Is the cuneiform nucleus a critical component of the mesencephalic locomotor region? An examination of the effects of excitotoxic lesions of the cuneiform nucleus on spontaneous and nucleus accumbens induced locomotion

The cuneiform nucleus and the pedunculopontine tegmental nucleus have both been suggested as possible sites for the mesencephalic locomotor region (MLR), an area from which controlled stepping on a treadmill can be elicited following electrical or chemical stimulation in a decerebrate animal. It has been shown that excitotoxic lesions of the pedunculopontine tegmental nucleus impair neither spontaneous locomotion nor locomotion induced by stimulation of the nucleus accumbens. Excitotoxic lesions of the cuneiform nucleus have not previously been investigated. Rats received either bilateral ibotenate or sham lesions of the cuneiform nucleus combined with bilateral implantation of guide cannulae aimed at the nucleus accumbens. On recovery from surgery spontaneous locomotion was tested, followed by accumbens-stimulated locomotion. For nucleus accumbens stimulation, each rat received bilateral microinjection of each of three doses of d-amphetamine (10.0, 20.0 and 30.0 μg) and a vehicle only injection. Locomotor activity was recorded following the injection. In comparison to the sham-lesioned group, the ibotenate-lesioned group showed no differences in either spontaneous or amphetamine-induced locomotor activity. These results suggest that, like the pedunculopontine tegmental nucleus, the cuneiform nucleus is not involved in the direct mediation of spontaneous or accumbens-induced locomotion, and thus is very unlikely to be the anatomical substrate of the MLR. The role of the cuneiform nucleus in other types of behavioural control is discussed.     

Distribution and morphology of tegmental neurons receiving nigral inhibitory inputs in the cat: an intracellular HRP study

Intracellular recordings and morphological identification of neurons by means of intracellular HRP staining were performed in the midbrain-pontine tegmentum of the cat. Electrical stimulation of the substantia nigra, pars reticulata, induced short-latency inhibitory postsynaptic potentials in tegmental neurons, as previously reported. These tegmental neurons were distributed not only in the pedunculopontine tegmental nucleus (PPTN) (26 cells), but also in the cuneiform nucleus (CNF) (13 cells), the central gray substance (CG) (four cells), the parabrachial nucleus (three cells), and the tegmentum between the inferior colliculus and the CG (two cells). The morphological characteristics of the HRP-stained tegmental neurons were analyzed by camera lucida drawings of 16 well-stained cells, i.e., ten PPTN neurons, three CNF neurons, two neurons in the tegmentum between the IC/CG, and one CG neuron. All of these neurons seem to be classified as "isodendritic" neurons. Regardless of the soma size (15-120 micron in diameter), most of the tegmental neurons showed wide dendritic fields of 1-2 mm, mediolaterally, and 0.5-1 mm, dorsoventrally. These results indicate that the nigrotegmental projections exert an inhibitory influence on the neurons located in a wide variety of nuclei of the midbrain-pontine dorsal tegmentum.     

Internal pallidum and substantia nigra control different parts of the mesopontine reticular formation in primate

The locomotor area has recently emerged as a target for deep brain stimulation to lessen gait disturbances in advanced parkinsonian patients. An important step in choosing this target is to define anatomical limits of its 2 components, the pedunculopontine nucleus and the cuneiform nucleus, their connections with the basal ganglia, and their output descending pathway. Based on the hypothesis that pedunculopontine nucleus controls locomotion whereas cuneiform nucleus controls axial posture, we analyzed whether both nuclei receive inputs from the internal pallidum and substantia nigra using anterograde and retrograde tract tracing in monkeys. We also examined whether these nuclei convey descending projections to the reticulospinal pathway. Pallidal terminals were densely distributed and restricted to the pedunculopontine nucleus, whereas nigral terminals were diffusely observed in the whole extent of both the pedunculopontine nucleus and the cuneiform nucleus. Moreover, nigral terminals formed symmetric synapses with pedunculopontine nucleus and cuneiform nucleus dendrites. Retrograde tracing experiments confirmed these results because labeled cell bodies were observed in both the internal pallidum and substantia nigra after pedunculopontine nucleus injection, but only in the substantia nigra after cuneiform nucleus injection. Furthermore, anterograde tracing experiments revealed that the pedunculopontine nucleus and cuneiform nucleus project to large portions of the pontomedullary reticular formation. This is the first anatomical evidence that the internal pallidum and the substantia nigra control different parts of the brain stem and can modulate the descending reticulospinal pathway in primates. These findings support the functional hypothesis that the nigro‐cuneiform nucleus pathway could control axial posture whereas the pallido‐pedunculopontine nucleus pathway could modulate locomotion. © 2011 Movement Disorder Society     

Locomotor behavior of bonnet monkeys after spinal contusion injury: footprint study

Analysis of gait functions following spinal cord injury has been widely studied in rats, mice but limited in primates. This investigation was performed to quantitatively analyze the degree of functional recovery in bipedal locomotion in bonnet monkeys after induced spinal cord contusion. The degree of locomotor recovery was examined by measuring four gait variables, viz., tip of opposite foot (TOF), print-length (PL), toe-spread (TS), and intermediary toe-spread (IT) from the recorded hindlimb prints of monkeys using ink and paper technique. Contusion was induced in spinal cord at T12-L1 level in anaesthetized monkeys by using the Allen's weight drop technique. Postoperatively, all spinal contused animals initially showed a significant decrease in TOF, which then gradually increased for longer duration and attained the near normal values by the sixth month. On the other hand, PL, TS, and IT variables in hindlimb prints of contused animals were found to dramatically increase initially and then slowly decrease subsequently. Later there was a recovery to insignificant levels which differed from the corresponding preoperative values by the fifth month. The observations of this study suggest that the functional contributions of the spared fibers, especially in ventral and ventrolateral funiculi, through collateral sprouts or synaptic plasticity that were formed in the contused spinal cord may be responsible for substantial recovery of hindlimb movements. Moreover, based on analysis of footprint variables observed in locomotion in these subjected monkeys, we understand that spinal automatism and development of responses by afferent stimuli from outside the cord could possibly contribute to recovery of the paralyzed hindlimbs.     

Nigral inputs to the pedunculopontine region: intracellular analysis

Intracellular recordings were made from neurons of the pedunculo-pontine region (PPR), the midbrain-pontine tegmentum around the brachium conjunctivum, in pentobarbital-anesthetized cats. Stimulation of the substantia nigra (SN) induced inhibitory postsynaptic potentials (IPSPs) in PPR neurons at a short latency (mean 2.17 ms, S.D. 0.66, n = 34) with a considerably long duration (mean 65.3 ms, S.D. 22.6). These neurons were distributed not only in the pedunculopontine tegmental nucleus (27 cells), but also in the cuneiform nucleus (5 cells) and the parabrachial nucleus (2 cells). Out of 34 cells, only two cells showed convergent synaptic inputs from SN and the cerebellar nuclei. Thus, it is concluded that PPR neurons receive mainly the inhibitory inputs from SN, one of the outputs of basal ganglia, and are infrequently influenced by the cerebellar outflow.     

Association of the mesencephalic locomotor region with locomotor activity induced by injections of amphetamine into the nucleus accumbens

Injections of amphetamine into the nucleus accumbens increased locomotor activity of rats. Subsequent injections of procaine into the midbrain, in the region of the pedunculopontine nucleus, significantly reduced the amphetamine-induced locomotor activity. Control experiments showed that procaine injections into the contralateral pedunculopontine nucleus had little or no effect, as well as ipsilateral injections dorsal and ventral to the pedunculopontine nucleus. These findings suggest that release of dopamine from amphetamine injections into the accumbens gives rise to ipsilateral descending influences on the region of the pedunculopontine nucleus, a major component of the mesencephalic locomotor region. Descending influences from the nucleus accumbens to mesencephalic locomotor region may serve as a link for limbic-motor integration in behavioral response initiation.     

Activity in the mesencephalic locomotor region during locomotion

The activity of single neurons in the mesencephalic locomotor region (MLR) was recorded extracellularly in cats during spontaneous locomotion on a treadmill. Although stimulation of the MLR is required to induce locomotion on a treadmill after a precollicular-postmamillary brain stem transection in the cat, spontaneous locomotion may occur after a precollicular-premamillary transection. The activity of flexor and extensor muscles of each limb also was recorded by EMG. Nearly 50% of the MLR neurons exhibited rhythmic firing patterns during locomotion. In about one-half of those cells, unit firing patterns could be correlated with the EMG activity in one or more muscles by using spike-triggered averaging. Single MLR neurons were found to be correlated to EMG activity in a single limb, and others were related to the EMG from muscles in two limbs or in all four limbs. Passive movement or stoppage of the limb(s) did not abolish rhythmicity in these neurons. In addition, somatosensory stimulation did not appear to affect the firing patterns of MLR neurons. Averaged EMGs of correlated forelimb muscles revealed a postspike mean latency of 7.1 ms. These measurements agreed well with reports of a 1- to 1.5-ms delay in MLR projections to reticulospinal neurons and a 5- to 6-ms delay (postspike) in reticulospinal activity correlated to EMGs during locomotion. These findings suggest that (a) MLR neurons are rhythmically active during locomotion, (b) the activity of MLR neurons can be correlated with that of EMGs in one or more limbs, (c) rhythmicity in MLR neurons may be independent of phasic sensory input, and (d) the downstream influence of the MLR may be relayed, at least in part, via reticulospinal neurons.     

Localization and characterization of neuropeptide Y in the brain of Microcebus murinus (Primate, Lemurian)

The distribution of neuropeptide Y (NPY) in the brain of the lemur Microcebus murinus was determined by immunocytochemistry with the aid of a highly specific antiserum against synthetic porcine NPY. When compared with previous immunohistochemical data obtained in primates and other mammalian species, the localization of NPY-immunoreactive (IR) structures in the Microcebus murinus brain revealed particular features. (1) Numerous NPY-IR perikarya and a dense network of IR nerve terminals were found in the supraoptic and suprachiasmatic nuclei, respectively. The occurrence of NPY-IR perikarya in the supraoptic nucleus, also reported in the squirrel monkey, seems to be specific to primates. In the squirrel monkey, the suprachiasmatic nucleus exhibits only a moderate innervation, whereas in humans it appears totally devoid of NPY-IR fibers. (2) IR perikarya and axon processes were observed in many upper brainstem areas, in particular in the interpeduncular, raphe pontine, dorsal tegmental, parabrachial, and dorsal raphe nuclei, in the locus coeruleus, the nucleus of the solitary tract, and the reticular formation; in this latter area, the occurrence of two categories of NPY-IR neurons was demonstrated on the basis of their morphology and localization, suggesting that they may play distinct roles. (3) NPY-IR nerve processes could be traced over a long distance. (4) For the first time, numerous NPY-IR terminals were observed close to the lumen of the various cerebral ventricles. The immunoreactive NPY-like peptide was characterized by combining high performance liquid chromatography (HPLC) analysis and radioimmunoassay quantification. The dilution curves obtained with synthetic porcine NPY and serial dilutions of occipital cortex, paraventricular and supraoptic hypothalamus, posterior hypothalamus, medulla oblongata, or preoptic area extracts were parallel. The highest amounts of NPY were measured in the hypothalamus and telencephalon. HPLC analysis resolved a single peak of NPY-like immunoreactivity that exhibited the same retention time as synthetic porcine NPY. The distribution of NPY in the lemurian brain is discussed with respect to phylogeny and putative functions.     

Projections of the pedunculopontine tegmental nucleus in the rat: evidence for additional extrapyramidal circuitry

The projections of the pedunulopontine tegmental nucleus (PPT) were studied in the rat using anterograde and retrograde transport methods. Ascending fibers to the substantia nigra, the subthalamic nucleus, the globus pallidus, the entopeduncular nucleus, the neostriatum, the ventral thalamus, and the medial and sulcal frontal cortical areas were identified. PPT has been reported to receive afferents from the substantia nigra, the subthalamic nucleus, the entopeduncular nucleus and the neostriatum. The connections of PPT provide an additional limb to extrapyramidal circuitry.     

The origins of cholinergic and other subcortical afferents to the thalamus in the rat

The origins of the cholinergic and other afferents of several thalamic nuclei were investigated in the rat by using the retrograde transport of wheat germ agglutinin conjugated-horseradish peroxidase in combination with the immunohistochemical localization of choline acetyltransferase immunoreactivity. Small injections placed into the reticular, ventral, laterodorsal, lateroposterior, posterior, mediodorsal, geniculate, and intralaminar nuclei resulted in several distinct patterns of retrograde labelling. As expected, the appropriate specific sensory and motor-related subcortical structures were retrogradely labelled after injections into the principal thalamic nuclei. In addition, other basal forebrain and brainstem structures were also labelled, with their distribution dependent on the site of injection. A large percentage of these latter projections was cholinergic. In the brainstem, the cholinergic pedunculopontine tegmental nucleus was retrogradely labelled after all thalamic injections, suggesting that it provides a widespread innervation to the thalamus. Neurons of the cholinergic laterodorsal tegmental nucleus were retrogradely labelled after injections into the anterior, laterodorsal, central medial, and mediodorsal nuclei, suggesting that it provides a projection to limbic components of the thalamus. Significant basal forebrain labelling occurred only with injections into the reticular and mediodorsal nuclei. Only injections into the reticular nucleus resulted in retrograde labelling of the cholinergic neurons in the nucleus basalis of Meynert. The results provide evidence for an organized system of thalamic afferents arising from cholinergic and noncholinergic structures in the brainstem and basal forebrain. The brainstem structures, especially the cholinergic pedunculopontine tegmental nucleus, appear to project directly to principal thalamic nuclei, thereby providing a possible anatomical substrate for mediating the well-known facilitory effects of brainstem stimulation upon thalamocortical transmission.     

The pedunculopontine nucleus projection to the parafascicular nucleus of the thalamus: an electrophysiological investigation in the rat

Summary. Extracellular electrophysiological recordings of neurons of the parafascicular nucleus of the thalamus were done in normal rats and in rats bearing lesions of either the cerebellar nuclei or the entopeduncular nucleus to investigate the functional control of the pedunculopontine nucleus on the parafascicular nucleus. A total of 97 neurons were recorded in the parafascicular nucleus in intact rats, 83 in rats bearing a chronic electrolytic lesion of the ipsilateral deep cerebellar nuclei, and 69 in rats bearing an ibotenate lesion of the ipsilateral entopeduncular nucleus. Lesions of the cerebellar nuclei or the entopeduncular nucleus were made to evaluate the participation of cerebellothalamic fibers or of polysynaptic basal ganglia circuits in the responses recorded in parafascicular neurons following electrical microstimulation of the ipsilateral pedunculopontine nucleus. Two types of excitation and one type of inhibition were the main responses observed in neurons of the parafascicular nucleus following stimulation of the pedunculopontine nucleus. The first type of excitation, observed in 49.5% of neurons recorded in normal rats, had an onset of 1.8 ± 0.6 ms, lasted 9.2 ± 0.8 ms and was able to follow high frequency stimulation over 300 Hz. The second type of excitation, observed in a smaller percentage of neurons recorded (3.1%), was a long-latency (8.3 ± 0.7 ms) activation lasting 19.0 ± 4.5 ms. It did not follow stimulation frequencies higher than 50–100 Hz. The inhibitory response was observed in 17.5% of the neurons recorded. The latency of this inhibition was 4.5 ± 1.8 ms and the duration 41.9 ± 6.8 ms. In rats bearing a lesion of the deep cerebellar nuclei or of the entopeduncular nucleus, the short-latency activation was still present in 24.1% and 31.9% of neurons recorded, respectively. However, the occurrence of the long-latency excitation rats bearing lesions of either the cerebellum or the entopeduncular nucleus increased to 12.1% and to 17.4%, respectively, while the occurrence of the inhibition rose to 22.9% and to 28.9%. These results show that an excitatory influence on the parafascicular nucleus is exerted by the pedunculopontine nucleus irrespectively of the presence of cerebellofugal fibers. This influence appears to be also independent from the integrity of basal ganglia circuits having a relay at the level of the entopeduncular nucleus. However, the variety of responses recorded suggests that the influences of the pedunculopontine nucleus on the parafascicular nucleus are by far more complex than those exerted on its basal ganglia targets such as the substantia nigra. The results are discussed according to a model of functioning of pedunculopontine fibers directed to thalamic and basal ganglia nuclei. Received December 16, 2002; accepted February 5, 2003 Published online April 22, 2003 Acknowledgements The present study has been supported by grants from Telethon (E0930), Ministero della Salute and Regione Lazio (Progetto Alzheimer), and Progetti d'Ateneo 2001–2002. A. C. and T. F. equally contributed to this work. Authors' address: Dr. T. Florio, Department of Biomedical Technology, University of L'Aquila, Via Vetoio Coppito 2, I-67100 L'Aquila, Italy, e-mail: Florio@univaq.it     

Nigropedunculopontine projection in the rat: an anterograde tracing study with phaseolus vulgaris-leucoagglutinin (PHA-L).

The termination of the substantia nigra pars reticulata efferents in the nucleus tegmenti pedunculopontinus was studied in the rat by using the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHA-L). Both large and small injections of PHA-L in various portions of the substantia nigra pars reticulata labeled varicose fibers in the ipsilateral and contralateral nucleus tegmenti pedunculopontinus, subnucleus dissipatus as well as in the ipsilateral nucleus tegmenti pedunculopontinus, subnucleus compactus. However, the bulk of the nigral fibers appeared to terminate in the medial two-thirds of the ipsilateral subnucleus dissipatus of the pedunculopontine nucleus and exhibited a discrete dorsoventral topographical pattern. The terminal plexus displayed patches of uneven density, which was partly due to the numerous fiber bundles passing through the pedunculopontine nucleus, but also to an obvious preference of nigral fibers for some cells. Electron microscopic examination confirmed that nearly all of the varicosities observed in the light microscope contained synaptic vesicles and represented either terminal boutons or boutons en passant. The labeled boutons were elongated (average length: 1.5 microns) and consistently contained a prominent group of mitochondria. The results suggest that the nigral input to the nucleus tegmenti pedunculopontinus may be directed toward specific subpopulation(s) of pedunculopontine neurons and may influence not only cells in the subnucleus dissipatus, but also in the subnucleus compactus.     

Subthalamic Nucleus Deep Brain Stimulation Induces Motor Network BOLD Activation: Use of a High Precision MRI Guided Stereotactic System for Nonhuman Primates

BackgroundFunctional magnetic resonance imaging (fMRI) is a powerful method for identifying in vivo network activation evoked by deep brain stimulation (DBS).ObjectiveIdentify the global neural circuitry effect of subthalamic nucleus (STN) DBS in nonhuman primates (NHP).MethodAn in-house developed MR image-guided stereotactic targeting system delivered a mini-DBS stimulating electrode, and blood oxygenation level-dependent (BOLD) activation during STN DBS in healthy NHP was measured by combining fMRI with a normalized functional activation map and general linear modeling.ResultsSTN DBS significantly increased BOLD activation in the sensorimotor cortex, supplementary motor area, caudate nucleus, pedunculopontine nucleus, cingulate, insular cortex, and cerebellum (FDR < 0.001).ConclusionOur results demonstrate that STN DBS evokes neural network grouping within the motor network and the basal ganglia. Taken together, these data highlight the importance and specificity of neural circuitry activation patterns and functional connectivity.     

High-frequency stimulation of the subthalamic nucleus modulates the activity of pedunculopontine neurons through direct activation of excitatory fibres as well as through indirect activation of inhibitory pallidal fibres in the rat

Recent data suggest a potential role of pedunculopontine nucleus (PPN) electrical stimulation in improving gait and posture in Parkinson's disease. Because the PPN receives fibres from the subthalamic nucleus (STN), we investigated the effects of STN-high-frequency stimulation (HFS) on PPN neuronal activity in intact rats and in rats bearing either an ibotenate lesion of the entopeduncular nucleus (EP) or a lesion of the substantia nigra (SN). The main response of PPN neurons to STN single-shock stimulations in the three experimental groups was a short latency (4.5 +/- 2.1 ms) and brief (15.3 +/- 6.5 ms) excitation. This response was maintained during 1-5 s of STN-HFS (130 Hz, 60 micros, 100-1000 microA). In EP-lesioned rats the percentage (75.0%) of PPN neurons showing a modulation of activity following STN-HFS was significantly higher compared with that observed in intact (39.7%) and in SN-lesioned rats (35.4%). Furthermore, in EP-lesioned rats the most frequent response of PPN neurons following STN-HFS was a 5-20 s excitation, which was present in 76.6% of responsive neurons in comparison to 15.4% and 9.1% of neurons responsive in intact and in 6-hydroxydopamine-lesioned rats, respectively. Neurons responsive to STN-HFS in the three experimental groups showed either a sharp positively skewed distribution of interspike intervals or multisecond oscillations in autocorrelograms. The results support that STN-HFS modulates the PPN through a balance of excitatory and inhibitory influences, which may be independent from the dopaminergic nigral neurons. In the absence of inhibitory EP fibres, the direct excitatory influence exerted by the STN on the PPN appears to predominate.     

The Organization of Projections from Subdivisions of the Auditory Cortex and Thalamus to the Auditory Sector of the Thalamic Reticular Nucleus in Galago

Anterograde and retrograde transport techniques were used to study the connexions between different subdivisions of the auditory cortex and thalamus with the thalamic reticular nucleus in the prosimian, Galago. In particular, the goal was to determine whether the primary auditory nucleus, GMv, and its cortical target, area I of the auditory cortex (A I), project to a different region of the auditory sector of the reticular nucleus from the secondary auditory nuclei, GMmc and Po and their cortical targets outside A I. The results show that the projections to and from the auditory sector are indeed segregated: injections of wheatgerm agglutinin-conjugated horseradish peroxidase into either GMmc or Po labelled cells and terminals along the medial, lateral and ventral borders of the auditory sector, forming a U-shaped pattern. Projections from area II of the auditory cortex produced almost an identical pattern of the terminal labelling in the auditory sector. In contrast, injections into GMv-labelled cells and terminals in the centre region of the auditory sector, in the 'interior' of the U-shaped region. Projections from A I were distributed to both the U-shaped border region and the central core of the auditory sector probably because A I received projections from GMmc, Po and GMv. The significance of these results depends on a comparison between the auditory and visual sectors of the reticular nucleus. Both sectors are divided into tiers or subsectors-one related to the primary relay nucleus, i.e. GLd or GMv, and the other related to the secondary relay nuclei, i.e. pulvinar nucleus, GMmc, Po, etc.     

Optogenetic excitation in the ventral tegmental area of glutamatergic or cholinergic inputs from the laterodorsal tegmental area drives reward

Converging evidence shows that ventral tegmental area (VTA) dopamine neurons receive laterodorsal tegmental nucleus (LDTg) cholinergic and glutamatergic inputs. To test the behavioral consequences of selectively driving the two sources of excitatory LDTg input to the VTA, channelrhodopsin‐2 (ChR2) was expressed in LDTg cholinergic neurons of ChAT::Cre mice (ChAT‐ChR2 mice) or in LDTg glutamatergic neurons of VGluT2::Cre mice (VGluT2‐ChR2 mice). Mice were tested in a 3‐chamber place preference apparatus where entry into a light‐paired chamber resulted in VTA light stimulation of LDTg‐cholinergic or LDTg‐glutamatergic axons for the duration of a chamber stay. ChAT‐ChR2 mice spent more time in the light‐paired chamber and subsequently showed conditioned place preference for the light‐paired chamber in the absence of light. VGluT2‐ChR2 mice, entered the light‐paired chamber significantly more times than a light‐unpaired chamber, but remained in the light‐paired chamber for short time periods and did not show a conditioned place preference. When each entry into the light‐paired chamber resulted in a single train of VTA light stimulation, VGluT2‐ChR2 mice entered the light‐paired chamber significantly more times than the light‐unpaired chamber, but spent approximately equal amounts of time in the two chambers. VTA excitation of LDTg‐glutamatergic inputs may be more important for reinforcement of initial chamber entry while VTA excitation of LDTg‐cholinergic inputs may be more important for the rewarding effects of chamber stays. We suggest that LDTg‐cholinergic and LDTg‐glutamatergic inputs to the VTA each contribute to the net rewarding effects of exciting LDTg axons in the VTA.     

Mesencephalic projections to the facial nucleus in the cat. An autoradiographical tracing study

In 33 cats the projections of different parts of the mesencephalon to the facial nucleus were studied with the aid of the autoradiographical tracing method. The results indicate the existence of many different mesencephalo-facial pathways. The dorsomedial facial subnucleus, containing motoneurons innervating ear muscles, receives afferents from 4 different mesencephalic areas: a, the most rostral mesencephalic reticular formation; b, the nucleus of Darkschewitsch and/or the ventral part of the rostral PAG; c, the interstitial nucleus of Cajal and/or the mesencephalic tegmentum dorsomedial to the red nucleus. These areas project bilaterally by way of an ipsilateral medial tegmental pathway. The medial part of the deep tectum. This area projects bilaterally by way of the tecto-spinal tract. The lateral mesencephalic tegmentum close to the parabigeminal nucleus. This area projects mainly contralaterally by way of a separate contralateral lateral tegmental fiber bundle. The mesencephalic tegmentum just dorsolateral to the red nucleus and perhaps from the dorsolateral red nucleus itself. This area projects contralaterally by way of the rubrospinal tract. The intermediate facial subnucleus containing motoneurons innervating the muscle around the eye, receives afferents from two different mesencephalic areas: The dorsal part of the rostral as well as caudal red nucleus (but not from its caudal pole) and from the dorsally adjoining mesencephalic tegmentum including the area of the nucleus of Darkschewitsch and the interstitial nucleus of Cajal. These areas project contralaterally by way of the contralateral rubrospinal tract. The nucleus of the optic tract and/or the olivary pretectal nucleus. This area projects contralaterally by way of a contralateral medial tegmental pathway. The lateral and ventrolateral facial subnuclei containing motoneurons innervating the muscles around the mouth receive afferents from two different mesencephalic areas: The lateral part of the deep tectal layers. This area projects contralaterally by way of the tecto-spinal tract. The nucleus raphe dorsalis and perhaps the nucleus centralis superior. This area projects by way of the lateral tegmentum of caudal pons and medulla.     

Glial response in the rat models of functionally distinct cholinergic neuronal denervations

Alzheimer's disease (AD) involves selective loss of basal forebrain cholinergic neurons, particularly in the nucleus basalis (NB). Similarly, Parkinson's disease (PD) might involve the selective loss of pedunculopontine tegmental nucleus (PPT) cholinergic neurons. Therefore, lesions of these functionally distinct cholinergic centers in rats might serve as models of AD and PD cholinergic neuropathologies. Our previous articles described dissimilar sleep/wake‐state disorders in rat models of AD and PD cholinergic neuropathologies. This study further examines astroglial and microglial responses as underlying pathologies in these distinct sleep disorders. Unilateral lesions of the NB or the PPT were induced with rats under ketamine/diazepam anesthesia (50 mg/kg i.p.) by using stereotaxically guided microinfusion of the excitotoxin ibotenic acid (IBO). Twenty‐one days after the lesion, loss of cholinergic neurons was quantified by nicotinamide adenine dinucleotide phosphate‐diaphorase histochemistry, and the astroglial and microglial responses were quantified by glia fibrillary acidic protein/OX42 immunohistochemistry. This study demonstrates, for the first time, the anatomofunctionally related astroglial response following unilateral excitotoxic PPT cholinergic neuronal lesion. Whereas IBO NB and PPT lesions similarly enhanced local astroglial and microglial responses, astrogliosis in the PPT was followed by a remote astrogliosis within the ipslilateral NB. Conversely, there was no microglial response within the NB after PPT lesions. Our results reveal the rostrorostral PPT‐NB astrogliosis after denervation of cholinergic neurons in the PPT. This hierarchically and anatomofunctionally guided PPT‐NB astrogliosis emerged following cholinergic neuronal loss greater than 17% throughout the overall rostrocaudal PPT dimension. © 2014 Wiley Periodicals, Inc.