Key Aspects of Neurovascular Control Mediated by Specific Populations of Inhibitory Cortical Interneurons.

Inhibitory interneurons can evoke vasodilation and vasoconstriction, making them potential cellular drivers of neurovascular coupling. However, the specific regulatory roles played by particular interneuron subpopulations remain unclear. Our purpose was therefore to adopt a cell-specific optogenetic approach to investigate how somatostatin (SST) and neuronal nitric oxide synthase (nNOS)-expressing interneurons might influence the neurovascular relationship. In mice, specific activation of SST- or nNOS-interneurons was sufficient to evoke hemodynamic changes. In the case of nNOS-interneurons, robust hemodynamic changes occurred with minimal changes in neural activity, suggesting that the ability of blood oxygen level dependent functional magnetic resonance imaging (BOLD fMRI) to reliably reflect changes in neuronal activity may be dependent on type of neuron recruited. Conversely, activation of SST-interneurons produced robust changes in evoked neural activity with shallow cortical excitation and pronounced deep layer cortical inhibition. Prolonged activation of SST-interneurons often resulted in an increase in blood volume in the centrally activated area with an accompanying decrease in blood volume in the surrounding brain regions, analogous to the negative BOLD signal. These results demonstrate the role of specific populations of cortical interneurons in the active control of neurovascular function.

Cortical regulation of dopaminergic neurons: role of the midbrain superior colliculus.

Dopaminergic (DA) neurons respond to stimuli in a wide range of modalities, although the origin of the afferent sensory signals has only recently begun to emerge. In the case of vision, an important source of short-latency sensory information seems to be the midbrain superior colliculus (SC). However, longer-latency responses have been identified that are less compatible with the primitive perceptual capacities of the colliculus. Rather, they seem more in keeping with the processing capabilities of the cortex. Given that there are robust projections from the cortex to the SC, we examined whether cortical information could reach DA neurons via a relay in the colliculus. The somatosensory barrel cortex was stimulated electrically in the anesthetized rat with either single pulses or pulse trains. Although single pulses produced small phasic activations in the colliculus, they did not elicit responses in the majority of DA neurons. However, after disinhibitory intracollicular injections of the GABAA antagonist bicuculline, collicular responses were substantially enhanced and previously unresponsive DA neurons now exhibited phasic excitations or inhibitions. Pulse trains applied to the cortex led to phasic changes (excitations to inhibitions) in the activity of DA neurons at baseline. These were blocked or attenuated by intracollicular administration of the GABAA agonist muscimol. Taken together, the results indicate that the cortex can communicate with DA neurons via a relay in the SC. As a consequence, DA neuronal activity reflecting the unexpected occurrence of salient events and that signaling more complex stimulus properties may have a common origin.

Adverse drug effects following oseltamivir mass treatment and prophylaxis in a school outbreak of 2009 pandemic influenza A(H1N1) in June 2009, Sheffield, United Kingdom.

During the containment phase of the 2009 influenza A(H1N1) pandemic, mass treatment and prophylaxis with oseltamivir was used to control an outbreak of pandemic influenza in a primary school in Sheffield, United Kingdom, where ten cases of pandemic influenza had been laboratory confirmed over a three day period in June 2009. A subsequent cross-sectional survey showed that 51 of 297 (17%) pupils and 10 of 58 (17%) reported an influenza-like illness. The most common symptoms were headache, cough, fever, tiredness, sore throat and nausea. Fifty-three staff and 273 pupils took oseltamivir for treatment or prophylaxis. Of this group, 41% (113/273) of pupils and 47% (25/53) of staff reported adverse effects. Overall, 14% (37/273) of pupils and 20% (11/53) of staff did not complete the course of oseltamivir, primarily due to adverse effects. Nausea, vomiting and rash were statistically significantly associated with failing to complete the course of oseltamivir. Given the potential for side effects from oseltamivir, particularly among those without influenza who receive the drug for prophylaxis, our findings have two important implications. Firstly, the benefits of mass treatment in an outbreak setting must clearly be greater than the benefits of targeted treatment. Secondly, any large scale regional or state level system for distribution of antiviral drugs for treatment should ideally include a robust quantification of an individual s probability of infection with influenza virus in order to avoid unnecessary treatment.

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.

Event or emergency? Two response systems in the mammalian superior colliculus.

Recent studies of the effects of stimulating the superior colliculus (SC) in rodents suggest that this structure mediates at least two classes of response to novel sensory stimuli. One class contains the familiar orienting response, together with movements resembling tracking or pursuit, and appears appropriate for undefined sensory 'events'. The second class contains defensive movements such as avoidance or flight, together with cardiovascular changes, that would be appropriate for a sudden emergency such as the appearance of a predator, or of an object on collision course. The two response systems appear to depend on separate output projections, and are probably subject to different sensory and forebrain influences. These findings (1) suggest an explanation for the complex anatomical organization of the SC, with multiple output pathways differentially accessed by a very wide variety of inputs, (2) emphasize the similarities between the SC and the optic tectum in non-mammalian species, and (3) suggest that the SC may be useful as a model for studying both the sensory control of defensive responses, and how intelligent decisions can be taken about relatively simple sensory inputs.

Is the short-latency dopamine response too short to signal reward error?

Unexpected stimuli that are behaviourally significant have the capacity to elicit a short-latency, short-duration burst of firing in mesencephalic dopaminergic neurones. An influential interpretation of the experimental data that characterize this response proposes that dopaminergic neurones have a crucial role in reinforcement learning because they signal error in the prediction of future reward. In this article we propose a different functional role for this 'short-latency dopamine response' in the mechanisms that underlie associative learning. We suggest that the initial burst of dopaminergic-neurone firing could represent an essential component in the process of switching attentional and behavioural selections to unexpected, behaviourally important stimuli. This switching response could be a crucial prerequisite for associative learning and might be part of a general short-latency response that is mediated by catecholamines and prepares the organism for an appropriate reaction to biologically significant events. Any act which in a given situation produces satisfaction becomes associated with that situation so that when the situation recurs the act is more likely than before to recur also. E.L. Thorndike (1911) 1.

Nociceptive responses of midbrain dopaminergic neurones are modulated by the superior colliculus in the rat.

Midbrain dopaminergic neurones exhibit a short-latency phasic response to unexpected, biologically salient stimuli. In the rat, the superior colliculus is critical for relaying short-latency visual information to dopaminergic neurones. Since both collicular and dopaminergic neurones are also responsive to noxious stimuli, we examined whether the superior colliculus plays a more general role in the transmission of short-latency sensory information to the ventral midbrain. We therefore tested whether the superior colliculus is a critical relay for nociceptive input to midbrain dopaminergic neurones. Simultaneous recordings were made from collicular and dopaminergic neurones in the anesthetized rat, during the application of noxious stimuli (footshock). Most collicular neurones exhibited a short-latency, short duration excitation to footshock. The majority of dopaminergic neurones (92/110; 84%) also showed a short-latency phasic response to the stimulus. Of these, 79/92 (86%) responded with an initial inhibition and the remaining 14/92 (14%) responded with an excitation. Response latencies of dopaminergic neurones were reliably longer than those of collicular neurones. Tonic suppression of collicular activity by an intracollicular injection of the local anesthetic lidocaine reduced the latency, increased the duration but reduced the magnitude of the phasic inhibitory dopaminergic response. These changes were accompanied by a decrease in the baseline firing rate of dopaminergic neurones. Activation of the superior colliculus by the local injections of the GABA(A) antagonist bicuculline also reduced the latency of inhibitory nociceptive responses of dopaminergic neurones, which was accompanied by an increased in baseline dopaminergic firing. Aspiration of the ipsilateral superior colliculus failed to alter the nociceptive response characteristics of dopaminergic neurones although fewer nociceptive neurones were encountered after the lesions. Together these results suggest that the superior colliculus can modulate both the baseline activity of dopaminergic neurones and their phasic responses to noxious events. However, the superior colliculus is unlikely to be the primary source of nociceptive sensory input to the ventral midbrain.

A direct projection from superior colliculus to substantia nigra pars compacta in the cat.

Dopaminergic neurons exhibit a short-latency, phasic response to unexpected, biologically salient stimuli. The midbrain superior colliculus also is sensitive to such stimuli, exhibits sensory responses with latencies reliably less than those of dopaminergic neurons, and, in rat, has been shown to send direct projections to regions of the substantia nigra and ventral tegmental area containing dopaminergic neurons (e.g. pars compacta). Recent electrophysiological and electrochemical evidence also suggests that tectonigral connections may be critical for relaying short-latency (<100 ms) visual information to midbrain dopaminergic neurons. By investigating the tectonigral projection in the cat, the present study sought to establish whether this pathway is a specialization of the rodent, or whether it may be a more general feature of mammalian neuroanatomy. Anterogradely and retrogradely transported anatomical tracers were injected into the superior colliculus and substantia nigra pars compacta, respectively, of adult cats. In the anterograde experiments, abundant fibers and terminals labeled with either biotinylated dextran amine or Phaseolus vulgaris leucoagglutinin were seen in close association with tyrosine hydroxylase-positive (dopaminergic) somata and processes in substantia nigra pars compacta and the ventral tegmental area. In the retrograde experiments, injections of biotinylated dextran amine into substantia nigra produced significant retrograde labeling of tectonigral neurons of origin in the intermediate and deep layers of the ipsilateral superior colliculus. Approximately half of these biotinylated dextran amine-labeled neurons were, in each case, shown to be immunopositive for the calcium binding proteins, parvalbumin or calbindin. Significantly, virtually no retrogradely labeled neurons were found either in the superficial layers of the superior colliculus or among the large tecto-reticulospinal output neurons. Taken in conjunction with recent data in the rat, the results of this study suggest that the tectonigral projection may be a common feature of mammalian midbrain architecture. As such, it may represent an additional route by which short-latency sensory information can influence basal ganglia function.

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.

Superior colliculus projections to midline and intralaminar thalamic nuclei of the rat.

The superior colliculus (SC) projections to the midline and intralaminar thalamic nuclei were examined in the rat. The retrograde tracer cholera toxin beta (CTb) was injected into one of the midline thalamic nuclei-paraventricular, intermediodorsal, rhomboid, reuniens, submedius, mediodorsal, paratenial, anteroventral, caudal ventromedial, or parvicellular part of the ventral posteriomedial nucleus-or into one of the intralaminar thalamic nuclei-medial parafascicular, lateral parafascicular, central medial, paracentral, oval paracentral, or central lateral nucleus. After 10-14 days, the brains from these animals were processed histochemically, and the retrogradely labeled neurons in the SC were mapped. The lateral sector of the intermediate gray and white layers of the SC send axonal projections to the medial and lateral parafascicular, central lateral, paracentral, central medial, rhomboid, reuniens, and submedius nuclei. The medial sector of the intermediate and deep SC layers project to the parafascicular and central lateral thalamic nuclei. The paraventricular thalamic nucleus is innervated almost exclusively by the medial sectors of the deep SC layers. The superficial gray and optic layers of the SC do not project to any of these thalamic areas. The discussion focuses on the role these SC-thalamic inputs may have on forebrain circuits controlling orienting and defense (i.e., fight-or-flight) reactions.

Parallel analyses of nociceptive neurones in rat superior colliculus by using c-fos immunohistochemistry and electrophysiology under different conditions of anaesthesia.

Multiple sensory inputs to the superior colliculus (SC) play an important role in guiding head and eye movements toward or away from biologically significant stimuli. Much is now known about the visual, auditory, and somatosensory response properties of SC neurones that mediate these behavioural reactions. Rather less is known about the responses of SC neurones to noxious stimuli, and thus far, most of this information has been obtained in anaesthetised animals. Therefore, the purpose of the present study was to use the c-fos immunohistochemical technique and standard extracellular electrophysiology as parallel measures of nociceptive activity in the SC under different conditions of anaesthesia. In unanaesthetised animals, experimental and control treatments induced a qualitatively similar pattern of Fos-like immunoreactivity (FLI) in the SC, which was quantitatively related to the severity or biologic salience of the treatment; thus, baseline control < control injections of saline < a nonpainful stressor (immobilisation) < noxious injections of formalin. Compared with baseline levels, urethane and avertin anaesthesia induced FLI expression in the SC intermediate layers, although the FLI response to both noxious stimulation and control conditions was differentially suppressed in different layers of the SC by anaesthesia. Parallel electrophysiologic recordings found that anaesthesia was associated with high levels of spontaneous activity in the SC intermediate layers, often in neurones which were also nociceptive. High rates of background spike activity were also induced in the SC intermediate layers by noxious stimulation in chronically recorded awake animals. Although these results point to some differences between the nociceptive responses of SC neurones in anaesthetised and unanaesthetised animals, both data sets support the view that there are different populations of nociceptive neurones in the rodent SC that may be related to different adaptive functions of pain.

Tonic desynchronisation of cortical electroencephalogram by electrical and chemical stimulation of superior colliculus and surrounding structures in urethane-anaesthetised rats.

Damage to the superior colliculus in rats impairs desynchronisation of the cortical electroencephalogram in response to light flashes. However, it is unclear which elements within the superior colliculus, and which efferent collicular pathways, might be involved in alerting cerebral cortex to visual stimuli. To investigate this problem, the superior colliculus and surrounding structures were stimulated either electrically (3 s trains of 0.2 ms 100 Hz cathodal pulses), or chemically (200 nl of 5 mM sodium L-glutamate), in rats anaesthetised with urethane. The cortical electroencephalogram was recorded bilaterally from frontal cortex. At each site tested with electrical stimulation the threshold current (up to 60 microA) required to produce tonic desynchronisation (outlasting stimulation-offset by at least 10 s) was determined. Comparison of the effects of electrical and chemical stimulation suggested the following: (1) stimulation of cells in the deep layers of the superior colliculus can desynchronise the cortical electroencephalogram. There may also be an additional effective area in the rostral part of the superficial layers, but this needs to be confirmed in unanaesthetised animals. (2) Stimulation of fibres in the deep white layers of caudal superior colliculus, and of cells in a wide area of caudal midbrain reticular formation, are also effective at desynchronising the cortical electroencephalogram. It is therefore possible that the ipsilateral descending pathway, that runs from the superior colliculus to terminate in the parabigeminal and cuneiform nuclei and surrounding reticular formation, is involved in mediating cortical desynchronisation initiated by the superior colliculus. Evidence from other studies indicates that some sites in this pathway may be part of a "defence arousal system". (3) Sites on the ascending pathways from the superior colliculus, to structures including dorsal thalamus, pretectum, zona incerta and rostral midbrain reticular formation, were relatively ineffective at tonically desynchronising the cortex. However, some of these pathways might mediate phasic, movement-related arousal of collicular origin.

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.

Photometric assessment of glyoxylic acid-induced fluorescence of dopamine in the caudate nucleus.

New procedure for quantitative photometric assessment of glyoxylic acid-induced fluorescence of dopamine in the caudate nucleus are presented. A recently published cryostat method was used to process a series of 24 micrometer sections taken from the caudate nucleus of each animal. Fluorescent light contained within a circular field (0.8 mm diameter) was measured photometrically. Several defined positions within the caudate nucleus on each tissue section were selected for measurement. Thus, a grid of measurements taken throughout the caudate nucleus provided a three-dimensional description of fluorescence intensity within this structure on both sides of the brain. Several experiments were performed to evaluate both the reliability and validity of these procedures as an index of the relative regional content of dopamine within the caudate: (1) the relative distribution of fluorescence intensity within the mouse striatum was in good agreement with previously reported distributions based on biochemical determination of regional dopamine levels within the rodent brain; (2) pharmacological manipulation of dopamine levels with gamma-butyrolactone and alpha-methyl-p-tyrosine combined with amphetamine produced predictable changes in the fluorescence intensity measurements of mouse caudate relative to untreated controls; (3) in rats pre-treated with alpha-methyl-p-tyrosine, unilateral electrical stimulation of the substantia nigra caused overall differences in fluorescence intensity between the caudate nucleus on each side of the brain, which were a function of both the duration of stimulation and the stimulating pulse frequency; (4) local injections of 6-hydroxydopamine unilaterally into the ventral tegmentum of animals pretreated with desmethylimipramine caused significant reductions in the intensity of fluorescence recorded from the ipsilateral striatum. It is concluded that the photometric procedures presented in this report constitute a significant improvement in the description of regional variations in the intensity of dopamine-related fluorescence in the caudate nucleus.

Functional validation of projection topography in the nigrostriatal dopamine system.

Anatomical investigations have revealed that the nigrostriatal pathway is topographically organised. In two experiments, nigrostriatal topography was investigated with catecholamine specific procedures, using paradigms which reflect the functional activity of dopaminergic neurones. Data were analysed with the intention of discovering possible relationships between the mesencephalic location of stimulating electrodes or injection cannulae, the extent and location of dopamine histofluorescence depletion within the striatum, and the effects of amphetamine and apomorphine on rotational behaviour. In animals pretreated with 250 mg/kg alpha-methyl-p-tyrosine it was found that unilateral stimulation with medially-placed nigral electrodes produced maximal depletion of dopamine histofluorescence in anterior dorso-medial regions of the striatum, while laterally-located electrodes principally depleted posterior, ventro-lateral areas. In the second experiment, 2 micrograms of 6-hydroxydopamine in a volume of 0.5 microliter was injected unilaterally at varying loci within the ventral midbrain of animals pre-treated with desmethylimipramine (25 mg/kg). It was discovered that the lateral injection coordinate was significantly associated with both the extent and location of the depletion of dopamine-related fluorescence from the ipsilateral striatum. Rotational behaviour, induced by dopamine-agonists was related firstly, to the overall extent of dopamine depletion from the striatum, and secondly, the contraversive turning induced by apomorphine in particular was related to the dorsoventral coordinate of the mesencephalic 6-hydroxydopamine injection. The results provide functional validation for the pattern of topographical projection within the nigrostriatal dopaminergic system proposed on the basis of intracellular tracing techniques.

Topographical organization of the nigrotectal projection in rat: evidence for segregated channels.

Recent evidence suggests that projections from the superior colliculus to the brainstem in rat are organized into a series of anatomically segregated output channels. To understand how collicular function may be modified by the basal ganglia it is important to know whether particular output modules of the superior colliculus can be selectively influenced by input from substantia nigra. The purpose of the present study was, therefore, to examine in more detail topography within the nigrotectal system in the rat. Small injections (10-50 nl) of a 1% solution of wheatgerm agglutinin conjugated with horseradish peroxidase were made at different locations within substantia nigra and surrounding structures. A discontinuous puff-like pattern of anterogradely transported label was found in medial and caudal parts of the ipsilateral intermediate layers of the superior colliculus. In contrast, the rostrolateral enlargement of the intermediate layers contained a greater density of more evenly distributed terminal label. Injection sites associated with this dense pattern of laterally located label were concentrated in lateral pars reticulata, while the puff-like pattern was produced by injections into ventromedial pars reticulata. Retrograde tracing experiments with the fluorescent dyes True Blue and Fast Blue revealed that injections involving the rostrolateral intermediate layers were consistently associated with a restricted column of labelled cells in the dorsolateral part of ipsilateral pars reticulata. Comparable injections into medial and caudal regions of the superior colliculus produced retrograde labelling in ventral and medial parts of the rostral two-thirds of pars reticulata. Both anterograde and retrograde tracing data indicated that contralateral nigrotectal projections arise from cells located in ventral and medial pars reticulata. The present results suggest that the main ipsilateral projection from substantia nigra pars reticulata to the superior colliculus comprises two main components characterized by regionally segregated populations of output cells and spatially separated zones of termination. Of particular interest is the apparent close alignment between terminal zones of the nigrotectal channels and previously defined populations of crossed descending output cells in the superior colliculus. Thus, the rostrolateral intermediate layers contain a concentration of terminals specifically from dorsolateral pars reticulata and output cells which project to the contralateral caudal medulla and spinal cord. Conversely, the medial and caudal intermediate layers receive terminals from ventral and medial pars reticulata and contain cells which project specifically to contralateral regions of the paramedian pontine and medullary reticular formation.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

Organization of the crossed tecto-reticulo-spinal projection in rat--I. Anatomical evidence for separate output channels to the periabducens area and caudal medulla.

The superior colliculus has been used to study principles of sensorimotor transformation underlying the guidance of orienting movements by multimodal sensory stimuli. We have previously suggested that there may be two different classes of mechanism which can produce orienting-like movements towards a novel event; one that locates a stimulus on the basis of remembered position, and another which uses continuous feedback relating to target velocity. The crossed descending pathway of the superior colliculus is widely considered the projection most likely to relay signals associated with the production of orienting movements. However, if different neural mechanisms are used to produce functionally distinct types of orienting, we might expect this pathway to have separate anatomical components related to function. The purpose of the present experiment was to see if collicular fibres innervating two important pre-motor targets of the crossed descending pathway, the periabducens area and the caudal medulla-spinal cord, come from the same population of tectal cells. One of the retrogradely transported fluorescent tracers (Diamidino Yellow) was injected into the periabducens area, and another (True Blue or Fast Blue) was injected into tectospinal fibres at the level of the ventromedial caudal medulla. Under these conditions we found: (i) less than 10% of labelled cells within the superior colliculus contained both tracers; (ii) the bulk of singly labelled cells projecting to the periabducens area or the caudal medulla were concentrated at different locations within the colliculus, (iii) in regions of the superior colliculus where there was overlap of singly labelled cells, neurons projecting to the periabducens area or the caudal medulla could be distinguished morphologically. These data provide three classes of evidence which indicate that the crossed descending projection in rat can be subdivided into at least two relatively independent anatomical components. This conclusion may, in part, provide an anatomical substrate for the functional dissociations proposed for orienting movements.

Feeding induced by injections of muscimol into the substantia nigra of rats: unaffected by haloperidol but abolished by large lesions of the superior colliculus.

Intense activation of central dopamine systems has been associated with oral stereotyped behaviour, whereas less intense stimulation of these systems can increase feeding in non-deprived animals. There are several lines of evidence which suggest that the gamma-aminobutyric acid-containing striatonigral and nigrotectal projections are essential pathways mediating dopamine-related oral stereotypy. The present series of experiments was conducted to examine whether the same output route also mediates dopamine-related feeding. In the first experiment it was shown that bilateral injections of a sub-stereotypic dose of muscimol (0.05 nM) into the substantia nigra increased feeding of non-deprived rats. In Experiment II the feeding response was further characterised by demonstrating that food intake was initially suppressed for 30 min after which it was potentiated for 90 min. In Experiment III it was shown that a single dose of haloperidol (0.4 mg/kg), which was adequate to suppress overall food intake, was ineffective in preventing the increase in feeding produced by intranigral muscimol (0.05 nM). In contrast, it was demonstrated in Experiment IV that large lesions of the superior colliculus completely abolished the muscimol-induced increase in feeding. These results suggest that the striatonigral and nigrotectal projections may be important efferent pathways for both the oral stereotypy and the feeding responses linked with central dopamine transmission.

Head and body movements produced by electrical stimulation of superior colliculus in rats: effects of interruption of crossed tectoreticulospinal pathway.

Stimulation of the superior colliculus in rats produces movements of the head and body that resemble either orientation and approach towards a contralateral stimulus, or avoidance of, or escape from, such a stimulus. A variety of evidence indicates that the crossed descending pathway, which runs in the contralateral predorsal bundle to the pontomedullary reticular formation and the spinal cord, is involved in orienting movements. The nature of this involvement was investigated, by assessing the effects on tectally-elicited movements of midbrain knife-cuts intended to section the pathway as it crosses midline in the dorsal tegmental decussation. As expected, ipsilateral movements resembling avoidance or escape were little affected by dorsal tegmental decussation section, whereas contralateral circling movements of the body were almost abolished. However, contralateral movements of the head in response to electrical stimulation were not eliminated, nor were orienting head movements to visual or tactile stimuli. There was some suggestion that section of the dorsal tegmental decussation increased the latency of head movements from electrical stimulation at lateral sites, and decreased the accuracy of orienting movements to sensory stimuli. These results support the view that the crossed tectoreticulospinal system is concerned with approach rather than avoidance movements. However, it appears that other, as yet unidentified, tectal efferent systems are also involved in orienting head movements. It is possible that this division of labour may reflect functional differences between various kinds of apparently similar orienting responses. One suggestion is that the tectoreticulospinal system is concerned less in open-loop orienting responses (that are initiated but not subsequently guided by sensory stimuli), than in following or pursuit movements.