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A wide range of microorganisms can infect the central nervous system (CNS). The immune response of the CNS provides limited protection against microbes penetrating the blood-brain barrier. This results in a neurological deficit and sometimes leads to high morbidity and mortality rates despite advanced therapies. For the last two decades, different studies have expanded our understanding of the molecular basis of human neuroinfectious diseases, especially concerning the contributions of mast cell interactions with other central nervous system compartments. Brain mast cells are multifunctional cells derived from the bone marrow and reside in the brain. Their proximity to blood vessels, their role as "first responders" their unique receptors systems and their ability to rapidly release pathogen responsive mediators enable them to exert a crucial defensive role in the host-defense system. This review describes key biological and physiological functions of mast cells, concerning their ability to recognize pathogens via various receptor systems, followed by a coordinated and selective mediator release upon specific interactions with pathogenic stimulating factors. The goal of this review is to direct attention to the possibilities for therapeutic applications of mast cells against bacterial and viral related infections. We also focus on opportunities for future research activating mast cells via adjuvants.

By the use of the indirect immunofluorescence and in situ hybridization techniques, the distribution of calcitonin gene-related peptide (CGRP)-like immunoreactivity (LI) and CGRP mRNA was studied in the spinal cord as well as in the midline raphe nuclei and the hypoglossal nucleus in the medulla oblongata of the monkey ( Macaca fascicularis ). In the spinal cord only a few large neurons in the motor nucleus contained CGRP-LI, while a majority of the neurons in the hypoglossal nucleus contained CGRP-LI. A relatively dense innervation by CGRP-immunoreactive (IR) fibers was also seen close to cell bodies and proximal dendrites of large neurons in the motor nucleus, especially in it ventral part. 5-Hydroxytryptamine (5-HT)-, substance P- and thyrotropin-releasing hormone (TRH)-IR varicosities were also observed in a similar postition around large neurons in the motor nucleus. Double labeling disclosed that the majority of CGRP-IR axon terminals also contained 5-HT-LI. Expression of CGRP mRNA was found in neurons in the medullary midline raphe nuclei and in large neurons in the motor nucleus at the cervical spinal cord level. In adjacent sections of the medulla oblongata, CGRP-labeled neurons in the midline raphe nuclei also expressed preprotachykinin mRNA. The present results show that CGRP- and 5-HT-LI coexist in fibers within the motor nucleus of the monkey spinal cord and that this coexistence is probably due to the presence of CGRP in the descending bulbospinal, serotonergic pathway.

Neuropeptide- and serotonin-like immunoreactivities were studied in the lumbar spinal cord of the cat after a longitudinal incision in the ventral funiculus. This lesion, which accomplishes a central axotomy of motoneurons, was accompanied by increased level of Met-enkephalin-like immunoreactivity in nerve endings in those parts of the motor nucleus (lamina IX) which harbored severed motoneurons. This increase, which was evident in the fluorescence microscope, could be verified photometrically by use of a confocal scanning laser microscope.

The effects of ricin (RCA-120) on non-injected dorsal root ganglion (DRG) cells, sharing the same DRG as the injected ones, were studied after ricin injections into the tibial nerve and B-HRP injections into the peroneal nerve. Numerous DRG cells containing B-HRP reaction product and exhibiting signs of advanced degeneration were observed. The findings suggest that ricin may be released from dying injected DRG neurons and taken up by adjacent non-injected DRG cells, which subsequently degenerate.

Calcitonin gene-related peptide (CGRP)-immunoreactive (IR) fibers in the rat dorsal horn superficial laminae vanish almost completely 3 weeks following unilateral dorsal rhizotomy. After a prolonged survival (20 weeks) of dorsal rhizotomy there is, however, a reappearance of CGRP-IR fibers in the corresponding laminae of the dorsal horn. The density of such IR fibres showed a clear gradient with the lowest number found in the midlesion region and an increase in density towards the neighboring, intact segments. In normal as well as lesioned rats, no neurons intrinsic to the dorsal horn contained detectable levels of CGRP-like immunoreactivity (LI). Furthermore, no cells could, by use of in situ hybridization, be demonstrated to contain detectable levels of mRNA encoding for CGRP in the dorsal horn. Based on these findings, we suggest that the CGRP-IR fibers observed following long-term survival of dorsal rhizotomy derive from proliferating collateral branches of primary afferents of neighboring intact segments.

The distribution of calcitonin gene-related peptide (CGRP)-immunoreactive (IR) fibers and cell bodies was studied in the spinal cord and the medulla oblongata of the grey monkey (Macaca fascicularis) using peroxidase-antiperoxidase (PAP) immunohistochemistry. At all levels of the spinal cord many CGRP-IR motoneurons and fibers were seen in the motor nuclei. In the medulla, CGRP-IR cell bodies were encountered in nucleus raphe obscurus, nucleus raphe pallidus and nucleus raphe magnus, nucleus reticularis lateralis as well as in the area dorsal to the inferior olive. Bulbar motoneurons were much more intensely stained than spinal cord motoneurons, indicating higher levels of CGRP-like immunoreactivity (L1) at the medullary level. The concentration of CGRP-LI measured by radioimmunoassay showed higher levels in the dorsal quandrants as compared to the ventral quadrants, but the dorsal/ventral ratio was lower than has previously been reported from the rat. The present results demonstrate that using the PAP technique CGRP-LI can be visualized in a larger number of spinal cord motoneurons of the monkey than earlier revealed by immunofluorescence. Moreover, the finding supports the view that the CGRP-IR nerve endings in the spinal motor nuclei originate from cell bodies in the medullary raphe nuclei.

The distribution of nerve growth factor receptor (NGFr)-like immunoreactivity and of calcitonin gene-related peptide (CGRP)-like immunoreactivity was studied in nerve fibers of the spinal and medullary dorsal horn of the monkey and the cat, using double-labelling immunohistochemistry with polyclonal CGRP antiserum and a monoclonal antibody against human NGFr. In both species there was an extensive distribution overlap between NGFr-LI and CGRP-LI. However, lack of NGRr-LI in many CGRP-immunoreactive axons suggests that not all CGRP-positive primary afferent fibers possess NGFr.

Trigeminal ganglia and brain stem of adult cats were studied following HRP injections into tooth pulps or after exposure of the cut end of the inferior alveolar nerve to HRP. Ipsilateral ganglion cells within a wide range of sizes were labeled in both experimental situations, whereas no labeled cells were observed in the contralateral ganglion in any animal. Labeled central branches of tooth pulp and inferior alveolar neurons were observed in all subdivisions of the ipsilateral trigeminal sensory complex. Terminal labeling in the tooth pulp experiments was confined to the dorsomedial parts of the main sensory nucleus and subnuclei oralis and interpolaris. Caudal to the obex terminal labeling was restricted to the medial halves of laminae I, IIa and V of the medullary dorsal horn. In the inferior alveolar nerve experiments dense terminal labeling was observed in the dorsal parts of the main sensory nucleus and subnuclei oralis and interpolaris. Caudal to the obex terminal labeling was located throughout laminae I to V in contrast to the tooth pulp experiments. Neither of the two experimental situations offers any evidence for a bilateral or contralateral brain stem projection of primary trigeminal neurons.

The retrograde transport of horseradish peroxidase (HRP) was used to examine the location of sympathetic ganglion cells with axons in facial motor branches of the cat. Large numbers of HRP-labeled neurons were observed in the rostro-anterior part of the superior cervical ganglion. In addition, some labeled neurons were found in the cervical sympathetic trunk, the accessory cervical, middle cervical and stellate ganglia.

The effects of sciatic nerve resection on lumbar dorsal root ganglion cells and their central branches have been studied in the adult rat. A quantitative analysis of the lumbar dorsal root ganglia indicated a 15–30% cell loss on the operated side. Argyrophilia indicating transganglionic degeneration was observed in Fink-Heimer stained sections from the lumbar spinal cord and the brainstem. The areas of degeneration argyrophilia were mainly located in the medial part of the ipsilateral L2–L6 dorsal horn laminae I–IV, the tract of Lissauer, the dorsal funiculus and the gracile nucleus. A few degenerating fibers could also be observed in the ipsilateral dorsal horn laminae V and VI, and in the ipsilateral ventral horn as well as in the contralateral dorsal and the gracile nucleus. The results confirm and extend previous findings at other levels and in other species. This suggests that cell loss and transganglionic degeneration may be general phenomena affecting a substantial proportion of primary sensory neurons following peripheral nerve injury.

Summary In 16 kittens either the frontal or the inferior alveolar nerve was transected and in 17 adult rats either the supraorbital, the infraorbital or the mental nerve was divided. The postoperative survival periods were kept at 3–28 days for the kittens and 15–26 days for the rats. Sections from the caudal brain stem and the upper part of the cervical cord were impregnated according to the Fink-Heimer method, procedure II. In the kittens degeneration was found after the 8th postoperative day ipsilaterally in both the spinal and main sensory trigeminal nuclei and the spinal trigeminal tract. In the rats degeneration was found in all cases in the same ipsilateral structures as in the kittens. The amount of degeneration was relatively great in the rats, whereas it was very modest in the kittens. A somatotopical pattern was found for the degeneration both within the spinal and the main sensory nuclei. It was in agreement with what has been found in earlier studies, where other techniques have been used. By a comparison with the results of a previous study on the trigeminal nerve in the rat, where partial lesions of the ganglia had been made, it was found that the degeneration in the present study did not cover the whole area receiving primary trigeminal afferents. Possible explanations for this are discussed.

Retrograde and transganglionic transport of horseradish peroxidase has been used to study the cell bodies of origin and the central projections of neurons innervating the rat masseter muscle. Labeled cell bodies were observed both in the trigeminal ganglion and in the mesencephalic trigeminal nucleus. Major central projections from mesencephalic trigeminal neurons were traced to the supratrigeminal nucleus and to the brainstem reticular formation. Smaller projections from these neurons could be followed to the borders of the solitary tract and hypoglossal nuclei as well as to lamina V of nucleus caudalis and corresponding areas in the dorsal horn at C1-C2 spinal cord segments. Labeling from trigeminal ganglion neurons was observed close to the trigeminal tract in all subdivisions of the trigeminal sensory nuclear complex and in the dorsal horn lamina I at C1 and C2 levels.

The distribution of degenerating fibers in the spinal cord was studied in Fink-Heimer-stained sections following treatment of the tibial nerve with ricinus communis agglutinin (RCA 120). The ricin was either injected into the nerve or applied in a capsule on the transected nerve. Short survival times and low doses of ricin resulted in degeneration in somatotopically appropriate parts of the medial dorsal horn. Longer survival times and higher doses resulted in degeneration which progressively expanded into inappropriate areas in the central and lateral parts of the dorsal horn and in deeper laminae regardless of the mode of application. Furthermore, the effect of a ricin injection into the tibial nerve on transganglionic transport of choleragenoid horseradish peroxidase (B-HRP) in the peroneal nerve was studied following a simultaneous or delayed B-HRP injection. A simultaneous ricin and a B-HRP injection resulted in primary afferent HRP labeling in the gray matter, regardless of the dose of ricin. Following a delayed B-HRP injection almost no primary afferent labeling was seen in the gray matter, unless a very low dose of ricin was injected. This study shows that treatment of a peripheral nerve with a high dose of ricin and a long survival time may result in a considerable non-selective degeneration of fibers in the spinal cord. A selective degeneration may, however, be obtained by using lower doses or shorter survival times.

The central projections of primary sensory neurons innervating the hard palate in the cat were studied by transganglionic transport of horseradish peroxidase conjugated to wheat germ agglutinin (WGA-HRP). Following injection of WGA-HRP in the incisive papilla terminal labeling was observed in all subdivisions of the sensory trigeminal nuclear complex. In the main sensory nucleus labeling was located in the dorsal part, especially in its most rostral portion. At the levels of nuclei oralis and interpolaris labeling was observed along the medial borders of the nuclei. In addition, at these levels distinct terminal labeling was located in patches within the trigeminal tract. In nucleus caudalis terminal labeling was confined to laminae I, II and V of the most rostral part of the nucleus. Some terminal labeling was observed also in the mid part of the solitary tract nucleus. After WGA-HRP injection in the posterior part of the hard palate a similar labeling pattern was found, but no labeling was observed in the solitary tract nucleus. The results in general indicate a relatively diffuse somatotopic organization of primary afferents innervating the palate. However, the somatotopic organization of palatine afferents within nucleus caudalis is at least partly consistent with the view that the central representation of the oral cavity is rotated 90 degrees to that of extraoral areas.

Horseradish peroxidase conjugates of either the lectin wheat germ agglutinin (WGA-HRP) or choleragenoid (B-HRP) have been shown to be sensitive neuroanatomical tracers. In the present study a comparison was made between these two conjugates as transganglionic tracers in trigeminal primary sensory neurons following injection into the rat mystacial vibrissae skin. Differences between the two tracers were observed in the labeling of cell bodies in the trigeminal ganglion. Injection of WGA-HRP resulted in labeling of predominantly small cell bodies, whereas B-HRP gave rise to labeling of somewhat larger cell bodies. By increasing the concentration of the injected WGA-HRP solution the number of labeled cells increased substantially, while a corresponding increase in the concentration of B-HRP resulted in a relatively small increase in the number of labeled cells. WGA-HRP injection resulted in labeling of primary afferents mainly in the substantia gelatinosa of the trigeminal subnucleus caudalis. When the concentration of the injected WGA-HRP solution was increased, labeling was also observed in the marginal and magnocellular zones. Following B-HRP injection, labeling was only observed in the magnocellular zone and innermost part of the substantia gelatinosa. This general pattern of labeling was the same when the concentration of the B-HRP solution was increased.

Transganglionic degeneration has been studied with the Fink-Heimer method in the trigeminal sensory nuclei of adult cats and rats following peripheral nerve transections. Degeneration was observed ipsilaterally as well as contralaterally in all cats, surviving 11–30 days after transection of the infraorbital nerve. In the rats the infraorbital or the auriculotemporal nerve was transected. After transection of the former nerve the first signs of transganglionic degeneration were observed after 7 days postoperative survival and even after 130 days there were still a lot of degenerating structures present. Between 7 and 14 days survival there was a small amount of degeneration in substantia gelatinosa. After transection of the auriculotemporal nerve, degeneration was observed only in the most caudal parts of the trigeminal sensory nuclear complex. Opposite to the situation in the cat, there was no contralateral degeneration in the rat. All degeneration areas were somatotopically organized, both in the cat and in the rat. The results are discussed in relation to a previous study of transganglionic degeneration in the trigeminal sensory nuclear complex by the authors and to anatomical and physiological studies of somatotopic organization in the trigeminal sensory nuclei. They clearky show the value of transganglionic degeneration used as a tool for analysis of central projections of primary sensory neurons.

In cats subjected to total spinal cord transection at the lower thoracic level, the calcitonin gene-related peptide (CGRP)-like immunoreactivity (LI) was studied in motoneuron cell bodies in the L6-L7 segments. In transected animals, the CGRP-immunoreactive labeling of the motoneurons was virtually absent. When combining the spinal cord transection with a unilateral rhizotomy of all dorsal roots below the transection, however, an apparently normal labelling pattern of CGRP-LI of the motoneurons was displayed on both sides. Thus, surgical interventions which affect afferent pathways to the motoneurons may have influence on the levels of CGRP-LI in otherwise intact motoneurons.

The effects of unilateral intercostal nerve transection have been studied in adult rats neonatally treated with capsaicin. Two rats were treated with capsaicin-free vehicle and served as controls. It is shown that capsaicin treatment leads to a dorsal root ganglion cell loss of about 43%, and about a 72% loss of unmyelinated dorsal root fibers. Myelinated dorsal root fibers remain unaffected. The cell size spectrum shows a 27% increase in median cell area in the capsaicin-treated rats, indicating a loss of preferentially smaller cells. A subsequent peripheral nerve transection resulted in a further cell loss of about 30% with no major change in cell size spectrum. The peripheral nerve transection also somewhat further reduces both the number of unmyelinated and myelinated dorsal root axons. The data indicate that neurons which die after a prripheral nerve transection belong to both the groups of cells, which are capsaicin-sensitive and capsaicin-resistant.

The postnatal development of cat triceps surae γ-motoneurones, retrogradely labelled with horseradish peroxidase (HRP), was studied light and electron microscopically. The mean diameter of the cell bodies of the γ-motoneurones increased by about 25% from birth to the adult stage, which was much less than the increase in cell body diameter of α-motoneurones (about 45%). Throughout development the only bouton types apposing the γ-motoneurones were the F- and S-types, with flattened and spherical synaptic vesicles, respectively. Thus, the C-, M- and T-types of boutons seen on α-motoneurones were completely lacking. The size of the boutons on the γ-motoneurones increased much less than what has been found for boutons on α-motoneurones. The number of boutons on the γ-motoneurone cell bodies seemed to decrease postnatally. This decrease was only moderate for S-type boutons but substantial for F-type boutons. In contrast, the number of boutons on the proximal dendrites appeared to increase and this was most evident for S-type boutons. The mentioned postnatal changes in synaptology were more differentiated with regard to bouton type and part of the neurones under study than what could be inferred from earlier studies on the postnatal development of α-motoneurones. These changes also occurred later than in α-motoneurones. The relative dominance of F-type boutons with probable inhibitory actions on the immature γ-motoneurone may explain the previously demonstrated poor encoding of muscle length by muscle spindles during the first postnatal weeks in the kitten.