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P Redgrave

Publications and source records attributed to P Redgrave.

At least 37 records · Page 2Linked to original sources
PubMed1997

A miniature CCD video camera for high-sensitivity light measurements in freely behaving animals.

We developed a miniaturized, high-sensitivity camera that can be placed in areas of difficult access in freely behaving animals for neural tissue imaging. The device consists of a charged coupled device (CCD) chip, a coherent image conduit and miniature light emitting diodes (LEDs). An amplifier circuit is constructed on the camera chip and nine wires are attached for external connections. Placement of LEDs around the image conduit perimeter provides dark-field illumination, which increases detection of cellular-related light scattering changes and doubles the depth-of-view over conventional reflectance imaging procedures. The device has been successfully used to record from several deep brain structures, including the ventral medullary surface of sleeping and waking cats. The procedure allows assessment of light scattering changes that result from neural activity or detection of vital dyes to metabolic or voltage-induced activation.

Analysis of Variance↗
PubMed1997

Anticonvulsant and behavioural effects of bicuculline injected into the mesencephalic locomoter region of rats.

Previous microinjection mapping studies in the mesencephalon established a significant association between the induction of locomotor activation and the suppression of tonic seizures in the electroshock model of epilepsy. The purpose of the present study was to see if this relationship also applies in an area of the brainstem commonly known as the mesencephalic locomotor region (MLR). The principal findings were the following. (i) Activation of extensive areas of the dorsal midbrain and tegmentum, including the MLR, by unilateral injections of the GABA antagonist bicuculline induced leg movements and suppressed the tonic component of electroshock-induced seizures. (ii) A highly significant correlation was observed between these two variables. (iii) In some cases, however, the induction of phasic leg movements was neither sufficient nor necessary for tonic seizure suppression. It is possible, therefore, that injection-elicited changes in tonic aspects of limb control may be more directly related to the suppression of tonic motor seizures in the electroshock model of epilepsy.

Animals↗
PubMed1997

Microinjections of muscimol into lateral superior colliculus disrupt orienting and oral movements in the formalin model of pain.

An important reaction in rodent models of persistent pain is for the animal to turn and bite/lick the source of discomfort (autotomy). Comparatively little is known about the supraspinal pathways which mediate this reaction. Since autotomy requires co-ordinated control of the head and mouth, it is possible that basal ganglia output via the superior colliculus may be involved; previously this projection has been implicated in the control of orienting and oral behaviour. The purpose of the present study was therefore, to test whether the striato-nigro-tectal projection plays a significant role in oral responses elicited by subcutaneous injections of formalin. Behavioural output from this system is normally associated with the release of collicular projection neurons from tonic inhibitory input from substantia nigra pars reticulata. Therefore, in the present study normal disinhibitory signals from the basal ganglia were blocked by injecting the GABA agonist muscimol into different regions of the rat superior colliculus. c-Fos immunohistochemistry was used routinely to provide regional estimates of the suppressive effects of muscimol on neuronal activity. Biting and licking directed to the site of a subcutaneous injection of formalin (50 microliters of 4%) into the hind-paw were suppressed in a dose-related manner by bilateral microinjections of muscimol into the lateral superior colliculus (10-50 ng; 0.5 microliter/side); injections into the medial superior colliculus had little effect. Bilateral injections of muscimol 20 ng into lateral colliculus caused formalin-treated animals to re-direct their attention and activity from lower to upper regions of space. Muscimol injected unilaterally into lateral superior colliculus elicited ipsilateral turning irrespective of which hind-paw was injected with formalin. Oral behaviour was blocked when the muscimol and formalin injections were contralaterally opposed; this was also true for formalin injections into the front foot. Interestingly, when formalin was injected into the perioral region, injections of muscimol into the lateral superior colliculus had no effect on the ability of animals to make appropriate contralaterally directed head and body movements to facilitate localization of the injected area with either front- or hind-paw. These findings suggest that basal ganglia output via the lateral superior colliculus is critical for responses to noxious stimuli which entail the mouth moving to and acting on the foot, but not when the foot is the active agent applied to the mouth. The data also suggest that pain produces a spatially non-specific facilitation of units throughout collicular maps, which can be converted into a spatially inappropriate signal by locally suppressing parts of the map with the muscimol.

Animals↗
PubMed1997

Funding a primary care led NHS: achieving a model for more equitable allocation of healthcare resources at a sub-district level.

BACKGROUND: Current resource allocation for health services have developed in a haphazard and inequitable way. This project aimed to determine a fairer and more rational way to distribute health authority's (HA's) money to general practitioners (GPs). METHODS: A dataset was developed to examine the way resources were spent on patients at the level of general practice. Important managerial aspects of the project were addressed. This involved the establishment of the 'Equity Group' of GPs to work with the HA. The group sought a measure of health need that was rigorous and scientifically based but was also practical and politically acceptable to GPs and the HA. The York Relative Needs Index (RNI) was chosen, and applied to populations at practice level. An implementation plan was then developed by the Equity Group. RESULTS: Results demonstrated considerable inequalities between practices in age-adjusted use of healthcare resources. There was low correlation between the level of need in practices and the per capita expenditure. Applying the York RNI to practice populations indicated current practice allocations were within the range 82-126 per cent of their needs-based target. The managerial implications of the proposed changes are described. CONCLUSIONS: The new methods for resource allocation appear to be an advance on the unplanned methods which have evolved. Full evaluation of the long-term results of redistributing health resources will be needed. Important aspects of this project were the participation of GPs and general development of the concept of equity in North Derbyshire.

Age Factors↗
PubMed1997

Regional distribution of the anticonvulsant and behavioural effects of bicuculline injected into the pontine reticular formation of rats.

Previous experimental work has established that activation of sites in the dorsal midbrain can suppress tonic hindlimb extension in the electroshock model of epilepsy. The most sensitive region for this effect is centred on the intercollicular area and is referred to as the dorsal midbrain anticonvulsant zone (DMAZ). Subsequent experiments have shown that the ipsilateral descending projection from this region to the ventrolateral pons is critically involved in mediating its tonic seizure-suppressing properties. The purpose of the present investigation was to test whether direct anticonvulsant effects in the electroshock model could be obtained from selective manipulation of DMAZ target regions in the ventrolateral pons. Animals were prepared with chronically implanted guide cannulae through which microinjections could be made directly into the lateral pontine reticular formation. Animals received injections of saline or bicuculline (25-100 pmol) administered either bilaterally or unilaterally. The effects of these injections on the animals' behaviour were determined in an open arena, after which maximal electroshock (1 s, 40 mA, 50 Hz AC) was administered via ear-clip electrodes and the duration of tonic hindlimb extension was recorded. Bilateral injections of bicuculline (100 pmol) suppressed tonic seizures at a significantly higher proportion of sites centred on DMAZ target regions of the ventrolateral pons than surrounding areas. For injections centred on this region the suppressive effects of bicuculline were dose-related in the range 25-100 pmol. Unilateral injections of bicuculline into the ventrolateral pons also effectively suppressed tonic seizures in the electroshock model. Within the ventral pons there was a significant association between the behavioural and anticonvulsant effects of bicuculline; injections suppressing tonic seizures were associated with the induction of fast continuous locomotor activity. These data confirm that the DMAZ recipient region of the ventrolateral pontine reticular formation is part of a circuit which can suppress the manifestation of tonic hindlimb extension in the electroshock model. Whether this property is related to the participation of this region in normal locomotion and posture remains to be determined.

Animals↗
PubMed1996

Analysis of nociceptive neurones in the rat superior colliculus using c-fos immunohistochemistry.

The superior colliculus (SC) has an established role in the sensory guidance of motor commands required to orient an animal towards novel stimuli. In addition to the representations of visual, auditory, and somatosensory stimuli, the SC also contains a large population of nociceptive neurones. The purpose of the present investigation was to see if nociceptive neurones in the SC can be characterised with c-fos immunohistochemistry as a prelude to establishing anatomical connectivity with specific target regions in the brainstem. To ensure comparability with previous electrophysiological investigations, the present study was conducted in animals anaesthetised with urethane. A series of independent issue relating to basic aspects of experimental protocol were investigated. The principal findings were: (i) Despite minimising the exposure of animals to extraneous stimuli, basal levels of immunostaining were observed. (ii) Urethane anaesthesia induced an increase in Fos-like immunoreactivity (FLI) over the basal condition. (iii) No additional labelling was induced by non-noxious tactile stimulation of the hindpaw. (iv) Unilateral noxious mechanical stimulation elicited a reliable increase in FLI over all control conditions. (v) This increase in FLI was expressed bilaterally and restricted largely to the intermediate white layer. (vi) The induction of FLI was related to noxious stimulation intensity. (vii) No reliable differences in the spatial topography of FLI expression were observed when unilateral noxious mechanical stimulation was administered to the face or hind foot. (vii) A higher level of urethane anaesthesia had a generally suppressive effect on FLI expression. (ix) There were no differences in the distribution of FLI induced by noxious mechanical or noxious chemical stimulation. (x) The increase in FLI induced by noxious pinch was abolished by a naloxone reversible pre-treatment with morphine. These data confirm that c-fos immunohistochemistry can be used to characterise nociceptive cells in the rat superior colliculus, and generally complement recent electrophysiological data. The identification of nociceptive cells in the stratum album intermediale, the source of collicular input to regions of the contralateral brainstem involved in orienting, suggests the SC may play a significant role in the localisation of pain.

Analgesics, Opioid↗
PubMed1996

Cerebral vasomotion: a 0.1-Hz oscillation in reflected light imaging of neural activity.

Imaging of scattered and reflected light from the surface of neural structures can reveal the functional architecture within large populations of neurons. These techniques exploit, as one of the principal signal sources, reflectance changes produced by local variation in blood volume and oxygen saturation related to neural activity. We found that a major source of variability in the captured light signal is a pervasive low-frequency (0.1-Hz) oscillation which apparently results from regional cerebral blood flow. This signal is present in brain parenchyma as well as the microvasculature and exhibits many characteristics of the low-frequency "vasomotion" signals observed in peripheral microcirculation. Concurrent measurements in brain with a laser Doppler flow meter contained an almost identical low-frequency signal. The presence of the 0.1-Hz oscillation in the cerebral microcirculation could underlie a portion of the previously described characteristics reported in reflected-light imaging studies. The prevalence of the oscillatory phenomena in the brain raises substantial temporal sampling issues for optical imaging and for other visualization techniques which depend on changes in regional cerebral blood dynamics, such as functional magnetic resonance imaging.

Animals↗
PubMed1996

Nociceptive neurones in rat superior colliculus. I. Antidromic activation from the contralateral predorsal bundle.

Accumulating evidence suggests that the rodent superior colliculus (SC) plays as important a role in avoidance and defensive behaviours as it does in orientation and approach. These two complementary behaviours are associated with two anatomically segregated tectofugal output pathways, such that orientation and approach are mediated by the crossed descending projection, whereas avoidance and defence are subserved via the uncrossed projection. Because nociceptive neurones in the SC have been presumed to participate in withdrawal or defensive behaviours, it has been proposed that they have direct access only to the uncrossed efferent pathway. However, in certain behavioural situations, the most adaptive response to injury, or to a painful object in prolonged contact with the skin, is to orient towards the source of discomfort so that the skin can be licked and/or the offending object removed. Presumably then, nociceptive as well as low-threshold neurones would have access to the crossed descending pathway in order to initiate such behaviours. Determining whether or not this is the case was the objective of the present study. Both nociceptive-specific (82%) and wide-dynamic-range (18%) SC neurones were identified using long-duration (up to 6 s), frankly noxious mechanical and thermal stimuli in urethane-anaesthetised Long-Evans hooded rats. The majority (85.7%) of the nociceptive neurones encountered were located within the intermediate layers, which corresponds with the location of the cells-of-origin of the crossed descending projection. Nearly half (44.9%) were activated antidromically from electrical stimulation of the crossed descending pathway at a site in the brainstem below its decussation. The mean conduction velocity of these nociceptive output neurones was 9.02 m/s, which corresponds well to previous estimates of conduction velocity in the crossed tecto-reticulo-spinal tract. These data demonstrate that a significant proportion of nociceptive neurones in the rat SC have axons that project to the contralateral brainstem via the crossed descending projection. Nociceptive neurones could, therefore, effect orientation responses to noxious stimuli via similar output pathways that low-threshold neurones utilize to initiate orientation to innocuous stimuli.

Animals↗
PubMed1996

Nociceptive neurones in rat superior colliculus. II. Effects of lesions to the contralateral descending output pathway on nocifensive behaviours.

A wealth of evidence implicates the crossed descending projection from the superior colliculus (SC) in orientation and approach behaviours directed towards novel, non-noxious stimuli. In our preceding paper, we identified a population of nociceptive neurones in the rat SC that have axons that project to the contralateral brainstem via this output pathway. The purpose of the present study was, therefore, to evaluate the prediction that the crossed descending projection of the SC is also involved in the control of orientation and approach movements of the head and mouth made during the localisation of persistent noxious stimuli. An independent-groups design was used to test the effects of interrupting the contralateral descending projection from the SC on the behavioural reactions elicited by noxious mechanical stimuli presented to the tail and hindpaws. In different groups of animals, a microwire knife was used to cut the contralateral descending fibres at two different locations: (1) a sagittal cut at the level of the dorsal tegmental decussation; (2) a bilateral coronal cut of the predorsal bundle at the level of the medial pontine reticular formation. Retrograde anatomical tracing techniques were then used to evaluate the effectiveness of the cuts and to assess possible involvement of non-collicular fibre systems in both lesioned and control animals. Additional behavioural procedures were performed to test for general neurological status and responsiveness of animals to non-noxious stimuli. Anatomical tracing data indicated that the largest population of neurones with fibres severed by both cuts were the cells-of-origin of the contralateral descending projection in the intermediate white layer of the SC. Behavioural results showed that significantly more animals in both lesion groups failed to locate and bite a mechanical clip placed on the tail. Instead of switching to motor behaviours to localise and remove noxious stimuli, they persisted with defensive reactions, which included freezing, vocalisation or forward and backward escape. In contrast, when the clip was placed on the hindpaws, it was successfully localised by most lesioned and control animals; however, lesioned animals had reliably longer latencies and spent less time in close contact with the clip. Consistent with the established role of the contralateral descending projection in non-noxious orientation, lesioned animals also showed orienting deficits to a range of non-noxious sensory stimuli. These data suggest that, under certain behavioural circumstances, nociceptive information from the SC is integral to the elaboration of orienting and approach movements of the head and mouth elicited by persistent noxious stimuli.

Animals↗
PubMed1996

Differential expression of fos-like immunoreactivity in the descending projections of superior colliculus after electrical stimulation in the rat.

In rodent, there is evidence that the orienting behaviour elicited by direct stimulation of the superior colliculus (SC) is partly mediated by contralateral descending projections, while avoidance-type behaviour is associated with ipsilateral descending projections. However, the identity of target structures in the brainstem which mediate these different behavioural responses is unknown. The c-fos immediate early gene is expressed polysynaptically in neurons in response to a wide range of extracellular stimuli, and hence has been proposed as a technique for mapping functional pathways. The purpose of this study was, therefore, to use the c-fos technique to investigate the functional specificity of brainstem regions which are innervated by the two main descending projections of the SC. Patterns of fos-like immunoreactivity (FLI) were observed throughout the brainstem following electrical stimulation of the SC in Urethane-anaesthetized rats. Previously, the electrical stimulation had been shown to elicit either approach-like or avoidance-like movement. The main results of this experiment were; (i) animals in which the stimulation elicited defensive behaviour had elevated levels of immunostaining in specific terminal areas of the ipsilateral descending projections, e.g. the ventrolateral midbrain/pontine reticular formation, the cuneiform area and rostral periaqueductal grey; (ii) there was no FLI expression in any of the terminal areas of the crossed descending projection, even in animals where the electrical stimulation elicited approach. Control experiments showed that the lack of expression in the crossed descending pathway was not due to the restricted range of stimulation parameters used in the main study, or to the effects of the anaesthetic. In conclusion, this experiment was able to identify likely substrates for the mediation of defensive reactions elicited by tectal stimulation. However, given the total lack of expression in a pathway which is known to be activated, it also provides further evidence that c-fos cannot simply be used as a high resolution neuronal activity marker for mapping functional pathways.

Animals↗
PubMed1996

Regional distribution of the anticonvulsant and behavioural effects of muscimol injected into the substantia nigra of rats.

Previous anatomical investigations have reported a direct projection from substantia nigra pars lateralis to the dorsal midbrain anticonvulsant zone. The present study tested the hypothesis that the anticonvulsant properties of nigral inhibition previously attributed to substantia nigra pars reticulata were, in fact, due to the suppression of neural activity in the adjacent pars lateralis. Using the electroshock model of epilepsy, a systematic map of the anticonvulsant effects of bilateral injections of muscimol (60 ng/0.5 mu l per side) into different parts of substantia nigra was constructed. Electroshock (1 s of 40 mA 50 Hz AC) was administered via ear-clip electrodes 5 or 60 min following injections of muscimol, or 60 min after control injections of saline. To provide insight into the functional mechanisms whereby nigral inhibition might suppress tonic seizures the behavioural effects elicited by muscimol were also noted. No evidence supporting the experimental prediction was found. The most sensitive region of substantia nigra for suppressing tonic hindlimb extension was caudal pars reticulata. These data indicate a serious mismatch between the results of microinjection mapping studies and underlying patterns of anatomical connectivity. The behavioural reaction most closely associated with tonic seizure suppression was stereotyped locomotion; both were obtained maximally from caudal pars reticulata. Rostral substantia nigra was associated more with oral stereotypy, while a raised head position was observed at lateral injection sites and a lowered positioning of the head at medial locations. These data suggest that the rat substantia nigra may contain a functional organization based on a form of somatomotor topography. This organization may influence which part of the substantia nigra is most effective in suppressing seizures expressed by different muscle groups of the body.

Animals↗
PubMed1995

The dorsal midbrain anticonvulsant zone--I. Effects of locally administered excitatory amino acids or bicuculline on maximal electroshock seizures.

Microinjections of bicuculline methiodide into the dorsal midbrain anticonvulsant zone, a region which includes the caudal deep layers of the superior colliculus, the adjacent mesencephalic reticular formation and the intercollicular nucleus, suppress tonic hindlimb extension induced by maximal electroshock. The purpose of the present experiments was to establish the most effective and convenient method for eliciting anticonvulsant properties from the dorsal midbrain using the electroshock model of epilepsy. A comparison of different injections of excitatory amino acids and bicuculline into the dorsal midbrain of the rat showed: (i) injections of kainate suppressed hindlimb extension but only at substantially larger doses (i.e. 200-400 pmol) than 50 pmol of bicuculline, which produced generally superior effects; (ii) quisqualate provided only weak protection against tonic seizures at doses that produced neurotoxic effects (2-40 nmol); (iii) N-methyl-D-aspartate was ineffective at doses which produced mild clonic seizure in their own right (2-4 nmol) and also produced some evidence of neurotoxicity; (iv) the suppression of hindlimb extension by bicuculline was dose related, and the lowest bilateral dose for producing reliable suppression was 50 pmol/400 nl per side; and (v) a unilateral injection of 100 pmol/400 nl also reliably suppressed hindlimb extension. The latter finding had important implications for the design and interpretation of the following lesion study. Injections of bicuculline into the dorsal midbrain also produced defence-like behavioural responses that included running and biting; the intensity of these responses correlated with the suppression of hindlimb extension.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

The dorsal midbrain anticonvulsant zone--II. Efferent connections revealed by the anterograde transport of wheatgerm agglutinin-horseradish peroxidase from injections centred on the intercollicular area in the rat.

Activation of the dorsal midbrain has a powerful anticonvulsant effect in the maximal electroshock model of epilepsy. The suppression of tonic seizures can be obtained most reliably from an area centred on the intercollicular nucleus overlapping into the deep layers of the superior colliculus and adjacent mesencephalic reticular formation. As part of a series of investigations to identify neural mechanisms responsible for mediating the anticonvulsant properties of the dorsal midbrain, the present study provides an anatomical description of the efferent projections of this region. Small amounts of wheatgerm agglutinin-horseradish peroxidase (10-30 nl of a 1% solution) were injected into the intercollicular nucleus and surrounding tissue. The resulting anterograde transport of the tracer was plotted on a set of standard atlas sections. Four major output pathways were identified: (i) an ipsilateral descending projection which had terminations in the microcellular tegmental nucleus, lateral and ventral pontine reticular nucleus pars oralis, ventrolateral tegmental nucleus, ventral and caudal pontine reticular nucleus pars caudalis, raphe magnus nucleus and the gigantocellular nucleus; (ii) a contralateral descending projection which for the most part targeted the same brainstem structures but with weaker terminal labelling; (iii) a projection to the contralateral dorsal midbrain with comparatively weak terminal label in the contralateral superior colliculus, intercollicular nucleus, periaqueductal gray, mesencephalic reticular formation and cuneiform area; (iv) ipsilateral ascending pathway with terminations in the red nucleus, zona incerta, peripeduncular area, parafascicular nucleus, lateral hypothalamus, parts of the pretectum and caudal thalamus. At a general level the dorsal midbrain anticonvulsant zone shares its major output projections and efferent targets with at least one of its near neighbours, including the superior colliculus, periaqueductal gray, the cuneiform nucleus and pedunculopontine nucleus. The possibility that anticonvulsant properties of the intercollicular area can simply be attributed to a unique set of efferent projections is therefore not supported by the anatomy.

Animals↗
PubMed1995

The dorsal midbrain anticonvulsant zone--III. Effects of efferent pathway transections on suppression of electroshock seizures and defence-like reactions produced by local injections of bicuculline.

Having provided an anatomical description of the efferent projections of the dorsal midbrain anticonvulsant zone [Shehab S. et al. (1995) Neuroscience 65, 681-695], our purpose in the present study was to establish which outputs from this region are responsible for mediating the anticonvulsant and behavioural properties of dorsal midbrain activation. The ability of unilateral injections of bicuculline into the dorsal midbrain anticonvulsant zone to suppress tonic hindlimb extension in the electroshock model of epilepsy was tested before and after three different knife cuts: (i) a transection of ipsilateral descending projections on the same side as the injection of bicuculline; (ii) an identical cut except it was placed contralateral to the injection; (iii) a cut which transected rostral projecting fibres from the dorsal midbrain anticonvulsant zone including most ipsilateral ascending and crossed descending projections. A fourth group of operated control animals was included to establish a baseline for the schedule of repeated testing. Qualitative observations of behaviour were taken immediately prior to administration of the electroshocks. Unilateral transection of ipsilateral descending efferents prevented the suppression of electroshock-induced hindlimb extension by injections of bicuculline into the dorsal midbrain anticonvulsant zone on the same side of the brain. Both the control cuts on the opposite side of the brain and the rostral cuts were ineffective. Transection of the ipsilateral descending projection on the same side as the injection of bicuculline also reduced the incidence of defensive reactions induced by the GABA antagonist, including explosive motor behaviour, oral attack and vocalization. Damage to this projection on the opposite side had little effect on the expression of behavioural reactions, neither did transection of the ascending efferents. These data suggest that ipsilateral descending efferents are critical for the suppression of electroshock-induced extension of the hindlimbs and the expression of defensive reactions elicited by activation of the dorsal midbrain.

Animals↗
PubMed1994

Opposing excitatory and inhibitory influences from the cerebellum and basal ganglia converge on the superior colliculus: an electrophysiological investigation in the rat.

We recently showed (Westby et al., Eur. J. Neurosci., 5, 1378-1388, 1993) that the cerebellar interpositus nucleus is a source of excitatory drive for a population of spontaneously active neurons in the lateral intermediate layers of the contralateral superior colliculus. Anatomical and physiological studies have shown that this region of the colliculus contains cells of origin of the crossed descending tectoreticulospinal tract and receives GABAergic input from the ipsilateral basal ganglia. In the present study we tested the hypothesis that the same neurons receiving excitatory drive from the cerebellum also receive tonic inhibitory input from the substantia nigra pars reticulata. From a sample of 73 spontaneously active collicular cells we found that in 53% the firing rate was suppressed by GABA microinjection into the contralateral deep cerebellar nuclei; a further 15% showed a frequency increase. Of the collicular cells identified as receiving excitatory cerebellar input, 85% were found to be disinhibited by nigral GABA microinjection. The remainder were all inhibited by nigral GABA. These data show that the main excitatory influence from the cerebellum and the main inhibitory influence from the substantia nigra converge on at least one population of spontaneously active cells in the lateral intermediate layers of the superior colliculus. This finding is discussed in relation to the possible function of these spontaneous cells in movement control and nociception.

Animals↗