Reward unpredictability inside and outside of a task context as a determinant of the responses of tonically active neurons in the monkey striatum.

Tonically active neurons (TANs) in the monkey striatum are involved in detecting motivationally relevant stimuli. We recently provided evidence that the timing of conditioned stimuli strongly influences the responsiveness of TANs, the source of which is likely to be the monkey's previous experience with particular temporal regularities in sequential task events. To extend these findings, we investigated the relationship of TAN responses to a primary liquid reward, the timing of which is more or less predictable to the monkey either outside of a task or during instrumental task performance. Reward predictability was indexed by the timing characteristics of the mouth movements. The responsiveness of TANs to reward increased with the range and variability of time periods before reward, notably when the liquid was delivered outside of a task. A change in the temporal order of events in a task context produced an increase of response to reward, suggesting an influence of the predicted nature of the event in addition to its time of occurrence. By contrast, we observed no substantial changes in neuronal activity at the expected time of reward when this event failed to occur, suggesting that these neurons do not appear to carry information about an error in reward prediction. These results demonstrate that TANs constitute a neuronal system that is involved in detecting unpredicted reward events, irrespective of the specific behavioral situation in which such events occur. The responses influenced by stimulus prediction may constitute a neuronal basis for the notion that striatal processing is crucial for habit learning.

Cannabinoid and nitric oxide signaling interplay in the modulation of hippocampal hyperexcitability: Study on electrophysiological and behavioral models of temporal lobe epilepsy in the rat.

A growing bulk of evidence suggests that cannabinoid system plays a pivotal role in the control of hyperexcitability phenomena. Notwithstanding, the anticonvulsant action of cannabinoids has not been fully addressed, in particular the involvement of potential cellular neuromodulators, for instance nitric oxide. In the current study, we focused on two distinct rat models of temporal lobe epilepsy, the Maximal Dentate Activation and the pilocarpine-induced acute seizures, providing both electrophysiological and behavioral data on cannabinoid and nitrergic system interplay. We evaluated the antiepileptic effects of WIN 55,212-2, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-Yl]-1-naphthalenylmethanone (WIN), a CB agonist, and of 7-Nitroindazole (7NI), a preferential neuronal nitric oxide synthase (nNOS) inhibitor, at different doses, alone and in combination. MDA study showed that these drugs protected animals in a dose-dependent manner from electrically induced epileptiform discharges. In pilocarpine model, a dose-related activity of 7NI and WIN: a) decreased the behavioral scoring, used to describe the severity of chemically induced acute seizures; b) affected latency of the onset of acute convulsions; c) dampened mortality rate. Interestingly, the combination of the treatments brought to light that individually ineffective doses of WIN turn into effective when nNOS activity is pharmacologically inhibited in both experimental conditions. This effect is mediated by CB1 receptor since the co-administration of N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251), a CB1 receptor specific antagonist, thwarted the 7NI-WIN convergent action. In the light of this, our findings suggest a putative antagonism between CBr-activated pathway and NO signaling in the context of neuronal hyperexcitability and contribute to elucidate possible synaptic processes underlying neuroprotective properties of cannabinoids, with a view to better integrate antiepileptic therapy.

Anticonvulsant activity of the noradrenergic locus coeruleus system: role of beta mediation.

Many experimental observations have demonstrated the modulatory role exerted by several neural structures and neurotransmitters on spontaneous and paroxysmal bioelectric activity of the hippocampus. Recently, the control exerted by locus coeruleus (LC) and its noradrenergic (NA) efferent pathway on different experimental models of epilepsy (e.g. cortical cobalt chronic epilepsy, amygdaloid and hippocampal kindling) was emphasised. On this basis, a series of experiments was performed to elucidate the functional role of LC-NA system on the hippocampal penicillin (PCN) focus and the type of adrenergic receptor involved. The experiments were carried out on 25 rats in which an epileptiform hippocampal focus was obtained through intrahippocampal PCN administration (100-200 I.U.). In these conditions, LC, ipsilateral to PCN hippocampal focus, was stimulated before and after intraperitoneal (i.p.) administration of a beta-adrenergic receptor antagonist propranolol (2 mg/kg). Results showed a significant reduction of hippocampal spiking frequency during LC stimulation; after i.p. propranolol injection, LC stimulation, at the same parameters, failed to induce any sort of modification of PCN hippocampal spiking frequency. Furthermore, intrahippocampal application of a beta-selective agonist 2-fluoro-noradrenaline (2-FNA) mimics the inhibitory effects of LC stimulation. All data suggest that the LC-NA system is able to induce a net reduction of hippocampal epileptiform focus and the inhibitory NA control involves the activation of adrenergic beta receptors.

Dopaminergic control of feline hippocampal epilepsy: a nigro hippocampal pathway.

Substantia nigra is a mesencephalic structure inserted along several circuits which appear to play a key role in epilepsy. In previous researches we postulated that substantia nigra pars compacta (SNpc) may be the site of a precise control of hippocampal epilepsy while substantia nigra pars reticulata (SNpr) may exert a modulation of both neocortical epilepsy and spreading of hyperactivity toward a motor target. In order to better understand mechanisms subserving nigral action in feline hippocampal epilepsy we electrically stimulated SNpc (dopaminergic), before and after sulpiride (dopamine receptor-antagonist) intravenous injection. Furthermore we compared hippocampal epileptiform activity prior to and after apomorphine (dopamine receptor-agonist) intrahippocampal injection as well as prior to and after SNpc electrolytic destruction. Results showed that SNpc is able to regulate hippocampal epilepsy. This effect is selectively antagonized by sulpiride while apomorphine exerts, synergically with SNpc stimulation, inhibitory effects. On the contrary SNpc lesions induces a significant enhancement of hippocampal epileptiform spikes. Experimental findings suggest that SNpc represents a strategic region for the control of hippocampal excitability and that this regulation appears to be dopaminergic in nature.

Lateral habenular influence on dorsal raphe neurons.

Previously, we have demonstrated that lateral habenula (LH) modulates the bioelectric activity of the hippocampus through the dorsal raphe nucleus functional involvement. In this study we have, preliminarily, electrophysiologically identified two types of raphe neurons: "slow" (S cells, serotonergic in nature); and "fast" (F cells, presumably GABAergic in nature). Then, we have shown that LH electrical stimulation at lower frequency induced an excitation of S and F neurons. LH stimulation at higher frequency inhibited only S neurons. Furthermore, iontophoretic NMDA excited S and F neurons. The excitatory effects of LH stimulation were antagonized by the iontophoretic 2-APV (NMDA antagonist). Iontophoretic GABA inhibited only S neurons. Iontophoretic bicuculline antagonized the LH-induced inhibition os S neurons. The data suggested a direct (NMDA-mediated) and indirect (through the F GABAergic inhibitory interneuron) influence of the LH on the serotonergic efferent neuron.

Lateral habenula and hippocampal units: electrophysiological and iontophoretic study.

In previous works we studied, on cats, the effects of lateral habenula (LH) stimulation on hippocampal units. In particular, the results showed an excitation or an inhibition in relation to the stimulation frequency (0.5-3.0 Hz or 5.0-20 Hz, respectively). All the LH stimulation effects were antagonised by iontophoretic intrahippocampal application of methysergide (MS). In this series of experiments it was possible to demonstrate, on rats, that LH stimulation causes an excitatory effect in a major number of hippocampal units in relation to the frequency increase. The inhibitory effect by iontophoretic serotonine application and the reversible blockade of habenular modulation after iontophoretic methysergide administration on hippocampal units suggest, on rats, the involvement of raphe. Such hypothesis, with anatomical evidences demonstrating an excitatory projection between LH and raphe, was confirmed by data concerning the effects of intraraphal NMDA iontophoretic application on hippocampal units (NMDA application for 30 s = excitation; NMDA administration for 10-15 min = inhibition). All the results suggest an habenular modulation of hippocampus through the involvement of the raphe in the context of which an interneurone is inhibitory on the efferent serotonergic raphe-hippocampus projection. This hypothesis finds further support from MS blockade effect during intraraphal NMDA iontophoretic administration.

Locus coeruleus noradrenaline system and focal penicillin hippocampal epilepsy: neurophysiological study.

Previous experimental investigations have shown that several neuronal systems modulate the spontaneous and paroxysmal electric activity of the hippocampus. The locus coeruleus-noradrenaline (LC-NA) system exerts an inhibitory influence on several brain areas including the ipsilateral hippocampus. Selective destruction of the LC increases the susceptibility to epileptiform phenomena in different models of experimental epilepsy. Our experiments were conducted on 34 rats in which a steady epileptiform interictal activity of the hippocampus was obtained by means of intrahippocampal administration of penicillin. Electrical stimulation of LC caused a significant decrease of penicillin spiking of hippocampus. Stimulation sessions given 10-15 min after i.p. propranolol administration (2 mg/kg) failed to induce any significant modification in the hippocampal spiking frequency. Intrahippocampal injection of L-noradrenaline mimicked the inhibitory effect of LC electrical stimulation on hippocampus. Finally, intrahippocampal administration of isoproterenol HCl, a beta-adrenoceptor agonist, caused a significant decrease of hippocampal penicillin spiking; this effect was antagonised by i.p. propranolol administration. The experimental data show a modulating influence of the LC-NA system on penicillin focal hippocampal epilepsy that probably involves beta-adrenoceptors.

Neuropsychology of selective attention and magnetic cortical stimulation.

Informed volunteers were asked to perform different neuropsychological tests involving selective attention under control conditions and during transcranial magnetic cortical stimulation. The tests chosen involved the recognition of a specific letter among different letters (verbal test) and the search for three different spatial orientations of an appendage to a square (visuo-spatial test). For each test the total time taken and the error rate were calculated. Results showed that cortical stimulation did not cause a worsening in performance. Moreover, magnetic stimulation of the temporal lobe neither modified completion time in both verbal and visuo-spatial tests nor changed error rate. In contrast, magnetic stimulation of the pre-frontal area induced a significant reduction in the performance time of both the verbal and visuo-spatial tests always without an increase in the number of errors. The experimental findings underline the importance of the pre-frontal area in performing tasks requiring a high level of controlled attention and suggest the need to adopt an interdisciplinary approach towards the study of neurone/mind interface mechanisms.

Accumbens-caudate-septal circuit as a system for hippocampal regulation: involvement of a GABAergic neurotransmission.

Hippocampal-based epileptiform activity may reach the basal ganglia via the nucleus accumbens. Previous data suggested that caudate nucleus is able to influence hippocampal epilepsy, probably sending a projection to the septum. In order to test the hypothesis of a retrograde activation of accumbens-caudate pathway in hippocampal regulation, we electrically stimulated both caudate nucleus and nucleus accumbens and studied modifications of hippocampal EEG in the feline focal epilepsy model. We also performed bilateral electrolytic lesion of nucleus accumbens and repeated caudate stimulation. Results showed that nucleus accumbens stimulation was ineffective in modifying hippocampal epilepsy; on the contrary, caudate stimulation caused a statistically significant decrease of hippocampal spike frequency and amplitude. On the other hand, in accumbens-lesioned animals caudate activation consistently reduced hippocampal epilepsy to a significant degree. As the caudate nucleus influences hippocampal activity and the septum may constitute a relay station of this functional relation, a possibility was tested concerning a GABAergic mediation. To this end, after a stable caudate-induced effect was reached, an intraseptal microinjection of picrotoxin (GABA receptor antagonist) was made and caudate stimulation repeated at the same parameters. Such a study showed that after intraseptal picrotoxin, caudate stimulation failed to elicit any type of modification of hippocampal activity. Experimental findings support the notion that the striatal modulation on hippocampus is mediated by an anterograde rather than a retrograde pathway, and underline the possibility of a GABAergic caudate-septal influence.

Electrophysiological and iontophoretic aspects of the habenular influence on hippocampal neurones.

In previous experimental studies, carried out on cats, we demonstrated that electrical stimulation of lateral habenula (LH) at 0.5-3.0 Hz or 5-20 Hz had a double effect (low frequency-excitation; high frequency-inhibition) on the spontaneous firing rate of single hippocampal neurones. Our results, in agreement with similar case studies, allowed us to hypothesise that in the habenular modulation of the hippocampus the raphe nucleus is probably involved. In fact, all the effects of LH stimulation were antagonised by the iontophoretic intrahippocampal application of methysergide. In the present series of experiments, performed on rats, it was possible to demonstrate that LH stimulation at 1-10 Hz causes an excitation of a progressively major number of hippocampal neurones depending upon the increase of frequency stimulation. The absence of habenulo-induced effects after a iontophoretic application of methysergide on single hippocampal units suggests the involvement of the raphe nucleus. Furthermore, in consideration of recent anatomical evidences demonstrating an excitatory projection between LH and raphe nucleus, intraraphal N-methyl-D-aspartate (NMDA) application, performed through a Hamilton microsyringe, induces an inhibitory effect. All the results suggest that in the raphe context it is possible to hypothesise the presence of an intrinsic interneurone, directly activated by the excitatory projection arising from the LH; this interneurone is likely inhibitory on the serotonergic raphe-hippocampus efferent neurone. This functional organization is responsible for the effect of LH stimulation at different frequencies as well as for the effects of intraraphal NMDA application.

Lamotrigine differently modulates 7-nitroindazole and L-arginine influence on rat maximal dentate gyrus activation.

The effects induced on the maximal dentate gyrus activation (MDA) by administering the anticonvulsant lamotrigine (LTG), the selective inhibitor of neuronal nitric oxide synthase 7-nitroindazole (7-NI) and the precursor of nitric oxide (NO) synthesis L-arginine, alone or in combination, were studied in urethane anaesthetized rats. Either 7-NI or LTG alone administration reduced the number of convulsing animals following angular bundle (AB) stimulation; their combined treatment induced a further increase of the anticonvulsant effect as also demonstrated by the decrease of MDA and afterdischarge (AD) durations in the animals still responding to AB stimulation. On the contrary, the injection of L-arginine induced an aggravation of the experimentally-induced paroxystic phenomena as evidenced by the augmentation of MDA and AD durations. LTG in co-administration with L-arginine was able to reverse the pro-convulsant effect induced by L-arginine alone. The results suggest an efficacious interaction between the nitrergic neurotransmission and LTG-induced effects on dentate seizures.

Involvement of nitric oxide-soluble guanylyl cyclase pathway in the control of maximal dentate gyrus activation in the rat.

Nitric oxide/soluble Guanylyl cyclase (NO/sGC) pathway on the maximal dentate gyrus activation (MDA) was studied in rats. The cerebral NO levels were modified by administrating 7-Nitroindazole (7-NI), a selective inhibitor of neuronal NOS, and L-arginine, a precursor of the synthesis of NO. 1H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one (ODQ), a specific inhibitor of the NO-sGC pathway, was administered to study the involvement of cGMP pathway. The epileptic activity of the dentate gyrus was obtained through the repetitive stimulation of the angular bundle; MDA parameters studied were: onset time, MDA duration and post-stimulus afterdischarge (AD) duration. 7-NI caused an increase of MDA onset time and a decrease of MDA and AD duration. L-arginine, induced an aggravation of the epileptiform phenomena. ODQ induced modifications of MDA parameters as those caused by 7-NI. Our results indicate that the nitrergic neurotransmission exerts a modulatory role in the proneness to the epileptogenic phenomena through the activation of sGC metabolic pathway.

Influence of the predicted time of stimuli eliciting movements on responses of tonically active neurons in the monkey striatum.

Changes in activity of tonically active neurons of the primate striatum are determined both by the behavioural significance of stimuli and the context in which stimuli are presented. We investigated how the responses of these neurons are modified by the temporal predictability of stimuli eliciting learned behavioural reactions. Single neurons were recorded from the caudate nucleus and putamen of two macaque monkeys performing a visual reaction time task under conditions in which the timing of the trigger stimulus was made more or less predictable. The monkeys' ability to predict the trigger onset was assessed by measuring arm movement reaction times and saccadic ocular reactions. Of 171 neurons responding to the unsignalled presentation of the trigger stimulus, 32% lost their response when an instruction cue preceded the trigger by a highly practised 1.5 s interval, and the response reappeared when this interval was varied randomly from 1 to 2.5 s or prolonged to 3 or 4. 5 s. Although 43% of the neurons remained responsive irrespective of task condition, the responses were stronger with longer intervals than with the accustomed 1.5 s interval. In addition, a number of neurons responding to the instruction lost their response when the trigger appeared more distant from the instruction. These findings demonstrate that neuronal responses to a movement-triggering signal become more numerous and pronounced when the degree of temporal predictability of that signal was decreased. We conclude that tonic striatal neurons are sensitive to temporal aspects of stimulus prediction.

Cortical stimulation and reflex excitability of spinal cord neurones in man.

The H reflex technique was used to evaluate the influence exerted by cortical conditioning on the excitability of the alpha-motoneurone pool and on IA interneuronal activity (reciprocal inhibition). In ten subjects at absolute rest electrical and magnetic stimulation of the motor cortex was transcranially applied during flexor carpi radialis H reflex eliciting and in conditions of reciprocal inhibition induced by radial nerve stimulation. The time courses showed that at intensities below motor threshold, electrical brain conditioning induced an increase in the amplitude of the test reflex when the cortical shock was given 4 ms after the test H reflex. On the contrary, reciprocal inhibition was reduced by electrical cortical conditioning when the scalp stimulation was applied 2-3 ms after the test stimulus. Magnetic transcranial stimulation induced an increase of H reflex amplitude when the test shock was administered 5 and 2 ms prior to the scalp shock; it did not modify the degree of reciprocal inhibition. The experimental findings could be considered the electrophysiological manifestation of a differential cortico-spinal control on the pathway alpha-motoneurone/IA interneurone. Considerations on the delay allow the hypothesis of a further synapse between the cortico-spinal ending and the IA interneurone. Discrepancies with magnetic conditioning might be ascribed to a preferential transsynaptic action of magnetic mode of neural activation.

Influence of predictive information on responses of tonically active neurons in the monkey striatum.

Influence of predictive information on responses of tonically active neurons in the monkey striatum. J. Neurophysiol. 80: 3341-3344, 1998. We investigated how the expectation of a signal of behavioral significance influences the activity of tonically active neurons in the striatum of two monkeys performing a simple reaction time task under two conditions, an uncued condition in which the trigger stimulus occurred randomly in time and a cued condition in which the same trigger was preceded by an instruction stimulus serving as a predictive signal for the forthcoming signal eliciting an immediate behavioral reaction. Both monkeys benefited from the presence of the instruction stimulus to reduce their reaction time, suggesting an increased ability to predict the trigger onset during cued trials compared with uncued trials. A majority of neurons (199/272, 73%) showed a phasic reduction in activity after the onset of the trigger stimulus in the uncued condition, whereas only 38% responded to the same stimulus when it was preceded by the instruction. Furthermore, magnitudes of trigger responses in the uncued condition were significantly higher than in the cued condition. Fifty-seven percent of the neurons responded to the instruction stimulus, and one-half of the neurons losing their response to the trigger in the cued condition responded to the instruction stimulus. These findings suggest that responses of tonic striatal neurons to a trigger stimulus for movement were influenced by predictive information.

[Diagnostic and therapeutic role of angiography in acute vascular insufficiency of the superior mesenteric artery]. / Ruolo diagnostico e terapeutico dell'angiografia nell'insufficienza vascolare acuta dell'arteria mesenterica superiore.

Sixteen patients were studied with acute arterial ischemia of the superior mesenteric artery: 2 thrombosis, 8 embolisms, and 6 non-occlusive ischemias. Six patients had intra-arterial selective perfusion of papaverine. Angiographic patterns of acute arterial ischemia of the superior mesenteric artery are described. The technique of intra-arterial injection of papaverine (fast bolus followed, if needed, by slow perfusion) is also described. The diagnostic value of plain abdominal radiography and arteriography, and the therapeutical value of pharmacoangiography are discussed.

Bilateral reciprocal organisation in man: focus on IA interneurone.

The H reflex of flexor carpi radialis and radial-induced reciprocal inhibition were recorded in normal subjects during conditioning stimulation of the contralateral median or radial nerves. It was found that stimulation of the contralateral median nerve enhanced the degree of reciprocal inhibition exerted by the radial nerve on the median nerve, while contralateral radial nerve stimulation reduced the reciprocal inhibition exerted by the extensor on the flexor. In two subjects in which a pure extensor H reflex was recorded specular features were observed following contralateral median and radial stimulation. These findings are considered to be the electrophysiological manifestation of contralateral modulation of reciprocal inhibition, which is likely to act at the level of the IA interneurone.

Lateral habenula and hippocampus: a complex interaction raphe cells-mediated.

The study has shown an excitatory influence exerted by lateral habenula (LH) on hippocampal pyramidal cells. The modulatory influence is paradoxically serotonine-mediated; in fact all LH stimulation effects were abolished by intrahippocampal iontophoretic methysergide application. The data suggest the involvement of dorsal raphe nucleus. In fact, the dorsal raphe nucleus stimulation caused on hippocampus an expected inhibitory effect antagonized by intrahippocampal iontophoretic methysergide application. In the context of this neural structure we have highlighted a disinhibitory relation between two types of cells: slow serotonergic efferent neurones and fast GABAergic interneurones. The disinhibitory hypothesis is also supported by the following experimental tests performed on both slow and fast raphe cells: a) LH stimulation at low and high frequencies; b) iontophoretic administration of NMDA and GABA; c) LH stimulation during intraraphe iontophoretic injection of 2-APV (NMDA antagonist) and bicuculline (GABA antagonist).