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The neuropeptide PACAP modulates synaptic transmission in the hippocampus exerting multiple effects through different receptor subtypes: the underlying mechanisms have not yet been completely elucidated. The neurotransmitter acetylcholine (ACh) also exerts a well-documented modulation of hippocampal synaptic transmission and plasticity. Since PACAP was shown to stimulate ACh release in the hippocampus, we tested whether PACAP acting through ACh might indirectly modulate glutamate-mediated synaptic transmission at a pre- and/or at a post-synaptic level. Using patch clamp on rat hippocampal slices, we tested PACAP effects on stimulation-evoked AMPA receptor-mediated excitatory post-synaptic currents (EPSCs AMPA ) in the CA3-CA1 synapse and on spontaneous miniature EPSCs (mEPSCs) in CA1 pyramidal neurons. A subnanomolar dose of PACAP (0.5nM) decreased EPSCs AMPA amplitude, enhanced EPSC paired-pulse facilitation (PPF) and reduced mEPSC frequency, indicating a pre-synaptic decrease of glutamate release probability: these effects were abolished by simultaneous blockade of muscarinic and nicotinic ACh receptors, indicating the involvement of endogenous ACh. The effect of subnanomolar PACAP was abolished by a PAC1 receptor antagonist but not by a VPAC receptor blocker. At a higher concentration (10nM), PACAP inhibited EPSCs AMPA : this effect persisted in the presence of ACh receptor antagonists and did not involve any change in PPF or in mEPSC frequency, thus was not mediated by ACh and was exerted post- synaptically on CA1 pyramidal neurons. We suggest that a high-affinity PAC1 receptor pre-synaptically modulates hippocampal glutamatergic transmission acting through ACh. Therefore, administration of PACAP at very low doses might be envisaged in cognitive diseases with reduced cholinergic transmission., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

In this paper we examined the neuronal activities of external cuneate nucleus, spinocerebellar Purkinje cells and interpositus nucleus during passive forelimb movements in anesthetized rats with the aim of identifying common or different patterns of activation across structures. By means of principal components analysis, we identified two main patterns of discharge which explained most of the dataset variance. One component characterized the movement-related activity of external cuneate and spinocerebellar cortical neurons, while the other reflected neuronal activity of the interpositus nucleus. We also found that both principal components were related to global forelimb kinematics but, while most of the variance of the activity of external cuneate cells and spinocerebellar Purkinje cells was explained by the limb axis orientation and orientation velocity, interpositus neurons' firing was best related to length and length velocity. This difference in the forelimb kinematics representation observed in external cuneate nucleus and spinocerebellar cortex compared with the interpositus nucleus is discussed with respect to the specific role that these structures may play also during active control of limb movements.

In an earlier study, we found that the encoding of limb position in the sagittal plane across the population of spinocerebellar Purkinje cells was anisotropic with a preferential gradient along horizontal direction. The aim of this study was to extend to a three-dimensional (3D) workspace the analysis of the relationships between Purkinje cells activity and rat's forelimb spatial position. In anesthetized animals, the extracellular activity of 121 neurons was recorded while a robot passively placed the limb in 18 positions within a cubic workspace (3x3x3 cm). In order to characterize the relationship between spatial locations and Purkinje cell activity we performed a backward stepwise regression starting from a model with three independent variables representing the antero-posterior, the medial-lateral and the vertical axes of workspace. Regression analysis showed that the firing of most cells was modulated exclusively along the antero-posterior (25%) or the medial-lateral (38%) axis, while a small portion was related only to the vertical axis (8%), indicating a generalized nonuniform sensitivity of Purkinje cells to limb displacement in 3D space.

The influences of the interpositus nucleus on pyramidal tract neurons were investigated by stimulating, in unanesthetized cats, interpositus nucleus foci which activated single muscles in limbs, while recording unitary discharges of pyramidal tract neurons located in foci (area 4 gamma) from which contraction was obtained in the same muscles as those excited from interpositus nucleus (agonist pyramidal tract neurons), in their antagonist (antagonist pyramidal tract neurons), or in heteronymous muscles (heteronymous pyramidal tract neurons). It was found that agonist pyramidal tract neurons were inhibited from the interpositus nucleus, whereas antagonist pyramidal tract neurons displayed a pure excitatory or an excitatory-inhibitory pattern, and the heteronymous neurons were not significantly influenced. A direct activation of interposito-thalamic efferents could be responsible for these effects. In fact, unitary discharge changes of pyramidal tract neurons, elicited from interpositus nucleus stimulation, persisted after chronic intermediate cortex ablation and dentate nucleus lesions, and disappeared following coagulations in the ventrolateral nucleus of the thalamus. These results suggest that interpositus nucleus efferents, which activate a given muscle, via the rubrospinal pathway, could inhibit the discharge of pyramidal neurons controlling that muscle, via collaterals direct to the thalamic ventrolateral nucleus.

The influences exerted by the substantia nigra on reticulospinal neurons and the nature of the synaptic transmitter subserving these projections have been studied in adult cats and rats. Nigral stimulation evokes discharge changes in a significant number of reticulospinal cells (32.4% in cats and 39.1% in rats) on both ipsi- and contralateral sides. The responses were short-latency inhibitions (69.5% in cats and 76.5% in rats), short-latency excitations (22.2% in cats and 23.6% in rats) and in the remaining few cases long-latency excitations. Short-latency excitations, quite similar to the nigra-induced ones, were the predominant response pattern (95.2% in cats and 96.9% in rats) elicited on reticulospinal cells following stimulation of cerebral peduncle. The stimulation of substantia nigra in rats submitted to chronic ablation of sensorimotor cortex elicited only inhibitory responses while stimulation of nigral area in rats with intranigral injection of kainic acid was still capable of evoking short-latency excitations but not short-latency inhibitions. Therefore, the former can be ascribed to activation of corticoreticular fibers running in the cerebral peduncle whereas the latter can be considered as depending on activation of nigral efferents. The nigra-influenced cells were both 'fast' and 'slow' reticulospinal neurons and resulted mainly located in most rostral regions of reticular formation. Ionophoretic application of GABA suppressed the spontaneous firing of reticulospinal cells while no effect was observed following application of dopamine. The nigra-induced inhibitions were abolished by GABA-antagonist bicuculline and not by dopamine-antagonist fluphenazine.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study was undertaken to provide anatomical evidence, in the rat, for a direct projection from the cerebellum towards structures, other than the red nucleus, which belong to the ventral midbrain tegmentum, by using the retrograde as well as the anterograde horseradish peroxidase transport method. Following unilateral injection in the ventral midbrain tegmentum of horseradish peroxidase, free or conjugated to wheat germ agglutinin, sparing the red nucleus, retrogradely labeled neurons were found in the contralateral cerebellar lateral nucleus and, at lower density, in the interpositus nucleus. No labeled neurons were found in the fastigial nucleus of either side. Anterogradely labeled axons from lectin coupled horseradish peroxidase injection sites in the lateral and interpositus nuclei reached the contralateral ventral midbrain tegmentum. Terminal labeling was observed in the entire red nucleus as well as in the lateral division of the ventral tegmental area of Tsai, in the dorsal region of the substantia nigra pars compacta, and in the medial part of the retrorubral field. No terminal labeling was found in the caudal linear nucleus, interfascicular nucleus, peripeduncular nucleus, rostral linear nucleus of the raphe, substantia nigra pars lateralis and the substantia nigra pars reticulata. Terminal labeling was also not observed in the ventral midbrain tegmentum following horseradish peroxidase injection in lateral and interpositus nuclei of rats pretreated with kainic acid. In conclusion, it is noteworthy that, besides the red nucleus, the sole structures of ventral midbrain tegmentum receiving cerebellar efferents are those with a higher density of dopaminergic cells.

The temporal sequence of electrophysiological and biochemical correlates of epilepsy induced by systemic injection of kainic acid (15 mg/kg i.p.) was investigated in male rats. A significant decrease in the hippocampal concentration of glutamate and aspartate was observed 20 min after the injection. These decreases preceded both electrographic and behavioral manifestations of epilepsy, thus suggesting a causal relationship between acidic amino acid changes and the genesis of kainate-induced hyperactivity. About 30-45 min after kainate injection, a decrease in glutamate, aspartate, glycine and taurine and no change in GABA concentration were observed. Bioelectrical activity, recorded in the regio inferior (CA3) of the hippocampus or in the fascia dentata revealed the presence of high frequency bursts separated by a long-lasting depression of discharge. About 55-75 min after the injection, the number of spikes in each burst increased and the duration and frequency of interictal pauses decreased. This stage was characterized by a decrease in glutamate and aspartate, restoration to normal of glutamine, glycine and taurine and a decrease in GABA.

In unanesthetized cats it has been found that pyramidal volleys elicited upon medullary pyramidal tract stimulation were capable of modifying the discharge of 41% of intracerebellar nuclear cells, via pontocerebellar systems impinging predominantly on the lateral cerebellar cortex. The incidence of responsive cells was 80% in the dentate nucleus compared with 10% in the fastigial nucleus, 11% in the anterior and 12% in the posterior division of the interpositus nucleus. The response was in 59% of the cases excitation followed by inhibition, in 30% of the cases a pure excitation and in 11% of the cases a pure inhibition. Excitation, pure or followed by inhibition, had a mean latency of 5.78 ms and a mean duration of 12.21 ms, while inhibition displayed a mean latency of 9.03 ms and a mean duration of 34.64 ms. The possible functional significance of the pyramidal input to the lateral cerebellum is briefly discussed in relation to a possible convergence of pyramidal and associative impulses in single cerebellar neurons.