Alleviation of response suppression to conditioned aversive stimuli by lesions of the dorsal noradrenergic bundle

Rats with neurotoxic lesions of the dorsal ascending noradrenergic bundle (DB) were compared with sham-operated (SH) controls on the acquisition, steady state and extinction of response suppression maintained by a classical (conditioned suppression) or an instrumental (discriminated punishment) contingency. DB lesions interfered neither with the acquisition of the reference response of sucrose-rewarded barpressing nor with unconditioned responding to the overhead flashing light subsequently used as a signal of shock. The acquisition of discriminated response suppression was also unaffected by the lesion under both types of contingency. However, once discriminated suppression had stabilized, both the conditioned and the discriminative stimulus used were significantly less effective in maintaining suppression in DB animals than in SH controls provided that low intensity footshock (0.2 mA) was used as the unconditioned stimulus (UCS). Upon increase of UCS intensity (to 0.5 mA) normal suppression was observed in the DB group under both contingencies. Extinction of the classical contingency reinstated the difference between DB and SH performance: DB lesion resulted in significantly faster extinction of fear. In contrast, extinction of the discriminated punishment contingency was unaffected by the lesion, although generalized response suppression dissipated faster in the DB than in the SH animals trained under this condition. Our results offer no support for the reinforcement hypothesis of DB function (normal acquisition of barpressing and of discriminated suppression of barpressing); mixed support (greater initial generalization of suppression in DB animals) and contradiction (more rapid extinction of conditioned suppression in DB animals) for the attentional hypothesis; and weak support (reduced suppression and more rapid extinction of suppression in DB animals, but only within limited experimental parameters) for the anxiety hypothesis of DB function. Hence none of the extant theories of DB function offer a ready explanation of the pattern of results presented here. A simple interpretation which conforms with the sparsity of positive behavioural findings in the literature on DB lesions is that forebrain noradrenaline contributes to the detection and utilization of conditioned stimuli; but that this contribution is critical only for the detection of stimuli with low associative strength.     

Reward, attention and the dorsal noradrenergic bundle

The resistance to extinction seen after lesion to the dorsal noradrenergic bundle has been suggested to arise from a deficit in internal inhibition or a 'perseverative' type of deficit. This hypothesis is tested by examining the ability of 6-hydroxydopamine-treated animals to inhibit a previously developed preference for saccharine solution as a result of poisoning with lithium chloride. Unimpaired taste aversion is found, arguing against a deficit in the ability to inhibit a prepotent response. An alternative explanation of the dorsal bundle extinction effect (DBEE), that of alterations in attention, is tested by acquisition and reversal of a successive light-dark discrimination. Both acquisition and reversal are severely impaired, suggesting that the treated animals have difficulty in attending to a specific stimulus in the environment when this is required in order to structure behaviour appropriately, and thus being consistent with a role for the dorsal bundle in the control of attentional processes.     

Alterations in noradrenergic innervation of the brain following dorsal bundle lesions in neonatal rats

Several seemingly conflicting sets of data have been reported on the regenerative capacity of central noradrenergic neurons, following transection of the ascending noradrenergic fiber tract in neonatal rats (Iacovitti et al., Dev Brain Res 1: 21-33, 1981; Jonsson and Sachs, Brain Res Bull 9: 641-650, 1982). In order to more fully investigate changes in noradrenergic neurons in the brain after such a transection, rats were lesioned at various times after birth, sometimes in conjunction with administration of the neurotoxin, 6-hydroxydopa (6-OHDOPA). Animals were sacrificed at 7, 10, 14, 28, 42 or 56 days after birth, in order to assess the pattern of noradrenergic neuronal damage, as well as the recovery rate. Dorsal bundle lesions were associated with neocortical and hippocampal hypoinnervation by noradrenergic fibers, and sprouting of a collateral fiber group, with production of noradrenergic hyperinnervation of the cerebellum and pons-medulla. Recovery of the norepinephrine (NE) content to control levels occurred in the neocortex at 8 weeks, when the dorsal bundle was lesioned at birth. When the lesion was produced at a later time (3 days or 5 days after birth), less recovery in the neocortex and hippocampus was found. Histofluorescent fiber number, as observed with a glyoxylic acid method, correlated with NE changes. It appears that 6-OHDOPA (20 micrograms/g IP) does not modify long-term recovery from a dorsal bundle lesion, when rats are co-treated at 3 days after birth. However, the length of the proximal noradrenergic fiber stump may be an important factor affecting the capacity for recovery from injury.(ABSTRACT TRUNCATED AT 250 WORDS)     

Behavioral effects of concurrent lesions of the nucleus basalis magnocellularis and the dorsal noradrenergic bundle.

The effects of separate and concurrent lesions to the cholinergic and noradrenergic (NE) systems were assessed in two water mazes. Lesion of the nucleus basalis magnocellularis (NBM) decreased performance in a spatial memory task (Morris water maze) while lesions of the dorsal NE bundle (DNB) enhanced the acquisition of this task independent of the NBM effects. Both lesions impaired performance on a water-escape motivated T-maze; however, the deficits induced by the combined lesion did not differ from the effects of either lesion alone. Neither lesion, nor their combination, had significant effects on open field activity. Biochemical analyses revealed almost total loss of NE in the cortex and hippocampus after DNB lesion, with relatively minor changes in other catecholamines or metabolites. Choline acetyltransferase activity was not significantly altered by the DNB lesion but was decreased in the cortex by the NBM lesion. These results suggest a task-specific effect of DNB lesion that is detectable under conditions of mild stress when floor effects are minimized.     

Effects of lesions to ascending noradrenergic neurones on performance of a 5-choice serial reaction task in rats; implications for theories of dorsal noradrenergic bundle function based on selective attention and arousal

Five experiments examined the effects of destruction of the dorsal noradrenergic bundle (DNAB), arising in the locus coeruleus, both on brightness and spatial visual discrimination, and selective attention. An analogue o Leonard's 5-choice serial reaction task for human subjects was used. Hungry rats were trained to detect brief (0.5 sec) flashes of light presented randomly in one of 5 locations with a fixed intertrial interval of 5 sec, paced by the rat. Correct responses were rewarded with food and incorrect responses punished by time-out (darkness + delay). Following training to high levels of accuracy (80%, with less than 20% errors of omission), rats received either 6-OHDA (4 micrograms/2 microliters) injected bilaterally into the trajectory of the dorsal bundle, or injection of vehicle (0.1% ascorbic acid in 0.9% saline). The 6-OHDA lesion was sufficient to reduce cortical NA by 84%. Performance on both the spatial discrimination and brightness (produced by graded reductions in the brightness of the stimuli) discrimination was unaffected by DNAB lesions. However, the DNAB lesion produced significant decreases in accuracy and increases in omissions when the stimuli were presented at faster, unpredictable rates. In addition, although intense white noise failed to produce differential impairments when presented simultaneously with the visual discriminanda, the DNAB lesion significantly impaired accuracy when the noise was presented immediately prior to, but not overlapping, the onset of the visual stimuli. The implications of this pattern of deficits in performance found following DNAB lesions is discussed in terms of disruptive effects of cortical NA depletion upon mechanisms of selective attention and arousal.     

Acquisition and extinction of continuously and partially reinforced running in rats with lesions of the dorsal noradrenergic bundle

Local injection of 6-hydroxydopamine was used to selectively destroy the dorsal ascending noradrenergic bundle (DB) in rats. Two lesion procedures were used, differing in the extent of depletion of forebrain noradrenaline they produced (>90% or 77%). In Experiments 1–3 the rats were run in a straight alley for food reward on continuous (CR) or partial (PR) reinforcement schedules. The smaller lesion reduced and the larger lesion eliminated the partial reinforcement acquisition effect (i.e. the faster start and run speeds produced by PR during training) and the partial reinforcement extinction effect (PREE, i.e. the greater resistance to extinction produced by PR training); these changes were due to altered performance only in the PR condition. Abolition of the PREE by the larger DB lesion occurred with 50 acquisition trials, but with 100 trials the lesion had no effect. In Experiment 4 rats were run in a double runway with food reward on CR in the second goal box, and on CR, PR or without reinforcement in the first. The larger lesion again eliminated the PREE in the first runway, but did not block the frustration effect in the second runway (i.e. the faster speeds observed in the PR condition after non-reward than after reward in the first goal box). These results are consistent with the hypothesis that DB lesions alter behavioural responses to signals of non-reward, but not to non-reward itself. They cannot be predicted from two other hypotheses: that the DB mediates responses to reward or that it subserves selective attention. Since septal and hippocampal, but not amygdalar, lesions have been reported to produce similar behavioural changes, it is proposed that the critical DB projection for the effects observed in these experiments is to the septo-hippocampal system.     

Lesions of the dorsal noradrenergic bundle impair attentional set-shifting in the rat

Rats with medial prefrontal cortex (mPFC) lesions are impaired in attentional set-shifting, when it is required to shift to a previously irrelevant perceptual dimension. The main source of noradrenergic input to the mPFC is from the locus coeruleus via the dorsal noradrenergic ascending bundle (DNAB). This study examined the effects of selective cortical noradrenaline depletion following 6-hydroxydopamine-induced lesions of the DNAB on attentional set-shifting and other aspects of discrimination learning and performance. Rats learned to dig in baited bowls, and then acquired discriminations based on one of two aspects of a bowl--odour or digging medium. The task tested acquisition of novel discriminations (both intra- and extra-dimensional) and reversal learning when contingencies were reversed with the same stimuli. At the conclusion of testing, the DNAB-lesioned rats were shown to have a selective depletion of noradrenaline of approximately 70% within the mPFC (cingulate and prelimbic cortex subregions), with no other significant changes in dopamine or 5-hydroxytryptamine. Rats required more trials to learn new discriminations when attentional shifting was required [extra-dimensional (ED)-shift]. Rats with dorsal noradrenergic ascending bundle (DNAB) lesions were impaired in novel acquisitions when an ED-shift was required, but were unimpaired in reversal learning and other aspects of discrimination learning, relative to controls. These data are consistent with other evidence implicating noradrenaline (NA) in attentional set-shifting, and contrast with effects of manipulations of 5-hydroxytryptamine (5-HT) and acetylcholine within the medial prefrontal cortex (mPFC). The findings are also relevant to recent theorizing about the functions of the coeruleo-cortical noradrenergic system.     

Lesions of the dorsal noradrenergic bundle simultaneously enhance and reduce responsivity to novelty in a food preference test

In conclusion, DNAB lesions have been shown to have two, apparently contradictory effects in a food preference test: to increase neophobia to a novel environment, and to increase the tendency to eat novel food in a novel environment. It has been suggested that these two effects occur because, although NA has a common action on neuronal firing in terminal fields, the dissociable consequences reflect the different functions of areas in receipt of these noradrenergic afferents. In addition, it has been shown that DNAB lesions, VNAB lesions, and a benzodiazepine, chlordiazepoxide, all have somewhat different behavioral effects in the food preference test. Taken together with the lack of correlation between the various behavioral measures used in these experiments, this suggests that neophobia does not reflect a single behavioral process, such as anxiety, or reactivity to novelty.     

Effects of dorsal striatum lesions in tone fear conditioning and contextual fear conditioning

It has been suggested that the striatum mediates hippocampus-independent memory tasks. Classical fear conditioning to a discrete stimulus such as a tone is not affected by hippocampal lesion, whereas contextual fear conditioning is an hippocampus dependent task. The purpose of the present study was to verify the effect of dorsal striatal lesions on tone and contextual fear conditioning. The lesioned rats were not impaired in contextual fear conditioning but in tone fear conditioning both electrolytically and neurotoxically lesioned animals showed less freezing compared with controls. The lesion effect was observed after a postoperative recovery period of 14 days but not after 2 months. The results support the hypothesis that the dorsal striatum is involved in hippocampus-independent memory tasks, but, in spite of this involvement, it does not seem to be a critical structure.     

The dorsal noradrenergic bundle modulates DNA remodeling in the rat brain upon exposure to a spatial novelty

A series of experiments were designed to study the role of the dorsal noradrenergic bundle (DNB) in the modulation of genomic remodeling in the mammalian brain. A series of experiments were designed to study the role of the dorsal noradrenergic system in relation to nonassociative tasks. Adult male Sprague-Dawley rats were either bilaterally lesioned in the DNB by intrabundle microinjection of 6-hydroxydopamine or were sham lesioned. All rats were given 50 μCi [³H-methyl]-thymidine and were sacrificed 0.5 h later. After the injection of the tracer, rats were either left undisturbed in the home cage or were exposed to a Làt-maze for 15 min after 15 min had passed from the time of injection. During the exposure to the maze, corner crossings and rearings were monitored. The rate of DNA synthesis was determined in several brain regions by measuring the amount of tracer incorporated into the DNA over a 0.5-h duration pulse. Under baseline conditions DNB-lesioned rats showed an increase in DNA synthesis in the hippocampus, hypothalamus, and rest of the brain. On the other hand, following exposure to the Làt-maze, sham-lesioned rats only showed an increase in DNA synthesis in the hippocampus, as compared to baseline conditions. Conversely, DNB-lesioned rats did not show an increase in hippocampal DNA synthesis as in the sham-lesioned rats. In contrast, DNA synthesis was increased in the neocortex and rest of the brain. In conclusion, the data support a role for noradrenergic systems in modulating brain DNA synthesis, probably of the unscheduled type, during information processing and storage. (This article was presented in abstract form at the Annual Meeting of the Society for Neuroscience, New Orleans, LA, 1991.)     

Evidence against a role of the rat's dorsal noradrenergic bundle in selective attention and place memory

In Experiment 1,6-hydroxydopamine-induced lesions of the dorsal noradrenergic bundle (DNB) in rats did not impair either acquisition of non-delayed alternation, retention of non-delayed alternation, or performance of alternation with delays in a T-maze, whether or not the goal arms of the maze were visually distinctive. These results were in contrast with those of a previous report indicating that DNB lesions impair learning of spatial alternation. In Experiment 2, the lack of a reliable effect of DNB lesions on learning performance of spatial alternation was confirmed. However, the rats with DNB lesions showed an impairment of spontaneous alternation. The negative results of the present study do not support either the hypothesis that depletion of forebrain noradrenaline impairs selective attention or the hypothesis that such depletion induces an amnesia for past places. On the other hand, the finding of impaired spontaneous alternation is consistent with previous observations suggesting that depletion of forebrain noradrenaline impairs habituation of fear reactions.     

Evidence suggesting that DMI-induced resistance to extinction is not mediated by the dorsal noradrenergic bundle

Rats were trained to press a lever for food rewards, then given a 5 week break, followed by a single extinction session. Animals which received 14 daily desmethylimipramine (DMI) injections, ending 4 days before the extinction session, showed resistance to extinction; no effect was seen in animals which received DMI during acquisition. The opposite pattern of results would be predicted if the effect were mediated by changes in the efficacy of the dorsal noradrenergic bundle.     

Lesions of the dorsal noradrenergic bundle and rewarded running: The role of pretraining

Local injection of 6-hydroxydopamine was used to selectively destroy the dorsal ascending noradrenergic bundle (DB), producing 75% loss of hippocampal noradrenaline. Lesioned and control rats were trained to run in a straight alley for food reward with or without pretraining (handling and habituation to the apparatus). Lesioned rats ran more slowly than controls only if they had not been pretrained. This result may explain previous discrepancies in the literature; it is discussed in relation to existing hypotheses of DB function.     

Field potentials in primate locus coeruleus following stimulation of the dorsal noradrenergic bundle

Stimulation of the dorsal noradrenergic bundle, but not of adjacent areas, elicited field potentials in the locus coeruleus in the stumptail monkey (Macaca arctoides). This result suggests a procedure for locating the dorsal noradrenergic bundle in vivo.     

Effect of dorsal periaqueductal gray lesion on cardiovascular and behavioural responses to contextual conditioned fear in rats

Contextual conditioned fear in the rat is characterized by a freezing immobility associated with a marked increase in blood pressure, a slow increase in heart rate, and ultrasonic vocalizations. A previous Fos study also revealed a marked activation of the ventrolateral part of the periaqueductal gray (VLPAG) and a much smaller activation of its dorsal part (DPAG). Recent chemical blockade experiments indicate that the main role of the VLPAG in the response is to impose the immobility necessary for the expression of the freezing component. We now test the role of the DPAG to see if its small activation (as revealed by Fos) is of any functional significance in the contextual fear response. Large N-methyl-D-aspartate (NMDA) excitotoxic lesions that destroyed most of the DPAG were made in 10 rats. Another group of 10 rats had sham lesions with saline. The animals were then implanted with blood pressure telemetric probes, fear conditioned, and finally tested. There was no significant difference in the amount of freezing and in the blood pressure response between the two groups. However, there was a complete abolition of ultrasonic vocalizations and a significantly greater increase in heart rate in the DPAG-lesioned group. The effect on vocalization and heart rate may be explained by lesion of adjacent structures: the lateral PAG and the superior colliculus (baroreflex alteration), respectively. Thus, most of DPAG appears to play little role in the expression of the contextual fear response.     

The effects of dorsal bundle lesions on serial and trace conditioning

The performance of rats with neurotoxic lesions of the dorsal ascending noradrenergic bundle (DB) was compared with that of sham-operated control animals under two behavioural conditions. Animals with DB lesions were slower than controls to acquire a classically-conditioned emotional response (conditioned suppression) with a trace interval interposed between the clicker conditioned stimulus (CS) and the shock reinforcer. However, if the latter half of the trace interval was filled by a second stimulus, a light, the DB-lesioned animals acquired conditioned suppression to the clicker faster than did controls under the same conditions. These results are discussed in terms of the attentional theory of DB function.     

Modulation of rat brain alpha- and beta-adrenergic receptor populations by lesion of the dorsal noradrenergic bundle

Bilateral lesion of the ascending noradrenergic fibers in the dorsal bundle of adult Wistar rats with 4 micrograms 6-hydroxydopamine caused extensive depletion of norepinephrine in all forebrain areas, but led to a 54% increase in norepinephrine levels in the cerebellum. beta-Adrenergic receptor binding of [3H]dihydroalprenolol was significantly increased in all forebrain areas depleted of norepinephrine except hypothalamus. The increase in [3H]dihydroalprenolol binding was due to 62% and 34% increases in the number of beta-receptor sites in the frontal cerebral cortex and hippocampus respectively. Binding of [3H]WB-4101 to alpha 1-adrenergic receptors after dorsal bundle lesion was augmented generally to a lesser extent than beta-receptor binding, with significantly increased numbers of sites only in the frontal cortex (74%), thalamus (20%) and septum. Both alpha 1- and beta-receptor binding sites were reduced in number by 25-28% in the cerebellum of dorsal bundle-lesioned rats, whereas intraventricular administration of 6-hydroxydopamine to adult rats, which depletes norepinephrine in the cerebellum by 96%, increased cerebellar alpha 1- and beta-receptor binding by 33-40%. Binding of [3H]clonidine to forebrain alpha 2-adrenergic receptors was significantly elevated in the frontal cortex, but reduced in the amygdala and septum, after dorsal bundle lesion.