Effects Of Locus Coeruleus Lesions Research Articles

Effects of locus coeruleus lesions on vigilance and attentive behaviour in cat

Previous data have suggested that in the cat, expectancy behaviour (waiting for a target to appear) and associated electrocortical, focal, synchronized activity ('mu' rhythms) are modulated by a noradrenergic system possibly originating from the locus coeruleus (LC). To test the latter hypothesis, we have examined the behavioural and ECoG changes induced after bilateral LC lesions. Our results demonstrated that destruction of the anterior 3/4th of the LC (A6 noradrenergic cell group) resulted in a considerable increase of mu rhythms and expectancy behaviour, without episodes of drowsiness that normally occur. Destruction of the posterior fourth of LC (A4 noradrenergic group) only increased the duration of slow sleep. Extending the A6 lesion to include the dorsal ascending noradrenergic bundle also increased the expectancy behaviour and mu rhythms. Finally, when the nucleus subcoeruleus was also involved, the duration of slow sleep and the frequency of paradoxical sleep episodes increased. These findings indicate that the LC exerts an inhibitory effect on structures involved in the induction and persistence of expectancy behaviour with accompanying mu rhythms.

Effects of locus coeruleus lesions on parkinsonian signs, striatal dopamine and substantia nigra cell loss after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in monkeys: A possible role for the locus coeruleus in the progression of Parkinson's disease

Six pairs of female squirrel monkeys were given a daily intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 9–14 days, beginning the same day on which they received either a bilateral 6-hydroxydopamine lesion or a sham lesion of the locus coeruleus. Sham animals developed typical parkinsonian signs (i.e. tremor, bradykinesia, hypokinesia and reduced blink rate) which largely recovered by six to nine weeks after the start of MPTP treatment. At nine weeks, post mortem levels of striatal dopamine in these same animals were partially reduced (by 45%), and this only in the putamen, compared to values obtained from three non-operated, normal control animals. Additionally, histological examination revealed a moderate loss of neuronal cell bodies in the substantia nigra, pars compacta. In marked contrast, the locus coeruleus-lesioned monkeys exhibited little or no recovery from the parkinsonian signs induced by MPTP. Post mortem examination of these animals revealed profound decreases in caudate (by 84%) and putamen (by 91%) dopamine content, and severe neuronal cell loss in the substantia nigra pars compacta of all animals. These neurological, biochemical and histological assessments indicate that lesioning of the locus coeruleus impairs the recovery which usually occurs from the parkinsonian manifestations induced by MPTP in squirrel monkeys. The results support the hypothesis that deficient locus coeruleus noradrenergic mechanisms underlie the progression of Parkinson's disease.

Effects of locus coeruleus lesions on the release of endogenous dopamine in the rat nucleus accumbens and caudate nucleus as determined by intracerebral microdialysis

Bilateral 6-hydroxydopamine lesions of the rat locus coeruleus (a) depleted forebrain norepinephrine levels by 67%, (b) reduced the basal release of dopamine in the nucleus accumbens and caudate nucleus by 26% and 19%, respectively, and (c) reduced (+)-amphetamine-induced release in the nucleus accumbens nucleus. The locus coeruleus appears to exert a tonic excitatory influence on striatal and limbic dopamine release in vivo.

Effects of locus coeruleus lesions on auditory, long-latency, event- related potentials in monkey

It has previously been demonstrated that monkeys exhibit certain event-related potential (ERP) components showing latency, polarity, and contingency similarities to those observed in humans. In the present study, monkey P300-like components were studied in order to evaluate the hypothesis that the noradrenergic locus coeruleus (LC) system participates in their generation or modulation. ERPs were recorded from untrained squirrel monkeys (Saimiri sciureus) twice a week for 4 weeks before and after bilateral LC lesions and interruption of dorsal bundle (DB) fibers. Stimuli consisted of 2 and 6 kHz tone pips (40 msec duration, 60 dB above nHL) presented once a second in random order. In most sessions, one tone constituted 90% of the stimuli and the other tone 10%, while in some sessions tones were made equiprobable to test the effects of manipulating stimulus probability. LC and DB lesions were made by first localizing the nucleus and creating an electrolytic lesion. Then, the electrode was placed at the anterior pole of the nucleus and a knife cut effected. The extent of damage to LC perikarya and ascending axons was assessed by reconstructing lesions from Nissl-stained sagittal sections through the brain stems. The effect of lesions on cortical noradrenergic axons was immunohistochemically verified utilizing antisera directed against dopamine-B-hydroxylase and tyrosine hydroxylase to label noradrenergic and dopaminergic axons, respectively. The prelesion ERP results replicated previous findings of P300-like components recorded in response to low-probability tones. The postlesion ERP data indicated that following damage to LC cell bodies, combined with interruption of histochemically detectable ascending noradrenergic axons, monkey P300-like potentials exhibited decreased areas, altered brain-surface distribution, and reduced sensitivity to stimulus probability. The correlation between the extent of cell body lesions and percentage reduction in the magnitude of P300-like responses was significant. However, interruption of DB fibers alone did not have similar effects. Neither type of lesion had any effect on amplitudes, latencies, or brain-surface distributions of P52, P172, or N250-900. There was, however, a significant effect on N106. Stimulus probability effects on the frontally distributed P52 and N106 were not altered by the lesions. These data support the hypothesis that the integrity of the LC nucleus and its ascending fibers is important in the generation and modulation of surface-recorded P300-like activity.

Functional consequences of unilateral lesion of the locus coeruleus: A quantitative [ 14C]2-deoxyglucose investigation

The functional consequences, as reflected in local rates of glucose utilization, of ablation of the locus coeruleus (the nucleus from which a major portion of the ascending noradrenergic fibres arise) have been examined in conscious rats with the quantitative autoradiographic [ 14C]2-deoxyglucose technique. Measurements of glucose utilization were made 72 h after histologically verified unilateral electrolytic lesions of the locus coeruleus. In the overwhelming majority of the 35 grey matter regions examined, the rate of glucose utilization was unaltered by lesions of the locus coeruleus, and in the limited number of CNS regions in which significant alterations were observed, the magnitude of the changes was invariably modest (less than 20% different from sham-operated control animals). Reductions in glucose use were observed in ipsilateral ventral (by 14%) and lateral thalamic nuclei (by 17%), and rates of glucose utilization in most regions of cerebral cortex were significantly lower (about 10%) in the ipsilateral hemisphere relative to the hemisphere contralateral to the lesion. In one region, the median raphe nucleus, glucose utilization was significantly elevated (by 19%) following lesions of the locus coeruleus. Attempts to accentuate the effects of locus coeruleus lesions by pharmacological manipulation of CNS adrenoreceptors by means of the systemic administration of phenoxybenzamine (30 mg/kg, 40 min prior to measurement of glucose use) in animals bearing unilateral locus coeruleus lesions were unsuccessful; the modest alterations in glucose utilization observed following locus coeruleus lesion alone were even less pronounced in lesioned animals receiving phenoxybenzamine. The alterations in local glucose utilization provoked by phenoxybenzamine were similar in sham-lesioned and locus coeruleus-lesioned animals. It would appear that the functional consequences, in terms of glucose utilization, are much less pronounced when a single neurotransmitter system (in the present studies, noradrenergic neurones) is lesioned than when a multiple neurotransmitter, functionally integrated pathway (such as the visual system) is disrupted.

Differential effects of locus coeruleus lesions upon metabolic activity in CNS nuclei involved in cardiovascular regulation

The alterations of local cerebral glucose utilization in 5 medullary and 6 supramedullary regions involved in cardiovascular regulation, which result from unilateral electrolytic lesions of the locus coeruleus, have been examined in conscious rats, using the quantitative autoradiographic [14C]2-deoxyglucose technique. Unilateral lesions of the locus coeruleus (72 h prior to study) did not result in any significant alteration in glucose utilization in any of medullary (e.g. nucleus of the tractus solitarius, dorsal motor nucleus of the vagus) or diencephalic (e.g. periventricular and paraventricular hypothalamic nuclei, lateral habenular nucleus) regions which were examined. However, the increased glucose utilization which occurred in some medullary nuclei (e.g. nucleus of the solitary tract, dorsal motor nucleus of the vagus) following administration of the alpha-receptor antagonist, phenoxybenzamine (30 mg/kg, i.v.), was significantly attenuated by lesions of the locus coeruleus, whereas the increased glucose utilization elicited in hypothalamic nuclei by the drug was unaffected by locus coeruleus lesions. In contrast, glucose utilization in the lateral habenular nucleus was elevated significantly following phenoxybenzamine only in animals bearing unilateral locus coeruleus lesion; the drug being without effect in this region in sham-lesioned rats. These differential consequences of locus coeruleus lesions upon glucose utilization in nuclei involved in cardiovascular regulation emphasize the complex nature of the influence of the locus coeruleus upon blood pressure control.

Effects of locus coeruleus lesions upon sleeping and waking in the rabbit

The effects of radiofrequency lesions in the region of the locus coeruleus (LC) upon sleep--waking states and behaviors were investigated in chronically implanted New Zealand White rabbits. Polygraphic recordings were taken prior to and at 5- and 14-day intervals following lesioning. In animals exhibiting absence of paradoxical sleep and the presence of bizarre motor behavior, additional recordings were taken 30 days postlesion. Prelesion sleep-wakefulness pattern data were comparable to those previously observed in intact rabbits, including the recently reported absence of sustained PS-related nuchal muscle atonia. Lesions histologically localized to the area of the locus coeruleus were of two types, i.e., those effecting bilateral destruction of greater than or equal to 80% (n = 11) or 30-50% (n = 11) of the LC. A transient period of inactivity was present immediately following lesioning, but by two weeks postlesion animals had generally regained normal waking behavioral and physiological functioning, e.g., eating, drinking and grooming behaviors had returned and respiration, micturition and general urological functioning were normal. The more extensive LC lesions were followed by increases in the proportion of total recording time spent in wakefulness, but primarily in quiet rather than active wakefulness. Sleep was fragmented by phasic muscular activation in proportion to the amount of LC destroyed. In animals with the most extensive lesions, slow wave sleep was interrupted by brief, abrupt episodes of twitching, and episodes of marked phasic muscular activation, often violent in nature, occurred following periods of slow wave sleep. The postlesion occurrence of PS was inversely related to the degree of LC destruction and, accordingly, to the presence of episodes of phasic motor activation. These results did not confirm earlier reports in other species implicating the LC in urogenital functioning and respiration, but do corroborate previous findings indicating that neural elements in the LC regions are essential to the integrity of sleep and are especially important to the control of motor mechanisms during sleep.

Effects of locus coeruleus lesions upon cerebral monoamine content, sleep-wakefulness states and the response to amphetamine in the cat

The purpose of the present study was to investigate the effects of complete lesions of the noradrenaline locus coeruleus neurons upon wakefulness and paradoxical sleep. Radiofrequency lesions of the nucleus were performed in 8 chronically implanted cats which were continuously recorded with an EEG for 5 days prior to and 21 days following the lesions, when they were sacrificed. In 3 of these animals amphetamine (2 mg/kg) was administered on one control day and on the 10th day post-lesion. Following sacrifice, monoamine content was assayed in discrete brain regions, and the lesion was examined in Nissl-stained sections of the pons. (1) The majority (x 69%) of the locus coeruleus was bilaterally destroyed by the lesions which only minimally exceeded the boundaries of the nucleus within the dorsolateral pontine tegmentum. Noradrenaline was depleted by a mean of 85% in the paleo- and neocortex and by a mean of 60% in the thalamus and midbrain. (2) EEG activation reappeared within 12-48 h following the lesion and represented a normal percentage of recording time on the 3rd and subsequent days post-lesion. The behavioral arousal and long-lasting EEG activation produced by amphetamine was qualitatively and quantitatively the same pre- and post-lesion. (3) Despite alteration of certain components, paradoxical sleep reappeared within 48 h and recovered to normal amounts by the second week post-lesion. Muscle atonia was permanently absent in 7 animals. Ponto-geniculo-occipital (PGO) spiking was acutely redistributed across all states and chronically reduced in frequency (by a mean of 50%) within paradoxical sleep. These results indicate that the noradrenaline locus coeruleus neurons are not necessary for the tonic maintenance of EEG activation that occurs in normal wakefulness and in amphetamine-produced arousal. Furthermore, these neurons are not necessary for the occurrence of paradoxical sleep, although they may be involved in modulation of PGO spiking.

96) - Effects of locus coeruleus lesions on hyperemotionality induced by olfactory bulb ablations in rats

96) - Effects of locus coeruleus lesions on hyperemotionality induced by olfactory bulb ablations in rats