Fastigial nucleus projections in the midbrain and thalamus in dogs

Efferent connections to midbrain and thalamus from portions of the cerebellar fastigial nucleus were investigated using autoradiographic techniques. Bipolar stimulating electrodes were placed in the fastigial nucleus of anesthetized beagles and the area which produced maximal increases in blood pressure and heart rate was localized in each dog. A mixture of [3H]leucine and [3H]proline (4:1) was injected into that area and autoradiograms were prepared. Injections filled the rostral and various parts of the caudal fastigial nucleus. The rostral-caudal extent of injection sites were mapped in the horizontal plane from sequential coronal, thionin-stained sections and "primary" and "secondary" injection zones were defined according to specific criteria. Labeled axons reached the mesencephalon via the contralateral uncinate fasiculus. Ascending fibers assembled in a diffuse contingent at the prerubral level adjacent to the ventrolateral periaqueductal gray. The heaviest projections were contralateral to the injection site, but ipsilateral terminals were observed as well. In the midbrain, axons entered the contralateral and ipsilateral superior colliculus to branch repeatedly and terminate in the deep and intermediate layers. Additional terminals were observed bilaterally in the nuclei of the posterior commissure and pretectal areas at the midbrain-diencephalic junction. In the thalamus, labeled axons formed into three groups which terminated in: the contralateral paraventricular complex and medial dorsal nucleus; the contralateral central medial, paracentral, parafasicular and central lateral nuclei, and the contralateral ventral medial and ventral lateral nuclei. There was a sparse projection to the ipsilateral ventral lateral nucleus. The contralateral projection to the ventral medial and ventral lateral nuclei was marked by dense clusters of label ventral to the internal medullary lamina extending, in the dorsal ventral lateral nucleus, to its rostral pole. Projections to specific somesthetic thalamus or the hypothalamus were not observed. These ascending projections in the canine brain generally conform to those described in other nonprimate mammals. The fastigial nucleus presumably provides information concerning equilibrium and body proprioception to the superior colliculus and to thalamic nuclei including both specific motor relay and "nonspecific" midline and intralaminar nuclei, much the same as reported in the cat. The projection to the ventral medial and ventral lateral thalamic nuclei terminate in areas known to participate in the control of axial and proximal limb muscle activity.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pallidofugal projections to thalamus and midbrain: A quantitative antidromic activation study in monkeys and cats

Summary The projections of monkey medial globus pallidus (and of cat entopeduncular nucleus) to thalamus and midbrain were studied with antidromic activation in order to determine the number of pallidal neurons sending axonal branches to the two sites. The animals were anesthetized with pentobarbital and several movable electrodes were used to stimulate the thalamic nuclear complex ventralis anterior — ventralis lateralis (VA-VL), the nucleus centre médian (CM), and the midbrain nucleus tegmenti pedunculopontinus (TPP). The responses of pallidal neurons were recorded with extracellular microelectrodes. In 3 monkeys 99% and 87% of 145 medial pallidal neurons responded antidromically to stimulation of VA-VL and TPP respectively. Reciprocal collision tests demonstrated that 86% of the 145 neurons sent axonal branches to the two sites. By comparison in 2 cats the tests demonstrated that 72% of 46 entopeduncular neurons branched to VA-VL and TPP. In 2 monkeys 68% of 53 medial pallidal neurons were shown to branch to VA-VL and CM thalamic nuclei. In the monkeys, the latencies of responses indicate that all pallidofugal fibers have the same mean conduction rate: 6 m/s. The fibers appear to branch profusely in VA-VL where less current was required to activate neurons antidromically than in TPP. The location of neurons in the medial pallidum is weakly correlated with the location of stimulation points in VA-VL activating the neurons antidromically at low threshold, suggesting some topography in the pallidothalamic projection. However there is no particular localization of medial pallidal neurons with and without branching projections. Apart from one exception, the 162 neurons recorded in the lateral pallidum failed to respond antidromically to the stimulation sites. We conclude that the great majority of medial pallidal neurons can send signals to both the thalamus and the midbrain in the cat and in the monkey.Supported by the Medical Research Council of CanadaPart of doctoral dissertationStudentship award from the Conseil de la recherche en sante du QuébecAssociate professor at the Dept. of Physiology of Laval University in Québec     

Mesopontine cholinergic projections to the hypoglossal motor nucleus

Mesopontine cholinergic (ACh) neurons have increased discharge during wakefulness, rapid eye movement (REM) sleep, or both. Hypoglossal (12) motoneurons, which play an important role in the control of upper airway patency, are postsynaptically excited by stimulation of nicotinic receptors, whereas muscarinic receptors presynaptically inhibit inputs to 12 motoneurons. These data suggest that ACh contributes to sleep/wake-related changes in the activity of 12 motoneurons by acting within the hypoglossal motor nucleus (Mo12), but the origins of ACh projections to Mo12 are not well established. We used retrograde tracers to assess the projections of ACh neurons of the mesopontine pedinculopontine tegmental (PPT) and laterodorsal tegmental (LDT) nuclei to the Mo12. In six Sprague-Dawley rats, Fluorogold or B subunit of cholera toxin, were pressure injected (5-20nl) into the Mo12. Retrogradely labeled neurons, identified as ACh using nitric oxide synthase (NOS) immunohistochemistry, were found bilaterally in discrete subregions of both PPT and LDT nuclei. Most retrogradely labeled PPT cells (96%) were located in the PPT pars compacta region adjacent to the ventrolateral tip of the superior cerebellar peduncle. In the LDT, retrogradely labeled neurons were located exclusively in its pars alpha region. Over twice as many ACh neurons projecting to the Mo12 were located in the PPT than LDT. The results demonstrate direct mesopontine ACh projections to the Mo12. These projections may contribute to the characteristic of wakefulness and REM sleep increases, as well as REM sleep-related decrements, of 12 motoneuronal activity.     

Differential vulnerability of cholinergic projections to the mediodorsal nucleus of the thalamus in senile dementia of Alzheimer type and progressive supranuclear palsy

The cholinergic innervation of the mediodorsal nucleus of the thalamus, which is thought to originate primarily in the laterodorsal tegmental nucleus and the substantia innominata, was studied by acetylcholinesterase histochemistry and immunohistochemistry with a polyclonal antiserum against human choline acetyltransferase on autopsy tissue from eight control subjects, five patients with progressive supranuclear palsy and four patients with senile dementia of Alzheimer type. In controls, cholinergic innervation of the mediodorsal nucleus of the thalamus was distributed heterogeneously in densely labelled patches surrounded by less heavily stained matrix. In patients with progressive supranuclear palsy, the density of choline acetyltransferase-positive varicosities decreased by 75% in the matrix and 60% in the patches. The number of choline acetyltransferase-positive cell bodies decreased by 84% in the laterodorsal tegmental nucleus, but more moderately (-33%) in the substantia innominata. In patients with senile dementia of Alzheimer type, choline acetyltransferase-positive varicosities decreased by 34% in the matrix, but 46% in the patches. Choline acetyltransferase-labelled cell bodies were spared in the laterodorsal tegmental nucleus, whereas severe loss (-80%) was observed in the substantia innominata. These results suggest that cholinergic innervation of mediodorsal nucleus matrix derives mainly from the laterodorsal tegmental nucleus and mediodorsal nucleus patches from the substantia innominata. Differential loss of innervation to the matrix and patches in progressive supranuclear palsy and senile dementia of Alzheimer type may in turn differentially affect mediodorsal nucleus innervation of the frontal cortex, resulting in dissimilar symptomatologies.     

Topographical projections from the thalamus to the putamen in the cat

Thalamic projections to the putamen (Put) in the cat were studied by the retrograde horseradish peroxidase method. Major thalamic projections to the Put originate from the midline and intralaminar nuclear regions including the centre médian-parafascicular complex (CM-Pf). The other thalamic projections to the Put arise mainly from the suprageniculate nucleus (Sg), magnocellular division of the medial geniculate nucleus (MGm), caudomedial part of the lateroposterior nucleus (LP) and ventrolateral part of the ventromedial nucleus (VM). The VM projects to the rostral Put, while the posterior thalamic regions (Sg, MGm, LP) project to the caudal Put.     

Nitric oxide synthase-containing projections to the ventrobasal thalamus in the rat

Microiontophoretic studies of thalamic neurons suggests that nitric oxide (NO) plays an important role in mediating somatosensory transmission. The thalamus contains few nitric oxide synthase (NOS)-immunoreactive neurons; thus, the major source of thalamic NO is presumably from NOS-positive axons of extrathalamic origin. The cells of origin of these putative NOS-containing pathways to the ventrobasal thalamus were investigated in rats by combining retrograde tracing with immunocytochemistry for NOS. The location and morphology of double-labeled neurons was compared with that of single-labeled neurons. The most significant sources of NOS-containing afferents to the thalamus were found to be the pedunculopontine (PPN) and laterodorsal tegmental (LDT) nuclei. NOS-immunoreactive neurons in these cholinergic nuclei project bilaterally to the thalamus, most strongly ipsilaterally. The thalamus appears to be a major target of PPN, since even selective thalamic injections result in retrograde labeling of at least one third of its NOS-immunoreactive neurons. A significant number of NOS-negative neurons in both the PPN and LDT also project to the thalamus. Minor sources of NOS-containing thalamic afferents include the lateral hypothalamus, the dorsal, median and pontine raphe nuclei, the parabrachial nuclei, and the pontomedullary reticular formation. In all these structures, NOS-negative thalamopetal neurons greatly outnumber the NOS-positive ones. Ascending sensory pathways to the thalamus, including those from the sensory trigeminal nuclei, the dorsal column nuclei, and the spinal cord, as well as the auditory and vestibular centers, arise exclusively from NOS-negative neurons. The major NOS-positive projections are implicated in affective and alerting systems, supporting that NO may act to modulate attentiveness in thalamic relay nuclei.     

Prefrontal projections to the medial nuclei of the dorsal thalamus in the rabbit

Retrograde transport of horseradish peroxidase (HRP) from the mediodorsal (MD), ventromedial (VM), ventroposterior (VP) and intralaminar (IL) nuclei of the dorsal thalamus revealed a topographical pattern of efferents from the frontal cortex. MD injections labeled the midline and insular regions of the prefrontal cortex (Pfc), including the anterior limbic, and most ventral part of the precentral agranular Pfc, as well as the agranular insular cortex. VM injections labeled only the most dorsomedial part of the granular insular cortex, whereas IL and VP injections labeled the dorsal precentral agranular Pfc and a strip of cortex that extended laterally across the superior aspect of the forceps minor. The IL injections also labeled cells that extended ventrally into the granular and agranular insular areas.     

The organization of afferent projections to the midbrain periaqueductal gray of the rat

The retrograde transport technique was utilized in the present study to investigate the afferent projections to the periaqueductal gray of the rat. Iontophoretic injections of horseradish peroxidase were made into the periaqueductal gray of 22 experimental animals and into regions adjacent to the periaqueductal gray in 6 control animals. Utilization of the retrograde transport method permitted a quantitative analysis of the afferent projections not only to the entire periaqueductal gray, but also to each of its four intrinsic subdivisions. The largest cortical input to this midbrain region arises from areas 24 and 32 in the medial prefrontal cortex. The basal forebrain provides a significant input to the periaqueductal gray and this arises predominantly from the ipsilateral lateral and medial preoptic areas and from the horizontal limb of the diagonal band of Broca. The hypothalamus was found to provide the largest descending input to the central gray. Numerous labeled cells occurred in the ventromedial hypothalamic nucleus, the lateral hypothalamic area, the posterior hypothalamic area, the anterior hypothalamic area, the perifornical nucleus and the area of the tuber cinereum. The largest mesencephalic input to the periaqueductal gray arises from the nucleus cuneiformis and the substantia nigra. The periaqueductal gray was found to have numerous intrinsic connections and contained a significant number of labeled cells both above and below the injection site in each case. Other structures containing significant label in the midbrain and isthmus region included the nucleus subcuneiformis, the ventral tegmental area, the locus coeruleus and the parabrachial nuclei. The medullary and pontine reticular formation provide the largest input to the periaqueductal gray from the lower brain stem. The midline raphe magnus and superior central nucleus also supply a significant fiber projection to the central gray. Both the trigeminal complex and the spinal cord provide a minor input to this region of the midbrain.The sources of afferent projections to the periaqueductal gray are extensive and allow this midbrain region to be influenced by motor, sensory and limbic structures. In addition, evidence is provided which indicates that the four subdivisions of the central gray receive differential projections from the brain stem as well as from higher brain structures.     

Postnatal development of septal projections to the midbrain central gray in female rats: tract-tracing analysis with DiI

The neural projection of the lateral septum (LS) to the rostral mesencephalic central gray (MCG) is sexually dimorphic and plays an important role in inhibiting female reproductive behavior. In this experiment, development of the LS-MCG connection from birth to 15 days after birth was examined in female rats by a tract-tracing method with DiI. On the birth day (D1 rat), and 5, 10 or 15 days after birth (D5, D10 or D15 rat, respectively) or 8 weeks after birth (adult), the brain was fixed by perfusion of a mixture of 4% PFA and 0.1% glutaraldehyde. DiI was pasted on the coronally cut-surface of the LS and the sample was incubated in PFA at 40 degrees C for up to 4 months. After incubation, 200-microm frozen parasagittal sections were prepared and observed by fluorescence microscopy. As a result, numerous DiI labeled fibers were found in the preoptic area, the anterior and posterior hypothalamus, and the MCG in adult rats. In D1 rats, several labeled axons extended caudal to the anterior hypothalamic area. In D5 rats, a few labeled fibers reached the MCG. Some labeled fibers were observed in the rostral MCG of D10 rats. In D15 rats, a considerable number of labeled fibers were seen to reach the rostral MCG and relative density of the fibers was comparable to that of adult. These results suggest that the neural pathway from the LS to the rostral MCG develops acutely during the period from 5-10 days up to more than 15 days after birth.     

Genetic networks controlling the development of midbrain dopaminergic neurons

Recent data have substantially advanced our understanding of midbrain dopaminergic neuron development. Firstly, a Wnt1-regulated genetic network, including Otx2 and Nkx2-2 , and a Shh-controlled genetic cascade, including Lmx1a , Msx1 and Nkx6-1 , have been unravelled, acting in parallel or sequentially to establish a territory competent for midbrain dopaminergic precursor production at relatively early stages of neural development. Secondly, the same factors (Wnt1 and Lmx1a/Msx1) appear to regulate midbrain dopaminergic and/or neuronal fate specification in the postmitotic progeny of these precursors by controlling the expression of midbrain dopaminergic-specific and/or general proneural factors at later stages of neural development. For the first time, early inductive events have thus been linked to later differentiation processes in midbrain dopaminergic neuron development. Given the pivotal importance of this neuronal population for normal function of the human brain and its involvement in severe neurological and psychiatric disorders such as Parkinson's Disease, these advances open new prospects for potential stem cell-based therapies. We will summarize these new findings in the overall context of midbrain dopaminergic neuron development in this review.     

The cholinergic innervation of the visual thalamus: an EM immunocytochemical study

Summary In this study we demonstrate at the ultrastructural level that both the dorsal lateral geniculate nucleus (dLGN), the visual relay of the thalamus, and the perigeniculate nucleus (PGN), the visual segment of the thalamic reticular nucleus (TRN), are densely innervated by fibres with Choline-Acetyl-Transferase (ChAT) like immuno-reactivity. These axons make synaptic contacts with interneurones considered to be inhibitory, both in the PGN and within the synaptic glomeruli of the dLGN. In addition, Chat positive terminals form intra- and extraglomerular synapses with dendrites thought to arise from relay cells. We interpret these results as evidence for direct cholinergic modulation of both relay cells and inhibitory interneurones.     

Projections from auditory cortex to midbrain cholinergic neurons that project to the inferior colliculus

We have shown that auditory cortex projects to cholinergic cells in the pedunculopontine tegmental nucleus (PPT) and laterodorsal tegmental nucleus (LDT). PPT and LDT are the sources of cholinergic projections to the inferior colliculus, but it is not known if the cortical inputs contact the cholinergic cells that project to the inferior colliculus. We injected FluoroRuby into auditory cortex in pigmented guinea pigs to label cortical projections to PPT and LDT. In the same animals, we injected Fast Blue into the left or right inferior colliculus to label PPT and LDT cells that project to the inferior colliculus. We processed the brain to identify cholinergic cells with an antibody to choline acetyltransferase, which was visualized with a green fluorescent marker distinguishable from both FluoroRuby and Fast Blue. We then examined the PPT and LDT to determine whether boutons of FluoroRuby-labeled cortical axons were in close contact with cells that were double-labeled with the retrograde tracer and the immunolabel. Apparent contacts were observed ipsilateral and, less often, contralateral to the injected cortex. On both sides, the contacts were more numerous in PPT than in LDT. The results indicate that auditory cortex projects directly to brainstem cholinergic cells that innervate the ipsilateral or contralateral inferior colliculus. This suggests that cortical projections could elicit cholinergic effects on both sides of the auditory midbrain.     

Cholinergic and non-cholinergic projections from the canine pontomesencephalic tegmentum (Ch5 area) to the caudal intralaminar thalamic nuclei

Summary The distribution and morphology of cholinergic and non-cholinergic neurons projecting to the caudal intralaminar thalamic nuclei from the Ch5 area in the dog were examined using a technique combining horseradish peroxidase (HRP) retrograde labeling with choline acetyltransferase (ChAT) immunocytochemistry. After processing for ChAT, cholinergic neurons were found primarily within the nucleus tegmenti pedunculopontinus (PPN) and the central tegmental tract (ctt). ChAT positive neurons were also located in the nucleus cuneiformis and among the fibers of the lateral lemniscus and medial longitudinal fasciculus. On the basis of immunocytochemical and cytoarchitectonic data, PPN was divided into two distinct cell groups — a compact cell group located dorsolateral to the brachium conjunctivum and a diffuse cell group intermingled among the fibers of the brachium conjunctivum. Tissue processed for WGA-HRP and ChAT following injections of lectin-conjugated horseradish peroxidase into either the centrum medianum (CM) or parafascicular (Pf) nucleus resulted in double labeled cholinergic projection neurons in both PPN and ctt. Injections which involved CM and the caudal part of the central lateral thalamic nucleus (CL) resulted in more retrogradely labeled neurons than did those injections involving Pf. Injections of CM and CL also resulted in more double labeled cells in the dorsolateral compact portion of PPN than did injections confined to Pf. In all cases a small number of cholinergic neurons located in the contralateral PPN were retrogradely labeled as well. A substantial number of retrogradely labeled neurons were not ChAT positive, and in some cases, comprised up to 27% of the total population of projection neurons. Measurements of cell soma areas indicated that cells comprising the general cholinergic population were mostly medium (300–600 m²) or large (>600 m²) in size. The majority of cholinergic projection neurons fell within the medium size category while the non-cholinergic projection neurons were significantly smaller than their cholinergic counterparts. The results of this study suggest that in the dog, Ch5 cholinergic neurons which project to the caudal intralaminar thalamic nuclei are medium in size and are located primarily within PPN and ctt. In addition, a parallel projection to the caudal intralaminar nuclei exists which originates from smaller, non-cholinergic neurons in these same regions. Based on the results of this study, it appears that cholinergic projections to intralaminar thalamic nuclei which in turn project to the neostriatum may be one of the pathways over which PPN can affect basal ganglia activity.     

Arterial vascularization of the human thalamus: extra-parenchymal arterial groups

The problem of the arterial vascularization of the human thalamus has been debated at length. Anatomical references concerning the thalamic arterial groups are contradictory and complex, preventing any solid application in practice. It is, therefore, difficult to produce reliable anatomical radio-clinical correlation. In this work, 12 adult human cerebellums (24 hemispheres) were dissected after intra-vascular injection. With care for clarification and standardization, the extra-parenchymal thalamic arteries were classified in six groups: pre-mamillary artery, perforating thalamic arteries, thalamo-geniculate arteries, perforating branches of the postero-medial, postero-lateral and anterior choroidal arteries. Variations in the pre-mamillary artery were rare. The origin of the perforating thalamic artery was unilateral in two of three cases. The origin of the thalamo-geniculate arteries arose between the posterior cerebral artery (53%) and the posterior choroidal arteries (43%). The postero-median choroidal artery was most often single and usually gave the perforating branches for the medial aspect of the thalamus. The postero-lateral choroidal artery was frequently multiple and essentially gave the perforating branches for the superior aspect of the thalamus. The pulvinarian branches most often rose from the postero-lateral choroidal arteries (two thirds of cases) and more rarely from the postero-median choroidal arteries (one third of cases). The anterior choroidal artery is a source of thalamic vascularization by its cisternal branches running towards the lateral thalamus. It can also participate in the vascularization of the pulvinar by the plexiform branches crossing the temporal horn of the lateral ventricle. This study has allowed definition of the intra-parenchymatous arterial map of the thalamus. This mapping is essential for producing anatomical radio-clinical correlations which are pertinent for therapeutic decisions.

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Vascularisation artérielle du thalamus humain: groupes artériels extra-parenchymateux

Résumé La vascularisation artérielle du thalamus humain est un problème débattu de longue date. Les références anatomiques concernant les groupes artériels thalamiques sont contradictoires et complexes interdisant toute application concrète en pratique. Il est donc difficile de réaliser des corrélations anatomo-radio-cliniques fiables. Dans ce travail, nous avons disséqué 12 encéphales adultes humains (24 hémisphères) après injection intra-vasculaire. Avec un souci de clarification et de standardisation, nous avons classé les artères thalamiques extra-parenchymateuses en 6 groupes : artère pré-mamillaire, artères thalamo-perforantes, artères thalamo-géniculées, rameaux perforants des artères choroïdiennes postéro-médiale, postéro-latérale et antérieure. Les variations de l'artère pré-mamillaire sont rares. L'origine des artères thalamo-perforantes est unilatérale dans 2/3 des cas. La naissance des artères thalamo-géniculées se partage entre l'artère cérébrale postérieure (53%) et les artères choroïdiennes postérieures (43%). L'artère choroïdienne postéro-médiane est le plus souvent unique et donne préférentiellement des rameaux perforants pour la face médiale du thalamus. L'artère choroïdienne postéro-latérale est fréquemment multiple et donne essentiellement des rameaux perforants pour la face supérieure du thalamus. Les rameaux pulvinariens naissent le plus souvent des artères choroïdiennes postéro-latérales (dans 2/3 des cas) et plus rarement des artères choroïdiennes postéro-médianes (tiers des cas). L'artère choroïdienne antérieure est une source de vascularisation du thalamus par ses branches cisternales se dirigeant vers le thalamus latéral. Elle peut également participer à la vascularisation du pulvinar par des branches plexuelles traversant la corne temporale du ventricule latéral. La poursuite de ce travail doit permettre de préciser les cartographies artérielles intra-parenchymateuses du thalamus. Ces cartographies sont indispensables à la réalisation de corrélations anatomo-radio-cliniques pertinentes pour la prise de décision thérapeutique.

     

K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons

The selective degeneration of dopaminergic (DA) midbrain neurons in the substantia nigra (SN) is a hallmark of Parkinson disease. DA neurons in the neighboring ventral tegmental area (VTA) are significantly less affected. The mechanisms for this differential vulnerability of DA neurons are unknown. We identified selective activation of ATP-sensitive potassium (K-ATP) channels as a potential mechanism. We show that in response to parkinsonism-inducing toxins, electrophysiological activity of SN DA neurons, but not VTA DA neurons, is lost owing to activation of K-ATP channels. This selective K-ATP channel activation is controlled by differences in mitochondrial uncoupling between SN and VTA DA neurons. Genetic inactivation of the K-ATP channel pore-forming subunit Kir6.2 resulted in a selective rescue of SN but not VTA DA neurons in two mechanistically distinct mouse models of dopaminergic degeneration, the neurotoxicological 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model and the mutant weaver mouse. Thus, K-ATP channel activation has an unexpected role in promoting death of DA neurons in chronic disease.