons rats (pink-eyed, pigmented, or non-dystrophic) received 1 microl intravitreal injections of murine recombinant IL-1beta (0.5, 2, or 5 microg ml(-1); at 3 or 4 weeks of age). Eyes were harvested 4 weeks later and outer nuclear layer profiles counted. Additional animals received intravitreal basic fibroblast growth factor (1000 microg ml(-1)), or vehicle alone. Others were treated with IL-1beta to evaluate the inflammatory response (CD45+ profiles) or visual function via opto-kinetic response. IL-1beta was associated with photoreceptor rescue that was both dose-dependent and comparable to that seen following high-dose basic fibroblast growth factor. Significant anatomical rescue relative to controls was seen in both pink-eyed and pigmented strains, although the degree and distribution varied between strains. Functional rescue was confirmed by opto-kinetic response using the pigmented strain. At 5 microg ml(-1), IL-1beta resulted in numerous CD45+ profiles within the retina and vitreous. Infiltration peaked at 48 hr and was minimal at 4 weeks, without dysplastic sequelae. IL-1beta therefore induces visually significant photoreceptor rescue in a potent, dose-dependent manner that need not entail cytoarchitectural disruption. This is consistent with the known association between injury and rescue in the rat retina. Neuroprotection may be a general, if under-appreciated, consequence of inflammatory cascade activation.

Animals↗
PubMed2001

Basal increase in c-Fos-like expression in superior colliculus of Royal College of Surgeons dystrophic rats can be abolished by intraocular injection of tetrodotoxin.

In normal rats maintained in the dark, very few cells in the primary visual centers, including the superior colliculus, show Fos-like immunoreactivity. By contrast, in rats presented with flashing lights many Fos-like immunoreactivity cells are observed distributed throughout the visual centers. In the dystrophic Royal College of Surgeons rat, in which there is major loss of photoreceptors over the first 3 months of life, similar numbers of Fos-like immunoreactivity cells are seen on light presentation, but in marked contrast, cell densities in the rats maintained in the dark are many times higher than in non-dystrophic rats maintained under similar conditions. Here we show that this elevated dark response can be abolished by intravitreal injection of the sodium channel blocker tetrodotoxin, indicating that this effect results from changed retinal activity, rather than being centrally generated. We suggest that since Fos-like immunoreactivity is not usually elicited by steady state conditions, the elevated levels in the superior colliculus in these animals reflect the return of waves of activity, first seen in development coursing across the retina, but lost with photoreceptor maturation.

Action Potentials↗
PubMed2001

Cell transplantation as a treatment for retinal disease.

It has been shown that photoreceptor degeneration can be limited in experimental animals by transplantation of fresh RPE to the subretinal space. There is also evidence that retinal cell transplants can be used to reconstruct retinal circuitry in dystrophic animals. Here we describe and review recent developments that highlight the necessary steps that should be taken prior to embarking on clinical trials in humans.

Animals↗
PubMed2000

Schwann cell grafting into the retina of the dystrophic RCS rat limits functional deterioration. Royal College of Surgeons.

PURPOSE: To examine whether congenic Schwann cells grafted into the subretinal space of dystrophic Royal College of Surgeons (RCS) rats can prevent photoreceptor loss and maintain visual function. METHODS: Purified neonatal Schwann cells derived from congenic rats were grafted into the subretinal space of 3- to 4-week-old dystrophic RCS rats. Graft placement was confirmed using Schwann cells labeled in vitro with the fluorescent dye Hoechst 33342 or in grafted eyes processed for electron microscopy (48-hour to 1-month survival). At longer intervals, up to 9 months after surgery, animals were examined for photoreceptor survival; preservation of a visual reflex, head-tracking to moving stripes; and preservation of visual receptive fields associated with the region of graft placement. RESULTS: One week after the graft was performed, Schwann cells had integrated into the subretinal space with little evidence of a reactive response. When screened for head-tracking to moving stripes, Schwann cell-grafted animals performed better than sham-treated or control dystrophic animals. Threshold sensitivity measurements and visual field assessment made by recording from the superior colliculus also showed a significant level of preserved function compared with control animals. Functional rescue was correlated with photoreceptor survival and could be observed for at least 9 months after grafting. CONCLUSIONS: Schwann cells injected into the subretinal space limit functional deterioration and prolong photoreceptor survival. It is suggested that they act by local release of growth factors that either support photoreceptors directly and/or stimulate phagocytosis in RPE cells.

Animals↗
PubMed2000

Sensory capacity of the royal college of surgeons rat.

PURPOSE: To apply noninvasive tests for examining visual and other sensory functions of pigmented Royal College of Surgeons (RCS) rats compared with pigmented and albino control animals. METHODS: Rats aged 3 and 7 months were tested with a general neurologic examination that assessed visual, auditory, tactile, and whisker displacement responses. Photophobic responses and visual discrimination were also measured. RESULTS: Dystrophic RCS rats failed the visual presentation tests, even at 3 months of age, and showed diminished performance on tactile tests. Auditory and whisker displacement performances were normal. Albino rats also showed diminished performance on the visual test, particularly to stimuli presented in the upper visual field. Photophobic responses were diminished in the dystrophic RCS rats compared with the pigmented control animals. Albino animals showed heightened photophobia. The dystrophic rats failed to reach criterion levels of performance on the visual discrimination test even with gratings of 0.045 cyc/deg. CONCLUSIONS: The tests used discriminate deteriorated complex visual functions in RCS rats at ages when some simple reflexes can still be demonstrated. As such, they provide easily executed tests for screening for the effects of reparative treatments such as transplantation, administration of growth factors, and gene transfer technology. The integrity of whisker and auditory function are important when using tests requiring polysensory inputs. The somatosensory defect is surprising but may be useful in searching for the gene locus of the retinal disorder. The aberrations seen in the albino rats may be attributable to the effects of light damage and unfiltered light.

Animals↗
PubMed1998

Changes in the pupillary light reflex of pigmented royal college of surgeons rats with Age.

We studied the latency and amplitude of the pupillary light reflex response of the Royal College of Surgeons rat from 10 to 52 weeks of age. The responses of these dystrophic rats were diminished compared to those of normal, non-dystrophic rats at all ages examined. This was most marked at the dimmest light intensity studied here and for the latency of dystrophic animals' responses. The latency deteriorated over the course of 52 weeks, although there was some evidence of improvement beyond 36 weeks of age. The amplitude of the dystrophic animals' responses also suggested some deterioration occurring up to 36 weeks of age, but with a substantial improvement beyond this time. In addition to these parameters, we also observed a break in the constriction phase of the pupillary light reflex that was unique to the dystrophic animals' responses. The frequency with which the anomaly occurred decreased in a light-dependent manner with age. The improvement of the pupillary light reflex at older ages, even when very few photoreceptors remain, may reflect compensatory events occurring in the inner retinal layers and/or in the central connections of the pupillary light reflex pathway. We suggest that the break in the constriction phase is a reflection of dual inputs driving the response, one of which is affected more by the degenerative events. This study provides baseline data on the effect of degeneration on function over time which can be used to evaluate the efficacy of repair strategies such as transplantation.

Aging↗
PubMed1998

An evaluation of linear model analysis techniques for processing images of microcirculation activity.

Sequences of images of the cortical surface can be processed to reveal information about the cortical microcirculation, regional cerebral blood flow (rCBF), and changes induced by neuronal activity. This study examined the use of different analysis methodologies on intrinsic optical images taken from rat sensory motor cortex and testes. Generalized linear model (GLM) analysis was used and compared with standard signal processing methods including principal component analysis. The GLM method has been used by Friston et al. (1994, Hum. Brain Map., 1: 214-220) in the analysis of functional magnetic resonance imagery to identify regions of focal activity. We investigated the use of this method to analyze video image data of the modulation of rCBF from rat cortex. The results revealed spatiotemporal variations in rCBF in response to stimulation within local regions of cortex. The advantage of the GLM method is that it augments ordinary signal processing methods with an estimate of statistical reliability. The use of different wavelengths of illumination reveals spatial structures with different temporal relationships. In image time series data collected under green and red illumination a phase difference was found in the low frequency approximately 0.1 Hz vasomotion oscillation. This phase difference occurred in data from both cortex and testes. A possible explanation of these differences is that the spectral absorption characteristics of the tissue reflect changes in the volume proportions of the different hemoglobin derivatives in interacting with the modulation of the volume of blood. It is suggested that the combination of these effects produces the phase differences we detect.

Animals↗
PubMed1998

Face processing impairments after encephalitis: amygdala damage and recognition of fear.

Face processing and facial emotion recognition were investigated in five post-encephalitic people of average or above-average intelligence. Four of these people (JC, YW, RB and SE) had extensive damage in the region of the amygdala. A fifth post-encephalitic person with predominantly hippocampal damage and relative sparing of the amygdala (RS) participated, allowing us to contrast the effects of temporal lobe damage including and excluding the amygdala region. The findings showed impaired recognition of fear following bilateral temporal lobe damage when this included the amygdala. For JC, this was part of a constellation of deficits on face processing tasks, with impaired recognition of several emotions. SE, YW and RB, however, showed relatively circumscribed deficits. Although they all had some problems in recognizing or naming famous faces, and had poor memory for faces on the Warrington Recognition Memory Test, none showed a significant impairment on the Benton Test of Facial Recognition, indicating relatively good perception of the face's physical structure. In a test of recognition of basic emotions (happiness, surprise, fear, sadness, disgust and anger), SE, YW and RB achieved normal levels of performance in comparison to our control group for all emotions except fear. Their results contrast with those of RS, with relative sparing of the amygdala region and unimpaired recognition of emotion, pointing clearly toward the importance of the amygdala in the recognition of fear.

Aged↗
PubMed1998

Retinal degeneration and transplantation in the Royal College of Surgeons rat.

The Royal College of Surgeons rat provides a valuable animal model for examining the ontogeny of inherited or acquired photoreceptor degeneration and for assessing various treatment paradigms. Here we describe a sequence of events in which photoreceptor loss induces secondary changes that ultimately result in a progressive loss of retinal ganglion cells. The functional consequences of photoreceptor loss are described and compared with those observed in dystrophic animals that received grafts of pigment epithelial cells at an early stage in the degenerative process. The results of this work suggest that transplantation might slow or halt the progress of photoreceptor loss in certain human retinal degenerative conditions, provided suitable safeguards have been put in place.

Animals↗
PubMed1997

Intraretinal transplantation to prevent photoreceptor degeneration.

There is great interest in the potential of transplantation to treat retinal degenerative diseases in humans; however, there are still fundamental questions to be addressed in experimental animal studies. We have concentrated on two of these using the Royal College of Surgeons (RCS) rat as a suitable animal model. Firstly, does the loss of photoreceptors lead to secondary changes in the inner retina, which might compromise any photoreceptor preservation strategy? Analysis has shown that there are not only histochemical changes in the inner plexiform layer but also degeneration of retinal ganglion cells. The latter, occurring as a result of a vascular event, appears to have a parallel in some human retinal degenerative diseases. Secondly, what are the functional implications of the progressive photoreceptor loss in the RCS rat and how may transplantation prevent or slow that process? A progressively enlarging visual field defect can be demonstrated in these rats which can be stabilized by transplantation of retinal pigment epithelial cells. There is also a loss or diminished performance in a variety of visual tasks, although the rate of deterioration depends on the task; this too can be limited by cell transplantation. Current results indicate an optimistic future for transplantation in human retinal degenerative disease, but also emphasize the many preparatory steps that still have to be made for a successful clinical outcome.

Animals↗
PubMed1994

Visual information processing by intracerebral retinal transplants in rats.

We have developed a simple system involving the implantation of retinae over the midbrain of rodents to examine whether, in a clearly defined system such as the primary optic pathway, it is possible to re-create circuits lost as a result of injury or developmental disorder. For much of the work, immature rat hosts have been used, in part to maximise optimal conditions and to provide a baseline for similar transplants in adults. In this review we summarise the sequence of studies that has led us to the conclusion that transplanted retinae are capable not only of differentiating and responding to light but also of relaying luminance information to visual centres of the host brain where appropriate behavioural responses are elaborated.

Animals↗
PubMed1991

The impact of intracerebral retinal transplants on types of behavior exhibited by host rats.

Retinae transplanted over the midbrain of newborn rats establish functional connections with host brain centers, which provide a substrate for several distinct visual functions. These responses provide insight into the relationship between anatomy and behavior under normal conditions and after brain injury, as well as into the strategies used by an animal to extract significant information from its visual environment.

Animals↗
PubMed1990

An investigation into the early stages of the inflammatory response following ibotenic acid-induced neuronal degeneration.

Injection of the excitatory neurotoxin ibotenic acid into the septum produces rapid destruction of neuronal cell bodies and accompanying gliosis. We have previously shown that following ibotenate-induced cell death this may also result in damage to healthy axons en passage (Coffey et al., Neurosci. Lett. 84, 178-184, 1988). We suggested that the axonal damage resulted from non-specific damage by recruited inflammatory cells. In this study we have further examined the phenotype of the cells involved in the inflammatory response in the rat. Immunocytochemical identification of cells in the region of the lesion site identifies them as being of haematopoitic origin and most of them have the phenotype of macrophages. The dramatic increase in their number following an ibotenate lesion is sensitive to irradiation of the body providing evidence that the majority are blood derived. The inflammatory response is accompanied by a loss of myelin and a breakdown of the blood-brain barrier in the region of the lesion site. We have shown that these two effects are consequences of the inflammatory response since reduction in the inflammatory response by prior irradiation will abrogate these two effects.

Animals↗