Decreased locomotor and investigatory exploration after denervation of catecholamine terminal fields in the forebrain of rats.

Exploratory behaviors were examined after bilateral microinjections of 6-hydroxydopamine into two hypothalamic sites that produced different patterns of denervation of forebrain catecholamine terminal fields. After anterolateral injections rats locomoted and reared less in a novel open field, responded abnormally to changes in the degree of novelty of the open field, and investigated a novel object less. These are deficits in exploratory behavior because they were not secondary to the inhibition of open-field behavior by hyperemotionality, by general motor disability, or by the failure to detect novel spaces or objects. Such anterolateral injections produced loss of catecholamine fibers, determined histochemically, in neocortical, hippocampal, anterolateral hypothalamic, mesolimbic, mesocortical, and anteromedioventral striatal terminal fields and loss of dopaminergic perikarya in the A10 and anteromedial A9 cell groups. No deficits in exploratory behaviors occurred, however, after bilateral anteromedial 6-hydroxydopamine injections that denervated neocortical, hippocampal, and anteromedial hypothalamic catecholamine terminal fields. A critical forebrain catecholaminergic innervation for exploratory responses to novel stimuli may be within areas that were denervated by anterolateral but not by anteromedial hypothalamic 6-nydroxydopamine injections. These areas are mesolimbic, mesocortical, anteromedioventral, and anterolateral hypothalamic terminal fields.     

L-Dopa repairs deficits in locomotor and investigatory exploration produced by denervation of catecholamine terminal fields in the forebrain of rats.

In a previous study rats were shown to have decreased locomotor and investigatory exploration after bilateral microinjections of 6-hydroxydopamine into the anterolateral hypothalamus. These deficits correlate with the loss of catecholamine terminals in neocortical, limbic, and anteromedioventral striatal brain sites. To test whether this correlation was causal, central catecholamines were increased by the intraperitoneal administration of L-3,4-dihydroxyphenylalanine (L-dopa), 10--40 mg/kg) after inhibition of extracerebral L-amino acid decarboxylase. Such treatment repaired the deficits in locomotor exploration and investigation in 6-hydroxydopamine rats. Pretreatment with the catecholamine antagonist chlorpromazine (1--2 mg/kg) blocked the increase in locomotor exploration and investigation produced by L-dopa in 6-hydroxydopamine rats. The results suggest, but do not prove, that L-dopa produced these behavioral effects by increasing central catecholamines at the denervated catecholamine receptor sites in the forebrain. These data and the data from the previous study are complementary evidence for the hypothesis that forebrain catecholamine synaptic action is necessary for normal exploratory behavior.     

Preoperative operant circling training facilitates recovery following unilateral substantia nigra lesion in rats.

This study was undertaken to examine (1) whether pre- and/or postoperative training, using water reinforcement, to turn in circles (rotation) affects the behavioral symptoms induced by unilateral 6-hydroxydopamine (6-OHDA)-induced DA denervation of the rat substantia nigra (SN); (2) whether there was any influence of this training on the temporal pattern of recovery; and (3) whether the rotational training influences turning induced by systemic injection of dopaminergic drugs. In the first experiment, rats were trained either ipsi- or contraversive (TI or TO) to the side to be damaged 11 days before and 23 days after lesion, and tested in an open field for rotational behavior following systemic administration of apomorphine and amphetamine. In the second experiment rats were trained only before the lesion was made and tested in the open field for spontaneous circling and thigmotactic behavior. The results of the first experiment indicated maintenance of the training performance after the lesion. At the 14th day after the lesion, the ipsiversive trained group showed a higher contraversive circling frequency after apomorphine injection in relation to the contralateral trained group. In the second experiment, rats trained only before the surgery, showed asymmetrical spontaneous circling in the trained direction before and 14 days after surgery, indicating, in a drug free condition, that training direction can be restored after unilateral SN lesions, even to the contralateral body side. Moreover, thigmotactic behavior indicated a lack of habituation in an open field in unilateral lesion rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dorsal striatal dopamine depletion impairs both allocentric and egocentric navigation in rats

Successful navigation requires interactions among multiple but overlapping neural pathways mediating distinct capabilities, including egocentric (self-oriented, route-based) and allocentric (spatial, map-based) learning. Route-based navigation has been shown to be impaired following acute exposure to the dopaminergic (DA) drugs (+)-methamphetamine and (+)-amphetamine, but not the serotoninergic (5-HT) drugs (±)-3,4-methylenedioxymethamphetamine or (±)-fenfluramine. The dopaminergic-rich neostriatum is involved in both allocentric and egocentric navigation. This experiment tested whether dorsal striatal DA loss using bilateral 6-hydroxydopamine (6-OHDA) injections impaired one or both types of navigation. Two weeks following 6-OHDA injections, rats began testing in the Cincinnati water maze (CWM) followed by the Morris water maze (MWM) for route-based and spatial navigation, respectively. 6-OHDA treatment significantly increased latency and errors in the CWM and path length, latency, and cumulative distance in the MWM with no difference on cued MWM trials. Neostriatal DA levels were reduced by 80% at 2 and 7 weeks post-treatment. In addition, 6-OHDA increased DA turnover and decreased norepinephrine (NE) levels. 6-OHDA injections did not alter monoamine levels in the prefrontal cortex. The data support that neostriatal DA modulates both types of navigation.     

Intra-habenular injection of 6-hydroxydopamine produces impaired acquisition of DRL operant behavior

The anatomical connections of the habenula complex indicate it provides a relay between limbic forebrain and midbrain. Somewhat paradoxically, consequences of nonspecific lesion of the habenula are ambiguous with little change in basic response evident within simple behavioral paradigms. However, the potential functional importance for this relay has more recently been indicated by the demonstration of deficits in the ability of lesioned animals to alter behavior appropriate to both internal and external stimuli in more demanding behavioral tasks. Doubts concerning the importance of the habenula remain because of the large number of descending fibers of passage through the habenula. To provide more substantive evidence, 6-hydroxydopamine was injected into the habenula of rats to provide more limited lesion of catecholaminergic terminals. Animals were subsequently trained on an operant DRL 20-s schedule for which deficits have been reported following nonspecific lesion of the habenula. Lesioned animals showed a tendency to overrespond and were significantly less efficient on the schedule with decreased number of reinforcements received relative to controls. While the neurotoxic lesion procedure used does not differentiate noradrenergic and dopaminergic damage, the importance of intact catecholaminergic systems within the habenula for effective DRL acquisition is consistent with the suggested importance of the habenula for feedback regulation of dopamine within the ventral tegmental area through ascending dopamine fibers to the habenula.     

Disturbances in exploratory behavior and functional recovery in the Y and radial mazes following dopamine depletion of the lateral septum

The effects of 6-hydroxydopamine (6-OHDA) injected into the lateral septum in rats were investigated for spontaneous alternation behavior in a Y maze and for spatially oriented behavior in an 8-arm radial maze. The performance of the animals in these tests was assessed under two physiological states, food-satiated and food-deprived. The selective depletion of septal dopaminergic concentrations leads to behavioral disturbances in both the Y and the radial mazes. These deficits disappeared when the animals with 6-OHDA lesions were food-deprived. These results confirm other studies from our laboratory and support two conclusions. First, lesions of dopaminergic neurons lead to behavioral impairments which resemble those found after the total lesion of the structure they innervate. Second, these behavioral impairments are responsive to therapeutic treatments, manipulations of the internal or external environment, or the level of arousal, since under certain conditions a recovery of function can occur in the absence of dopaminergic neurons. These two points provide additional support for a nonspecific role for the dopaminergic neurons originating in the ventral tegmental area. These neurons could have a permissive role in the functioning of the forebrain structures they innervate.     

Activation-induced restoration of sensorimotor functions in rats with dopamine-depleting brain lesions.

Bilateral electrolytic lesions of the lateral hypothalamus or intraventricular 6-hydroxydopamine injections produced substantial depletions of striatal dopamine in rates. All animals with brain damage showed marked sensorimotor impairments. However, they began to move and respond appropriately to environmental stimuli when placed in a sink of water, in a shallow ice bath, or among a colony of cats or rats. A reversal of the sensorimotor dysfunctions was still apparent shortly after the animals were removed from each activating situation. However, the terapeutic effects dissipated rapidly, and by 4 hr after an exposure the rats responded as poorly as they had prior to activation. These findings are strikingly similar to the "paradoxical kinesia" seen in parkinsonism, a clinical disorder attributed to degeneration of central dopamine-containing neurons. Collectively, they suggest the importance of activation in maintaining responsiveness to senory stimuli in rats following dopamine-depleting brain lesions.     

The dorsal tegmental noradrenergic projection: an analysis of its role in maze learning.

The hypothesis that the noradrenergic projection from the locus coeruleus (LC) to the cerebral cortex and hippocampus is an important neural substrate for learning was evaluated. Maze performance was studied in rats receiving either electrolytic lesions of LC or 6-hydroxydopamine (6-OHDA) lesions of the dorsal tegmental noradrenergic projection. The LC lesions did not disrupt the acquisition of a running response for food reinforcement in an L-shaped runway, even though hippocampal-cortical norepinephrine (NE) was reduced to 29%. Greater telencephalic NE depletions (to 6% of control levels) produced by 6-OHDA also failed to disrupt the acquisition of this behavior or to impair the acquisition of a food-reinforced position habit in a T-maze. Neither locomotor activity nor habituation to a novel environment was affected by the 6-OHDA lesions. Rats with such lesions were, however, found to be significantly more distractible than were controls during the performance of a previously trained response. The hypothesis that telencephalic NE is of fundamental importance in learning was not supported. The data suggest that this system may participate in attentional mechanisms.     

Sound sequence discrimination learning motivated by reward requires dopaminergic D2 receptor activation in the rat auditory cortex

We have previously reported that sound sequence discrimination learning requires cholinergic inputs to the auditory cortex (AC) in rats. In that study, reward was used for motivating discrimination behavior in rats. Therefore, dopaminergic inputs mediating reward signals may have an important role in the learning. We tested the possibility in the present study. Rats were trained to discriminate sequences of two sound components, and licking behavior in response to one of the two sequences was rewarded with water. To identify the dopaminergic inputs responsible for the learning, dopaminergic afferents to the AC were lesioned with local injection of 6-hydroxydopamine (6-OHDA). The injection attenuated sound sequence discrimination learning, while it had no effect on discrimination between the sound components of the sequence stimuli. Local injection of 6-OHDA into the nucleus accumbens attenuated sound discrimination learning. However, not only discrimination learning of sound sequence but also that of the sound components were impaired. SCH23390 (0.2 mg/kg, i.p.), a D1 receptor antagonist, had no effect on sound sequence discrimination learning, while it attenuated the licking behavior to unfamiliar stimuli. Haloperidol (0.5 mg/kg, i.p.), a D2 family antagonist, attenuated sound sequence discrimination learning, while it had no clear suppressive effect on discrimination of two different sound components and licking. These results suggest that D2 family receptors activated by dopaminergic inputs to the AC are required for sound sequence discrimination learning.     

Central noradrenergic neurons: differential effects on body weight of electrolytic and 6-hydroxydopamine lesions in rats.

The ventral noradrenergic bundle (VB) of the rate brain has been proposed as the substrate for the hyperphagia and obesity produced by ventromedial hypothalamic lesions. To determine the relationship between body weight and damage to the VB, the effects of bilateral electrolytic and 6-hydroxy-dopamine (6-OHDA) lesions of the VB were compared. When rats were fed only a standard laboratory diet, no significant differences were found between groups. When a high-fat diet supplement was introduced, the group with electrolytic lesions became significantly heavier than the control group; however, the 6-OHDA group did not differ from the controls. Norepinephrine depletion was significantly greater following the 6-OHDA than the electrolytic lesions. Both lesions reduced telencephalic dopamine and serotonin only slightly. A second study in which both types of lesions were placed at a rostral ventromedial hypothalamic site yielded the same pattern of results. Diet-dependent increases in body weight were attributed to the destruction of a non-noradrenergic system, which was spared by the relatively selective 6-OHDA lesion but damaged by the nonselective electrolytic lesion.     

5, 7-dihydroxytryptamine lesions: Effects on body weight,irritability, and muricide

Forty-four male rats were subjected to injections of 5,7dhydroxytryptamine (40 μg/4 μ1) in the ascending 5-hydroxytryptamine projection or control operations. The injections resulted in depletion of forebrain 5-hydroxytryptamine, weight loss, irritability, and muricide. No significant correlations were found between any of these effects. It is suggested that the neural systems mediating regulation of body weight and muricide are substantially distinct.     

Electrolytic, but not 5,7-dihydroxytryptamine, lesions of the nucleus medianus raphe impair acquisition of a radial maze task

We have previously reported that electrolytic lesions of the nucleus medianus raphe (MR) produce a deficit in the acquisition of an 8-arm radial maze task (Wirtshafter and Asin 1983). In an attempt to determine whether or not this deficit is secondary to serotonin depletion resulting from the lesion, we investigated and compared the effects of electrolytic and 5,7-dihydroxytryptamine (5,7-DHT) lesions of the MR on the acquisition of the radial maze task. Although forebrain serotonin levels after 5,7-DHT injections were reduced as much as those following electrolytic lesions, only rats with an electrolytic MR lesion were impaired on the acquisition of both a free-running maze task and on a related task, where animals were replaced into the same arm between arm choices. In contrast, 5,7-DHT-treated rats were unimpaired on both tasks compared to an ascorbate-injected control group. These findings provide further evidence that most of the profound behavioral deficits shown by rats with electrolytic MR damage are not due to serotonin depletion and are consistent with the results of other studies indicating strong similarities between the behavioral effects of limbic and MR lesions.     

Effects of selective forebrain noradrenaline loss on behavioral inhibition in the rat.

Virtually total depletion of cortical and hippocampal noradrenaline by stereotaxic injection of 6-hydroxydopamine into the fibers of the dorsal noradrenergic bundle produced no impairment in acquisition learning of a runway response for food reward. Extinction of this response, once learned, was markedly slower in the treated group than in controls, the treated animals perseverating in rapid running to the goal box even with no food present there. Similarly, no impairment was found on acquisition of a continuously reinforced lever-pressing response for food. Extinction of this response, however, was again slower in the treated group. Subsequent acquisition of a successive light-dark discrimination task was also slower in the treated group, with these animals perseverating in responding to the negative stimulus. Although selective forebrain noradrenaline loss does not impair the acquisition of appetitive responses, the suppression of responses in the absence of reward is impeded. A parallel is drawn with those effects found classically after surgical lesion to the hippocampus.     

Long-term effects of cerebellar pathology on cognitive functions

Twelve patients with circumscribed chronic neocerebellar lesions but without CT-evidence of forebrain damage (other than the effects of shunting) were investigated for deficits of cognitive functions. Two different mechanisms were considered as possible causes of cognitive impairment: (1) Damage to the dentato-thalamo-cortical projection leading to impairments of cortical functions, and (2) prolonged intracranial pressure resulting in diffuse forebrain damage and subcortical dementia. Patients with lesions in the left neocerebellum showed deficits in cognitive operations in three dimensional space, consistent with the right forebrain dominance for spatial functions. Prolonged intracranial pressure, on the other hand, resulted in a mild overall cognitive impairment.     

Cortical neuroanatomical correlates of behavioral deficits produced by lesion of the basal forebrain in rats

Morphological changes in the frontoparietal cortex were assessed in rats that exhibited deficits in a go/no go alternation task due to electrolytic lesion of the basal forebrain. Cortical area, laminar thickness, neuronal density, and soma area were examined in frontal, hindlimb, forelimb, and parietal areas of the cortex. Quantitative morphological analysis of the frontoparietal cortex in lesioned rats revealed a decrease in laminar thickness due to reduced soma size in particular cortical laminae. Neuronal density was not affected. These effects were present in all cortical areas examined and most pronounced in laminae II-III. Similar morphological changes were observed in the same cortical areas following lesions of the basal forebrain made with ibotenic acid, allowing a discrimination of lesion effects from those induced by damage to fibers of passage or differential behavioral testing. Lesions of the basal forebrain have previously been shown to produce both behavioral deficits and changes in cortical cholinergic activity. The cortical morphological changes observed in the present study following basal forebrain lesion provide further evidence for the importance of ascending cholinergic inputs to the cortex and their role in learning and memory.     

Compensatory changes in striatal dopamine neurons following recovery from injury induced by 6-OHDA or methamphetamine: a review of evidence from microdialysis studies

This paper presents evidence from microdialysis experiments that three different behavioural outcomes of depletion of striatal dopamine (DA) by either 6-hydroxydopamine or methamphetamine (sparing of function, recovery of function, and loss of function) may be related to differences in the ability of residual DA neurons to maintain extracellular concentrations of DA. It is shown that when up to 80% of the mesostriatal DA system is destroyed, the remaining DA terminals maintain normal extracellular dopamine concentrations. Following a lesion in the 80-95% range, most animals maintain a relatively normal extracellular concentration of DA, but the ability to respond to increased demand is reduced in some animals. When over 95% of the normal DA input to the striatum is destroyed, there is a sharp drop in the extracellular concentration of DA and a nearly complete loss in the ability to increase DA release upon demand. Thus, this new method of sampling extracellular DA and its metabolites in freely moving animals provides insights into the behavioural capacities of animals and into the neural mechanisms that underlie recovery of function following brain damage.     

Inhibition of Intermediate-Term Memory Following Passive Avoidance Training in Neonate Chicks by a Presynaptic Cholinergic Blocker

The effects of a specific presynaptic cholinergic antagonist, toosendanin, on memory formation following a passive avoidance training experience in day-old chicks was investigated. Bilateral injection of toosendanin into the neostriatal/hyperstriatal region of the chick forebrain produced memory impairment in a dose-dependent manner. Retention deficits were apparent from 20 min following training in chicks treated with toosendanin, regardless of the injection time relative to training. Chicks that received injections of the drug at corresponding times prior to retention tests showed normal retention levels, suggesting that toosendanin has no effect on performance and memory retrieval. These results indicate an involvement of cholinergic transmission during an early stage of memory formation.     

Projection of the Magnocellular Red Nucleus to the Region of the Accessory Abducens Nucleus in the Rabbit

The projection of the magnocellular red nucleus (RNm) to the region of the accessory abducens nucleus (AABD) was traced in rabbit using the bidirectional tracer wheat germ agglutinin-horseradish peroxidase (WGA-HRP). In one set of animals, recordings of antidromic responses from RNm neurons elicited by electrical stimulation of the rubrospinal tract were used to localize injections of WGA-HRP for orthograde labeling of RNm terminals. In a different set of animals, horseradish peroxidase was injected into the retractor bulbi muscle to retrogradely label motoneurons of the AABD. The positions of RNm fibers and terminals were examined and compared to the locations and distribution of AABD cell bodies and labeled dendrites. Analyses revealed that along the entire rostrocaudal extent of the AABD, RNm efferents terminate primarily lateral to, or in the lateral aspects of, labeled motoneurons. For the rostral AABD, RNm efferents terminate only lateral to the nucleus. Although the terminals are not positioned to contact cell bodies of the AABD, they could overlap with dendrites that extend in the lateral direction. RNm efferents terminate more extensively within the posterior AABD, overlapping within both dendritic and cell body regions of the nucleus. Even in this posterior region, however, RNm efferents were distributed primarily over the lateral half of the nucleus. These data show that RNm can monosynaptically influence the AABD, through primarily its lateral and posterior aspects. Our findings also show that a major target of RNm efferents is the reticular cell population located lateral to the AABD, suggesting that the RNm also may affect AABD motoneuronal output indirectly through its projection to reticular cells.