György Benedek

The Relationship Among Neuregulin 1–Stimulated Phosphorylation of AKT, Psychosis Proneness, and Habituation of Arousal in Nonclinical Individuals

BACKGROUNDnPrevious studies reported an association between weak habituation of skin conductance orienting response and psychosis proneness. The aim of this study was to investigate the relationship among neuregulin 1 (NRG1)-stimulated AKT phosphorylation (a putative marker of psychosis), orienting response habituation, delusional ideas, anxiety, and depression in nonclinical individuals.nnnMETHODSnOne hundred twenty individuals participated in the skin conductance measurements. Weak and strong habituators were compared on measures of NRG1-stimulated AKT phosphorylation in B lymphoblasts, delusional ideas, anxiety, and depression. The predictors of delusional ideas were determined by multiple regression analysis.nnnRESULTSnWeak habituators displayed higher levels of delusional ideas/anxiety and a lower ratio of phosphorylated AKT as compared with strong habituators. There were 3 significant predictors of delusional ideas: decreased habituation, NRG1-induced AKT phosphorylation, and anxiety. Age, gender, education, IQ, and depression did not predict delusional ideas.nnnCONCLUSIONSnThese results suggest that decreased habituation of arousal, NRG1-induced AKT phosphorylation, and anxiety are related to delusional ideation in the general population.

Fragile X protein expression is linked to visual functions in healthy male volunteers

Fragile X syndrome (FXS) is characterized by the impairment of the magnocellular/dorsal visual system. In this study, we explored how fragile X protein (FMRP) expression may affect visual functions in healthy participants. The percentage of FMRP-positive lymphocytes was measured using a rapid antibody test in blood smears of 100 male volunteers. CGG triplet expansion was also determined. Results revealed that participants with fewer FMRP-positive lymphocytes exhibited lower performances on tests biasing information processing toward the magnocellular pathway and dorsal visual stream (contrast sensitivity at low spatial/high temporal frequency and motion coherence). It was not observed in the case of tests biasing information processing toward the parvocellular pathway and ventral stream (contrast sensitivity at high spatial/low temporal frequency and form coherence). These results suggest that healthy persons with lower peripheral FMRP expression display a visual phenotype similar to that described in patients with FXS.

Long-lasting, distinct changes in central opioid receptor and urinary bladder functions in models of schizophrenia in rats

Ketamine treatments and social isolation of rats reflect certain features of schizophrenia, among them altered pain sensitivity. To study the underlying mechanisms of these phenomena, rats were either housed individually or grouped for 33 days after weaning, and treated with either ketamine or saline for 14 days. After one month re-socialization, the urinary bladder capacity by ultrasound examination in the anesthetized animals, and changes of μ-opioid receptors by saturation binding experiments using a specific μ-opioid agonist [(3)H]DAMGO were determined. G-protein signaling was investigated in DAMGO-stimulated [(35)S]GTPγS functional assays. Ketamine treatment significantly decreased the bladder volume and isolation decreased the receptor density in cortical membranes. Among all groups, the only change in binding affinity was an increase induced by social isolation in the cortex. G-protein signaling was significantly decreased by either ketamine or social isolation in this tissue. Ketamine treatment, but not housing, significantly increased μ-opioid receptor densities in hippocampal membranes. Both ketamine and isolation increased the efficacy, while the potency of signaling was decreased by any treatment. Ketamine increased the receptor density and G-protein activation; while isolation decreased the efficacy of G-protein signaling in hippocampal membranes. The changes in the co-treated group were similar to those of the isolated animals in most tests. The distinct changes of opioid receptor functioning in different areas of the CNS may, at least partially, explain the augmented nociceptive threshold and morphine potency observed in these animals. Changes in the relative urinary bladder suggest a detrusor hyperreflexia, another sign of schizophrenia.

Development of visual contour integration in children with migraine without aura

Introduction: As migraine attacks pose insult to cerebral circulation and ion homeostasis, migraine has the potential to interfere with the development of different brain structures, producing functional deficits. It is known that visual contour integration (CI) is a function with a protracted development. Therefore, we sought to establish whether migraine interferes with its development. Methods: Forty-eight migraineurs (without aura) and 48 age- and sex-matched controls participated in the study, divided into three cohorts by age. Stimuli were presented on cards with a contour consisting of Gabor patches embedded in random noise. Difficulty was varied by the manipulation of relative noise density. The task was to identify and show the contour. Results: A significant difference was found between the performance of migraineurs and controls in the 10–14-year-old and 15–18-year-old cohorts (pu2009<u20090.05). Development between all three cohorts was significant in the control group (pu2009<u20090.017), while it was not significant in migraineurs between 6 and 14 years. Correlation between age and CI threshold was stronger in controls than in migraineurs. Conclusion: Children with paediatric migraine exhibited a less marked development in the Gabor patch-based CI task.

Inhibition of itch-related responses at spinal level in rats

The goal was to develop a rat model for determination of the effects of intrathecally administered drugs on the peripherally induced pruritic behaviors. After chronic intrathecal catheterization, a serotonin derivative (5-methoxytryptamine: MeOT, 200 μg on both sides) was injected into the lower leg skin. After the first period (phase 0: 0-30 min) MeOT injection was repeated and opioid antagonist naltrexone (10 μg), NMDA receptor antagonists ketamine (10-100 μg), kynurenic acid (1-10 μg) or their combinations were injected intrathecally. The second observational period lasted for 60 min (phases I and II, 30-60 and 60-90 min, respectively). MeOT produced pruritic behavior with high degree of interindividual differences. The second MeOT injection caused an enhanced pruritic behavior in Phase I. Naltrexone decreased the pruritic activity, while neither doses of ketamine influenced the effects of MeOT. The higher doses of kynurenic acid resulted in notable decreases in the pruritic behavior. The combinations of naltrexone with ketamine or kynurenic acid produced a prolonged antipruritic effect. Our data suggest an important direction for the development of a new itch model in rats that focuses on the spinal mechanism of itching. Besides, the results revealed the role of the spinal opioid and NMDA receptors in this process.

The antinociceptive potency of N-arachidonoyl-dopamine (NADA) and its interaction with endomorphin-1 at the spinal level

The endogenous N-arachidonoyl-dopamine (NADA) activates both transient receptor potential vanilloid1 (TRPV1) and cannabinoid-1 (CB(1)) receptors. The goal of this study was to characterize the antinociceptive potential of NADA on inflammatory thermal hyperalgesia in rats at spinal level, and to determine its interaction with endomorphin-1 (EM) at the spinal level. The effects of NADA and EM on thermal hyperalgesia were evaluated in rats with a unilateral hind paw carrageenan-induced inflammation. Intrathecal injection of either EM (0.03-10 μg) or NADA (1.5-50 μg) caused dose-dependent antihyperalgesia, but NADA was 5.4 times less potent than EM. The antihyperalgesia caused by 15 μg NADA was inhibited by the TRPV1 antagonist AMG9810, but not by CB(1) antagonist/inverse agonist AM 251, whereas the effect of 50 μg NADA was decreased by both drugs. Co-administration of EM with NADA in 1:15 and 1:50 ratios produced a short-lasting potentiation, but isobolographic analysis for the whole investigated period revealed additive interaction between the two endogenous ligands. The results show that both TRPV1 and CB(1) receptor activation play a substantial role in the antinociceptive effects of NADA at spinal level, while co-administration of NADA with EM did not show potentiation.

Direct projection from the visual associative cortex to the caudate nucleus in the feline brain

Recent morphological and physiological studies support the assumption that the extrageniculate ascending tectofugal pathways send visual projection to the caudate nucleus (CN) in amniotes. In the present study we investigate the anatomical connection between the visual associative cortex along the anterior ectosylvian sulcus (AES) and the CN in adult domestic cats. An anterograde tracer - fluoro-dextrane-amine - was injected into the AES cortex. The distribution of labeled axons was not uniform in the CN. The majority of labeled axons and terminal like puncta was found only in a limited area in the dorsal part of the CN between the coordinates anterior 12-15. Furthermore, a retrograde tracer - choleratoxin-B - was injected into the dorsal part of the CN between anterior 12 and 13. We detected a large number of labeled neurons in the fundus and the dorsal part of the AES between the coordinates anterior 12-14. Based upon our recent results we argue that there is a direct monosynaptic connection between the visual associative cortex along the AES and the CN. Beside the posterior thalamus, the AES cortex should also participate in the transmission of the tectal visual information to the CN. This pathway is likely to convey complex information containing both sensory and motor components toward the basal ganglia, which supports their integrative function in visuomotor actions such as motion and novelty detection and saccade generation.

Neuronal code of spatial visual information in the caudate nucleus

Earlier reports described huge overlapping visual receptive fields and the absence of retinotopic organization in the dorsolateral, caudal part of the caudate nucleus. In the present study we suggest a possible alternative mechanism for the coding of spatial visual information. Extracellular microelectrode recordings were carried out in halothane-anesthetized, immobilized, artificially ventilated cats. In order to investigate the responsiveness of the single neurons to visual information arriving from different sites of the receptive field, we divided the visual fields to 20 parts of equal size and stimulated the individual parts one-by-one. We found that each single visual caudate nucleus (CN) neuron can carry information about stimulus locations throughout the whole physically approachable visual field of the investigated eye. A large majority (85%) of these neurons exhibited significantly different responses to stimuli appearing in different regions of their huge receptive field. Thus these neurons appear to have the ability to provide information on the site of the stimulus via their discharge rate. The huge receptive fields in combination with the spatial selectivity suggest that these caudate nucleus neurons may serve as panoramic localizers. On the population level, the sites of maximal responsiveness of the visual neurons are distributed over the whole extent of the receptive fields. We argue that groups of these panoramic localizer neurons with different locations of maximal stimulus preference should have the ability to accurately code the locations of visual stimuli. We propose this distributed population code of visual information as an alternative information processing mechanism.

Visual stimulation synchronizes or desynchronizes the activity of neuron pairs between the caudate nucleus and the posterior thalamus

Recent morphological and physiological studies have suggested a strong relationship between the suprageniculate nucleus (Sg) of the posterior thalamus and the input structure of the basal ganglia, the caudate nucleus (CN) of the feline brain. Accordingly, to clarify if there is a real functional relationship between Sg and CN during visual information processing, we investigated the temporal relations of simultaneously recorded neuronal spike trains of these two structures, looking for any significant cross-correlation between the spiking of the simultaneously recorded neurons. For the purposes of statistical analysis, we used the shuffle and jittering resampling methods. Of the recorded 288 Sg-CN neuron pairs, 26 (9.2%) showed significantly correlated spontaneous activity. Nineteen pairs (6.7%) showed correlated activity during stationary visual stimulation, while 21 (7.4%) pairs during stimulus movement. There was no overlap between the neuron pairs that showed cross-correlated spontaneous activity and the pairs that synchronized their activity during visual stimulation. Thus visual stimulation seems to have been able to synchronize, and also, by other neuron pairs, desynchronize the activity of CN and Sg. In about half of the cases, the activation of Sg preceded the activation of CN by a few milliseconds, while in the other half, CN was activated earlier. Our results provide the first piece of evidence for the existence of a functional cooperation between Sg and CN. We argue that either a monosynaptic bidirectional direct connection should exist between these structures, or a common input comprising of parallel pathways synchronizing them.

A new, behaving, head restrained, eye movement-controlled feline model for chronic visual electrophysiological recordings

BACKGROUNDnAnesthetized, paralyzed domestic cats are often used as model organisms in visual neurophysiology. However, in the last few decades, behaving animal models have gathered ground in neurophysiology, due to their advantages over anesthetized, paralyzed models.nnnNEW METHODnIn the present study a new, behaving, awake feline model is described, which is suitable for chronic visual electrophysiological recordings. Two trained, head- fixed cats were suspended in a canvas harness in a specially designed stand. The animals had been trained to fixate the center of a monitor during static and dynamic visual stimulation. Eye movements were monitored with implanted scleral coil in a magnetic field. Cell-level activity was recorded with eight electrodes implanted in the caudate nucleus.nnnRESULTSnOur two trained cats could maintain accurate fixation, even during optic flow stimulation, in an acceptance window of ±2.5° and ±1.5°, respectively. The model has yielded accurate recordings for over two years.nnnCOMPARISON WITH EXISTING METHOD(S)nTo our knowledge, this is the first awake, behaving feline model with rigorous eye movement control for chronic, cell-level visual electrophysiological recordings, which has actually proven to work during a longer period.nnnCONCLUSIONSnThe new model is optimal for chronic visual electrophysiological recordings in the awake, behaving domestic cat.