G. Benedek

Visual, somatosensory, auditory and nociceptive modality properties in the feline suprageniculate nucleus

Response properties of 252 single-units to visual, auditory, somatosensory and noxious stimulation were recorded by means of extracellular microelectrodes in the suprageniculate nucleus of anaesthetized, immobilized cats. Of the 141 units tested for modality properties the majority (n=113, 80.1%) was found unimodal in the sense that stimuli of exclusively one sensory modality were able to elicit an activation of the unit. Twenty-four (17.0%) cells were bimodal and four (2.8%) were trimodal (visual, somatosensory and auditory). The visual modality dominated the unimodal cells (n=74, 65.5%), while cells responsive to somatic stimulation (n=20, 17.6%), auditory stimulation (n=16, 14.1%) or noxious stimulation of the tooth pulp (n=3, 2.6%) were less frequently encountered. Visual sensitivity dominated the multisensory cells, too. The visually responsive units were characterized by having a sensitivity to stimuli moving in a rather large, uniform receptive field that covered the contralateral lower quadrant, and encompassed a flanking area of about 20 degree width in both the upper contralateral and lower ipsilateral visual fields. Many cells (n=52, 47%) were sensitive to the direction of the stimulation and reacted to stimuli moving at a high velocity (20-200 deg/s). Most cells responded differently to stimuli of a variety of sizes. Somatosensory units reacted to stimuli presented over a wide area on the contralateral side of the body, thus showing no sign of somatotopic organization. The auditory sensitivity fell within a wide range of acoustic stimuli in extremely large auditory receptive fields. The physiological properties of suprageniculate nucleus cells strongly resemble the sensory properties of cells found along the ventral bank of the anterior ectosylvian sulcus and the deeper layers of the superior colliculus. Our results provide further support for the notion of a separate tecto-suprageniculate-anterior ectosylvian sulcus/insular pathway that takes part in the processing of multimodal signals important for various types of sensory related behaviours.

Spatial contrast sensitivity of migraine patients without aura

Visual disturbances are frequent symptoms in migraine. Since there is a possibility of separate damage in the magno- or parvo-cellular visual pathway in migraine patients, we performed a study including the measurement of static and dynamic spatial contrast sensitivity on 15 patients suffering from migraine without aura under photopic and scotopic conditions. Fifteen healthy volunteers without primary headache served as controls. The results revealed a marked decrease in contrast sensitivity at low spatial frequencies in the migraine patients. Spatial contrast sensitivity demonstrated some lateralization, as the sensitivity to low spatial frequencies obtained through separate eyes showed significantly larger side-differences in migraine patients than in control subjects. These findings suggest that the mechanisms responsible for vision at low spatial frequencies are impaired in migraine patients. This might indicate impaired function of the magnocellular pathways in this condition.

Enhancement of fentanyl analgesia by clonidine plus verapamil in rats

An investigation was made of the analgesic effects of the subcutaneous coad ministration of fentanyl, an opioid μ- agonist (15 μg/kg), clonidine, an α2-agonist (100 μg/kg), and verapamil, a calcium channel blocker (10 mg/kg) in rats. Nociceptive sensitivity was assessed with hot-plate and tail-flick techniques. None of the three drugs alone was associated with appreciable analgesic effects in the doses used. The simultaneous administration of the three drugs resulted in marked analgesia superior to that of all binary combinations of these drugs. Two-way analysis of variance showed statistically significant differences in hot-plate and tail-flick latencies after drug treatments (P < 0.001). The significant differences in the area under the time-response curve values (P < 0.001) might indicate not only an increased analgesic effect, but also a prolongation of anti- nociception. These results suggest the existence of hitherto unreported interactions between drugs involved in the production of analgesia.

Spatial and temporal visual properties of single neurons in the suprageniculate nucleus of the thalamus

The spatial and temporal visual sensitivity to drifting sinusoidal gratings was studied in 105 neurons of the suprageniculate nucleus of the feline thalamus. Extracellular single-unit recordings were performed in halothane-anesthetized, immobilized, artificially ventilated cats. Most suprageniculate nucleus cells were strongly sensitive to the direction of drifting gratings. The suprageniculate nucleus units had a clear preference for very low spatial frequencies with a mean of 0.05 cycle/deg. The spatial resolution was also very low with a mean of 0.16 cycle/deg. Most of the cells displayed low-pass spatial tuning characteristics, while the remainder of the units were band-pass tuned. The suprageniculate nucleus units were extremely narrowly tuned, to spatial frequencies with a mean spatial bandwidth of 1.07 octaves. A majority of the units responded optimally to high temporal frequencies, with a mean of 8.53 Hz. The temporal frequency tuning functions predominantly revealed a band-pass character, with a mean temporal bandwidth of 1.66 octaves. These results demonstrate that the neurons in the suprageniculate nucleus display particular spatial and temporal characteristics. The spatial and temporal tuning properties of the suprageniculate nucleus neurons are very similar to those of the superior colliculus and the anterior ectosylvian cortex, structures that provide the main visual afferentation toward the suprageniculate nucleus. This suggests their common function in motion perception, and especially in the recording of movements of the visual environment relative to the body, and the related behavioral action.

Why is vision impaired in fragile X premutation carriers? The role of fragile X mental retardation protein and potential FMR1 mRNA toxicity

Dysfunctions of the geniculo-striatal magnocellular (M) visual pathway and its cortical recipients have been documented in fragile X syndrome and in FMR1 premutation carriers. However, the mechanism of this impairment is less clear. To elucidate this issue, we completed the measurement of visual functions at different stages of information processing: low-level mechanisms (contrast sensitivity biasing information processing toward the M and parvocellular [P] pathways), primary visual cortex (motion-defined and static Vernier threshold), and higher-level form and motion processing (coherence thresholds). Results revealed that FMR1 premutation carriers, relative to non-carrier controls, exhibited lower contrast sensitivity for M pathway-biased stimuli, higher Vernier threshold for motion-defined stimuli, and higher global motion coherence threshold. Although both elevated FMR1 mRNA and reduced fragile X mental retardation protein (FMRP) levels were associated with impaired visual functions, regression analysis indicated that FMRP was the primary factor. In premutation carriers, a toxic gain-of-function of elevated FMR1 mRNA has been suggested, whereas reduced FMRP is linked to neurodevelopmental aspects. Here, we showed that FMRP may the primary factor associated with visual dysfunctions.

Rolipram, an Antidepressant That Increases the Availability of cAMP, Transiently Enhances Wakefulness in Rats

A study was carried out on the effects on sleep of rolipram, an antidepressant that increases the availability of cAMP by inhibiting a phosphodiesterase isoenzyme. Rats were treated with rolipram (0.1 or 1 mg/kg) twice a day (at light and dark onset) for 11 days, after a chronic period of injection of physiological saline for habituation purposes. The sleep-wake activity was recorded for 12 h following the injection at light onset on the baseline day (physiological saline), on rolipram days 1, 5, and 11, and also on day 12, when physiological saline was injected again (withdrawal day). The high (1 mg/kg) dose of rolipram enhanced wakefulness (W) in postinjection h 1 on day 1 of rolipram treatment. After administration of 0.1 mg/kg rolipram, only a tendency to an increase in W was noted. The promotion of W might be attributed, at least in part, to an increased release of noradrenaline due to a cAMP-mediated stimulation of tyrosine hydroxylase.

Sex-specific alterations in behavioral and cognitive functions in a "three hit" animal model of schizophrenia.

Whereas schizophrenia affects both human sexes, there are known sex-dependent disparities. We developed a chronic animal model that shows some schizophrenia-related deficits in rats by applying selective breeding after subchronic ketamine administration connected with postweaning social isolation (complex treatment). Our aim was to determine the sex-specific effects of these interventions on several processes. Sensory gating to acoustic stimulation, pain sensitivity, motor behavior, spatial learning and memory deficits on the hole-board test were assessed in the 17th generation of selectively bred Wistar rats compared to their naive counterparts with or without complex treatment. We found differences between the sexes: selectively bred males with complex treatment showed the lowest pain sensitivity; however, the results of the prepulse inhibition test indicated that female rats showed enhanced impairment of sensory gating and increased acoustic startle reaction. The cognitive performance, working and reference memory ratios were significantly decreased by selective breeding and showed sex-specific alterations, with the smallest value in male rats of the new substrain. Based on these results, the animals of the new substrain could be classified into the high-risk for schizophreniform phenotype with the highest sensitivity of males with complex treatment. Decreased cognitive performance highlighted spatial learning deficits in the selectively bred and treated rats that escalate the validity of our new and complex rat model of schizophrenia. The results indicate the same sex selectivity as observed in humans, with increased incidence of risk ratios for men to develop schizophrenia relative to women.

Overlap of nigrothalamic terminals and thalamostriatal neurons in the feline lateralis medialis-suprageniculate nucleus.

The lateralis medialis-suprageniculate nucleus (LM-Sg) of the feline posterior thalamus is a relay nucleus with a clear visuomotor function. In this study, we examined the distribution of axon terminals of the nigral afferent to the LM-Sg following injection of an anterograde tracer, biocytin, into the substantia nigra pars reticulata, and the distribution of the thalamostriatal projection neurons in the LM-Sg following the injection of wheat germ agglutinin conjugated with horseradish peroxidase (WGA-HRP) as a retrograde tracer into the caudate nucleus. The biocytin-labeled terminal-like puncta were located in the ventromedial portion of this nucleus in such a way that most of the labeled elements took the form of swellings having boutons in places, while a minority appeared in clusters of 3-5 large terminal-like puncta. The retrograde WGA-HRP-labeled neurons were also found in the ventromedial part of the LM-Sg, and the distributions of labeled nigrothalamic axon terminals and labeled thalamostriatal projection neurons therefore overlapped in this region. The present results indicate that the nigral afferent may make synaptic contacts directly with the thalamostriatal projection neurons within the LM-Sg.

Visual receptive field properties of excitatory neurons in the substantia nigra

The substantia nigra has been widely regarded as a structure involved in visuomotor co-ordination, but little is known about the sensory background of its function. Here we give a detailed description of the visual receptive field properties of excitatory substantia nigra neurons. The visual responses of 59 excitatory neurons were recorded in both the substantia nigra pars reticularis and the pars compacta of halothane-anesthetized, immobilized, artificially respirated cats. The substantia nigra neurons were not responsive or exhibited very low sensitivity to stationary visual stimulation. The units responded optimally to small stimuli moving at intermediate or high velocities in their extremely large receptive field. We observed no signs of retinotopical organization within the substantia nigra. A majority of the units exhibited narrow direction tuning and high direction selectivity, while a smaller proportion of them were broadly tuned and not direction-sensitive. Our results suggest that the visual properties of the excitatory substantia nigra units are quite similar to those of the superior colliculus and other extrastriatal structures that receive tectal afferents. This supports the notion that the substantia nigra processes dynamic visual information and that its excitatory visual neurons are modulated by the extrageniculate tectal visual system of the mammalian brain.

Molecular and functional changes in glucokinase expression in the brainstem dorsal vagal complex in a murine model of type 1 diabetes.

Glucose concentration changes in the nucleus tractus solitarius (NTS) affect visceral function and metabolism by influencing central vagal circuits, especially inhibitory, GABAergic NTS neurons. Acutely elevated glucose can alter NTS neuron activity, and prolonged hyperglycemia and hypoinsulemia in animal models of type 1 diabetes results in plasticity of neural responses in the NTS. NTS neurons contributing to metabolic regulation therefore act as central glucose sensors and are functionally altered in type 1 diabetes. Glucokinase (GCK) mediates cellular utilization of glucose, linking increased glucose concentration to excitability changes mediated by ATP-sensitive K(+) channels (KATP). Using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot, and in vitro electrophysiology, we tested the hypothesis that changes in GCK expression in the NTS accompany the development of diabetes symptoms in the streptozotocin (STZ)-treated mouse model of type 1 diabetes. After several days of hyperglycemia in STZ-treated mice, RNA expression of GCK, but not Kir6.2 or SUR1, was decreased versus controls in the dorsal vagal complex. Electrophysiological recordings in vitro indicated that neural responses to acute hyperglycemia, and synaptic responsiveness to blockade of GCK with glucosamine, were attenuated in GABAergic NTS neurons from STZ-treated mice, consistent with reduced molecular and functional expression of GCK in the vagal complex of hyperglycemic, STZ-treated mice. Altered autonomic responses to glucose in type 1 diabetes may therefore involve reduced functional GCK expression in the dorsal vagal complex.