Ipsilateral Nucleus Research Articles

Rubral astrocytic reactions to proximal and distal axotomy of rubrospinal neurons in the rat

Spinal tractotomy-induced perineuronal astrocytic reaction of the rat rubrospinal system was studied using an antiserum to the astrocyte-specific glial fibrillary acidic protein as a marker. The effect of the proximity of axonal cut to cell bodies was also studied by comparing astrocytic reactions elicited by upper cervical and lower thoracic tractotomy. Fast blue was used as a retrograde tracer to identify axotomized neurons, which were found to concentrate in the caudal part of the contralateral red nucleus. The length of reactive astrocytic processes in the dorsomedial and ventrolateral parts of the nucleus was quantified separately since neurons in these two parts project to cervical and lumbar spinal cord, respectively. Those of the ipsilateral nucleus were also quantified. Sham operation caused a transient increase in reactive astrocytic processes one day after surgery. An early and a late increase of reactive astrocytic processes was found 2–5 days and 2–8 weeks following both thoracic and cervical tractotomy. Cervical axotomy of lumbar-cord-projecting rubral neurons caused an increase of reactive astrocytic processes similar in magnitude to that generated by thoracic axotomy. Following thoracic axotomy, the uninjured dorsomedial area of the contralateral nucleus also displayed an increase concomitant with that which occurred within the neighboring, injured ventrolateral nuclear area suggesting the action of diffusible factor(s). Surprisingly, cervical and thoracic tractotomy also elicited a similar increase of reactive astrocytic processes in the ipsilateral nuclei, independent of the number of ipsilaterally projected neurons present in each nucleus. This may be attributed to the retrograde influence from the denervated spinal target sites which were carried by fibers of the intact rubrospinal tract known to terminate bilaterally. In the lesioned nucleus, reactive astrocytic processes were often located close to axotomized cell bodies as early as 3 days following upper cervical and also, to a lesser extent, lower thoracic tractotomy. However, reactive astrocytic processes in the ipsilateral nucleus usually remained in the neuropil. These results suggest that axotomy induces two levels of retrograde astrocytic reactions within the soma area of intrinsic central neurons. Reactive astrocytic processes located proximally to axotomized cell bodies may have a different functional role from those distributed in the neuropil.

GABAergic inputs to the nucleus rotundus (pulvinar inferior) of the pigeon (columba livia).

The avian nucleus rotundus, a nucleus that appears to be homologous to the inferior/ caudal pulvinar of mammals, is the major target of an ascending retino-tecto-thalamic pathway. Further clarification of the inputs to the rotundus and their functional properties will contribute to our understanding of the fundamental role of the ascending tectal inputs to the telencephalon in all vertebrates, including mammals. We found that the rotundus contains a massive plexus of glutamic acid decarboxylase (GAD)-immunoreactive axons using antibodies against GAD. The cells within the rotundus, however, were not immunoreactive for GAD. The retrograde tracer cholera toxin B fragment was injected into the rotundus to establish the location of the afferent neurons and determine the source of the gamma-aminobutyric acid (GABA) inputs into the rotundus. In addition to the recognized bilateral inputs from layer 13 of the tectum, we found intense retrograde labeling of neurons within the ipsilateral nuclei subpretectalis (SP), subpretectalis-caudalis (SPcd), interstitio-pretecto-subpretectalis (IPS), posteroventralis thalami (PV), and reticularis superior thalami (RS). All the neurons of the SP, SPcd, IPS, and PV were intensely GAD-immunoreactive. The neurons of layer 13 of the tectum were not immunoreactive for GAD. Following the destruction of the ipsilateral SP/IPS complex, we found a major reduction in the intensity of the GAD axonal immunoreactivity within the ipsilateral rotundus, but this destruction did not diminish the intensity of the GAD-immunoreactivity within the contralateral rotundus. Our studies indicated that the source of the massive GAD-immunoreactive plexus within the rotundus was from the ipsilateral SP, SPcd, IPS, and PV nuclei. These nuclei, in turn, received ipsilateral tectal input via collaterals of the neurons of layer 13 in the course of their projections upon the rotundus. We suggest that the direct bilateral tecto-rotundal projections are excitatory, whereas the indirect ipsilateral projections from the SP/IPS and PV are mainly inhibitory, possibly acting via a GABA-A receptor.

Turning behavior induced by injections of glutamate receptor antagonists into the substantia nigra of the rat.

We have found recently that muscimol microinjections into the subthalamic nucleus produce contralateral turning activity [Murer and Pazo (1993) NeuroReport, 4:1219-1222]. To test the hypothesis that a reduced glutamate action on substantia nigra pars reticulata neurons mediates this turning response, we examined the effect of unilateral intranigral microinjections of the AMPA/kainate receptor antagonist 6,7-dinitro-quinoxaline-2,3-dione (DNQX) and the competitive N-methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-5-phosphonovaleric acid (AP-5). DNQX and AP-5 both produced a dose-dependent contralateral turning response, while vehicle administration did not induce turning activity. Application of glutamate receptor antagonists at adjacent regions of the mesencephalic tegmentum were also ineffective. Coadministration of NMDA or AMPA significantly reduced the turning response induced by AP-5 or DNQX, respectively. Lesions of the nigrostriatal pathway by 6-hydroxydopamine did not modify the response to DNQX or AP-5 administration into the nigra. However, their behavioral effects were significantly reduced by a lesion of the ipsilateral subthalamic nucleus. Our results show that the blockade of a tonic input acting on AMPA/kainate and NMDA receptors located at the substantia nigra produces contralateral turning behavior. The effect seems to involve pars reticulata cells since this area remains unchanged after destruction of dopaminergic neurons. The subthalamic nucleus seems to be the endogenous source of the agonist acting on the nigral glutamate receptors related to turning behavior.

Efferent pathways of the nucleus of the optic tract in monkey and their role in eye movements

To clarify the role of the pretectal nucleus of the optic tract (NOT) in ocular following, we traced NOT efferents with tritiated leucine in the monkey and identified the cell groups they targeted. Strong local projections from the NOT were demonstrated to the superior colliculus and the dorsal terminal nucleus bilaterally and to the contralateral NOT. The contralateral oculomotor complex, including motoneurons (C-group) and subdivisions of the Edinger-Westphal complex, including motoneurons (C-group) and subdivisions of the Edinger-Westphal complex, also received inputs. NOT efferents terminated in all accessory optic nuclei (AON) ipsilaterally; contralateral AON projections arose from the pretectal olivary nucleus embedded in the NOT. Descending pathways contacted precerebellar nuclei: the dorsolateral and dorsomedial pontine nuclei, the nucleus reticularis tegmenti pontis, and the inferior olive. Direct projections from NOT to the ipsilateral nucleus prepositus hypoglossi (ppH) appeared to be weak, but retrograde tracer injections into rostral ppH verified this projection; furthermore, the injections demonstrated that AON efferents also enter this area. Efferents from the NOT also targeted ascending reticular networks from the pedunculopontine tegmental nucleus and the locus coeruleus. Rostrally, NOT projections included the magnocellular layers of the lateral geniculate nucleus (lgn); the pregeniculate, peripeduncular, and thalamic reticular nuclei; and the pulvinar, the zona incerta, the mesencephalic reticular formation, the intralaminar thalamic nuclei, and the hypothalamus. The NOT could generate optokinetic nystagmus through projections to the AON, the ppH, and the precerebellar nuclei. However, NOT also projects to structures controlling saccades, ocular pursuit, the near response, lgn motion sensitivity, visual attention, vigilance, and gain modification of the vestibulo-ocular reflex. Any hypothesis on the function of NOT must take into account its connectivity to all of these visuomotor structures.

Bicuculline microinjections into the ventral tegmental area of the rat: alteration of self-stimulation thresholds and of cytochrome oxidase activity in the brain

Abuse of drugs that potentiate GABAergic neurotransmission, namely benzodiazepines, is difficult to understand because this potentiation should elicit, among other effects, a decrease in activity within the mesolimbic system. Abuse of benzodiazepines is difficult to understand since the opposite, namely an increase in mesolimbic activity, has been implicated in drug abuse as well as in the rewarding effect of direct mesolimbic stimulation. In order to evaluate how the activity of the mesolimbic system depends on mesolimbic GABAergic influence, a GABA A receptor antagonist, bicuculline methiodide, was unilaterally injected into the ventral tegmental area and its effect on self-stimulation thresholds derived from stimulations applied to the same area was evaluated. Microinjection of 15, 20 and 30 ng increased the stimulation threshold. This decrease in stimulation efficiency lasted no more than 15 min after which baseline levels were obtained. Such a decrease is paradoxical considering that the manipulation should have released the ventral tegmentum from a tonic inhibitory influence. The metabolic consequences of repeated injections of 30 ng bicuculline were furthermore evaluated by cytochrome oxidase histochemistry. The staining was found to be weak around the injection site and dense in the ipsilateral nucleus accumbens. Release of a tonic GABAergic inhibition added to some cytotoxic damage probably resulted in an increased metabolic activity of this system. The presently reported paradoxical response of the ventral tegmentum and mesolimbic system to a GABAergic challenge may account for the paradoxical relationship between some behavioral properties of the mesolimbic system and GABAergic drugs.

Role of γ-Aminobutyric Acid B Receptors in Baroreceptor Reflexes in Hypertensive Rats

Previous studies demonstrated that stimulation of gamma-aminobutyric acid B (GABA(B)) receptors in the nucleus tractus solitarius of spontaneously hypertensive rats (SHR) elicited a larger increase in arterial pressure compared with control Wistar-Kyoto rats. Since stimulation of GABA(B) receptors in the nucleus tractus solitarius attenuates cardiovascular responses evoked by electrical stimulation of the aortic depressor nerve in normotensive rats and there is evidence of a central neural attenuation of aortic depressor nerve-evoked responses in SHR, we conducted studies to test the hypothesis that enhanced stimulation of GABA(B) receptors in the nucleus tractus solitarius in SHR is responsible for the attenuation of the aortic depressor nerve-evoked responses. Electrical stimulation of the left aortic depressor nerve resulted in frequency-dependent decreases in arterial pressure, heart rate, and splanchnic sympathetic nerve activity in urethane-anesthetized control rats. These responses were not significantly altered by injection of the GABA(B) receptor antagonist CGP 35348 into the ipsilateral nucleus tractus solitarius. The responses evoked by aortic depressor nerve stimulation were attenuated in SHR. This attenuation was particularly apparent with more prolonged periods (>15 seconds) of high-frequency (25-Hz) stimulation, with the depressor and sympathetic nerve responses diminishing during the course of stimulation. This time- and frequency-dependent attenuation of baroreceptor-evoked depressor responses was reversed by injection of CGP 35348 into the ipsilateral nucleus tractus solitarius. Rats made hypertensive by treatment with deoxycorticosterone plus salt did not have attenuated aortic depressor nerve-evoked responses. These results suggest that alterations in GABA b-mediated neural transmission in the nucleus tractus solitarius contribute to the attenuation of the baroreceptor reflex observed in SHR.

Seeing beyond the midline: the role of the contralateral isthmotectal projection in the leopard frog.

The ground level visual field of each eye of the leopard frog includes the entire ipsilateral 180-deg field and approximately 60 deg into the frontal contralateral field. When one eye is covered with an opaque patch, a frog responds to prey stimuli over the entire field of the other eye. Nevertheless, when one optic nerve is cut, the animal responds to prey in the ipsilateral hemifield of the connected eye, but only responds as far as about 30 deg past the frontal midline. If one optic tract is cut, the animal does not respond to prey past the frontal midline. We hypothesized that the responses past the frontal midline might be mediated by input from contralaterally projecting isthmotectal fibers. These fibers originate in the nucleus isthmi, a posterior midbrain structure. We found that when we placed an opaque patch over one eye and either ablated the ipsilateral nucleus isthmi, or cut crossing isthmotectal fibers in the optic chiasm, or blocked input to nucleus isthmi by ablating the ipsilateral tectal lobe, animals did not respond to prey stimuli past the frontal midline. We found that when we placed an opaque patch over one eye and cut crossing optic fibers in the anterior part of the optic chiasm (sparing crossing isthmotectal fibers), animals responded to prey stimuli in the nasal half of the seeing eye's contralateral frontal field. Our results suggest that contralaterally projecting isthmotectal fibers enable the frog to respond to stimuli past the frontal midline. We suggest a one-dimensional model of how nucleus isthmi influences tectal function.

The pharmacology of mesolimbic dopamine neurons: a dual-probe microdialysis study in the ventral tegmental area and nucleus accumbens of the rat brain

Receptor-specific compounds were applied by retrograde microdialysis to the ventral tegmental area (VTA) of the rat brain. The effect of the intrategmental infusions on extracellular dopamine in the ipsilateral nucleus accumbens were recorded with a second microdialysis probe. Intrategmental infusion of muscimol (10-40 microM) or baclofen (50 microM) decreased extracellular dopamine in the nucleus accumbens. Intrategmental infusion of NMDA (1 mM, 15 min) or kainate (50 microM, 15 min) increased extracellular dopamine in the nucleus accumbens. The effects of the excitatory amino acids were suppressed by co-infusion of MK-801 (1 MM), (+)-3-amino-1-hydroxy-2-pyrrolidone [(+)-HA966; 1 mM], (+/-)-3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP; 100 microM), and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX;300 microM). Intrategmental infusion of of carbachol (50 microM) increased extracellular dopamine in the nucleus accumbens. These results provide evidence for localization of GABAA, GABAB NMDA, non-NMDA, and cholinergic receptors on dopamine neurons in the VTA. Infusions of CPP, (+)-MK-801, (+)-HA966, CNQX, mecamylamine, atropine, or 3-[[(3,4-dichlorophenyl)methyl]propyl](diethoxymethyl) phosphonic acid (CGP 52432) into the VTA did not modify extracellular dopamine in the nucleus accumbens. Infusion of bicuculline (50 microM) and (-)-sulpiride (50 microM) was followed by an increase in extracellular dopamine in the nucleus accumbens. These data suggest that dopamine neurons in the VTA are tonically inhibited by GABA and dopamine by acting on GABAA, and D2 receptors, respectively. A tonic stimulation by glutamatergic or cholinergic neurons was not detected. Finally, results on A10 neurons are compared with earlier data on A9 neurons. A striking difference was found in that GABAA-dopamine interactions are indirect in the substantia nigra and direct in the VTA.

Perineuronal microglial reactivity following proximal and distal axotomy of rat rubrospinal neurons

Microglial reactivity in the red nucleus of rats was studied following upper cervical and lower thoracic rubrospinal tractotomy using the lectin binding method. Following axotomy, the contralateral nucleus containing the axotomized neurons was identified using the retrograde tracer Fast blue. It was subdivided into dorsomedial (DM) and ventrolateral (VL) portions known to project to the cervical and lumbar spinal cord, respectively. Lectin-labeled microglial cells and processes on the contralateral as well as in the ipsilateral nucleus were then quantified. An early and a late increase in microglial reactivity was observed in the nucleus at 2–5 days and 2–8 weeks following thoracic and cervical tractotomy with the latter producing a more pronounced reactivity. In rats subjected to thoracic axotomy, a similar microglial increase also occurred in the intact contralateral DM nuclear area suggesting the possible action of diffusible factor(s) that might have triggered the microglial activation from the axotomized VL nuclear area. The uninjured ipsilateral nucleus also exhibited a similar pattern of microglial reactivity irrespective of the number of ipsilaterally projecting neurons following both cervical and thoracic axotomy. This could have been elicited by the retrograde influence from the denervated targets carried by the intact rubrospinal fibers of the opposite side since many of them in fact terminate bilaterally (Antal M. et al., J. Comp. Neurol., 325 (1992) 22–37). In all the axotomized or intact nucleus, microglial processes did not appear to surround neuronal cell bodies. The characteristic responses of microglial cells in the red nucleus may be related to the failure of rubrospinal neurons to regenerate following the severance of their axons.

Influences exerted by the frontal eye field on accessory oculomotor nuclei neurons of the rat.

The medial agranular cortex (AGm), considered the rat's analogous to the frontal eye fields of the monkey, sends a conspicuous projection towards the accessory oculomotor nuclei (AON), i.e. the nucleus of posterior commissure (NPC), the nucleus of Darkschewitsch (NDK) and the interstitial nucleus of Cajal (INC). The nature of the synaptic influences exerted by AGm on the AON neurons and the receptor(s) which mediates these cortical-evoked effects were studied in adult rats. Electrical stimulation of a single site within the AGm elicited changes in firing rate of a significant fraction of cells belonging to the ipsilateral accessory oculomotor nuclei (50% in INC, 52.3% in NDK and 52% in NPC). In the 82.9% of cases, the responses were excitations, most of which having latencies and response characteristics compatible with a monosynaptic linkage. The remaining 17.1% of cases were inhibitions with latencies ranging between 4 and 11 ms. Extracellular field potential recordings within the accessory oculomotor nuclei were interpreted as arising from impulses propagating along excitatory axons projecting in a bundle from the cortex. Effects of exogenously applied excitatory amino acid N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovaleric acid (2APV) and of selective non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) were examined on synaptic excitation. Monosynaptic excitations induced by the cortical stimulation were abolished by microiontophoretic application of 2APV and not of DNQX. This finding indicates that cortical inputs activate specifically NMDA receptors of AON neurons.

Apoptosis and c-Jun in the thalamus of the rat following cortical infarction.

Cortical infarction produces secondary neuronal damage in the thalamus. In this study we examined the thalamus of the rat following 2 h occlusion of the middle cerebral artery (MCA), and found degeneration and gliosis in the ipsilateral ventropostero-medial thalamic nucleus in those rats that showed cortical infarction 7 and 14 days after occlusion. This was accompanied by isolated cells with fragmented DNA, as revealed by in situ labelling of nuclear DNA fragmentation, and showing morphological features of apoptosis, i.e. chromatin condensation, extreme nuclear shrinkage and apoptotic bodies. In addition, cells immunoreactive for c-Jun showing morphological signs of apoptosis were observed. These results provide evidence of apoptosis in the ipsilateral thalamus following cortical infarction, and suggest that c-Jun is involved in this process.

The nucleus of the optic tract (NOT) and the dorsal terminal nucleus (DTN) of opossums (Didelphis marsupialis aurita).

Wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) was injected unilaterally into the pretectocollicular region of opossums (Didelphis marsupialis aurita), primarily to investigate the existence of a commissural subcortical pathway but also to reveal afferents and efferents of the nucleus of the optic tract (NOT) and dorsal terminal nucleus (DTN) in this species. Labelled cells and terminals were observed in the contralateral NOT-DTN. Furthermore, HRP was injected bilaterally in the region of the inferior olive (IO) to verify if the distribution of labelled cells in the NOT-DTN overlapped the region of commissural labelled cells. The two subpopulations of retrogradely labelled cells coincided, being distributed within the retinal terminal field attributed to the NOT-DTN, as revealed by contralateral eye injections of HRP. The commissural cells were located slightly more ventral than the olivary cells in the optic tract. The pretectocollicular WGA-HRP injections also labelled cells and terminals bilaterally in the lateral terminal nucleus (LTN), interstitial nucleus of the superior fasciculus, posterior fibers (INSFp), ventral lateral geniculate nucleus (vLGN), and superior colliculus (SC) and ipsilaterally in the medial terminal nucleus (MTN). In addition, further caudally, labelled cells and terminals were observed bilaterally in the nuclei prepositus hypoglossi (PH) and in the medial (MVN) and lateral (LVN) vestibular nuclei. Labelled terminals were found in the ipsilateral nucleus reticularis tegmenti pontis (NRTP) and in the IO with ipsilateral predominance. This study allowed an anatomical delimitation of the NOT-DTN in this opossum species, as defined by the olivary and commissural subpopulations, as well as a hodological evaluation of this region. The existence of some common anatomical aspects with other mammalian species is discussed.

Connections of Octaval and Lateral Line Nuclei of the Medulla in the Goldfish, Including the Cytoarchitecture of the Secondary Octaval Population in Goldfish and Catfish (Part 2 of 2)

Cytoarchitectural analyses combined with injections of the tracer horseradish peroxidase in various structures in the brain of the goldfish, <i>Carassius auratus, </i>have defined some of the major components of acoustic and lateral line mechanosensory circuits between the medulla and midbrain. The main acoustic receptor in <i>Carassius, </i>the saccule, is known to provide a major input to the dorsomedial zone of the descending octaval nucleus. The dorsomedial zone in turn projects bilaterally to the secondary octaval population (SO) and to nucleus centralis of the torus semicircularis. The SO is composed of three major subdivisions which are also present in a related otophysan, the catfish <i>Ictalurus punctatus. </i>The SO in <i>Carassius </i>projects bilaterally to nucleus centralis and to the saccular recipient zones of the ipsilateral descending octaval nucleus. By contrast, the mechanosensory lateral line receptors are known to direct most of their input to nucleus medialis. Nucleus medialis in turn projects bilaterally to nucleus praeeminentialis, nucleus ventrolateralis of the torus semicircularis, and the optic tectum, and to the contralateral nucleus medialis. We also provide evidence for a bilateral projection of nucleus medialis to the sensory trigeminal nucleus, and for a reciprocal input from the sensory trigeminal nucleus to the ipsilateral nucleus medialis.

Alpha-2-Adrenergic activation of proopiomelanocortin-containing neurons in the arcuate nucleus causes opioid-mediated hypotension and bradycardia.

Treatment of rats for 4 days with alpha-methyldopa, 200 mg/kg/day i.p., increases steady state levels of proopiomelanocortin (POMC) mRNA in the mediobasal hypothalamus, as measured by DNA excess solution hybridization. The increase is prevented by parallel treatment with yohimbine, 2 mg/kg/day i.p., but not by naltrexone, 2 mg/kg/day i.p. Treatment with the peripheral vasodilator hydralazine, 2 mg/kg/day, does not affect POMC mRNA levels. In situ hybridization histochemistry with a cRNA probe for POMC indicates that POMC-containing cells are located within the confines of the arcuate nucleus both in control and in alpha-methyldopa-treated rats, and confirms the increase in POMC mRNA in the latter. Microinjection of 2 micrograms of alpha-methylnorepinephrine unilaterally into the arcuate nucleus of urethane-anesthetized rats causes hypotension and bradycardia, which can be inhibited by 200 ng of yohimbine microinjected into the same site, or by 100 ng l-naloxone microinjected into the ipsilateral nucleus tractus solitarii, but not into the arcuate nucleus. These findings are interpreted to indicate that activation of alpha 2-adrenergic receptors located on POMC-containing neurons in the arcuate nucleus causes beta-endorphin release and stimulation of opiate receptors in the NTS, which results in hypotension and bradycardia, and that this mechanism contributes to the hypotensive action of alpha-methyldopa.

1644 Excitotoxic lesions of the unilateral pedunculopontine tegmental nucleus produce contralateral hemiparkinsonism in the japanese monkey

Accommodative responses were evoked by microstimulation of a circumscribed area in the lateral suprasylvian (LS) cortex of the cat. We studied anatomical connections of this area with WGA-HRP. We identified an accommodation-related area by systematic microstimulation of the LS cortex in each of nine cats. Accommodative and pupillary responses were monitored by an infrared optometer and a pupillometer, respectively. WGA-HRP was injected into the accommodation-related area where accommodative responses were elicited with low-intensity microstimulation, but pupillary responses were not evoked. Retrogradely labeled cells were found mainly in ipsilateral areas 17, 18 and 19, the pulvinar, the lateral posterior nucleus of the thalamus (LP) and the contralateral LS area. Fewer labeled cells were found in ipsilateral areas 20 and 21, the ventral lateral suprasylvian area (VLS), the splenial visual area (SVA) and the lateral geniculate nucleus (LGN). Anterogradely labeled terminals were located mainly in the ipsilateral LP, the rostral portion of the pontine nuclei and the superficial layers of the ipsilateral superior colliculus which corresponds to the representation of the central visual field. Less dense labeled terminals were also found in the ipsilateral nucleus of the optic tract (NOT) in two cats.

C-fos Expression in the rat brain after unilateral labyrinthectomy and its relation to the uncompensated and compensated stages.

The expression of the immediate early gene c-fos has been studied in the entire brain of rats 3, 6 and 24 h after surgical unilateral labyrinthectomy. We combined in situ hybridization for c-fos messenger RNA with immunocytochemistry for Fos protein to document very early changes in c-fos expression and to identify with cellular resolution neuronal populations activated by unilateral labyrinthectomy. Three hours after unilateral labyrinthectomy a bilateral increase in both c-fos messenger RNA and protein levels was seen in the superior, medial and spinal vestibular nuclei, nucleus Y, and prepositus hypoglossal nucleus. These changes were asymmetric in the medial vestibular nucleus, being most prominent in the dorsal part of the contralateral nucleus (where second order vestibular neurons are located) and in the ventral part of the ipsilateral nucleus (where commissural neurons acting on the medial vestibular nucleus of the intact side are located). An increase in c-fos messenger RNA expression was seen bilaterally, but with an ipsilateral predominance, in the vermal and paravermal areas of the cerebellar cortex, flocculus and paraflocculus, as well as in the precerebellar lateral and paramedian reticular nuclei. c-fos messenger RNA and protein levels increased in a few regions of the contralateral inferior olive. A predominantly ipsilateral increase in c-fos expression also occurred in the caudate-putamen. A bilateral but not exactly symmetric increase in both c-fos messenger RNA and protein levels was present in several nuclei of the dorsal pontine tegmentum (parabrachial nucleus, locus coeruleus and laterodorsal tegmental nucleus), mesencephalic periaqueductal gray, and several hypothalamic, thalamic and cerebrocortical regions. No change was seen in the cerebellar nuclei, lateral vestibular nucleus and red nucleus. The increased expression of c-fos observed 3 h after unilateral labyrinthectomy, in conjunction with the sudden occurrence of postural and motor deficits, usually declined 6-24 h after the lesion, i.e. during the development of vestibular compensation. In the dorsal part of the medial vestibular nucleus, however, the pattern of c-fos expression observed 3 h after unilateral labyrinthectomy was reversed 6-24 h after the lesion: both c-fos messenger RNA and protein levels increased on the ipsilateral side, but greatly decreased on the contralateral side. In conclusion, asymmetric changes in c-fos expression occurred within 3 h after unilateral labyrinthectomy, but gradually declined or reversed 6 and 24 h after the lesion, thus being temporally related to the appearance and development of vestibular compensation.

Striatal dopamine depletion, tremors, and hypokinesia following the intracranial injection of S-adenosylmethionine: a possible role of hypermethylation in parkinsonism.

The major symptoms of Parkinson disease (PD) are tremors, hypokinesia, rigidity, and abnormal posture, caused by the degeneration of dopamine (DA) neurons in the substantia nigra (SN) and deficiency of DA in the neostriatal DA terminals. Norepinephrine (NE) and serotonin (5-HT) levels in the neostriatum and tyrosine hydroxylase and melanin pigments in the substantia nigra are also decreased, and brain cholinergic activity is increased. The cause of PD is unknown, but PD is an age-related disorder, suggesting that changes that occur during the aging process may help to precipitate PD. Methylation increases in aging animals. Increased methylation can deplete DA, NE, and 5-HT; increase acetylcholine; and cause hypokinesia and tremors. These effects are similar to changes seen in PD, and interestingly also, they are similar to some of the changes that are associated with the aging process. It is suggested, therefore, that increased methylation may be an inducing factor in parkinsonism. Accordingly, the effects of an increase in methylation in the brain of rats were studied. S-adenosylmethionine (AdoMet), the limiting factor in the methylation process, was injected into the lateral ventricle of rats. Specific behavioral changes that resemble changes seen in PD were investigated. The results showed that AdoMet caused tremors, rigidity, hypokinesia, and depleted DA. The hypokinetic effects of a single dose of AdoMet lasted for about 90 min. AdoMet has a dose-dependent hypokinetic effect. A dose of 9.4 nmol reduced movement time (MT) by 68.9% and increased rest time (RT) by 20.7%, and a dose of 400 nmol reduced MT by 92.4% and increased RT by 27.6%. The normethyl analog of AdoMet, S-adenosylhomocysteine, did not cause hypokinesia or tremors, but it blocked the AdoMet-induced motor effects. L-dopa, the precursor of DA, also blocked the AdoMet-induced motor effects. These data suggest that the methyl group of AdoMet as well as DA depletion are involved in the AdoMet-induced motor effects. A dose of 0.65 mumol of AdoMet depleted DA in the ipsilateral caudate nucleus (CN) or neostriatum by 50.1%, and DA in the contralateral CN was reduced by 9.3%. Double the dose of AdoMet did not increase the depletion of DA on the ipsilateral CN, but DA in the contralateral CN was decreased by 26.3%. Taken together, the results suggest that increased methylation may contribute to the symptoms of PD.

Pretectofugal fibers from the nucleus of the optic tract in monkeys

The nucleus of the optic tract (NOT) is the visuo-motor relay between the retina and preoculomotor structures in the pathway mediating optokinetic nystagmus (OKN). NOT lesions in monkeys produce no OKN toward the lesioned side. Then, efferent fibers from the NOT course through the brainstem and may reach the vestibular nucleus, which is proposed to be the final nucleus to the motor nucleus. In the present study, the tracer was injected through a micropipette in the NOT in four monkeys. Labeled terminals were observed ipsilaterally in the parabigeminal nucleus, superficial layers of the superior colliculus, dorsal and lateral terminal nuclei of the accessory optic system and pretectal nuclei and contralaterally in the NOT and superficial layers of the superior colliculus. Descending fibers from the NOT consisted of two major pathways: (1) fibers descended medially from the injection site through the reticularis pontis oralis to reach the lateral part of the ipsilateral nucleus reticularis tegmenti pontis; (2) fibers projecting into the dorsal cap of inferior olive, by far the greatest number of labeled fibers, descended ventrally along the lateral border of the reticularis pontis oralis and reached the medial lemniscus where they descended further and branched into the dorsolateral pontine nucleus, the lateral part of the nucleus reticularis tegmenti pontis, the peduncular pontine nucleus, the lateral pontine nucleus, the nucleus prepositus hypoglossi, the medial vestibular nucleus and finally the dorsal cap of the inferior olive. Consistent with the physiological data, the direct terminals to the medial vestibular nucleus could serve to drive the storage mechanisms and to produce OKN in the monkey.

Rapid compensation of horizontal optokinetic nystagmus in hemilabyrinthectomized rats: a fast return to symmetry.

In the rat, after unilateral labyrinthectomy the loss of unit responses in the deafferented ipsilateral vestibular nucleus should lead to a complete postlesional asymmetry in H-OKN. The compensation process of this oculomotor deficit were recorded by means of a search coli technique using amplitude detection in 30 pigmented rats, 8 animals as control and 22 submitted to left hemilabyrinthectomy. Recording sessions were performed from day 1 to 8 after the lesion. Velocity steps of visual stimulation were delivered in clockwise (CW) and counterclockwise (CCW) directions at velocities from 2 to 40 degrees/s. The H-OKN was not observable on postlesional day 2. It reappeared asymmetrical on day 2 with depressed responses to CW stimulation while the response to the CCW stimulation were almost as large as in intact animal. This asymmetry was quantified by the gain values (eye velocity/stimulus velocity) of the nystagmic responses which were, at 5 degrees/s of stimulus velocity, 0.37 for CW stimulation and almost twice as large, 0.72 for CCW stimulation. Later this asymmetry was consistently reduced by a progressive increase of the CW responses and a parallel decrease of the CCW. This process led to the responses to reach almost symmetrical values on day 8 with a gain of 0.52 and 0.63 for CW and CCW responses respectively at the same stimulus velocity. However the gain of intact animals was never attained. The initial eye velocity was symmetrically altered on day 2 and remained unchanged until postlesional day 8. These results demonstrate that the deficit appeared to be compensated more by a restoration of a symmetry than by a restitution of a gain of responses equivalent to that of an intact animal.

Independent efferent populations in the nucleus of the optic tract: an anatomical and physiological study in rat and cat.

The efferent projections of the nucleus of the optic tract (NOT) and dorsal terminal nucleus of the accessory optic system (DTN) to the contralateral NOT-DTN, ipsilateral inferior olive (IO), ipsilateral nucleus prepositus hypoglossi (NPH), and ipsilateral dorsal lateral geniculate nucleus (LGNd) were examined in pigmented rats and in cats by using anterograde and retrograde tract tracing, as well as extracellular recording and electrical stimulation. Anterograde tracing in the rat revealed a dense termination field of NOT-DTN efferents throughout the homologous contralateral territory. In both species three different cell populations, projecting to the contralateral NOT-DTN, ipsilateral IO, and ipsilateral LGNd, respectively, were distinguished by means of multiple retrograde tracing. No clear topographical segregation of the different NOT-DTN relay cell populations was observed. On the other hand, a large proportion (at least 60%) of NOT-DTN neurons projecting to the ipsilateral NPH were found to bifurcate upon the IO in the rat. Electrophysiologically, NOT-DTN neurons projecting to the IO were identified by their directionally selective responses. Such neurons were never activated by electrical stimulation of either the contralateral NOT-DTN or the ipsilateral LGNd. Neurons antidromically activated from the contralateral NOT-DTN could not be activated from the ipsilateral LGNd. Thus, in both cat and rat the NOT-DTN includes at least three independent relay cell populations. As a consequence, the NOT-DTN must serve functions additional to the generation of eye movements during optokinetic nystagnus, a function subserved by the directionally selective NOT-DTN cells.