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At least 19 recordsLinked to original sources
PubMed1979

Studies on the dense-core vesicles in the ontogenesis of locus coeruleus. III. Statistical reconstruction of the diameter distribution of the dense-core vesicles in locus coeruleus during rat ontogenesis.

The method for statistical reconstruction of the diameters of dence-core vesicles, described in the previous work, is applied for studying the changes of these vesicles in the perikarya, the axonal boutons and the neuropile of the rat locus coeruleus during ontogenesis. The data obtained show the presence of the population during the embryonal development and of two populations of dense-core vesicles after birth in the structures studied. This finding is interpreted in connection with the different function of the dense-core vesicles and of the transmitters, respectively, in the development and function of the main noradrenergic nucleus in the brain of mammals -- locus coeruleus.

Age Factors↗
PubMedDate not supplied

Raphe projections to the locus coeruleus in the rat.

Afferent projections to the locus coeruleus from the various raphe nuclei, particularly of the midbrain (nuclei raphe dorsalis and medianus) and pons (nuclei raphe pontis and magnus), have been studied in the rat by retrograde transport methods using horseradish peroxidase (HRP). The locus coeruleus, in both its dorsomedial and ventrolateral divisions, and in its various anterior-posterior components, were injected with 0.05 microliters of horseradish peroxidase following which various structures of the brainstem, particularly the raphe nuclei, were examined for HRP reactive cells. It was found that injections in most components of the locus coeruleus were associated with HRP positive cells in varying degrees of density in the nuclei raphe dorsalis, medianus, pontis, and magnus, with considerably sparser labelling in the anterior aspects of the medullary raphe nuclei pallidus and obscurus. Labelled cells were also seen in the nuclei of the solitary tract, contralateral locus coeruleus. lateral reticular areas of the pons and midbrain, nuclei pontis oralis and caudalis, vestibular nuclei, mesencephalic nucleus of the trigeminal nerve, fastigial nuclei of cerebellum and medial parabrachial nuclei. These data, showing widespread innervation of the locus coeruleus from all raphe nuclei, as well as many other brainstem areas, in the rat support the general view of heavy innervation of the locus coeruleus from both extra-raphe and raphe nulcei. These latter raphe projections, probably serotonergic in nature, provide anatomical support for the various experiments indicating considerable regulation of locus coeruleus activities, such as phasic events of REM sleep, among other, by widespread projections from most raphe nuclei was well as several other regions of the brainstem.

Afferent Pathways↗
PubMed1979

NGF and anti-NGF: evidence against effects on fiber growth in locus coeruleus from cultures of perinatal CNS tissues.

The present study examines whether the developing noradrenergic neurons of locus coeruleus depend on endogenous nerve growth factor (NGF) for nerve fiber production and if exogenous NGF stimulates fiber growth in this nucleus, using a collagen gel tissue culture technique. Lucus coeruleus from perinatal rat brain was used in three culture experiments: (1) lucus coeruleus, parietal cerebral cortex, and the superior cervical ganglion, prepared from newborn rats and cultured in different sectors of the same dishes; (2) locus coeruleus and parietal cerebral cortex from 17-day-old rat fetuses cultured in the same manner, and (3) locus coeruleus from 17-day-old rat fetuses co-cultured with spinal, sympathetic and ciliary ganglia from 8-day chick embryos. Experiments 1 and 2 were run with and without addition of NGF and anti-NGF, experiment 3 with and without anti-NGF. Total fiber production in all cultured tissues was evaluated daily by dark field and phase contrast microscopy during 4 days. Adrenergic nerve fiber production was then studied in the same locus coeruleus and superior cervical ganglia from the rats by Falck-Hillarp fluorescence histochemistry. Locus coeruleus and cortex cerebri from fetal rats produced dense fiber halos in culture. Locus coeruleus from newborn rats produced considerably less fibers, newborn cortex only few fibers. Superior cervical ganglia from the same newborn animals produced no or almost no fibers. Addition of NGF was not able to stimulate fiber growth in locus coeruleus nor in cortex cerebri as observed both in the living cultures and by fluorescence microscopy. Likewise, addition of anti-NGF did not affect fiber production in the CNS areas. The negative results with NGF on newborn locus coeruleus and cortex cerebri were in sharp contrast to the strong, highly significant fiber growth response demonstrated by the superior cervical ganglion from the same animals cultured in the same dishes. The third experiment tested whether locus coeruleus in tissue culture contained or produced nerve growth factor or any one of the three chick embryo ganglia. No response whatsoever in these three ganglia was observed. It is concluded that the developing locus coeruleus area does not contain or produce NGF, does not depend on NGF for fiber production, and is not stimulated by exogenous NGF.

Animals↗
PubMed1977

Suppression of an eplieptiform type of electrocortical activity in the rat by stimulation in the vicinity of locus coeruleus.

Stimulation of the locus coeruleus, or in the vicinity of this nucleus or of its ascending tracts, could markedly suppress the appearance of epileptiform-like ECoG bursts. The latter were induced in rats by a subconvulsive dose of pentylenetetrazol. Electrode sites were identified histologically. A unilateral stimulus suppressed bursts bilaterally. An individual burst already in progress could be aborted, stopping within less than 0.5-1 sec after onset of a stimulus train. The antiepileptiform actions occurred with no evidence of any desynchronizing effect of the stimulus on the resting ECoG; they appear to be different in sites of origin and nature from those reported for stimulation of the reticular activating system. It is proposed that stimulation of the ascending noradrenergic system in the brain stem may limit the development and spread of hyperexcitatory, epileptiform states.

Animals↗
PubMed1977

Ascending projections of the locus coeruleus in the rat. II. Autoradiographic study.

The ascending projections of the locus coeruleus were studied using an autoradiographic method. The major projection of locus coeruleus neurons ascends in a dorsal pathway traversing the midbrain tegmentum in a position ventrolateral to the periaqueductal gray. At the caudal diencephalon the locus coeruleus axons descend to enter the medial forebrain bundle at a caudal tuberal hypothalamic level. They are jointed in the medial forebrain bundle by a much smaller locus coeruleus projection which takes a ventral course through the midbrain tegmentum and enters the medial forebrain bundle via the mammillary peduncle and ventral tegmental area. Terminal projections are evident in the midbrain to the periaqueductal gray, tegmentum and raphe nuclei. There are widespread projections to the dorsal thalamus. The heaviest of these are to the intralaminar nuclei, the anteroventral and anteromedial nuclei, the dorsal lateral geniculate and the paraventricular nucleus. In the hypothalamus the largest projections are to the lateral hypothalamic area, periventricular nucleus, supraoptic nucleus and paraventricular nucleus. As the locus coeruleus projection ascends in the medial forebrain bundle, fibers leave it to traverse the lateral hypothalamus and zona incerta and enter the internal capsule, the ventral amygdaloid bundle and ansa peduncularis. These appear to terminate in the amygdaloid complex and, via the external capsule, in the lateral and dorsal neocortex. At the level of the septum 4 projections are evident. One group of fibers enters the stria medullaris to terminate in the paraventricular nucleus and habenular nuclei. A second group joins the stria terminalis to terminate in the anygdaloid complex. The third group turns into the diagonal band and medial septum; some fibers terminate in the septal nuclei and others continue into the fornix to termimate in hippocampus. A large component continues around the corpus callosum into the cingulum to terminate in the cingulate and adjacent neocortex, the subiculum and hippocampus. The remaining fibers continue rostrally in the medial forebrain bundle to terminate in olfactory forebrain and frontal neocortex. Commissural projections arise at 4 locations. The first decussation occurs in the dorsal tegmentum just below the central gray rostral to the locus coeruleus. The crossing fibers enter the contralateral dorsal bundle. A second group of fibers leaves the ipsilateral dorsal pathway, crosses in the posterior commissure and enters the contralateral dorsal pathway at the level. The third commissural projection arises more rostrally and crosses in the dorsal supraoptic commissure to enter the contralateral medial forebrain bundle. The fourth commissural projection is through the anterior commissure. The termination of the contralateral projection appears similar to that of the ipsilateral projection.

Afferent Pathways↗
PubMed1979

Regional topography within noradrenergic locus coeruleus as revealed by retrograde transport of horseradish peroxidase.

A hitherto unsuspected degree of regional topographic organization in the noradrenergic nucleus, locus coeruleus, was revealed by the use of retrograde transport of horseradish peroxidase (HRP) from terminal areas receiving noradrenergic innervation. HRP was injected into hippocampus, hypothalamus, thalamus, caudate-putamen, septum, amygdala-piriform cortex, cerebellum and cortex. Successful transport was obtained from all areas, including the caudate-putamen and cerebral cortex. The pattern of HRP positive cells in the ipsilateral locus coeruleus was markedly different depending on the location of the HRP injection. Thus, hippocampal injections labeled cells in the dorsal locus coeruleus but not at all in the ventral tip. Injections of HRP into caudate-putamen or cerebellum labeled the ventral tip along with the rest of the dorsal portion. HRP injections into the septum labeled cells only in the dorsal half of the dorsal locus coeruleus. There thus exists a three tier division of locus coeruleus into the ventral one third, dorsal one third and intermediate one third. A further division was seen in the anterior-posterior plane with HRP injections into the thalamus labeling the posterior pole of locus very intensely but with little transport to more anterior levels; conversely HRP injection into the hypothalamus resulted in intense labeling only in the anterior pole of locus coeruleus. Amygdala-piriform cortex HRP injections revealed a further pattern with very intensely reactive cells scattered sparsely throughout the nucleus. Cortical HRP injections yielded weaker labeling also in occasional, scattered cells. All HRP transport to locus coeruleus was shown to be noradrenergic by degeneration with 6-hydroxydopamine and due to terminal, rather than fiber of passage, uptake by control injection into the dorsal NA bundle. It is concluded that the locus coeruleus is not an homogenous nucleus with respect to the origin of the noradrenergic projections to sundry forebrain, spinal and cerebellar areas but is comprised of distinct subdivisions of noradrenergic neurons.

Amygdala↗
PubMed1979

Serotonergic innervation of the locus coeruleus from the dorsal raphe and its action on responses to noxious stimuli.

The connexions between the dorsal raphe nucleus and the nucleus locus coeruleus were studied in urethane anaesthetized rats. 1. Cells in the locus coeruleus gave an excitatory response to a noxious stimulus, e.g. leg pinch. 2. This excitatory response was blocked by either a parenteral or an ionophoretic injection of morphine and recovered after an injection of naloxone. 3. Electrical stimulation in the region of the dorsal raphe blocked excitatory locus coeruleus responses to noxious stimuli. 4. While naloxone did not antagonize the effects of the dorsal raphe stimulation towards locus coeruleus activity, these effects were absent in rats pretreated with a serotonin synthesis inhibitor, PCPA or with 5,7-DHT which destroys serotonin-containing terminals, and were reduced by the serotonin antagonist methysergide. 5. A serotonin-containing inhibitory pathway between the dorsal raphe and the locus coeruleus is proposed to account for these results.

Action Potentials↗
PubMed1977

[Afferent pathway from locus coeruleus to the nucleus solitarius].

After the destruction of the nucleus tractas solitarii, just caudally to the writing pen by means of a stereotaxic instrument, the system of afferent fibres to the nucleus in question was investigated by the methods of Nauta and Fink--Heimer. The fibre terminals were revealed near locus coeruleus. Investigation of the locus coeruleus by Golgi method demonstrated that it usually has neurons of reticular type and transitional ones which resemble by their form the neurons specific for sensory formations. It is possible to conclude that locus coeruleus posesses connections of visceral origin which may play a part in the afferent influence of locus coeruleus on the brain cortex.

Animals↗
PubMed1978

The locus coeruleus noradrenergic system--evidence against a role in attention, habituation, anxiety and motor activity.

Lesions of the locus coeruleus system were induced by combined stereotaxic injections of 6-OH-dopamine to the ascending fibres and just lateral to the locus coeruleus itself, to deplete the noradrenaline content of both the cerebral and cerebellar cortices. A group of rats with cortical noradrenaline concentrations of less than 30 ng/g were compared with a group with lesser destruction of the system (mean noradrenaline concentration 71 +/- 44 ng/g) and with controls (mean noradrenaline 347 +/- 58 ng/g). Lesioned rats showed normal motor activity and exploration (assessed with a holeboard) and showed normal habituation of these behaviours. The lesioned rats gave no evidence of increased susceptibility to distracting auditory stimuli whilst licking for water, and the groups did not differ in their rate of habituation to these stimuli, or in dishabituation. In a social interaction test, lesioned animals showed a decrease in social contacts in an unfamiliar situation (interpreted as a response to anxiety) of similar magnitude to that seen in the control group. In this test, lesioned animals engaged in more 'aggressive' behaviour (boxing and wrestling) than did the controls. These findings are incompatible with hypotheses that the locus coeruleus system is an integral part of the physiological mechanisms which control gross motor behaviour, attention, habituation or anxiety. Together with previous findings with the benzodiazepines, the results with the social interaction test make it unlikely that the benzodiazepines exert their anxiolytic effects by inhibiting the locus coeruleus system.

Acoustic Stimulation↗
PubMed1978

The cerebellar projection from locus coeruleus as studied with retrograde transport of horseradish peroxidase in the cat.

The cerebellar afferent projection from locus coeruleus has been studied in the cat by means of retrograde axonal transport of horseradish peroxidase. Labelled cells are present bilaterally in locus coeruleus only following injections in the cerebellar vermis (especially its anterior and posterior parts), the ventral paraflocculus and the flocculus. The labelled cells are restricted to the caudal half of the nucleus. A few labelled cells are also present in locus coeruleus following injections in the fastigial nucleus, and in nucleus interpositus anterior. The findings are discussed in relation to other studies on the efferent and afferent connections of the locus coeruleus.

Animals↗
PubMed1979

Loss of nerve cell bodies in caudal locus coeruleus following treatment of neonates with 6-hydroxydopa.

The locus coeruleus is a well defined nucleus in cresylechtviolet preparations and the perikarya are easily distinguished. The coeruleus neurons are thought to be noradrenergic and during development can be selectively affected by the neurotoxin, 6-hydroxydopa (6-OHDOPA). In 6-month-old rats that were treated on day of birth with 6-OHDOPA (60 mg/kg, i.p.) there was a 32% loss of nerve cell bodies in the locus coeruleus. While it was apparent that loss of cell bodies occurred throughout the entire nucleus, the greatest loss of perikarya was from the caudal extent of the nucleus. It is known that sprouting of noradrenergic terminals occurs in the cerebellum of rats following treatment of newborns with 6-OHDOPA. That there are fewer cell bodies to contribute additional terminals further dramatizes this sprouting phenomenon.

Animals↗
PubMed1977

Ascending projections of the locus coeruleus in the rat. I. Axonal transport in central noradrenaline neurons.

Axonal transport of protein and metabolites of L-[3H(G)]3, 4-dihydroxyphenylalanine ([3H]DOPA) was studied in the central noradrenaline neurons of the pontine nucleus locus coeruleus and was correlated with regional alterations of noradrenaline content following destruction of the nucleus. Unilateral lesions of the locus coeruleus produce a partial depletion of noradrenaline in the ipsilateral hypothalamus and telencephalon, indicating that these neurons project widely to the ipsilateral forebrain. Twenty-four to 48 h following local injections of 50 micronCi [3H]proline, locus coeruleus neurons take up labeled material and transport it, presumably as protein, to ipsilateral structures in the midbrain, diencephalon and telencephalon including the neocortex. Similarly 8 h after injection of 25 micronCi [3H]DOPA into the locus coeruleus, transport of material including catecholamines occurs to ipsilateral diencephalon and telencephalon. Axonal transport of proteins to telencephalic structures is greatly diminished by selective lesions of catecholamine terminals with 6-hydroxydopamine (6-OHDA) and following destruction of the medial forebrain bundle. These results provide further support for the view that noradrenaline neurons of the locus coeruleus nucleus project widely within the neuraxis to ipsilateral structures of the brain stem, diencephalon and telencephalon, including all cortical areas. In addition, evidence is presented for a contralateral projection with a similar distribution. The rate of axonal transport of labeled protein and metabolites of [3H]DOPA including [3H]catecholamines in central noradrenaline neurons is estimated to be 3-4 mm/h and is accordingly similar to that reported for noradrenaline neurons of the peripheral sympathetic nervous system.

Adrenergic Fibers↗
PubMed1979

Functional reinnervation of rat hippocampus by locus coeruleus implants.

Transplants of the embryonic locus coeruleus (LC) region were implanted into the circuity of the hippocampal formation in adult rats in which the normal adrenergic afferents to the hippocampus had been removed. The growth of new adrenergic axons from the implant in the denervated hippocampus was followed for 1-14 months after surgery by means of fluorescence histochemistry, and the function of the implant-hippocampal connections was tested electrophysiologically after 2-3 months survival. In the successful cases the entire hippocampal formation was reinnervated from the LC implant within 3-6 months after operation, and the newly formed innervation still persisted unchanged by 14 months. The reinnervation was equally effective irrespective of the route by which the axons entered the hippocampus, i.e. along the lesioned fornix-fimbria or along a retrosplenial route. The pattern formed by the ingrowing LC axons mimicked to a large extent that of the normal LC afferents. Little growth was seen into denervated terminal fields of the commissural, septal or entorhinal afferents, pointing to a preference of the ingrowing LC fibers for the areas normally innervated by adrenergic afferents. In the electrophysiological experiments, stimulation of the LC implants caused (in 20 out of 29 cells monitored) an inhibition of the spontaneous activity of neurons in the host hippocampus. This inhibition had a relatively long latency and a long duration, similar to that observed after stimulation of the innate LC in the intact rat. As in the normal rat, the inhibitory responses were blocked by systemic or local application of the beta-adrenergic receptor blockers propranolol or sotalol. It is concluded that the adult rat brain is capable of carrying out all steps involved in correct functional reinnervation of a denervated region. Moreover, the implant-hippocampal preparation should be a highly suitable model system for functional studies of a central noradrenergic connection.

Adrenergic Fibers↗
PubMed1978

Effects of catecholamine depleting drugs and d-amphetamine on self-stimulation of the substantia nigra and locus coeruleus.

6-Hydroxydopamine treatments which preferentially depleted either norepinephrine or dopamine were used to define the importance of these transmitter systems in the behavioral alterations produced by catecholamine synthesis inhibitors and d-amphetamine on self-stimulation of the locus coeruleus and substantia nigra. After chronic reduction of brain dopamine, an acute depression of self-stimulation of both the locus coeruleus and substantia nigra occurred. Preferential depletion of norepinephrine with 6-hydroxydopamine did not result in a significant decrease in self-stimulation of locus coeruleus or substantia nigra. However, a dose of alpha-methyltyrosine wihch had no effect in control rats or in rats with brain norepinephrine depleted caused a significant reduction in responding at both electrode placements in animals depleted of brain dopamine. Administration of U-14,624 affected neither substantia nigra nor locus coeruleus self-stimulation, even though it produced an additional 70% depletion of norepinephrine. When d-amphetamine sulfate was given to 6-hydroxydopamine-treated rats, the facilitation of self-stimulation produced by this compound was significantly attenuated in rats with prior depletion of brain dopamine. Depletion of brain norepinephrine did not affect the actions of d-amphetamine on self-stimulation. In other experiments, the actions of d-amphetamine to increase self-stimulation of animals pretreated with reserpine was found to be antagonized by alpha-methyltyrosine but not by U-14,624. Results suggest that drugs can alter self-stimulation of a site in brain anatomically associated with noradrenergic neural pathways and self-stimulation of a site primarily associated with dopaminergic pathways in a similar manner. These data also provided evidence for the involvement of dopamine fibers in the pharmacological actions of d-amphetamine, reserpine and alpha-methyltyrosine.

Animals↗
PubMed1977

Behavioral effects of neuroleptics, apomorphine and amphetamine after bilateral lesion of the locus coeruleus in rats.

Bilateral lesions of the locus coeruleus (LC) markedly increased susceptibility to the cateleptogenic effects of neuroleptics. The apomorphine-induced stereotypy was enhanced in rats with lesioned LC whilst amphetamine stereotypy was only slightly increased. No changes in locomotor activity have been observed in LC-lesioned rats treated with apomorphine and amphetamine. This data indicates that lesions of the LC produce decreased activity of dopaminergic brain neurons as well as supersensitivity of dopaminergic receptors.

Animals↗
PubMed1975

Biochemical mapping of the noradrenergic projection from the locus coeruleus. A model for studies of brain neuronal pathways.

Mapping of the noradrenergic projection from neurons in the rat locus coeruleus has been examined by combining a sensitive radioisotopic assay for catecholamines with a microdissection technique to remove multiple separate brain nuclei. The effect of a unilateral locus coeruleus lesion on norepinephrine concentration in 19 brain regions ipsilateral and contralateral to the lesion was determined. Evidence for ipsilateral and bilateral innervation to specific regions is presented, and many regions appear to receive combined innervation from other noradrenergic loci, in addition to that from the locus coeruleus. Fluorescence rating was correlated with biochemical measurement of amine content with these techniques and proportionality was observed over a narrow range. With this proportionality taken into consideration, mapping results obtained by biochemical and fluorescence methods are compared.

Animals↗
PubMed1979

Distribution of hypertrophied locus coeruleus projection to adult cerebellum after neonatal 6-hydroxydopamine.

Following treatment as neonates with a high subcutaneous dose of 6-hydroxydopamine (6-OHDA), the projections of the locus coeruleus were mapped in the brains of adult rats. This was done using the technique of unilateral lesions in the nucleus followed by simultaneous determinations of norepinephrine (NE) levels, dopamine-beta-hydroxylase (DBH) activity and synaptosomal [3H]NE uptake in various terminal areas. In particular the cerebellum was subdivided into 3 areas in order to assess any changes from normal in the distribution of the hypertrophied noradrenergic projections here. In vehicle-control rats the lesions resulted in an 80--85% loss of NE in the parietal cortex ipsilateral to the lesion and a 15--20% loss contralaterally. In the control cerebellum the locus coeruleus projection, based upon changes in all 3 markers, is distributed 2/3 ipsilaterally and 1/3 contralaterally with the same pattern present in all 3 subregions. The neonatal 6-OHDA treatment resulted in virtually complete loss of noradrenergic terminals in the cerebral cortex. Following neonatal 6-OHDA treatment cerebellar levels of NE, DBH and [3H]NE uptake increased by between 20--60%, with the smallest increases occurring in [3H]NE uptake. In these rats the locus coeruleus accounted for at least 75--80% of the cerebellar noradrenergic parameters. Unlike control rats however, the lesions in these rats produced only ipsilateral decreases in NE and DBH. On the other hand changes in [3H]NE uptake indicated a normal 2/3 ipsilateral, 1/3 contralateral pattern. It is suggested that two separable events occur in the noradrenergic projection to the cerebellum. The first is the regeneration of an increased number of nerve terminals, or sprouting, and the second is a build-up of synaptic vesicles, or collateral accumulation. The sprouting, judging from the [3H]NE uptake data, occurs with apparently normal distribution, but the accumulation of NE and DBH is confined predominantly to the ipsilaterally projecting axon terminals. This may be the consequence of collateral accumulation resulting from the degeneration of the largely ipsilateral coeruleocortical projection.

Animals↗
PubMed1978

Atonia after carbachol microinjections near the locus coeruleus in cats.

The effect of microinjections of carbachol into the dorsolateral pontine tegmentum on the behaviour of cats is investigated. Injections of small amounts (50 and 500ng) of carbachol into the pontine reticular formation induced muscular atonia in otherwise awake animals. The atonia is not due to cholinergic stimulation of the noradrenergic cells of the locus coeruleus or the dorsolateral pons, since the most effective sites were situated ventrally to the locus coeruleus and alpha- and beta-adrenergic blocking agents did not affect the antonia. The results are discussed in view of the postulated role of the locus coeruleus in paradoxical sleep.

Animals↗