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The dorsal ventricular ridge (DVR), which is the largest component of the avian pallium, contains discrete partitions receiving tectovisual, auditory, and trigeminal ascending projections. Recent studies have shown that the auditory and the tectovisual regions can be regarded as complexes composed of three highly interconnected layers: an internal senso-recipient one, an intermediate afferent/efferent one, and a more external re-entrant one. Cells located in homotopic positions in each of these layers are reciprocally linked by an interlaminar loop of axonal processes, forming columnar-like local circuits. Whether this type of organization also extends to the trigemino-recipient DVR is, at present, not known. This question is of interest, since afferents forming this sensory pathway, exceptional among amniotes, are not thalamic but rhombencephalic in origin. We investigated this question by placing minute injections of neural tracers into selected locations of vital slices of the chicken telencephalon. We found that neurons of the trigemino-recipient nucleus basorostralis pallii (Bas) establish reciprocal, columnar and homotopical projections with cells located in the overlying ventral mesopallium (MV). "Column-forming" axons originated in B and MV terminate also in the intermediate strip, the fronto-trigeminal nidopallium (NFT), in a restricted manner. We also found that the NFT and an internal partition of B originate substantial, coarse-topographic projections to the underlying portion of the lateral striatum. We conclude that all sensory areas of the DVR are organized according to a common neuroarchitectonic motif, which bears a striking resemblance to that of the radial/laminar intrinsic circuits of the sensory cortices of mammals., (© 2021 Wiley Periodicals LLC.)

Our knowledge of the avian sensory trigeminal system has been largely restricted to the principal trigeminal nucleus (PrV) and its ascending projections to the forebrain. Studies addressing the cytoarchitecture and organization of afferent input to the sensory trigeminal complex, which includes both the PrV and the nuclei of the descending trigeminal tract (nTTD), have only been performed in pigeons and ducks. Here we extend such an analysis to a songbird, the zebra finch (Taeniopygia guttata). We describe the cytoarchitecture of the sensory trigeminal complex, the patterns of calbindin-like and substance P-like immunoreactivity, and the organization of afferents from the three branches of the trigeminal nerve and from the lingual branch of the hypoglossal nerve. On the basis of cytoarchitecture and immunohistochemistry, the sensory trigeminal column can be subdivided from caudal to rostral, as in other species, into cervical dorsal horn, subnucleus caudalis, subnucleus interpolaris, subnucleus oralis, and nucleus principalis. The relative positions of the terminal fields of the three trigeminal branches move from medial to lateral in the dorsal horn to dorsomedial to ventrolateral in nTTD, whereas in PrV there is considerable overlap of mandibular and ophthalmic terminal fields, with only a small maxillary input ventrally. The hypoglossal afferents, which terminate medially in the dorsal horn and dorsolaterally in nTTD, terminate in specific cell groups in the dorsolateral nTTDo and in PrV. This work sets the grounds for further analyses of the ascending connections of the nTTD and the afferents from the syrinx to the trigeminal sensory column., (© 2017 Wiley Periodicals, Inc.)

In our traditional view of the avian somatosensory system, input from the beak and head reaches the telencephalon via a disynaptic pathway, involving projections from the principal sensory nucleus (PrV) directly to nucleus basorostralis (previously called nucleus basalis), whereas input from the rest of the body follows a trisynatic pathway similar to that in mammals, involving projections from the dorsal column nuclei to the thalamus, and thence to somatosensory wulst. However, the role of the nuclei of the descending trigeminal tract (nTTD) in this scenario is unclear, partly because their ascending projections have been examined in only one species, the mallard duck. Here we examine the ascending projections of the nTTD in the zebra finch, using in vivo injections of biotinylated dextran amine and verification of projections by means of retrograde transport of the beta subunit of cholera toxin. The results show a high degree of interconnectivity within the nTTD, and that these nuclei project to PrV. We also find a projection from nTTD to the contralateral thalamic nucleus uvaeformis, a multi-sensory nucleus connected to the song system. Furthermore, our finding of a projection from nTTD to the contralateral somatosensory thalamic nucleus dorsalis intermedius ventralis anterior (DIVA) is consistent with the well-known projection in mammals from nTTD to the ventrobasal thalamus, suggesting that the ascending trigeminal pathways in birds and mammals are more similar than previously thought., (© 2017 Wiley Periodicals, Inc.)

Trigeminal mesencephalic nucleus (Vmes) neurons are primary afferents conveying deep sensation from the masticatory muscle spindles or the periodontal mechanoreceptors, and are crucial for controlling jaw movements. Their cell bodies exist in the brain and receive descending commands from a variety of cortical and subcortical structures involved in limbic (emotional) systems. However, it remains unclear how the lateral habenula (LHb), a center of negative emotions (e.g., pain, stress and anxiety), can influence the control of jaw movements. To address this issue, we examined whether and how the LHb directly projects to the Vmes by means of neuronal tract tracing techniques in rats. After injections of a retrograde tracer Fluorogold in the rostral and caudal Vmes, a number of neurons were labeled in the lateral division of LHb (LHbl) bilaterally, whereas a few neurons were labeled in the medial division of LHb (LHbm) bilaterally. After injections of an anterograde tracer, biotinylated dextranamine (BDA) in the LHbl, a small number of labeled axons were distributed bilaterally in the rostral and caudal levels of Vmes, where some labeled axonal boutons contacted the cell body of rostral and caudal levels of Vmes neurons bilaterally. After the BDA injection into the LHbm, however, no axons were labeled bilaterally in the rostral and caudal levels of Vmes. Therefore, the present study for the first time demonstrated the direct projection from the LHbl to the Vmes and the detailed projection patterns, suggesting that jaw movements are modulated by negative emotions that are signaled by LHbl neurons., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Repetitive electrical microstimulation to the cortical masticatory area (CMA) evokes distinct patterns of rhythmical jaw muscle activities (RJMAs) in animals. This study aimed to investigate the characteristics of the descending projections from the CMA, associated with distinct patterns of RJMAs, to the thalamus, midbrain, pons and medulla in guinea pigs. RJMAs with continuous masseter and digastric bursts (CB-RJMAs) and stimulus-locked digastric sub-bursts (SLB-RJMAs) were induced from the anterior and posterior areas of the rostral region of the lateral agranular cortex, and chewing-like RJMAs from the rostral region of the granular cortex. Anterograde tracer, biotinylated dextran amine, was injected into the three cortical areas. The cortical area inducing CB-RJMAs had strong ipsilateral projections to the motor thalamus, red nucleus, midbrain reticular formation, superior colliculus, parabrachial nucleus, and supratrigeminal region, and contralateral projections mainly to the lateral reticular formation around the trigeminal motor nucleus (Vmo). The cortical area inducing SLB-RJMAs had moderate projections to the motor thalamus and lateral reticular formation around the Vmo, but few projections to the midbrain nuclei. The cortical area inducing chewing-like RJMAs had strong projections to the ipsilateral sensory thalamus and contralateral trigeminal sensory nuclei, and moderate projections to the lateral reticular formation. The three cortical areas consistently had few projections to the ventromedial reticular formation. The present study demonstrates that multiple direct and indirect descending projections from the CMA onto the premotor systems connecting the trigeminal motoneurons represent the neuroanatomical repertoires for generating RJMAs during the distinct phases of natural ingestive behavior., (Copyright © 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

In order to understand the underlying principles of orofacial pain it is important to understand the corresponding anatomy and mechanisms. Paper 1 of this series explains the central nervous and peripheral nervous systems relating to pain. The trigeminal nerve is the 'great protector' of the most important region of our body. It is the largest sensory nerve of the body and over half of the sensory cortex is responsive to any stimulation within this system. This nerve is the main sensory system of the branchial arches and underpins the protection of the brain, sight, smell, airway, hearing and taste, underpinning our very existence. The brain reaction to pain within the trigeminal system has a significant and larger reaction to the threat of, and actual, pain compared with other sensory nerves. We are physiologically wired to run when threatened with pain in the trigeminal region and it is a 'miracle' that patients volunteer to sit in a dental chair and undergo dental treatment. Clinical Relevance: This paper aims to provide the dental and medical teams with a review of the trigeminal anatomy of pain and the principles of pain assessment.

Specializations of the trigeminal sensory system are present in all three infraclasses of mammals (metatheria, eutheria, prototheria or monotremata). The trigeminal sensory system has been suggested as a critically important modality for sampling the path to the pouch and detecting the nipple or milk patch, but the degree to which that system may be required to function at birth varies significantly. Archived sections of the snout and brainstem of embryonic and postnatal mammals were used to test the relationship between structural maturity of the two ends of the trigeminal nerve pathway and the body size of mammalian young in metatherians, rodents and monotremes. A system for staging different levels of structural maturity of the vibrissae and trigeminal sensory was applied to embryos, pouch young and hatchlings and correlated with body length. Dasyurids are born at the most immature state with respect to vibrissal and trigeminal sensory nucleus development of any available metatherian, but these components of the trigeminal system are also developmentally advanced relative to body size when dasyurids are compared to other metatherians. Vibrissal and trigeminal sensory nucleus development is at a similar stage of development at birth and for a given body size in non-dasyurid metatherians; and trigeminal sensory nucleus development in monotremes is at a similar stage at birth to metatherians. Rodents reach a far more advanced stage of vibrissal and trigeminal sensory nucleus development at birth than do metatherians, and in the case of the mouse have a more developmentally advanced trigeminal system than all available metatherians at any given body length. Precocious development of the trigeminal sensory pathway relative to body size is evident in dasyurids, as might be expected given the small birth size of those metatherians. Nevertheless, the trigeminal sensory system in metatherians in general is not precocious relative to body size when these species are considered alongside the pace of trigeminal somatosensory development in rodents.

Pit vipers (Crotalinae) have a specific sensory system that detects infrared radiation with bilateral pit organs in the upper jaw. Each pit organ consists of a thin membrane, innervated by three trigeminal nerve branches that project to a specific nucleus in the dorsal hindbrain. The known topographic organization of infrared signals in the optic tectum prompted us to test the implementation of spatiotopically aligned sensory maps through hierarchical neuronal levels from the peripheral epithelium to the first central site in the hindbrain, the nucleus of the lateral descending trigeminal tract (LTTD). The spatial organization of the anatomical connections was revealed in a novel in vitro whole-brain preparation of the western diamondback rattlesnake (Crotalus atrox) that allowed specific application of multiple neuronal tracers to identified pit-organ-supplying trigeminal nerve branches. After adequate survival times, the entire peripheral and central projections of fibers within the pit membrane and the LTTD became visible. This approach revealed a morphological partition of the pit membrane into three well-defined sensory areas with largely separated innervations by the three main branches. The peripheral segregation of infrared afferents in the sensory epithelium was matched by a differential termination of the afferents within different areas of the LTTD, with little overlap. This result demonstrates a topographic organizational principle of the snake infrared system that is implemented by maintaining spatially aligned representations of environmental infrared cues on the sensory epithelium through specific neuronal projections at the level of the first central processing stage, comparable to the visual system., (© 2014 Wiley Periodicals, Inc.)

In this study we combined ultra-high field diffusion MRI fiber tracking and super-resolution track density imaging (TDI) to map the relay locations and connectivity of the somatosensory pathway in paraformaldehyde fixed, C57Bl/6J mouse brains. Super-resolution TDI was used to achieve 20 μm isotropic resolution to inform the 3D topography of the relay locations including thalamic barreloids and brainstem barrelettes, not described previously using MRI methodology. TDI-guided mapping results for thalamo-cortical connectivity were consistent with thalamo-cortical projections labeled using virus mediated fluorescent protein expression. Trigemino-thalamic TDI connectivity maps were concordant with results obtained using anterograde dye tracing from brainstem to thalamus. Importantly, TDI mapping overcame the constraint of tissue distortion observed in mechanically sectioned tissue, enabling 3D reconstruction and long-range connectivity data. In conclusion, our results showed that diffusion micro-imaging at ultra-high field MRI revealed the stereotypical pattern of somatosensory connectivity and is a valuable tool to complement histologic methods, achieving 3D spatial preservation of whole brain networks for characterization in mouse models of human disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In previous experiments performed on anaesthetised rats, we demonstrated that whisking neurons responsive to spontaneous movement of the macrovibrissae are located within the trigeminal mesencephalic nucleus (Me5) and that retrograde tracers injected into the mystacial pad of the rat muzzle extensively labelled a number of Me5 neurons. In order to evaluate the electrophysiological characteristics of the Me5-whisker pad neural connection, the present study analysed the Me5 neurons responses to artificial whisking induced by electrical stimulation of the peripheral stump of the facial nerve. Furthermore, an anterograde tracer was injected into the Me5 to identify and localise the peripheral terminals of these neurons in the mystacial structures. The electrophysiological data demonstrated that artificial whisking induced Me5 evoked potentials as well as single and multiunit Me5 neurons responses consistent with a direct connection. Furthermore, the neuroanatomical findings showed that the peripheral terminals of the Me5 stained neurons established direct connections with the upper part of the macrovibrissae, at the conical body level, with fibres spiralling around the circumference of the vibrissae shaft. As for the functional role of this sensory innervation, we speculated that the Me5 neurons are possibly involved in encoding and relaying proprioceptive information related to vibrissae movements to other CNS structures., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Three families of probe-foraging birds, Scolopacidae (sandpipers and snipes), Apterygidae (kiwi), and Threskiornithidae (ibises, including spoonbills) have independently evolved long, narrow bills containing clusters of vibration-sensitive mechanoreceptors (Herbst corpuscles) within pits in the bill-tip. These 'bill-tip organs' allow birds to detect buried or submerged prey via substrate-borne vibrations and/or interstitial pressure gradients. Shorebirds, kiwi and ibises are only distantly related, with the phylogenetic divide between kiwi and the other two taxa being particularly deep. We compared the bill-tip structure and associated somatosensory regions in the brains of kiwi and shorebirds to understand the degree of convergence of these systems between the two taxa. For comparison, we also included data from other taxa including waterfowl (Anatidae) and parrots (Psittaculidae and Cacatuidae), non-apterygid ratites, and other probe-foraging and non probe-foraging birds including non-scolopacid shorebirds (Charadriidae, Haematopodidae, Recurvirostridae and Sternidae). We show that the bill-tip organ structure was broadly similar between the Apterygidae and Scolopacidae, however some inter-specific variation was found in the number, shape and orientation of sensory pits between the two groups. Kiwi, scolopacid shorebirds, waterfowl and parrots all shared hypertrophy or near-hypertrophy of the principal sensory trigeminal nucleus. Hypertrophy of the nucleus basorostralis, however, occurred only in waterfowl, kiwi, three of the scolopacid species examined and a species of oystercatcher (Charadriiformes: Haematopodidae). Hypertrophy of the principal sensory trigeminal nucleus in kiwi, Scolopacidae, and other tactile specialists appears to have co-evolved alongside bill-tip specializations, whereas hypertrophy of nucleus basorostralis may be influenced to a greater extent by other sensory inputs. We suggest that similarities between kiwi and scolopacid bill-tip organs and associated somatosensory brain regions are likely a result of similar ecological selective pressures, with inter-specific variations reflecting finer-scale niche differentiation.

Prey-catching behavior (PCB) of the frog consists of a sequence of coordinated activity of muscles which is modified by various sensory signals. The aim of the present study was, for the first time, to examine the involvement of the trigeminal afferents in the swallowing phase of PCB. Experiments were performed on Rana esculenta, where the trigeminal and glossopharyngeal (IX)-vagus (X) nerves were labeled simultaneously with different fluorescent dyes. Using confocal laser scanning microscope, close appositions were detected between the trigeminal afferent fibers and somatodendritic components of the IX-X motoneurons of the ambiguus nucleus (NA). Neurolucida reconstruction revealed spatial distribution of the trigeminal afferents in the functionally different parts of the NA. Thus, the visceromotor neurons supplying the stomach, the heart and the lung received about two third of the trigeminal contacts followed by the pharyngomotor and then by the laryngomotor neurons. On the other hand, individual motoneurons responsible for innervation of the viscera received less trigeminal terminals than the neurons supplying the muscles of the pharynx. The results suggest that the direct contacts between the trigeminal afferents and IX-X motoneurons presented here may be one of the morphological substrate of a very quick response during the swallowing phase of PCB. Combination of direct and indirect trigeminal inputs may contribute to optimize the ongoing motor execution., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Little is known about the projections from the orofacial areas of the secondary somatosensory cortex (S2) to the pons and medulla including the second-order somatosensory neuron pools. To address this in rats, we first examined the distribution of S2 neurons projecting to the trigeminal principal nucleus (Vp) or oral subnucleus (Vo) of the trigeminal sensory nuclear complex (TSNC) after injections of a retrograde tracer, Fluorogold (FG), into five regions in the Vp/Vo which were responsive to stimulation of trigeminal nerves innervating the orofacial tissues. A large number of FG-labeled neurons were found with a somatotopic arrangement in the dorsal areas of S2 (orofacial S2 area). This somatotopic arrangement in the orofacial S2 area was shown to closely match that of the orofacial afferent inputs by recording cortical surface potentials evoked by stimulation of the trigeminal nerves. We then examined the morphology of descending projections from these electrophysiologically defined areas of the orofacial S2 to the pons and medulla after injections of an anterograde tracer, biotinylated dextranamine (BDA), into the areas. A large number of BDA-labeled axon fibers and terminals were seen only in some of the second-order somatosensory neuron pools, most notably in the contralateral TSNC, although the labeled terminals were not seen in certain rostrocaudal levels of the contralateral TSNC including the rostrocaudal middle level of the trigeminal interpolar subnucleus. The projections to the TSNC showed somatotopic arrangements in dorsoventral, superficial-deep and rostrocaudal directions. The somatotopic arrangements in the Vp/Vo closely matched those of the electrophysiologically defined central projection sites of the orofacial trigeminal afferents in the TSNC. The present results suggest that the orofacial S2 projects selectively to certain rostrocaudal levels of the contralateral TSNC, and the projections may allow the orofacial S2 to accurately modulate orofacial somatosensory transmission to higher brain centers including the orofacial S2 itself., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

The amygdala is activated by fear and plays an important role in the emotional response to life-threatening situations. When rats feel threatened, they respond by biting fiercely. Bite strength is regulated by the trigeminal motor nucleus and the mesencephalic trigeminal nucleus (Me5). The Me5 relays proprioceptive signals from the masticatory muscles and the periodontal ligaments to the trigeminal motor and premotor nuclei. The amygdala projects to the trigeminal motor nucleus and the premotor reticular formation. However, it is unknown whether the amygdala projects directly to the Me5. In the present study, neurons of the central amygdaloid nucleus (ACe) were labeled following injection of a retrograde tracer, Fast Blue, into the caudal Me5, and fibers and terminal buttons from the ACe to the Me5 were examined after injections of an anterograde neuronal tracer, biotinylated dextran amine into the ACe. Furthermore, wheat germ agglutinin-conjugated to horseradish peroxidase was injected into the ACe, and labeled fibers and terminal buttons in the Me5 were examined by electron microscopy. Labeled terminal buttons on Me5 somata were more abundant in the caudal than the rostral Me5. Electron microscopic observation revealed that a part of these terminal buttons formed axo-somatic synapses. These results indicate that the ACe sends direct projections to the Me5, and suggest that the amygdala regulates bite strength by modifying neuronal activity in the Me5., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The ganglion-cells in the mesencephalic trigeminal nucleus (Me5) process proprioceptive signals from the masticatory muscles and the periodontal ligaments, and are considered to regulate the rhythm of biting and bite strength. The locus coeruleus (LC) is the major source of noradrenergic projections in the brain and plays an important role in stressful situations and aggressive behavior. The two nuclei are adjacently located to each other in the lateral part of the periaqueductal gray matter of the fourth ventricle. In the present study, a small number of neurons were labeled in the LC with a neuronal tracer biotinylated dextran amine. The labeled single axons were traced from the labeled LC neuronal somata to the ipsilateral Me5 region where they produced terminal-like swellings. Some of the swellings appeared to make contact with the ganglion-cells of the Me5. These results suggest that the LC regulates the bite strength by modifying the ganglion-cell activity in the Me5. Additionally, these findings shed light on the enigma of why the main part of the Me5 at the level of pons is located at the lateral end of the gray matter ventral to the fourth ventricle, instead of at the trigeminal ganglion., (2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

The mesencephalic trigeminal sensory nucleus (Me5), which receives signals originating from oral proprioceptors, becomes active at weaning and contributes to the acquisition of active exploratory behavior [Ishii, T., Furuoka, H., Kitamura, N., Muroi, Y., and Nishimura, M. (2006) Brain Res. 1111, 153-161]. Because cognitive functions play a key role in animal exploration, in the present study we assessed the role of Me5 in spatial learning and memory in the water maze. Mice with bilateral Me5 lesions exhibited severe deficits in both a reversal learning and a reversal probe test compared with sham-operated mice. In spite of these reversal tests, Me5 lesions had no effect on a hidden platform test. These results suggest that Me5-lesioned mice show a perseveration of the previously learned spatial strategy rather than an inability to learn a new strategy, resulting in reduced spatial memory resetting. Moreover, adult neurogenesis in the dentate gyrus of the hippocampus, which has been proposed to have a causal relationship to spatial memory, was stimulated in Me5-lesioned mice. Thus, a stimulation of hippocampal neurogenesis observed after Me5 lesions may lead to a rigidity and perseverance of the previously learned strategy because of inferential overuse of past memories in a novel situation. These results suggest that Me5 contributes to spatial memory resetting by controlling the rate of hippocampal neurogenesis through an ascending neuronal pathway to the hippocampus., (Copyright 2010 Elsevier B.V. All rights reserved.)

Almost every odor we encounter in daily life has the capacity to produce a trigeminal sensation. Surprisingly, few functional imaging studies exploring human neuronal correlates of intranasal trigeminal function exist, and results are to some degree inconsistent. We utilized activation likelihood estimation (ALE), a quantitative voxel-based meta-analysis tool, to analyze functional imaging data (fMRI/PET) following intranasal trigeminal stimulation with carbon dioxide (CO(2)), a stimulus known to exclusively activate the trigeminal system. Meta-analysis tools are able to identify activations common across studies, thereby enabling activation mapping with higher certainty. Activation foci of nine studies utilizing trigeminal stimulation were included in the meta-analysis. We found significant ALE scores, thus indicating consistent activation across studies, in the brainstem, ventrolateral posterior thalamic nucleus, anterior cingulate cortex, insula, precentral gyrus, as well as in primary and secondary somatosensory cortices-a network known for the processing of intranasal nociceptive stimuli. Significant ALE values were also observed in the piriform cortex, insula, and the orbitofrontal cortex, areas known to process chemosensory stimuli, and in association cortices. Additionally, the trigeminal ALE statistics were directly compared with ALE statistics originating from olfactory stimulation, demonstrating considerable overlap in activation. In conclusion, the results of this meta-analysis map the human neuronal correlates of intranasal trigeminal stimulation with high statistical certainty and demonstrate that the cortical areas recruited during the processing of intranasal CO(2) stimuli include those outside traditional trigeminal areas. Moreover, through illustrations of the considerable overlap between brain areas that process trigeminal and olfactory information; these results demonstrate the interconnectivity of flavor processing.

The purpose of this study was to demonstrate a micro-computed tomography (CT) method for observations of the mouse embryo. At 13.0 days post-coitum, mouse embryos were fixed in 4% paraformaldehyde for 24 h and stained en bloc by osmium tetroxide overnight. The embryos were then embedded in paraffin using standard methods for 24 h. Specimens were analyzed by micro-CT and image processing was performed. Organs containing nervous and blood systems could be viewed as a result of different osmium-staining densities. The trigeminal ganglion was imaged using three-dimensional techniques. Observation of the embryo was possible by micro-CT with osmium tetroxide staining.

Mandibular movements occur through the triggering of trigeminal motoneurons. Aberrant movements by orofacial muscles are characteristic of orofacial motor disorders, such as nocturnal bruxism (clenching or grinding of the dentition during sleep). Previous studies have suggested that autonomic changes occur during bruxism episodes. Although it is known that emotional responses increase jaw movement, the brain pathways linking forebrain limbic nuclei and the trigeminal motor nucleus remain unclear. Here we show that neurons in the lateral hypothalamic area, in the central nucleus of the amygdala, and in the parasubthalamic nucleus, project to the trigeminal motor nucleus or to reticular regions around the motor nucleus (Regio h) and in the mesencephalic trigeminal nucleus. We observed orexin co-expression in neurons projecting from the lateral hypothalamic area to the trigeminal motor nucleus. In the central nucleus of the amygdala, neurons projecting to the trigeminal motor nucleus are innervated by corticotrophin-releasing factor immunoreactive fibers. We also observed that the mesencephalic trigeminal nucleus receives dense innervation from orexin and corticotrophin-releasing factor immunoreactive fibers. Therefore, forebrain nuclei related to autonomic control and stress responses might influence the activity of trigeminal motor neurons and consequently play a role in the physiopathology of nocturnal bruxism.

The trigeminal motor system participates in the control of respiration as well as suckling and mastication. However, the central mechanism underlying respiratory activity in trigeminal motoneurons is not well-understood. In this study, we aimed to elucidate brainstem circuitry for rhythm generation and signal transmission of trigeminal respiratory activity in in vitro neonatal rat brainstem-spinal cord preparations. We further examined the role of midline-crossing trigeminal interneurons in the bilateral synchronization of respiratory and suckling activity in trigeminal motor nerves. The results of brainstem-sectioning experiments indicated that respiratory rhythms were generated in the medulla and ipsilaterally transmitted to trigeminal motoneurons in the pons. We conclude that the trigeminal motor system, as well as the hypoglossal and phrenic motor system, is regulated by medullary respiratory networks, and that pontine interactions between bilateral trigeminal interneurons are not critical for the generation or synchronization of trigeminal respiratory activity, but are crucial for trigeminal suckling activity.

The primary goal of this study was to examine whether the locus coeruleus (LC) provides collateral projections to whisker-related, sensorimotor brain regions. After injections of retrograde tracers into the primary sensory (S1) barrel field/primary whisker motor (M1) cortices, ventroposteromedial (VPM)/ventrolateral (VL) thalamic nuclei, or principal sensory trigeminal (Pr5)/facial motor (Mo7) nuclei, the distribution of double-labeled neurons within the LC was examined. Our observations indicated that a large number of individual LC cells provided axon collaterals to S1-M1 or VPM-VL regions, whereas only a few projected to Pr5-Mo7 nuclei. The laterality and the distribution of dual-projecting LC neurons were as follows. 1) The neurons projecting to the S1-M1 cortices were predominantly ipsilateral (96% +/- 0.7%). Labeled neurons were located ventrally at the rostral pole but were evenly distributed along the dorsoventral aspect of the principal LC. 2) The cells projecting to the VPM-VL nuclei were bilateral, with ipsilateral (68% +/- 2.3%) dominance. Neurons were observed at the rostrocaudal extent of the LC, where the labeling was most pronounced at the ventral, principal LC. 3) The neurons projecting to the Pr5-Mo7 regions exhibited slightly contralateral (56% +/- 2.9%) dominance, where labeled cells were confined within the ventral margin of the principal subdivision. Taken together, the present observations demonstrate that each subdivision of the LC possesses a differential functional organization with respect to its collateral projection to whisker-related sensorimotor targets, suggesting that the nucleus might play a modulatory role in vibrissal sensorimotor integration that allows the guidance of behavioral action essential for the survival of the animal.

Little is known about the organization of corticofugal projections controlling antagonistic jaw muscles. To address this issue, we employed retrograde (Fluorogold; FG) and anterograde (biotinylated dextran amine; BDA) tracing techniques in rats. Three groups of premotoneurons were identified by injecting FG into the jaw-closing (JC) and -opening (JO) subdivisions of the trigeminal motor nucleus (Vmo). These were 1) the intertrigeminal region (Vint) and principal trigeminal sensory nucleus for JC nucleus; 2) the reticular region medial to JO nucleus (RmJO) for JO nucleus; and 3) the parabrachial (Pb) and supratrigeminal (Vsup) nuclei, reticular regions medial and ventral to JC nucleus, rostrodorsomedial oralis (Vor), and juxtatrigeminal region (Vjuxt) containing a mixture of premotoneurons to both the nuclei. Subsequently, FG was injected into the representative premotoneuron structures. The JC and JO premotoneurons received main afferents from the lateral and medial agranular fields of motor cortex (Agl and Agm), respectively, whereas afferents to the nuclei with both JC and JO premotoneurons arose from Agl also and from primary somatosensory cortex (S1). Finally, BDA was injected into each of the three cortical areas representing the premotoneuron structures to complement the FG data. The Agl and Agm projected to reticular regions around the Vmo, whereas the Pb, Vsup, Vor, and Vjuxt received input from Agl. The S1 projected to the trigeminal sensory nuclei as well as to the Pb, Vsup, and Vjuxt. These results suggest that corticofugal projections to Vmo via premotoneuron structures consist of multiple pathways, which influence distinct patterns of jaw movements.

The trigeminocerebellar artery (TCA) is a unique branch of the basilar artery supplying both the trigeminal nerve root and the cerebellar hemisphere. In this study, we describe and demonstrate the microanatomy of the TCA in 45 brainstems and discuss the neurological, neuroradiological and neurosurgical significance. This is the largest series of cadavers in the literature. The close relationship of the TCA to the trigeminal nerve root may have clinical implications including for the etiology of trigeminal neuralgia, thus the neurosurgeon must be aware of the vasculature of the trigeminal nerve root area and the anatomical variations.

In vertebrates, sensory specializations are usually correlated with increases in the brain areas associated with that specialization. This correlation is called the 'principle of proper mass' whereby the size of a neural structure is a reflection of the complexity of the behavior that it subserves. In recent years, several comparative studies have revealed examples of this principle in the visual and auditory system of birds, but somatosensory specializations have largely been ignored. Many species rely heavily on tactile information during feeding. Input from the beak, tongue and face, conveyed via the trigeminal, facial, glossopharyngeal and hypoglossal nerves, is first processed in the brain by the principal sensory nucleus of the trigeminal nerve (PrV) in the brainstem. Previous studies report that PrV is enlarged in some species that rely heavily on tactile input when feeding, but no extensive comparative studies have been performed. In this study, we assessed the volume of PrV in 73 species of birds to present a detailed analysis of the relative size variation of PrV using both conventional and phylogenetically based statistics. Overall, our results indicate that three distinct groups of birds have a hypertrophied PrV: waterfowl (Anseriformes), beak-probing shorebirds (Charadriiformes), and parrots (Psittaciformes). These three groups have different sensory requirements from the orofacial region. For example, beak-probing shorebirds use pressure information from the tip of the beak to find buried prey in soft substrates, whereas waterfowl, especially filter-feeding ducks, use information from the beak, palate, and tongue when feeding. Parrots likely require increased sensitivity in the tongue to manipulate food items. Thus, despite all sharing an enlarged PrV and feeding behaviors dependent on tactile input, each group has different requirements that have led to the independent evolution of a large PrV., (2009 S. Karger AG, Basel.)

This study was performed to understand the anatomical substrates of hypothalamic modulation of jaw movements. After cholera toxin B subunit (CTb) injection into the parvicellular reticular formation (RFp) of the rat medulla oblongata, where many trigeminal premotor neurons have been known to exist, numerous CTb-labeled neurons were found in the posterior lateral hypothalamus (PLH) bilaterally with a clear-cut ipsilateral dominance. After ipsilateral injections of biotinylated dextran amine (BDA) into the PLH and CTb into the motor trigeminal nucleus (Vm), the prominent distribution of BDA-labeled axon terminals around CTb-labeled neurons was found in the RFp region just ventral to the nucleus of the solitary tract and medial to the spinal trigeminal nucleus ipsilateral to the injection sites. Within the neuropil of the RFp, BDA-labeled axon terminals made an asymmetrical synaptic contact predominantly with dendrites and additionally with somata of the RFp neurons, some of which were labeled with CTb. It was further revealed that these BDA-labeled axon terminals were immunoreactive for vesicular glutamate transporter 2. The present data suggest that the PLH plays an important role in the control of jaw movements by exerting its glutamatergic excitatory action upon RFp neurons presynaptic to trigeminal motoneurons.

The aim of this study was to investigate whether primary vestibular afferent fibers establish direct connections with the motor and sensory trigeminal system in the brainstem of the frog. The experiments were carried out on Rana esculenta. In anaesthetized animals the trigeminal and vestibular nerves were prepared, and their proximal stumps were labeled either with fluorescein binding dextran amine (trigeminal nerve) or tetramethylrhodamine dextran amine (vestibulocochlear nerve). With a confocal laser scanning microscope we could detect close connections between the vestibular fibers and branches of the dorsal dendritic array of the jaw-closing motoneurons, suggestive of monosynaptic contacts. In the other parts of the brainstem, vestibular terminals were detected in the termination areas of the mesencephalic trigeminal nucleus and of the Gasserian (Vth) ganglion and they were probably involved in polysynaptic connections. In agreement with the results obtained in mammalian species, the present findings suggest that the vestibulotrigeminal relationship is quite complex and uses multiple pathways to connect the vestibular apparatus with the motor and sensory nuclei of the trigeminal nerve in the anurans as well.

Mice lacking the growth-associated protein GAP-43 (KO) show disrupted cortical topography and no barrels. Whisker-related patterns of cells are normal in the KO brainstem trigeminal complex (BSTC), while the pattern in KO ventrobasal thalamus (VB) is somewhat compromised. To better understand the basis for VB and cortical abnormalities, we used small placements of DiI to trace axonal projections between BSTC, VB, and barrel cortex in wildtype (WT) and GAP-43 KO mice. The trigeminothalamic (TT) pathway consists of axons from cells in the Nucleus Prinicipalis that project to the contralateral VB thalamus. DiI-labeled KO TT axons crossed the midline from BSTC and projected to contralateral VB normally, consistent with normal BSTC cytoarchitecture. By contrast, the KO thalamocortical axons (TCA) projection was highly abnormal. KO TCAs showed delays of 1-2 days in initial ingrowth to cortex. Postnatally, KO TCAs showed multiple pathfinding errors near intermediate targets, and were abnormally fasciculated within the internal capsule (IC). Interestingly, most individually labeled KO TCAs terminated in deep layers instead of in layer IV as in WT. This misprojection is consistent with birthdating analysis in KO mice, which revealed that neurons normally destined for layer IV remain in deep cortical layers. Early outgrowth of KO corticofugal (CF) axons was similar for both genotypes. However, at P7 KO CF fibers remained bundled as they entered the IC, and exhibited few terminal branches in VB. Thus, the establishment of axonal projections between thalamus and cortex are disrupted in GAP-43 KO mice.

Florida manatees have an extensive, well-developed system of vibrissae distributed over their entire bodies and especially concentrated on the face. Although behavioral and anatomical assessments support the manatee's reliance on somatosensation, a systematic analysis of the manatee thalamus and brainstem areas dedicated to tactile input has never been completed. Using histochemical and histological techniques (including stains for myelin, Nissl, cytochrome oxidase, and acetylcholinesterase), we characterized the relative size, extent, and specializations of somatosensory regions of the brainstem and thalamus. The principal somatosensory regions of the brainstem (trigeminal, cuneate, gracile, and Bischoff's nucleus) and the thalamus (ventroposterior nucleus) were disproportionately large relative to nuclei dedicated to other sensory modalities, providing neuroanatomical evidence that supports the manatee's reliance on somatosensation. In fact, areas of the thalamus related to somatosensation (the ventroposterior and posterior nuclei) and audition (the medial geniculate nucleus) appeared to displace the lateral geniculate nucleus dedicated to the subordinate visual modality. Furthermore, it is noteworthy that, although the manatee cortex contains Rindenkerne (barrel-like cortical nuclei located in layer VI), no corresponding cell clusters were located in the brainstem ("barrelettes") or thalamus ("barreloids")., (Copyright 2007 Wiley-Liss, Inc.)

It has been suggested that in mammals, trigeminal lamina I neurons play a role in the processing and transmission of sensory information from the orofacial region. We investigated the physiological and morphological properties of trigeminal subnucleus caudalis (Sp5C) lamina I neurons in slices prepared from the medulla oblongata of 13- to 15-day-old postnatal rats using patch-clamp recordings and subsequent biocytin-streptavidin-Alexa labeling. Twenty-five neurons were recorded and immunohistochemically stained. The Sp5C lamina I consisted of several types of neurons which, on the basis of their responses to somatic current injection, can be classified into four groups: tonic neurons, which fired throughout the depolarizing pulse; phasic neurons, which expressed an initial burst of action potentials; delayed onset neurons, which showed a significant delay of the first action potential; and single spike neurons, characterized by only one to five action potentials at the very beginning of the depolarizing pulse even at high levels of stimulation intensity. Electrical stimulation of the spinal trigeminal tract evoked AMPA receptor-mediated excitatory postsynaptic currents (EPSC) exhibiting a strong polysynaptic component. AMPA receptor-mediated miniature excitatory postsynaptic currents (mEPSC) were characterized by a 10-90% rise time of 0.50+/-0.06 ms and a decay time constant of 2.5+/-0.5 ms. The kinetic properties of NMDA receptor-mediated EPSCs were measured at +40 mV. The 10-90% rise time was 8+/-2 ms and the deactivation time constants were 94+/-31 and 339+/-72 ms, respectively. Intracellular staining and morphological analysis revealed three groups of neurons: fusiform, pyramidal, and multipolar. Statistical analysis indicated that the electrophysiological properties and morphological characteristics are correlated. Tonic and phasic neurons were fusiform or pyramidal and delayed onset and single spike neurons were multipolar. Our results show that both the physiological and morphological properties of Sp5C lamina I neurons exhibit significant differences, indicating their specific integration in the processing and transmission of sensory information from the orofacial region.

Morphometric and histological studies of the pons were performed by light microscopy in 28 cases of externally normal human fetuses ranging from 90 to 246 mm in crown-rump length (CRL) and from 13 to 28 weeks of gestation. The brainstems of fetuses were embedded in celloidin or paraffin, and transverse sections were prepared. The pons was divided into two regions at the most ventral margin of the medial lemniscus at the level of the motor trigeminal nucleus. The relationships between the total dorsoventral length, ventral length, and dorsal length of the pons versus CRL and gestational ages were calculated, and empiric formulas were fitted. It was found that the ventral portion increased in size more rapidly than the dorsal portion. The proportion of the ventral portion in the total dorsoventral length was constitutively higher than that of the dorsal portion in the present range of CRL. In the pontine nuclei, from 235 mm in the CRL, some large cells with rich cytoplasm, pale nuclei, and a distinct nucleolus appeared on the dorsal side of the pyramidal tract. According to Weigert stained preparations, the first myelinated fibers in each motor root of the trigeminal, abducent, and facial nerves were recognized at 130-140 mm in CRL and the medial lemniscus at 230-235 mm.

Physiological evidence indicates that vestibular signals modulate the activity of motoneurons innervating the masseter muscle. Recently, experiments using transynaptic retrograde transport of pseudorabies virus provided anatomical evidence that many neurons concentrated in the dorsomedial part of the parvicellular division of the medial vestibular nucleus (MVePC) and the caudal prepositus hypoglossi (PH) provide inputs to motoneurons innervating the lower third of the superficial layer of the masseter muscle. However, it was not clear whether this vestibulo-trigeminal projection was monosynaptic or polysynaptic. The present study sought to determine whether neurons in the MVePC or PH project directly to motoneurons controlling the masseter muscle in rats. For this purpose, an anterograde tracer (biotinylated dextran amine, BDA) was injected into vestibular nuclei (mainly MVePC) or PH and a retrograde tracer (the beta-subunit of cholera toxin, b-CT) was injected into the masseter muscle ipsilateral or contralateral to the BDA injection site. Following injections of BDA into the vestibular nuclei or PH, anterogradely labeled axon terminals were observed bilaterally in the motor trigeminal nucleus (Mo5), particularly in the ventral, medial, and lateral portions of the nucleus; projections to dorsal Mo5 were sparse. In addition, retrogradely labeled motoneurons were located in the ventral and lateral portions of the ipsilateral Mo5. Moreover, anterogradely labeled terminals were observed to be in close proximity to motoneurons in the Mo5 that were retrogradely labeled from b-CT injections into the masseter muscle. This study provides direct evidence that a monosynaptic pathway exists between the MVePC and PH and masseter motoneurons.

Post-weaning mice fed exclusively milk display low-frequency exploratory behavior [Ishii, T., Itou, T., and Nishimura, M. (2005) Life Sci. 78, 174-179] compared to mice fed a food pellet diet. This low-frequency exploratory behavior switched to high-frequency exploration after a switch from exclusively milk formula to a food pellet diet. Acquisition of the high-frequency exploratory behavior was irreversible. Recently, we demonstrated that the mesencephalic trigeminal nucleus (Me5) is involved in the control of feeding and exploratory behavior in mice without modulating the emotional state [Ishii, T., Furuoka, H., Itou, T., Kitamura, N., and Nishimura, M. (2005) Brain Res. 1048, 80-86]. We therefore investigated whether the Me5 is involved in acquisition of high-frequency exploratory behavior induced by the switch in diet from an exclusively milk formula to food pellets. Mouse feeding and exploratory behaviors were analyzed using a food search compulsion apparatus, which was designed to distinguish between the two behaviors under standard living conditions. Immunohistochemical analysis of immediate early genes indicated that the Me5, which receives signals from oral proprioceptors, is transiently activated after the diet change. The change from low-frequency to high-frequency exploratory behavior was prevented in milk-fed mice by bilateral lesion of the Me5. These results suggest that the Me5 is activated by signals associated with mastication-induced proprioception and contributes to the acquisition of active exploratory behavior.

Functional magnetic resonance imaging (fMRI) has become a powerful tool for studying the normal and diseased human brain. The application of fMRI in detecting neuronal signals in the trigeminal system, however, has been hindered by low detection sensitivity due to activation artifacts caused by cardiac pulse-induced brain and brainstem movement. A variety of cardiac gating techniques have been proposed to overcome this issue, typically by phase locking the sampling to a particular time point during each cardiac cycle. We sought to compare different cardiac gating strategies for trigeminal system fMRI. In the present study, we used tactile stimuli to elicit brainstem and thalamus activation and compared the fMRI results obtained without cardiac gating and with three different cardiac gating strategies: single-echo with TR of 3 or 9 heartbeats (HBs) and dual-echo T2*-mapping EPI (TR = 2 HBs, TE = 21/55 ms). The dual-echo T2* mapping and the single-echo with TR of 2 and 3 HBs cardiac-gated fMRI techniques both increased detection rate of fMRI activation in brainstem. Activation in the brainstem and the thalamus was best detected by cardiac-gated dual-echo EPI.

The neural framework and synaptic organization of trigeminal proprioceptive afferent-mediated jaw-tongue coordination were studied in rats using multiple electrophysiological and neuroanatomical approaches. Electrostimulation of the masseter nerve evoked short-latency responses (5.86 +/- 2.59 ms) in hypoglossal premotor pools including the parvocellular (PCRt) and intermediate (IRt) reticular nuclei and the dorsomedial part of the spinal trigeminal nucleus oralis (Vodm) and interpolaris (Vidm). Biocytin-labelled axon terminals from these areas traveled into the hypoglossal nucleus (XII) and contacted motoneurons. Double labelling of biotinylated dextran amine (BDA) tracing and cholera toxin B (CTB) transport demonstrated that labelled axons and terminals from the mesencephalic trigeminal nucleus (Vme) overlapped with XII premotor neurons in the alpha division and in PCRt, IRt, Vodm and Vidm. Confocal microscopic observations revealed that Vme terminals closely contacted XII premotor neurons. Dual labelling of intracellular neurobiotin staining of jaw-muscle spindle afferents (JMSAs) combined with horseradish peroxidase (HRP) retrograde transport revealed that 498 JMSA boutons apposed to 146 HRP-labelled premotor neurons. Electron microscopic observations demonstrated that 127 JMSA boutons made both axodendritic (68%) and axosomatic (32%) synapses with XII premotor neurons. Eighty-three per cent of synapses were asymmetric and the rest (17%) were symmetric. Thirty-nine per cent of JMSA boutons received presynaptic contacts from P-type terminals. Varieties of synaptic organizations were found. These results provide evidence that trigeminal proprioceptive afferents mediate jaw-tongue coordination through XII premotor neurons. Ultrastructural findings demonstrated that synapses between JMSA boutons and XII premotor neurons are predominantly excitatory, and synaptic transmission to XII motoneurons is modified on XII premotor neurons by presynaptic mechanisms. These frameworks and synaptic organizations are most probably the neural substrate for trigeminal proprioceptive afferent-mediated jaw-tongue coordination.

The sensory trigeminal nucleus of teleosts is the rostralmost nucleus among the trigeminal sensory nuclear group in the rhombencephalon. The sensory trigeminal nucleus is known to receive the somatosensory afferents of the ophthalmic, maxillar, and mandibular nerves. However, the central connections of the sensory trigeminal nucleus remain unclear. Efferents of the sensory trigeminal nucleus were examined by means of tract-tracing methods, in a percomorph teleost, tilapia. After tracer injections to the sensory trigeminal nucleus, labeled terminals were seen bilaterally in the ventromedial thalamic nucleus, periventricular pretectal nucleus, medial part of preglomerular nucleus, stratum album centrale of the optic tectum, ventrolateral nucleus of the semicircular torus, lateral valvular nucleus, prethalamic nucleus, tegmentoterminal nucleus, and superior and inferior reticular formation, with preference for the contralateral side. Labeled terminals were also found bilaterally in the oculomotor nucleus, trochlear nucleus, trigeminal motor nucleus, facial motor nucleus, facial lobe, descending trigeminal nucleus, medial funicular nucleus, and contralateral sensory trigeminal nucleus and inferior olive. Labeled terminals in the oculomotor nucleus and trochlear nucleus showed similar densities on both sides of the brain. However, labelings in the trigeminal motor nucleus, facial motor nucleus, facial lobe, descending trigeminal nucleus, and medial funicular nucleus showed a clear ipsilateral dominance. Reciprocal tracer injection experiments to the ventromedial thalamic nucleus, optic tectum, and semicircular torus resulted in labeled cell bodies in the sensory trigeminal nucleus, with a few also in the descending trigeminal nucleus., (J. Comp. Neurol. 495:279-298, 2006. (c) 2006 Wiley-Liss, Inc.)

The perception of external sensory information by the brain requires highly ordered synaptic connectivity between peripheral sensory neurons and their targets in the central nervous system. Since the discovery of the whisker-related barrel patterns in the mouse cortex, the trigeminal system has become a favorite model for study of how its connectivity and somatotopic maps are established during development. The trigeminal brainstem nuclei are the first CNS regions where whisker-specific neural patterns are set up by the trigeminal afferents that innervate the whiskers. In particular, barrelette patterns in the principal sensory nucleus of the trigeminal nerve provide the template for similar patterns in the face representation areas of the thalamus and subsequently in the primary somatosensory cortex. Here, we describe and review studies of neurotrophins, multiple axon guidance molecules, transcription factors, and glutamate receptors during early development of trigeminal connections between the whiskers and the brainstem that lead to emergence of patterned face maps. Studies from our laboratories and others' showed that developing trigeminal ganglion cells and their axons depend on a variety of molecular signals that cooperatively direct them to proper peripheral and central targets and sculpt their synaptic terminal fields into patterns that replicate the organization of the whiskers on the muzzle. Similar mechanisms may also be used by trigeminothalamic and thalamocortical projections in establishing patterned neural modules upstream from the trigeminal brainstem.

Functional imaging studies and clinical evidence suggest that structures in the brainstem contribute to migraine pathophysiology with a strong association between the brainstem areas, such as periaqueductal gray (PAG), and the headache phase of migraine. Stimulation of the superior sagittal sinus (SSS) in humans evokes head pain. Second-order neurons in the trigeminal nucleus that are activated by SSS stimulation can be inhibited by PAG stimulation. The present study was undertaken to identify pontine and medullary structures that respond to noxious stimulation of the superior sagittal sinus or to ventrolateral PAG stimulation. The distribution of neurons expressing the protein product (fos) of the c-fos immediate early gene were examined in the rostral medulla and caudal pons of the cat after (i) sham, (ii) stimulation of the superior sagittal sinus, (iii) stimulation of the superior sagittal sinus with PAG stimulation, or (iv) stimulation of the PAG alone. The structures examined for fos were the trigeminal nucleus, infratrigeminal nucleus, reticular nuclei, nucleus raphe magnus, pontine blink premotor area, and superior salivatory nucleus. Compared with all other interventions, fos expression was significantly greater in the trigeminal nucleus and superior salivatory nucleus after SSS stimulation. After PAG with SSS stimulation, on the side ipsilateral to the site of PAG stimulation, fos was significantly greater in the nucleus raphe magnus. These structures are likely to be involved in the neurobiology of migraine.

It is currently thought that the hypothalamus influences motor output through connections with premotor structures which in turn project to motor nuclei. However, hypocretinergic/orexinergic projections to different motor pools have recently been demonstrated. The present study was undertaken to examine whether hypocretinergic/orexinergic neurons are the only source of projections from the hypothalamus to the trigeminal motor nucleus in the guinea-pig. Cholera toxin subunit b was injected into the trigeminal motor nucleus in order to retrogradely label premotor neurons. Two anatomically separated populations of labeled neurons were observed in the hypothalamus: one group was distributed along the dorsal zone of the lateral hypothalamic area, the lateral portion of the dorsomedial hypothalamic nucleus and the perifornical nucleus; the other was located within the periventricular portion of the dorsomedial hypothalamic nucleus. Numerous cholera toxin subunit b+ neurons in both populations displayed glutamate-like immunoreactivity. In addition, premotor neurons containing hypocretin/orexin were distributed throughout the lateral dorsomedial hypothalamic nucleus, perifornical nucleus and lateral hypothalamic area. Other premotor neurons were immunostained for melanin concentrating hormone; these cells, which were located within the lateral hypothalamic area and the perifornical nucleus, were intermingled with glutamatergic and hypocretinergic/orexinergic neurons. Nitrergic premotor neurons were located only in the periventricular zone of the dorsomedial hypothalamic nucleus. None of the hypothalamic premotor neurons were GABAergic, cholinergic or monoaminergic. The existence of diverse neurotransmitter systems projecting from the hypothalamus to the trigeminal motor pool indicates that this diencephalic structure may influence the numerous functions that are subserved by the trigeminal motor system.

Vagal nerve stimulation has been reported to enhance memory in both rats and humans, and to be an effective treatment for epilepsy in some patients, but the underlying neuroanatomical substrate(s) responsible for these effects remains unknown. Since there is no direct anatomical projection from the nucleus tractus solitarius, the main vagal relay site of the brain, to the hippocampus, we tested whether a multisynaptic pathway exists. Pseudorabies virus, a pig herpesvirus that can be used as a retrograde transneuronal tracer, was injected into the ventral CA1 hippocampus of rats, and after 4 days, pseudorabies virus infected neurons were identified in the general visceral portion of the nucleus tractus solitarius, with the majority being localized in the A2 noradrenergic cell group. Other autonomic brainstem nuclei, including the parabrachial nucleus, locus coeruleus, A1 and A5 noradrenergic cell groups, and C1 adrenergic cell group, were labeled. In order to identify some of the potential relay sites of the nucleus tractus solitarius-->hippocampal pathway, immunotoxin lesions of the ventral CA1 region were made that selectively destroyed either the noradrenergic or cholinergic fibers. After 2 weeks' recovery, pseudorabies virus was injected in this same CA1 area, and 4 days later, the transneuronal labeling in the nucleus tractus solitarius was reduced by approximately 65%. These findings suggest that the noradrenergic neurons of the locus coeruleus and cholinergic neurons of the medial septum/diagonal band are likely to be relay sites for this pathway. Other potential linkages are discussed. In summary, this is the first anatomical report to show that the general visceral region of nucleus tractus solitarius is linked via multisynaptic relays to the hippocampus.

We examined the functional organization of the rat trigeminal nuclear complex and its developmental dynamics using a multiple-site optical recording technique. Brainstem preparations were dissected from embryonic day 12 (E12)-E16 rat embryos, and stimulation was applied individually to the three branches of the trigeminal nerve (V1-V3). The action potential activity of presynaptic fibers was detected from E13, and the glutamate-mediated postsynaptic response was significantly observed from E15 on. At E14, the evoked signals usually consisted of only the action potential-related fast component. However, when extracellular Mg2+ was removed, a significant dl-2-amino-5-phosphonovaleric acid-sensitive slow component appeared. These results suggest that postsynaptic function mediated by NMDA receptors is latently generated as early as E14. The response area of the three branches of the trigeminal nerve showed some functional somatotopic organization, with the ophthalmic (V1) nerve area medially located and the mandibular (V3) nerve area laterally located. The center of the trigeminal nuclear complex in which the activity of neurons and synaptic function was greatest shifted caudally with development, suggesting that the functional architecture of the trigeminal nuclear complex is not fixed but changes dynamically during embryogenesis. By electron microscopy, we could not observe clear correlations between functional data and morphological information; when we surveyed E16 preparations, we could not identify typical synaptic structures between the 1,1'-dioctyldecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate-labeled trigeminal nerve terminals and the neurons in the trigeminal nuclear complex. This implies that postsynaptic function in the trigeminal nuclear complex is generated before the appearance of the morphological structure of conventional synapses.

Projections to the forebrain from lamina I of spinal and trigeminal dorsal horn were labeled anterogradely with Phaseolus vulgaris-leucoagglutinin (PHA-L) and/or tetramethylrhodamine-dextran (RHO-D) injected microiontophoretically. Injections restricted to superficial laminae (I/II) of dorsal horn were used primarily. For comparison, injections were also made in deep cervical laminae. Spinal and trigeminal lamina I neurons project extensively to restricted portions of the ventral posterolateral and posteromedial (VPL/VPM), and the posterior group (Po) thalamic nuclei. Lamina I also projects to the triangular posterior (PoT) and the ventral posterior parvicellular (VPPC) thalamic nuclei but only very slightly to the extrathalamic forebrain. Furthermore, the lateral spinal (LS) nucleus, and to a lesser extent lamina I, project to the mediodorsal thalamic nucleus. In contrast to lamina I, deep spinal laminae project primarily to the central lateral thalamic nucleus (CL) and only weakly to the remaining thalamus, except for a medium projection to the PoT. Furthermore, the deep laminae project substantially to the globus pallidus and the substantia innominata and more weakly to the amygdala and the hypothalamus. Double-labeling experiments reveal that spinal and trigeminal lamina I project densely to distinct and restricted portions of VPL/VPM, Po, and VPPC thalamic nuclei, whereas projections to the PoT appeared to be convergent. In conclusion, these experiments indicate very different patterns of projection for lamina I versus deep laminae (III-X). Lamina I projects strongly onto relay thalamic nuclei and thus would have a primary role in sensory discriminative aspects of pain. The deep laminae project densely to the CL and more diffusely to other forebrain targets, suggesting roles in motor and alertness components of pain., (Copyright 2003 Wiley-Liss, Inc.)

This study investigates, in the anesthetized rat, the dendritic extent of parabrachial (PB) neurons whose nociceptive response to noxious stimuli has been previously recorded with an extracellular micropipette. The PB neurons were then injected with biocytin through the recording micropipette, via a juxtacellular technique. The dendritic arborization of individual PB neurons was carefully compared with the projections of medullary (trigeminal) and spinal lamina I neurons. The latter projections were labeled in separate animals that received injections of Phaseolus vulgaris-leucoagglutinin restricted to the superficial layers of spinal or medullary dorsal horn. We report here that: 1) PB neurons excited chiefly by noxious stimulation of the face have their dendritic tree located primarily within the field of lamina I trigeminal projections, i.e., in the caudal portion of PB area, around the external medial and the caudal part of the external lateral subnuclei; and 2) PB neurons excited chiefly by noxious stimulation of the paw or the tail have their dendritic tree located primarily within the field of lamina I spinal projections, i.e., in PB mid-extent, around the borderline between the external lateral and both the lateral crescent and the superior lateral subnuclei. Our results suggest the presence of an extensive excitatory axodendritic link between lamina I projections and PB nociceptive neurons around the lateral crescent and the external medial subnuclei. These findings strengthen the possibility of involvement of a subgroup of PB neurons in nociceptive processes., (Copyright 2003 Wiley-Liss, Inc.)

Peripheral input convergence on trigeminal premotor neurons in the vicinity of trigeminal motor nucleus has been investigated. Thirty neurons were identified by their antidromic responses to microstimulation of the masseteric subnucleus of trigeminal motor nucleus (NVmot-mass). Peripheral receptive fields were found in the buccal mucosae, periodontal ligaments, palate, tongue and vibrissae for 16 neurons located in the intertrigeminal area (NVint), supratrigeminal area (NVs), main sensory trigeminal nucleus (NVsnpr) and subnucleus gamma of the oral nucleus of the spinal trigeminal tract (NVspo-gamma). Eleven neurons in the NVint, NVs and NVspo-gamma responded to passive jaw opening: nine neurons were activated and two were inhibited. None of the neurons responded to both the orofacial mechanical stimulation and passive jaw opening. Forty-six percent of neurons (13 out of 28 tested) received inputs from the inferior alveolar nerve (IAN) and 53% of neurons (8 out of 15 tested) received inputs from the infraorbital nerve (ION). Out of 15 neurons tested for inputs from the IAN and ION, 7 neurons in the NVsnpr and NVspo-gamma received input from both. Sixteen percent of neurons (4 out of 25) received inputs from the masseteric nerve (MassN). None of the neurons with inputs from IAN and/or ION also received inputs from the MassN. We suggest that trigeminal premotor interneurons with projections to the NVmot-mass fall into two broad categories, those with inputs from the IAN and/or ION and those with inputs from the MassN, possibly muscle spindle afferents, and no neuron receiving inputs from both.

Possible involvement of ATP-sensitive K(+) (K(ATP)) channels in the cerebral blood flow (CBF) response to neuronal functional activation was investigated in unanesthetized rats. Glibenclamide (1, 2, or 10 micromol/l), a specific inhibitor of K(ATP) channels, was infused intracisternally continuously for 30 min prior to and during the 1-min period of measurement of CBF. Unilateral functional activation was maintained throughout the measurement of CBF by continuous stroking of the vibrissae on the left side of the face. Local CBF was determined bilaterally by the quantitative autoradiographic [14C]iodoantipyrine method in four structures of the whisker-to-barrel cortex pathway and in 18 structures unrelated to the pathway. Glibenclamide tended to lower baseline CBF in almost all regions examined, statistically significantly (P<0.05) in the cerebellar lobules with all doses, in the cerebellar cortex with 10 micromol/l, in the pontine nuclei with 2 and 10 micromol/l, and in the spinal trigeminal nucleus of the unstimulated side with all doses. Vibrissal stimulation increased CBF unilaterally in all the stations of the pathway, but the percent increases were not statistically significantly affected by the glibenclamide treatment, except in the spinal trigeminal nucleus where it was reduced statistically significantly (P<0.05) only by 2 micromol/l glibenclamide. These results indicate that K(ATP) channels may play a role in the tonic regulation of baseline CBF in some regions but provide no support for their role in the increases in CBF evoked by functional activation., (Copyright 2002 Elsevier Science B.V.)

A characteristic peculiarity of the trigeminal sensory system is the presence of two distinct populations of primary afferent neurons. Most of their cell bodies are located in the trigeminal ganglion (TG) but part of them lie in the mesencephalic trigeminal nucleus (MTN). This review compares the neurochemical content of central versus peripheral trigeminal primary afferent neurons. In the TG, two subpopulations of primary sensory neurons, containing immunoreactive (IR) material, are identified: a number of glutamate (Glu)-, substance P (SP)-, neurokinin A (NKA)-, calcitonin gene-related peptide (CGRP)-, cholecystokinin (CCK)-, somatostatin (SOM)-, vasoactive intestinal polypeptide (VIP)- and galanin (GAL)-IR ganglion cells with small and medium-sized somata, and relatively less numerous larger-sized neuropeptide Y (NPY)- and peptide 19 (PEP 19)-IR trigeminal neurons. In addition, many nitric oxide synthase (NOS)- and parvalbumin (PV)-IR cells of all sizes as well as fewer, mostly large, calbindin D-28k (CB)-containing neurons are seen. The majority of the large ganglion cells are surrounded by SP-, CGRP-, SOM-, CCK-, VIP-, NOS- and serotonin (SER)-IR perisomatic networks. In the MTN, the main subpopulation of large-sized neurons display Glu-immunoreactivity. Additionally, numerous large MTN neurons exhibit PV- and CB-immunostaining. On the other hand, certain small MTN neurons, most likely interneurons, are found to be GABAergic. Furthermore, NOS-containing neurons can be detected in the caudal and the mesencephalic-pontine junction portions of the nucleus. Conversely, no immunoreactivity to any of the examined neuropeptides is observed in the cell bodies of MTN neurons but these are encircled by peptidergic, catecholaminergic, serotonergic and nitrergic perineuronal arborizations in a basket-like manner. Such a discrepancy in the neurochemical features suggests that the differently fated embryonic migration, synaptogenesis, and peripheral and central target field innervation can possibly affect the individual neurochemical phenotypes of trigeminal primary afferent neurons.

The paratrigeminal nucleus, which receives sensory input from trigeminal, glossopharyngeal and vagus nerves, has efferent projections to bulbar, pontine and possibly to thalamic structures associated with nociception, thermoregulation and cardiovascular control. Anterograde neuronal tracers were used to study paratrigeminal efferent connections. Labeled terminal fibers, evidencing bilateral efferent paratrigeminal projections were observed in the medial and caudal solitary tract (sol), lateral reticular nucleus (LRt), ambiguus nucleus (Amb), rostroventrolateral reticular nucleus (RVL), while ipsilateral projections were found in the parabrachial (PB) nuclei and ventral portion of the ventral posteromedial thalamic nucleus (VPM). This extends other findings that describe paratrigeminal projections. Retrograde neuronal transport tracers, microinjected in the defined projection areas were used to map distribution of the paratrigeminal neurons originating different efferent connections. Microinjection of latex microspheres containing fluorescein or rhodamine and Fluoro-gold in the ventral VPM, PB, RVL, Amb, LRt and NTS revealed sets of labeled paratrigeminal nucleus neurons respectively organised in a rostral-caudal sequence. The largest extent of the paratrigeminal nucleus (medial portion) contained neurons projecting to the RVL/Amb, structures associated with cardiovascular regulation. The data show a segmented topographical organization of the nucleus, with different sets of neurons within delimited segments, projecting to neuronal structures associated with different functions. This points to a complex and extensive role for the paratrigeminal nucleus in the integration of somatosensory reflexes related to cardiovascular, respiratory and pain mechanisms. The nucleus may act as a medullary relay interposed between sensory afferents and different structures related to homoeostatic functions.

Comparisons of microscopical neuroanatomic data from different experiments and investigators are typically hampered by the use of different section planes and dissimilar techniques for data documentation. We have developed a framework for visualization and comparison of section-based, spatial distribution data, in brain stem nuclei. This framework provides opportunities for harmonized data presentation in neuroinformatics databases. Three-dimensional computerized reconstructions of the rat brain stem and precerebellar nuclei served as a basis for establishing internal coordinate systems for the pontine nuclei and the precerebellar divisions of the sensory trigeminal nuclei. Coordinate based diagrams were used for presentation of experimental data (spatial distribution of labelled neurons and axonal plexuses) from standard angles of view. Each nuclear coordinate system was based on a cuboid bounding box with a defined orientation. The bounding box was size-adjusted to touch cyto- and myeloarchitectonically defined boundaries of the individual nuclei, or easily identifiable nearby landmarks. We exemplify the use of these internal coordinate systems with dual retrograde neural tracing data from pontocerebellar and trigeminocerebellar systems. The new experimental data were combined, in the same coordinate based diagrams, with previously published data made available via a neuroinformatics data repository (www.nesys.uio.no/Database, see also www.cerebellum.org). Three-dimensional atlasing, internal nuclear coordinate systems, and consistent formats for presentation of neuroanatomic data in web-based data repositories, offer new opportunities for efficient analysis and re-analysis of neuroanatomic data.

Retrograde tracing methods are employed here to demonstrate that neurons in the trigeminal mesencephalic nucleus (5me) project to the superior colliculus (SC) in the rat. These neurons, mainly of small size, are situated bilaterally in the caudal part of the nucleus. Anterograde tracing studies demonstrated the existence of SC projections to neurons in 5me. The SC fibers contact 'en passant' small as well as large cell bodies of 5me neurons. These pathways suggested a role of the 5me neurons in oculomotor control and associated oro-facial functions.

The trigeminal nerve is the largest and most complex of twelve cranial nerves. Its vast size and influence are greatly appreciated when one attempts to diagnose and treat patients suffering from orofacial pain and temporomandibular joint disorders. Without a thorough knowledge of the trigeminal nerve, the efficacy of diagnostic and therapeutic procedures will be very disappointing. This is the first of a four-part series of articles about the trigeminal nerve, a basic over-view of both the gross and neuroanatomical structures is presented.