Daniel Galey

Behavioral effects of lesions in the A10 dopaminergic area of the rat.

Experiments have been carried out with 150 rats in order to study some psychophysiological functions of the mesencephalocortico limbic dopaminergic A10 group. Lesions in the A10 area were made by using 6-hydroxydopamine (6-OHDA) local injections; 2 small volumes of injections were used at the same concentration (2 mug/1 mul or 1 mug/0.5 mul). In a first experiment the effects of these two injections were tested on locomotor activity measured in a circular corridor, 10 and 30 days after surgery. Injections provoked hyperactivity, mainly during nocturnal basal activity periods, but not during initial exploratory activity periods. The larger the injection, the more important the hyperactivity was. The larger injections induced important food spillage evidence through the wire floor of the home cage and perturbation in a passive avoidance learning. There was no change in body weight or in amount of ingested food. In a second experiment, the effects of local injection of 6-OHDA in the other CA structures or bundles situated in or near the ventral tegmental area were tested. Injections in the substantia nigra compacta, in the noradrenergic ventral bundle, in the dorsal periventricular system-tegmental radiations did not provoke locomotor hyperactivity. In a third experiment, a possible role of the median raphe (MR) nucleus in the A10-lesion induced hyperactivity was tested: first, radiofrequency MR lesions were made and no durable significant hyperactivity was recorded; secondly, 6-OHDA (1 mug/0.5 mul) was injected into the A10 area and activity was measured 10 days later: these injections provoked significant hyperactivity during the nocturnal basal and the diurnal basal activity periods. It might be concluded that neither the neighboring CA fibers nor the MR were directly involved in the ventral tegmental -- 6-OHDA lesions syndrome. Anatomical controls by using the Fink-Heimer silver impregnating method have demonstrated, first, that the 6-OHDA injections did not destroy fibers other than catecholaminergic and secondly, that the degenerations are found in the forebrain and cortical limbic A10 projections. Hypotheses are made about a possible general inhibitory role of the A10 in behavior, in the sence of selective and attentive arousal processes, often impaired in some mental illnesses.

Silver impregnation of dopaminergic systems after radiofrequency and 6-OHDA lesions of the rat ventral tegmentum

Nauta and Fink-Heimer silver impregnation techniques were used to study the anterior degeneration produced by radiofrequency (RF) or 6-OHDA lesions in the medial and lateral ventral mesencephalic tegmentum (VMT), substantia nigra and dorsalis tegmental decussation (DTD) in rats. Both Nauta and Fine-Heimer impregnating methods showed that RF lesion of the VNT produced degeneration in three major pathways: a ventral pathway corresponding to the fasciculus medialis prosencephali (FMP), an intermediate pathway projecting to the ventral thalamus, and a dorsal pathway to the medio-dorsal thalamus and to the nucleus lateralis habenulae. In addition, the Fink-Heimer method demonstrated prejections of the dopaminergic A10 and A9 cell group in the VMT to the nucleus caudatus after RF or 6-OHDA lesions. Projections to nucleus accumbens, tuberculum olfactorium, stria terminalis, and cortex frontalis were observed only after 6-OHDA lesion of the A10 cell group. Degeneration in cortex cinguli and entorhinalis was seen mainly after 6-OHDA lesion of the A9 cell group. The limbic forebrain cortical projections of the A10 group provide a coherent anatomical basis for the behavioral syndrome provoked by RF and 6-OHDA lesions in the VMT.

Differential hippocampal and cortical cholinergic activation during the acquisition, retention, reversal and extinction of a spatial discrimination in an 8-arm radial maze by mice

Possible differentiation of the intervention of cholinergic septohippocampal and magnocellular forebrain (NBM) projections to cortex during learning and memory processes has been investigated directly using mice. High-affinity choline uptake velocities in the hippocampus and cortex were analyzed, in parallel, at various periods during the acquisition, over 8 days, as were the subsequent retention, reversal and extinction of a spatial discrimination in an 8-arm radial maze. Initial acquisition induced an immediate (30 s) and long-lasting (approx. 3 h) increase in mean hippocampal (+33%) and cortical (+23%) cholinergic activities. The time course of this activation was structure-dependent and correlations of hippocampal-cortical cholinergic activities showed large and consistent alterations as a function of time after training. Cholinergic activation in both brain regions was observed immediately following each daily training session with amplitudes which did not vary significantly in spite of a progressive daily increment in performance. Following acquisition mice were tested for retention, reversal and extinction: 30 s following the retention session, cholinergic activation was observed in both cortex and hippocampus, with magnitudes similar to those observed at the end of acquisition. However, in the reversal and extinction groups, a treatment-dependent attenuation of cholinergic activation was observed which was accompanied by a significant loss of correlation of cholinergic activity between these two brain regions. The results are discussed in relation to the concepts of reference and working memory and also to novelty, stress, arousal and frustrative non-reward. The data constitute direct experimental evidence for a differential involvement of cholinergic septohippocampal and NBM-cortical projections in learning and memory processes.

Radiofrequency lesion of the ventral mesencephalic tegmentum: Neurological and behavioral considerations

Abstract Radiofrequency ablation of the ventral mesencephalic tegmentum provoked hyperactivity and hyper-reactivity in rats. The critical lesion zone for the appearance of hyperactivity surrounds the nucleus interpeduncularis, a region occupied by fibers corresponding to the fasciculus medialis prosencephali and by the A10 group of mesolimbic dopaminergic cells. The behavioral syndrome appeared 8 days after the lesions and persisted throughout the experiment (210 days), whereas only minor sleep disturbances were observed in animals with lesions. A role of the A10 mesolimbic dopaminergic system in the behavioral effects of these lesions in rats is discussed.

The intermediate stage of sleep in mice

Seven mice of Balb/C strain were implanted with electrodes to perform sleep-waking recordings. In 100% of the cases, the mice showed, prior to paradoxical sleep, the intermediate stage of sleep characterized by high-amplitude cortical spindles interspersed with slow waves and low-frequency theta rhythm in the dorsal hippocampus. Consequently, the intermediate stage which seems to correspond to a transient functional isolated forebrain does exist in the rat, cat and mouse. in the rat, cat and mouse.

In vivo modulation of septo-hippocampal cholinergic activity in mice: relationships with spatial reference and working memory performance

Dopaminergic afferents to the septum mediate a tonic and trans-synaptic inhibitory control on the cholinergic neurones of the septo-hippocampal pathway. Lesion of these afferents using 6-hydroxydopamine (6-OHDA) results in a chronic and specific increase of hippocampal cholinergic activity in mice. The consequence of this in vivo modulation of hippocampal cholinergic activity on the acquisition of both a spatial discrimination and a working memory (delayed non-matching to place) task in an 8-arm radial maze by C57BL/6 mice were investigated. Combined neurochemical and behavioural analyses revealed significant correlations between hippocampal sodium-dependent high-affinity choline uptake activation induced by testing and performance measures. In the first experiment 6-OHDA-treated mice compared to control and vehicle-injected mice showed a transient (day 2) but significant facilitation of their spatial discrimination performance which appears to be better related to the working but not to the reference memory component of the task. This hypothesis is strengthened by the results of the second experiment which shows an amelioration of working memory performance when the septo-hippocampal cholinergic pathway is specifically activated in vivo.

Selective Degeneration of Central Dopaminergic Systems After Injection of 6-Hydroxydopamine in the Ventral Mesencephalic Tegmentum of the Rat. Demonstration by the Fink-Heimer Stain

SummaryFollowing local injection of 6-hydroxydopamine (6-OHDA, 1 μg/ 0.5 μl) in the nigrostriatal (A9) and mesolimbic (A10) cellular groups, terminal degenerations were shown by the Fink and Heimer technique, in the nucleus caudatus-putamen and the nucleus accumbens respectively.In order to test the selective action of 6-OHDA, we studied non aminergic rostro-caudal projections of the fasciculus medians prosencephali at the level of the nucleus dorsalis tegmenti with a 6-OHDA injection in the A10 cells group and a lesion by electrocoagulation in the contralateral A10 area. Terminal degenerations were observed only on the ipsilateral side to the lesion produced by electrocoagulation.The combined use of local injection of 6-OHDA and of Fink and Heimers stain may be envisaged for the anatomical study of central catecholaminergic systems.

The Cholinergic Septo-Hippocampal Pathway, Learning and Memory

This paper summarizes the results of parallel behavioral, neurochemical and pharmacological experiments aimed at studying the role of septo-hippocampal cholinergic neurones in learning and memory processes in mice. A large body of evidence from pharmacological experiments supports the association of central cholinergic mechanisms with many aspects of behavior (De Feudis, 1974) and in particular with information encoding storage and/or retrieval (Deutsch, 1971; Biederman, 1974; Matthies, 1974; Squire and Davis, 1981). The hypothesis that the hippocampus plays a key role in memory processes (Isaacson, 1974) has focussed considerable attention on the possibility that the cholinergic neurones of the septo-hippocampal pathway (Lewis and Shute, 1967) may mediate control on some mechanisms involved in mnemonic function (Routtenberg, 19S4). To circumvent the difficulties deriving from the frequently used approach of pharmacological studies utilising peripheral drug injections which have often generated discordant results on this problem, we have adopted the research strategy of investigating the modulation of learning and memory processes in selected inbred mouse strains combined with direct neurochemical methods to investigate hippocampal cholinergic activity.

Facilitation of memory consolidation by post-training electrical stimulation of the medial septal nucleus: is it mediated by changes in rhythmic slow activity?

Sinusoidal (100 Hz) electrical stimulation was applied at a weak intensity (7.5 muA peak to peak) through bipolar electrodes located in the medial septal nucleus after partial acquisition of an appetitive operant conditioning task in a Skinner box. Analysis of performance in a retention test 24 hr later showed that (i) the presence of stimulation electrodes by itself impaired retention-test performance, and (ii) electrical stimulation applied 30 sec after the end of the acquisition session improves retention; this facilitatory effect disappeared when the treatment was delayed 15 min. Both impairment and facilitation were found to vary (considerably) among subjects. Electrodes located in the center of the medial septal nucleus led to both a greater impairment in unstimulated subjects and a greater facilitation in stimulated subjects than more anterior placements in the vicinity of the diagonal band. Finally, spectral analysis of hippocampal EEG showed that stimulation had no effect on rhythmic slow activity (RSA). These results are discussed in relation to studies showing that RSA is associated with memory-storage processes and our own hypothesis which underlines the importance of activation of septo-hippocampal cholinergic neurons in the early stages of these mnemonic processes.

Memory of a choice direction in a T maze as measured by spontaneous alternation in mice: Effects of intertrial interval and reward.

Spontaneous alternation in a T maze was studied as a one trial learning paradigm in mice of the BALB/c strain. In the first experiment the combined effects of time interval between the first and second trial (intertrial interval: ITI), food deprivation and feeding given during the first trial, were shown to affect performance. Thus, on the one hand, the percentage of spontaneous alternation decreased as ITI increased; on the other hand, food reward dramatically improved spontaneous alternation for the 24-h ITI, but had no significant effect for 30-sec and 1-h ITI. Since the effect of feeding might be due either to an increase of arousal, thus favoring input of informations associated with the first choice, or to an improvement in memory consolidation, a second experiment was aimed at testing the effect of food given after the first trial. It was shown that, as in the first experiment, post-trial feeding improved spontaneous alternation on the second trial given 24 hours later with a temporal gradient of effect less than 30 min. These results clearly showed that the reinforcement of run to one side (first trial) increased the tendency to go to the other side 24 hours later. It is concluded that reinforcement might have two distinct effects: (i) according to SR theory, reinforcement increases conditioned responses and (ii), as shown here, acts on memory processes by preventing memory traces from fading. The fact that this last effect was only observed for long ITI suggests that short-term or transient memory and long-term memory are two relatively independent processes.