Trigeminal Brainstem Nuclear Complex Research Articles

Tear secretion by Diquafosol suppresses the excitability of trigeminal brainstem nuclear complex neurons by reducing excessive P2Y2 expression in the trigeminal ganglion in dry eye rats

The P2Y2 receptor agonist, diquafosol sodium, is commonly used to treat the signs and symptoms of dry eye disease (DE) patients. Although diquafosol improves tear film stability, the neural mechanisms underlying the reduction in ocular pain are not well defined. This study determined if repeated application of diquafosol reduces the sensitization of nociceptive neurons in the lower trigeminal brainstem nuclear complex (TBNC) via peripheral P2Y2 mechanisms in a rat model for DE. Diquafosol was applied to the ocular surface daily for 28 days, starting at day 0 or day 14, after exorbital gland removal. The number of eyeblinks, P2Y2-immunoreactive neurons in the trigeminal ganglion (TG), and correlates of TBNC neural excitability (i.e., cFos protein and phosphorylated extracellular signal-regulated kinase (pERK) expression) were assessed in male rats. Diquafosol increased spontaneous tear volume and reduced the number of ocular surface-evoked eyeblinks in DE rats. Fluorogold-labeled TG neurons that supply the cornea expressed P2Y2. The number of P2Y2-immunoreactive neurons was increased in DE rats and suppressed by diquafosol. Diquafosol also reduced the number of cFos- and pERK-immunoreactive neurons in the TBNC in DE rats. These findings suggest that diquafosol, regardless of late-phase treatment, relieves ocular nociception in DE by reducing peripheral P2Y2 expression.

Cessation Of Migraine After Thalamic Infarction

The thalamus is a key center in migraine: nociceptive signals are conveyed there from the trigeminal brainstem nuclear complex. Not surprisingly, it is activated during the acute attack and some drugs like triptanss or propanolol elicit their pain-relief effect by locally activating thalamic neurons. By the same token, thalamic structural lesions could potentially modify the course of this disorder. We support this possibility by a clinical case. A 65 year-old woman suffered from migraine without aura and migraine with aura from her twenties. Her course was chronic and refractory to preventive and to sympomatic treatment, so that in the last four years she had abandoned neurological follow-up and drug intake. In this situation, she was affected by a painlees episode of right hemiparesis and paresthesias, without visual symtoms and clearly distinctive from her auras. An acute left thalamic infarction, localized in its anteromedial area, was disclosed. Motor recovery was good. In addition, 15 months later she remained completely free of headache and of aura, with no other intervening treatment. The interruption of the pain signals from the thalamus is the proposed mechanism for making the pain recedes. According to the lesion, a differentiation of the cingular, medial temporal and prefrontal cortex is suggested. It could be worth seeking the relationship between migraine and its evolution in larger series of thalamic infractions.

Null mutations of NT-3 and Bax affect trigeminal ganglion cell number but not brainstem barrelette pattern formation

Trigeminal ganglion (TG) neurons innervate the grid-like array of whisker follicles on the face of the mouse. Central TG axons project to the trigeminal (V) brainstem nuclear complex, including the nucleus principalis (PrV) and the spinal subnucleus interpolaris (SpVi), where they innervate barrelettes that are organized in a pattern that recapitulates the whisker pattern on the face. Neurotrophin-3 (NT-3) supports a population of TG cells that supply slowly adapting mechanoreceptors in the whisker pad. We examined mice at embryonic day 17 (E17) and on the day of birth (P0) with null mutations of NT-3, Bax, a proapoptotic gene associated with naturally occurring cell death, and Bax/NT-3 double knockout (KO) mutants to determine if: (1) the number of TG cells would be reduced; (2) eliminating the Bax gene would rescue the NT-3-dependent neurons; and (3) the central projections of the rescued axons in the Bax/NT-3 double KO mice would fail to develop the barrelette patterns in the PrV and SpVi subnuclei. In mice at E17, NT-3−/− mutants had 65% fewer TG neurons than found in age-matched wild-type (WT) mice, and at P0, the number was reduced by 55% (p < 0.001 for both). Bax null mutant mice at E17 had 132% of the WT number of TG cells (p < 0.001), although the numbers returned to WT levels by P0. Bax/NT-3 double KO mice at E17 had TG cell numbers equal to those seen in WT, but the double KO failed to retain WT TG neuron numbers in P0 mice (39% fewer cells; p < 0.001). In all cases of reduced experimental neuron numbers, and in the E17 Bax−/− mice with supernumerary cells, the barrelette patterns in the PrV and SpVi were normal. Only a slight qualitative reduction in overall barrelette field area and clarity of barrelettes were seen. These results suggest that NT-3 is not necessary for barrelette pattern formation in the brainstem.

The Role of Sensory Fiber Demography in Trigeminal and Postherpetic Neuralgias

In this study, we systematically investigated fiber demography, based on function and distribution, from the periphery to their destinations in the various central (sub) nuclei in the trigeminal brainstem nuclear sensory complex. Conventional and novel compelling information is provided, demonstrating that the ratio and somatotopy of types A and C sensory fibers at the site of a lesion can elucidate important puzzles in TNP disorders. For instance, we explain how of a major shift in the fibers’ direction and ratio at the level of the trigeminal root entry zone (REZ) influences the pathophysiology of pre- and typical trigeminal neuralgia. As a result, there is a high A/C ratio of oral and peri-oral fibers in the supero-medial region of the REZ, which is mostly susceptible to vascular compression. However, this A/C ratio varies considerably at lower proportions in other areas along the peripheral trigeminal pathway, where an injury (viral, vessel compression, or trauma) can lead to a broader spectrum of fiber involvement and, consequently, pain outcome. In summary, we explain how fiber demography can influence pain quality, location, temporal features, progress, and treatment prognosis of TNP in those patients who develop it.

Amygdalotrigeminal projection in the rat: An anterograde tracing study

Previous neurophysiological studies have demonstrated that the amygdala has a direct influence upon trigeminal motoneuron activity. The existence of a direct amygdalotrigeminal pathway in rats was proved by anterograde tracing with the neuroanatomical tracer, biotinylated dextran amine (BDA). After ipsilateral BDA application to the central nucleus of the amygdala (AmCe), widespread ipsilateral projections emerging from its medial subnucleus were traced to the trigeminal brainstem nuclear complex, including the principal sensory (Pr5) and mesencephalic trigeminal nucleus (Me5), and their premotoneurons and interneurons, located in the supratrigeminal, intertrigeminal and peritrigeminal nuclei. Sparse BDA-labeled axons and their terminals were also distributed in the contralateral Pr5, interpolar and caudal subnuclei of the spinal trigeminal nucleus. The central lateral amygdaloid nucleus gives rise to a light ipsilateral projection to the pontine part of the Me5. The present data indicate that AmCe sends massive efferents to the trigeminal nuclei in the brainstem, wherein its medial subnucleus sends the major input to them. The medial amygdaloid nucleus sparsely innervates Me5 neurons, specifically those located in its mesencephalic portion, while basomedial and basolateral efferents do not target the trigeminal nuclear complex. These results suggest that the amygdaloid input may modulate the activity of trigeminal sensory and motor neurons and, thus, the amygdala is possibly involved in the control of masticatory behavior.

Differential activation of the human trigeminal nuclear complex by noxious and non‐noxious orofacial stimulation

There is good evidence from animal studies for segregation in the processing of non-nociceptive and nociceptive information within the trigeminal brainstem sensory nuclear complex. However, it remains unknown whether a similar segregation occurs in humans, and a recent tract tracing study suggests that this segregation may not exist. We used functional magnetic resonance imaging (fMRI) to define and compare activity patterns of the trigeminal brainstem nuclear complex during non-noxious and noxious cutaneous and non-noxious and noxious muscle orofacial stimulation in humans. We found that during cutaneous pain, signal intensity increased within the entire rostrocaudal extent of the spinal trigeminal nucleus (SpV), encompassing the ipsilateral oralis (SpVo), interpolaris (SpVi) and caudalis (SpVc) subdivisions. In contrast, muscle pain did not activate SpVi, but instead activated a discrete region of the ipsilateral SpVo and SpVc. Further, muscle noxious stimulation activated a region of the ipsilateral lateral pons in the region of the trigeminal principal sensory nucleus (Vp). Innocuous orofacial stimulation (lip brushing) also evoked a significant increase in signal intensity in the ipsilateral Vp; however, non-noxious muscle stimulation showed no increase in signal in this area. The data reveal that orofacial cutaneous and muscle nociceptive information and innocuous cutaneous stimulation are differentially represented within the trigeminal nuclear complex. It is well established that cutaneous and muscle noxious stimuli evoke different perceptual, behavioural and cardiovascular changes. We speculate that the differential activation evoked by cutaneous and muscle noxious stimuli within the trigeminal sensory complex may contribute to the neural basis for these differences.

Vulnerability of macaque cranial nerve neurons to ethanol is time- and site-dependent

The present study tested the hypotheses that vulnerability to ethanol depends upon (1) population-based characteristics of the neuronal progenitors and (2) the maturation of that population by examining the effects of prenatal exposure to ethanol on brainstem nuclei derived from different rhombomeres and from the alar and basal plates. Macaca nemestrina received an ethanol-containing solution 1 day per week during the first 6 (Et6) or 24 (Et24) weeks of gestation. Control animals received an equivalent volume of saline. The treatment regime for some animals included early gastrulation (gestational day [G] 19 or G20), whereas others were treated later (on G21 or G24). Brainstems were cryosectioned and stained with cresyl violet. Stereological methods were used to determine the numbers of neurons in six different nuclei: the abducens, vagal, and hypoglossal motor nuclei and sensory components of the trigeminal brainstem nuclear complex (the principal, oral, and interpolar subnuclei). There were no differences in the numbers of neurons in any of the nuclei between controls and Et6-, or controls and Et24-treated monkeys. In contrast, the number of trigeminal sensory neurons was significantly ( P < .05) lower in animals treated on G19/G20 than in control. No differences between controls and monkeys treated on G21/G24 were detected. No motor nuclei exhibited an ethanol-induced change. These data together with data on the trigeminal motor nucleus show that vulnerability to ethanol (1) is greater in sensory nuclei than in motor nuclei and (2) is temporally restricted to the time of gastrulation.

Central Projections of Trigeminal Afferents Innervating the Face in Naked Mole‐Rats (Heterocephalus glaber)

In this study, we examined the topography of projections from facial afferents to the trigeminal brainstem nuclear complex (TBNC) in naked mole-rats using the neuronal tracer CTB-HRP. Tracer injections were made in a ventral to dorsal sequence that included the tooth pulp and dental ligament, ventral buccal pad, vibrissae, and the forehead. Labeled terminals were identified throughout the rostrocaudal extent of the TBNC, including the principal nucleus (Pr5), pars oralis (Sp5O), pars interpolaris (Sp5I), and pars caudalis (Sp5C) of the spinal trigeminal nucleus. Injections that labeled afferents from the tooth pulp and dental ligament resulted in heavy transport to dorsomedial portions of the TBNC, whereas injections made into progressively more dorsal regions of the face resulted in labeled terminals progressively more ventral and lateral in the nuclei. Injections that included dental afferents also labeled the mesencephalic nucleus of V, whereas injections into the skin of the face labeled cell bodies in the facial nucleus, and in most cases the motor nucleus of 5. Dental afferents in more rostral portions of the TBNC were coextensive with a cytochrome oxidase-dense region visible in alternate sections processed for chemoarchitecture.

Central sensitisation and cutaneous allodynia in migraine: implications for treatment.

Cutaneous allodynia, pain resulting from application of a non-noxious stimulus to normal skin, is a recently described symptom of migraine, with a potential role in directing optimal treatment for migraine attacks. Manifestations of cutaneous allodynia include discomfort when combing the hair, shaving, and wearing glasses, contact lenses, earrings or tight clothing. The exact mechanism by which a migraine attack is triggered is not known, but it has been theorised that, in some patients, once the attack has begun, central neurons can propagate information about the pain process without the need for further external stimuli. This process is termed central sensitisation. The trigeminal nerves, which innervate intracranial and extracranial tissues, account for head pain and other symptoms in migraine. The first-order neurons in the trigeminal ganglion receive input from the dural blood vessels, which is transmitted to second-order neurons in the trigeminal brain stem nuclear complex and is finally sent to the third-order neurons in the thalamus. Studies in humans and animals have shown that migraine pain progresses along this neural pathway, with throbbing head pain occurring early in the attack (sensitisation of first-order neurons), followed by central sensitisation and cutaneous allodynia within the referred pain area (second-order) and finally extracephalic allodynia (third-order). The data also indicate that once central sensitisation is established in the second- and third-order neurons, migraine treatment designed to prevent the initiation of central sensitisation can lessen the pain to some extent but cannot reverse it. Thus, treatment affecting the initiation of central sensitisation should be administered immediately after the onset of migraine pain to prevent intracranial hypersensitivity and the establishment of allodynia. The serotonin 5-HT(1B/1D) agonist anti-migraine agents (the 'triptans') block meningeal nociceptor transmission at presynaptic sites in the dorsal horn. Studies have shown that triptan therapy can abort pain prior to the development of central sensitisation, but not after allodynia has been established. Therefore, in the subset of patients who report symptoms of cutaneous allodynia with migraine attacks, early initiation of triptan therapy is currently the best intervention to achieve rapid, complete and sustained pain relief.

Chemoanatomical separation of vibrissal trigeminal primary afferents in the rat: a special central representation of supraorbital vibrissae

A choleratoxin B subunit transganglionic labelling technique and NPY immunohistochemistry were applied in the rat to achieve the chemoanatomical separation of myelinated vibrissal primary afferents, previously considered to be morphologically indistinguishable. Further, a special central representation pattern of supraorbital vibrissae was observed in the trigeminal brainstem nuclear complex: (1) Choleratoxin-labelled supraorbital vibrissal primary afferents terminated densely in their appropriate barrelettes in the trigeminal principal sensory nucleus, in the spinal oral subnucleus, in the caudal part of the spinal interpolar subnucleus, and in lamina IV of the caudal part of the spinal caudal subnucleus. (2) A second population of choleratoxin-labelled vibrissal afferents was also observed, terminating only in lamina III of the caudal subnucleus. (3) After peripheral nerve transection, NPY-immunoreactive supraorbital vibrissal primary afferent fibres appeared in their appropriate barrelettes in the principal sensory nucleus and the caudal part of the interpolar subnucleus, while in the caudal part of the caudal subnucleus NPY-immunoreactive vibrissal primary afferent terminals were found exclusively in the inner part of lamina II, extending over the outer part of lamina III. NPY-immunoreactive supraorbital vibrissal primary afferents were never found in the oral subnucleus. In contrast with the rules of the central representation of the mystacial (infraorbital) vibrissae, the multiple representation of the supraorbital vibrissae in the caudal subnucleus and the dense, barrelette-like terminal arborization of the choleratoxin-labelled supraorbital vibrissal primary afferents in the oral subnucleus apparently indicate an enhanced role of supraorbital vibrissae in reflexes that protect the eyes and the head from damage.

Trigeminal disynaptic circuit mediating corneal afferent input to M. depressor palpebrae inferioris motoneurons in the pigeon (Columba livia).

Corneal afferent projections to the trigeminal brainstem nuclear complex (TBNC) and associated structures, as determined by transganglionic transport of various tracers, were found to be predominantly concentrated in two distinct patches in the dorsolateral medulla at periobex levels. One was in the external cuneate nucleus, and the other was in the ventralmost part of the ophthalmic division of the TBNC. The projections of putative second-order neurons in these regions, as determined by injections of wheat germ agglutinin conjugated to horseradish peroxidase into the dorsolateral medulla, were found to include the dorsal trigeminal motor nucleus (Vd), which innervates the M. depressor palpebrae inferioris. Electrical stimulation of Vd, which elicited lower eyelid movements, was then used to guide injections of tracer into Vd, which retrogradely labeled clusters of neurons in the corneal afferent recipient regions of the dorsolateral medulla. The lower eyelid of pigeons, unlike the nictitating membrane and upper lid, does not appear to be appreciably involved in either reflex blinking in response to relatively mild stimulation of the cornea (e.g., air puff), or in eye closure during the saccade-like head movements associated with walking, or in eye closure during pecking; but in response to a stimulus that makes corneal contact, an upward movement of the lower lid follows descent of the nictitating membrane and upper lid as part of a defensive eye-closing mechanism. The anatomical results thus appear to define a dedicated disynaptic trigeminal sensorimotor circuit for the control of lower eyelid motility in response to mechanical or noxious stimuli of the cornea. Injections of tracers into the lower and upper eyelids labeled palpebral sensory afferents that terminated predominantly in maxillary and ophthalmic portions, respectively, of the dorsal horn of upper cervical spinal segments. These terminal fields were therefore largely separate from those of corneal afferents. There were no specific corneal afferent projections upon accessory abducens motoneurons that innervate the two muscles controlling the nictitating membrane.

Cells of origin of the trigeminohypothalamic tract in the rat.

Recent studies have demonstrated that a large number of spinal cord neurons convey somatosensory and visceral nociceptive information directly from cervical, lumbar, and sacral spinal cord segments to the hypothalamus. Because sensory information from head and orofacial structures is processed by all subnuclei of the trigeminal brainstem nuclear complex (TBNC) we hypothesized that all of them contain neurons that project directly to the hypothalamus. In the present study, we used the retrograde tracer Fluoro-Gold to examine this hypothesis. Fluoro-Gold injections that filled most of the hypothalamus on one side labeled approximately 1,000 neurons (best case = 1,048, mean = 718 +/- 240) bilaterally (70% contralateral) within all trigeminal subnuclei and C1-2. Of these neurons, 86% were distributed caudal to the obex (22% in C2, 22% in C1, 23% in subnucleus caudalis, and 18% in the transition zone between subnuclei caudalis and interpolaris), and 14% rostral to the obex (6% in subnucleus interpolaris, 4% in subnucleus oralis, and 4% in subnucleus principalis). Caudal to the obex, most labeled neurons were found in laminae I-II and V and the paratrigeminal nucleus, and fewer neurons in laminae III-IV and X. The distribution of retrogradely labeled neurons in TBNC gray matter areas that receive monosynaptic input from trigeminal primary afferent fibers innervating extracranial orofacial structures (such as the cornea, nose, tongue, teeth, lips, vibrissae, and skin) and intracranial structures (such as the meninges and cerebral blood vessels) suggests that sensory and nociceptive information originating in these tissues could be transferred to the hypothalamus directly by this pathway.

Widespread Elimination of Naturally Occurring Neuronal Death inBax-Deficient Mice

The proapoptotic molecule BAX is required for death of sympathetic and motor neurons in the setting of trophic factor deprivation. Furthermore, adult Bax-/- mice have more motor neurons than do their wild-type counterparts. These findings raise the possibility that BAX regulates naturally occurring cell death during development in many neuronal populations. To test this idea, we assessed apoptosis using TUNEL labeling in several well-studied neural systems during embryonic and early postnatal development in Bax-/- mice. Remarkably, naturally occurring cell death is virtually eliminated between embryonic day 11.5 (E11.5) and postnatal day 1 (PN1) in most peripheral ganglia, in motor pools in the spinal cord, and in the trigeminal brainstem nuclear complex. Additionally, reduction, although not elimination, of cell death was noted throughout the developing cerebellum, in some layers of the retina, and in the hippocampus. Saving of cells was verified by axon counts of dorsal and ventral roots, as well as facial and optic nerves that revealed 24-35% increases in axon number. Interestingly, many of the supernumerary axons had very small cross-sectional areas, suggesting that the associated neurons are not normal. We conclude that BAX is a critical mediator of naturally occurring death of peripheral and CNS neurons during embryonic life. However, rescue from naturally occurring cell death does not imply that the neurons will develop normal functional capabilities.

Neurobiology of ocular pain

Abstract Ocular irritation and pain are associated with many clinical situations (e.g. accidental injury, eye diseases, surgery and contact lens wearing). Pain and related ocular sensations begin with stimulation by injurious stimuli of first-order sensory neurons of the trigeminal ganglion. Neurons responding solely to application in their receptive field of noxious mechanical forces (mechanonociceptive neurons), or of irritant chemicals and heat (polymodal nociceptive neurons), have been identified electrophysiologically in the conjunctiva, cornea, sclera, iris, ciliary body and choroid. The cornea is additionally innervated by neurons responding to low temperatures, which may account for corneal discomfort caused by cold. Also, low-threshold mechanoreceptive and cold-sensitive neurons supply the conjunctiva and sclera, possibly mediating touch and thermal sensations aroused by innocuous stimuli in the front of the eye. Ocular sensory information is transmitted from the trigeminal ganglion to specific higher-order neurons located in the trigeminal brainstem nuclear complex, the thalamus and the cerebral cortex. Local ocular inflammatory responses enhance injury-induced neural activity both in ocular nociceptive terminals and in higher order neurons. In addition to signalling acute lesions, ocular primary sensory neurons participate in post-injury processes, contributing to local inflammatory reactions (neurogenic inflammation) and to the repair of damaged tissues. These effects are mediated at least in part, by substance P and CGRP, two neuropeptides contained in ocular sensory nerve cells that are released peripherally upon tissue damage. Ocular tissues have a trophic interdependence with their sensory neurons. Ocular tissues are the source of neurotrophic factors that are critical for the early development and survival of trigeminal sensory neurons. On the other hand, the morphofunctional integrity of some ocular tissues like the cornea, appears to be dependent on the presence of an intact sensory innervation. Stimulation of ocular sensory pathways by noxious mechanical, chemical and thermal stimulation of cornea, conjunctiva or of other eye structures, evokes distinct types of ocular sensations. Differences in the quality of pain sensation presumably result from the magnitudes of activation of the various sub-populations of ocular nociceptive neurons by different stimulus modalities. In addition to conscious sensations, injurious stimuli evoke protective reflexes (blinking and lacrimation) aimed at protecting the eye and minimizing further ocular damage by noxious stimuli.

Release of immunoreactive substance P in the trigeminal brain stem nuclear complex evoked by chemical stimulation of the nasal mucosa and the dura mater encephali — a study with antibody microprobes

In order to study a possible involvement of substance P in the processing of chemonociceptive input from the nasal mucosa and the dura mater encephali in the spinal trigeminal nucleus, the release of immunoreactive substance P was measured in the trigeminal brain stem nuclear complex in anaesthetized rats. Microprobes coated with antibody to substance P were inserted into the lateral area of the brain stem up to 1 mm posterior to the obex corresponding to the trigeminal subnucleus caudalis. When the nasal mucosa was stimulated by topical administration of mustard oil (1% and 5%) into the nostrils, immunoreactive substance P was mainly detected in the dorsal region of the trigeminal brain stem nuclear complex with a maximum in the superficial gray matter. When the dura mater encephali was stimulated by topical administration of Tyrode's solution (pH 6.2), immunoreactive substance P was mainly released in the ventral region of the trigeminal brain stem nuclear complex; with pH 5.5 the release was more diffuse extending from the ventral to the dorsal part of the spinal trigeminal nucleus. Release was maximal rather after than during the administration of the stimuli, and it considerably outlasted the stimulation periods. These data suggest that substance P plays an important role in the processing of chemonociceptive inputs from the nasal mucosa and the dura mater encephali in the trigeminal brain stem nuclear complex. Substance P may be important, therefore, in the generation of those headaches that are caused by affections of the nasal mucosa and the dura mater encephali. Since enhanced levels of immunoreactive substance P were present for considerable time periods beyond the administration of the stimuli, substance P and neurokinin-1 receptors may be involved in long-lasting neuronal events following noxious stimulation.

Central projections of identified trigeminal primary afferents after molar pulp deafferentation in adult rats.

It is known that removal of the tooth pulp from mandibular molar teeth in adult rats alters the mechanoreceptive field properties of many low-threshold mechanoreceptive neurons in the trigeminal brainstem nuclear complex. The present study investigates one possible way that such deafferentation-induced receptive field changes could occur: altered central projections of uninjured trigeminal low-threshold mechanoreceptive primary afferent fibers. Intra-axonal injection of horseradish peroxidase (n = 22) or neurobiotin (n = 44) into characterized fibers was performed ipsilateral to, and 10-32 days after, removal of the coronal pulp from the left mandibular molars in adult rats. Collaterals were reconstructed, quantified, and compared by means of multivariate analyses of variance to equivalent fibers stained in normal adult rats. Stained mechanosensitive fibers from experimental animals were rapidly conducting and responded to light mechanical stimulation of one vibrissa, one tooth, oral mucosa, facial hairy skin, or guard hairs. Their central projections were indistinguishable from those of control axons in all four trigeminal subnuclei. The numbers of collaterals, areas subtended by collateral arbors, numbers of boutons per collateral, and arbor circularity did not differ from those of control afferents. Collateral somatotopy was also unaffected. These data suggest that following pulpotomy, the central collaterals of uninjured trigeminal afferents display normal morphologies and maintain normal somatotopy. Changes in the morphology of low-threshold primary afferents cannot account for the changes that occur in the receptive field properties of trigeminal brainstem neurons after pulp deafferentation.

Primary afferent plasticity following partial denervation of the trigeminal brainstem nuclear complex in the postnatal rat

Although interaxonal competition is believed to be an essential component of the normal development of numerous mammalian neuronal populations, there is considerable debate regarding the role of competition in the development and maintenance of the somatic sensory system. The results of recent investigations suggest that trigeminal primary afferents may compete for target territory in the brainstem, but it is unclear whether these interactions continue after birth. The present study explored this important issue by examining the response of individual trigeminal primary afferent neurons to partial denervation of the trigeminal brainstem nuclear complex at early postnatal ages. We utilized intracellular recording and HRP injection techniques to label primary afferent central terminal arbors in rats that sustained electrocautery of mystacial vibrissae in rows A, C, and E on the day of birth. A total of 42 low-threshold trigeminal primary afferent neurons were labeled in subnucleus interpolaris. Twenty-eight of these afferents supplied undamaged B or D row vibrissae while 14 supplied lesioned vibrissae. Qualitative and quantitative analyses revealed that the arbors associated with undamaged afferents were enlarged (mean arbor area of 13512 +/- 790.67 microns 2 vs normal area of 6130 +/- 214 microns 2) and were oriented toward the adjacent (partially denervated) territory. There was no significant change in the size of the lesioned afferent arbor area. The perimeter of the lesioned afferent arbors was increased, however, suggesting that the arbor shape had changed. This was confirmed with a form factor calculation that indicated that the circularity of the arbors associated with lesioned vibrissae was significantly reduced. Thus, while the arbors of undamaged afferents were enlarged and oriented in the direction of the partially denervated territory, the lesioned afferent arbors were not enlarged but assumed a flattened/elongate morphology within their appropriate row. The lesion-induced increase in the size of the undamaged afferent arbors was not associated with an increase in the number of bouton-like fiber swellings. The density of boutons was only 25% the value seen in normal animals. Thus, while the area supplied by the undamaged afferent arbors increased, there was no evidence that the absolute amount of terminal arbor was similarly increased (as would be the case if sprouting had occurred; see Renehan et al., 1989). We would therefore conclude that the undamaged afferents had undergone arbor expansion, but not sprouting. These data are consistent with prior suggestions that trigeminal primary afferents utilize some form of competitive interaction(s) to establish their final form and disposition. This competition would appear to continue into early postnatal periods.(ABSTRACT TRUNCATED AT 400 WORDS)

The peripheral and central projections of the Edinger-Westphal nucleus in the rat. A light and electron microscopic tracing study

The peripheral and central efferent projections of the rostral part of the Edinger-Westphal nucleus in the rat were investigated at the light and electron microscopic level by means of iontophoretic injections of the anterograde tracer Phaseolus vulgaris-leucoagglutinin and retrograde tracer injections of Fast blue and Nuclear yellow into the facial nucleus and into the principal olive. Two pathways leaving the rostral part of the Edinger-Westphal nucleus were studied, a peripheral and a central descending pathway. Fluorescent experiments demonstrated that the central pathway fibers originated from distinct individual Edinger-Westphal neurons. These neurons were mainly distributed throughout the rostral part of the Edinger-Westphal nucleus and had fusiform cell bodies. The neurons rarely form collateral projections. The central descending pathway left the Edinger-Westphal nucleus medially and terminated bilaterally in the principal olive, in the subnuclei A, B and C of the inferior olive and ipsilaterally in the medial accessory olive. The central pathway also terminated contralaterally in the lateral parabrachial nucleus, the facial nucleus, the trigeminal brainstem nuclear complex, the lateral reticular nucleus and the rostroventral reticular nucleus. The projection to the facial nucleus provides evidence for the existence of a polysynaptic loop forming the central part of the corneal blink reflex. Projections from the Edinger-Westphal nucleus to the cerebellar cortex or the deep nuclei, as described in cat and primate, could not be confirmed. The peripheral pathway left the Edinger-Westphal nucleus ventrally and terminated on dendrites of ciliary ganglion cells, along smooth muscle cells of ciliary ganglion associated arterioles and in the proximity of ciliary ganglion associated venules. The central and peripheral terminals that originate in the Edinger-Westphal nucleus all had similar ultrastructural features: clear, round vesicles and electron dense mitochondria. The terminals originating from the central descending pathway were often found to be arranged in glomerular-like structures. The central and peripheral terminals made asymmetric synaptic membrane specializations (Gray type one), except terminals innervating the ciliary ganglion associated vessels, which showed no synaptic contacts.

Central projections of the sensory innervation to the middle cerebral artery in the squirrel monkey.

To analyze the brainstem projections of the innervation to the middle cerebral artery (MCA) in the squirrel monkey, transganglionic tracing of wheat germ agglutinin conjugated with horseradish peroxidase (WGA-HRP) was used. After application of WGA-HRP to the middle cerebral artery (MCA), labelled cell bodies were identified in the ipsilateral trigeminal and superior cervical ganglia. In the brainstem, positive labelling indicative of preterminals and terminals occurred in a discontinuous pattern throughout the trigeminal brainstem nuclear complex. At the level of the obex, nerve terminations were identified in the nucleus tractus solitarius, nucleus motorius dorsalis nervi vagi and the nucleus nervi hypoglossi. Positive WGA-HRP profiles were also observed in the periaqueductal gray matter.

Trigeminal primary afferent projections to “non‐trigeminal” areas of the rat central nervous system

The central projections of rat trigeminal primary afferent neurons to various "non-trigeminal" areas of the central nervous system were examined by labeling the fibers with wheat germ agglutinin-horseradish peroxidase (WGA-HRP) transported anterogradely from the trigeminal ganglion. This technique produced a clear and comprehensive picture of trigeminal primary afferent connectivity that was in many ways superior to that which may be obtained by using degeneration, autoradiography, cobalt labeling, or HRP transganglionic transport techniques. Strong terminal labeling was observed in all four rostrocaudal subdivisions of the trigeminal brainstem nuclear complex, as well as in the dorsal horn of the cervical spinal cord bilaterally, numerous brainstem nuclei, and in the cerebellum. Labeling in the ipsilateral dorsal horn of the cervical spinal cord was very dense at C1, moderately dense at C2 and C3, and sparse at C4-C7. Numerous fibers crossed the midline in the medulla and upper cervical spinal cord and terminated in the contralateral pars caudalis and dorsal horn of the spinal cord from C1-C5. The latter axons terminated most heavily in the mandibular and ophthalmic regions of the contralateral side. Extremely dense terminal labeling was observed in the ipsilateral paratrigeminal nucleus and the nucleus of the solitary tract, moderate labeling was seen in the supratrigeminal nucleus and in the dorsal reticular formation, and small numbers of fibers were observed in the cuneate, trigeminal motor, lateral and superior vestibular nuclei, and in the cerebellum. The latter fibers entered the cerebellum in the superior cerebellar peduncle and projected to the posterior and anterior lobes as well as to the interposed and lateral deep cerebellar nuclei. Most projections in this study originated from fibers in the dorsal part of the spinal tract of V, suggesting a predominantly mandibular origin for these fibers. Projections from the ophthalmic and maxillary divisions, in contrast, were directed mainly to the cervical spinal cord bilaterally, to contralateral pars caudalis, and to certain areas of the reticular formation. In conclusion, this study has demonstrated that somatosensory information from the head and face may be transmitted directly to widespread and functionally heterogeneous areas of the rat central nervous system, including the spinal cord dorsal horn, numerous brainstem nuclei, and the cerebellum.(ABSTRACT TRUNCATED AT 400 WORDS)