Microglia and Inhibitory Circuitry in the Medullary Dorsal Horn: Laminar and Time-Dependent Changes in a Trigeminal Model of Neuropathic Pain.

Craniofacial neuropathic pain affects millions of people worldwide and is often difficult to treat. Two key mechanisms underlying this condition are a loss of the negative control exerted by inhibitory interneurons and an early microglial reaction. Basic features of these mechanisms, however, are still poorly understood. Using the chronic constriction injury of the infraorbital nerve (CCI-IoN) model of neuropathic pain in mice, we have examined the changes in the expression of GAD, the synthetic enzyme of GABA, and GlyT2, the membrane transporter of glycine, as well as the microgliosis that occur at early (5 days) and late (21 days) stages post-CCI in the medullary and upper spinal dorsal horn. Our results show that CCI-IoN induces a down-regulation of GAD at both postinjury survival times, uniformly across the superficial laminae. The expression of GlyT2 showed a more discrete and heterogeneous reduction due to the basal presence in lamina III of 'patches' of higher expression, interspersed within a less immunoreactive 'matrix', which showed a more substantial reduction in the expression of GlyT2. These patches coincided with foci lacking any perceptible microglial reaction, which stood out against a more diffuse area of strong microgliosis. These findings may provide clues to better understand the neural mechanisms underlying allodynia in neuropathic pain syndromes.

Divergent influences of the locus coeruleus on migraine pathophysiology.

Migraine is a common disabling neurological condition that is associated with several premonitory symptoms that can occur days before the headache onset. The most commonly reported premonitory symptom is marked fatigue that has been shown to be highly predictive of an ensuing migraine attack. The locus coeruleus (LC) is a key nucleus involved in arousal that has also been shown to impact pain processing. It provides one of the major sources of noradrenaline to the dorsal horn of the spinal cord and neocortex. Given the clinical association between migraine, sleep-wake regulation, and fatigue, we sought to determine whether LC modulation could impact migraine-related phenotypes in several validated preclinical models of migraine. To determine its role in migraine-related pain, we recorded dural nociceptive-evoked responses of neurons in the trigeminocervical complex, which receives trigeminal primary afferents from the durovascular complex. In addition, we explored the susceptibility to cortical spreading depression initiation, the presumed underlying phenomenon of migraine aura. Our experiments reveal a potent role for LC disruption in the differential modulation of migraine-related phenotypes, inhibiting dural-evoked activation of wide dynamic neurons in the trigeminocervical complex while increasing cortical spreading depression susceptibility. This highlights the potential divergent impact of LC disruption in migraine physiology, which may help explain the complex interactions between dysfunctional arousal mechanisms and migraine.

NR2B-Tyr phosphorylation regulates synaptic plasticity in central sensitization in a chronic migraine rat model.

BACKGROUND: Although the mechanism of chronic migraine (CM) is unclear, it might be related to central sensitization and neuronal persistent hyperexcitability. The tyrosine phosphorylation of NR2B (NR2B-pTyr) reportedly contributes to the development of central sensitization and persistent pain in the spinal cord. Central sensitization is thought to be associated with an increase in synaptic efficiency, but the mechanism through which NR2B-pTyr regulates synaptic participation in CM-related central sensitization is unknown. In this study, we aim to investigate the role of NR2B-pTyr in regulating synaptic plasticity in CM-related central sensitization. METHODS: Male Sprague-Dawley rats were subjected to seven inflammatory soup (IS) injections to model recurrent trigeminovascular or dural nociceptor activation, which is assumed to occur in patients with CM. We used the von Frey test to detect changes in mechanical withdrawal thresholds, and western blotting and immunofluorescence staining assays were performed to detect the expression of NR2B-pTyr in the trigeminal nucleus caudalis (TNC). NR2B-pTyr was blocked with the Src family kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)-pyrazolo [3,4-d] pyrimidine (PP2) and the protein tyrosine kinase inhibitor genistein to detected the changes in calcitonin gene-related peptide (CGRP), substance P (SP), and the synaptic proteins postsynaptic density 95 (PSD95), synaptophysin (Syp), synaptotagmin1 (Syt-1). The synaptic ultrastructures were observed by transmission electron microscopy (TEM), and the dendritic architecture of TNC neurons was observed by Golgi-Cox staining. RESULTS: Statistical analyses revealed that repeated infusions of IS induced mechanical allodynia and significantly increased the expression of NR2B Tyr-1472 phosphorylation (pNR2B-Y1472) and NR2B Tyr-1252 phosphorylation (pNR2B-Y1252) in the TNC. Furthermore, the inhibition of NR2B-pTyr by PP2 and genistein relieved allodynia and reduced the expression of CGRP, SP, PSD95, Syp and Syt-1 and synaptic transmission. CONCLUSIONS: These data indicate that NR2B-pTyr might regulate synaptic plasticity in central sensitization in a CM rat model. The inhibition of NR2B tyrosine phosphorylation has a protective effect on threshold dysfunction and migraine attacks through the regulation of synaptic plasticity in central sensitization.

Orofacial neuropathic pain induced by oxaliplatin: downregulation of KCNQ2 channels in V2 trigeminal ganglion neurons and treatment by the KCNQ2 channel potentiator retigabine.

Abstract: Neuropathic pain induced by chemotherapy drugs such as oxaliplatin is a dose-limiting side effect in cancer treatment. The mechanisms underlying chemotherapy-induced neuropathic pain are not fully understood. KCNQ2 channels are low-threshold voltage-gated K+ channels that play a role in controlling neuronal excitability. Downregulation of KCNQ2 channels has been proposed to be an underlying mechanism of sensory hypersensitivity that leads to neuropathic pain. However, it is currently unknown whether KCNQ channels may be downregulated by chemotherapy drugs in trigeminal ganglion neurons to contribute to the pathogenesis of chemotherapy-induced orofacial neuropathic pain. In the present study, mechanical sensitivity in orofacial regions is measured using the operant behavioral test in rats treated with oxaliplatin. Operant behaviors in these animals show the gradual development of orofacial neuropathic pain that manifests with orofacial mechanical allodynia. Immunostaining shows strong KCNQ2 immunoreactivity in small-sized V2 trigeminal ganglion neurons in controls, and the numbers of KCNQ2 immunoreactivity positive V2 trigeminal ganglion neurons are significantly reduced in oxaliplatin-treated animals. Immunostaining is also performed in brainstem and shows strong KCNQ2 immunoreactivity at the trigeminal afferent central terminals innervating the caudal spinal trigeminal nucleus (Vc) in controls, but the KCNQ2 immunoreactivity intensity is significantly reduced in oxaliplatin-treated animals. We further show with the operant behavioral test that oxaliplatin-induced orofacial mechanical allodynia can be alleviated by the KCNQ2 potentiator retigabine. Taken together, these findings suggest that KCNQ2 downregulation may be a cause of oxaliplatin-induced orofacial neuropathic pain and KCNQ2 potentiators may be useful for alleviating the neuropathic pain.

Enhancement of ERK phosphorylation and photic responses in Vc/C1 neurons of a migraine model.

Although it is well known that migraine pain is enhanced by photic stimulation of the eye, the mechanisms underlying this response are not yet understood. Noxious stimulation to the dura is known to activate trigeminal spinal subnucleus caudalis and upper cervical spinal cord (Vc/C1) neurons, causing migraine pain. Intense photic stimulation to the eye is also known to activate certain Vc/C1 neurons, thus increasing migraine pain. In this study, we hypothesized that Vc/C1 neurons receiving noxious dural input would be further activated by intense photic stimulation, resulting in the enhancement of migraine pain. However, mechanisms underlying the interactions between dural and photic sensory information in Vc/C1 neurons is unknown. To evaluate the above hypothesis, we studied phosphorylated extracellular signal-regulated kinase (pERK) -immunoreactive (IR) cells in Vc/C1 in dural mustard oil (DMO)-administrated rats. The change in neuronal excitability of Vc/C1 nociceptive neurons receiving input from the dura in DMO rats was examined and tested if those neurons were modulated by intense flush light stimulation. There were many pERK-IR cells in the lateral portion of Vc/C1 after MO administration to the dura. Flashlight presentation to the eye in DMO rats caused an enhancement of ERK phosphorylation in Vc/C1 neurons and pERK-IR cells were significantly suppressed after intracisternal administration of MEK1 inhibitor PD98059. Dura-light sensitive (DL) neurons were recorded in the lateral portion of Vc/C1 and photic responses of DL neurons were significantly enhanced following dural MO administration. These findings indicate that DL Vc/C1 neurons in DMO rats intensified their responses to intense photic stimulation and that ERK phosphorylation in Vc/C1 neurons receiving noxious dural input increased with intense photic stimulation, suggesting that Vc/C1 nociceptive neurons are involved in the enhancement of dural nociception associated with intense light stimulation.

Botulinum toxin in migraine: Role of transport in trigemino-somatic and trigemino-vascular afferents.

Migraine secondary to meningeal input is referred to extracranial regions innervated by somatic afferents that project to homologous regions in the trigeminal nucleus caudalis (TNC). Reported efficacy of extracranial botulinum toxin (BoNT) in treating migraine is surprising since a local extracranial effect of BoNT cannot account for its effect upon meningeal input. We hypothesize that intradermal BoNT acts through central transport in somatic afferents. Anesthetized C57Bl/6 mice (male) received unilateral supraorbital (SO) injections of BoNT-B (1.5 U/40 µl) or saline. 3 days later, mice received ipsilateral (ipsi)-SO capsaicin (20 µl of 0.5mM solution) or meningeal capsaicin (4 µl of 0.35 µM). Pre-treatment with ipsi-SO BoNT-B i) decreased nocicsponsive ipsilateral wiping behavior following ipsi-SO capsaicin; ii) produced cleavage of VAMP in the V1 region of ipsi-TG and in TG neurons showing WGA after SO injection; iii) reduced expression of c-fos in ipsi-TNC following ipsi-SO capsaicin; iv) reduced c-fos activation and NK-1 internalization in ipsi-TNC secondary to ipsi-meningeal capsaicin; and vi) SO WGA did not label dural afferents. We conclude that BoNT-B is taken up by peripheral afferents and transported to central terminals where it inhibits transmitter release resulting in decreased activation of second order neurons. Further, this study supports the hypothesis that SO BoNT exerts a trans-synaptic action on either the second order neuron (which receives convergent input from the meningeal afferent) or the terminal/TG of the converging meningeal afferent.

Anatomical changes within the medullary dorsal horn in chronic temporomandibular disorder pain.

Accumulated evidence from experimental animal models suggests that neuroplastic changes at the dorsal horn are critical for the maintenance of various chronic musculoskeletal pain conditions. However, to date, no study has specifically investigated whether neuroplastic changes also occur at this level in humans. Using brain imaging techniques, we sought to determine whether anatomical changes were present in the medullary dorsal horn (spinal trigeminal nucleus caudalis) in subjects with the chronic musculoskeletal pain. In twenty-two subjects with painful temporomandibular disorders (TMDs) and forty pain-free controls voxel based morphometry of T1-weighted anatomical images and diffusion tensor images were used to assess regional grey matter volume and microstructural changes within the brainstem and, in addition, the integrity of ascending pain pathways. Voxel based morphometry revealed significant regional grey matter volume decreases in the medullary dorsal horn, in conjunction with alterations in diffusivity properties, namely an increase in mean diffusivity, in TMD subjects. Volumetric and mean diffusivity changes also occurred in TMD subjects in regions of the descending pain modulation system, including the midbrain periaqueductal grey matter and nucleus raphe magnus. Finally, tractography revealed altered diffusivity properties, namely decreased fractional anisotropy, in the root entry zone of the trigeminal nerve, the spinal trigeminal tract and the ventral trigeminothalamic tracts of TMD subjects. These data reveal that chronic musculoskeletal pain in humans is associated with discrete alterations in the anatomy of the medullary dorsal horn, as well as its afferent and efferent projections. These neural changes may be critical for the maintenance of pathological pain.

Analysis of pain in the rabbit temporomandibular joint after unilateral splint placement.

AIMS: To determine whether behavioral, anatomical, and physiologic endpoints widely used to infer the presence of pain in rodent models of temporomandibular disorders (TMD) were applicable to the rabbit model of TMD associated with altered joint loading. METHODS: Unilateral molar dental splints were used to alter temporomandibular joint (TMJ) loading. Changes in nociceptive threshold were assessed with a mechanical probing of the TMJ region on nine splinted and three control rabbits. Fos-like immunoreacitivty in the trigeminal subnucleus caudalis was assessed with standard immunohistochemical techniques from three splinted and six control animals. Retrogradely labeled TMJ afferents were studied with patch-clamp electrophysiologic techniques from three splinted and three control animals. Remodeling of TMJ condyles was assessed by histologic investigations of three splinted and three control animals. A Student t test or a Mann-Whitney U test was used with significance set at P < .05 to compare splinted to control samples. RESULTS: While variable, there was an increase in mechanical sensitivity in splinted rabbits relative to controls. The increase in Fos+ cells in splinted rabbits was also significant relative to naïve controls (86 ± 8 vs 64 ± 15 cells/section, P < .05). The rheobase (364 ± 80 pA) and action potential threshold (-31.2 ± 2.0 mV) were higher in TMJ afferents from splinted rabbits compared to controls (99 ± 22 pA and -38.0 ± 2.0 mV, P < .05). There was significant remodeling in the condylar fibrocartilage layers as manifested by a change in glycosaminoglycan distribution and a loss of defined cell layers. CONCLUSION: Behavioral and anatomical results were consistent with an increase in nociceptive signaling in concert with condylar remodeling driven by altered TMJ loading. Changes in excitability and action potential waveform were consistent with possible compensatory changes of TMJ afferents for an overall increase in afferent drive associated with joint degeneration. These compensatory changes may reflect pain-adaption processes that many patients with TMJ disorders experience.

Corneal pain activates a trigemino-parabrachial pathway in rats.

Corneal pain is mediated by primary afferent fibers projecting to the dorsal horn of the medulla, specifically the trigeminal nucleus caudalis. In contrast to reflex responses, the conscious perception of pain requires transmission of neural activity to higher brain centers. Ascending pain transmission is mediated primarily by pathways to either the thalamus or parabrachial nuclei. We previously showed that some corneal afferent fibers preferentially contact parabrachial-projecting neurons in the rostral pole of the trigeminal nucleus caudalis, but the role of these projection neurons in transmitting noxious information from the cornea has not been established. In the present study, we show that noxious stimulation of the corneal surface activates neurons in the rostral pole of the nucleus caudalis, including parabrachially projecting neurons that receive direct input from corneal afferent fibers. We used immunocytochemical detection of c-Fos protein as an index of neuronal activation after noxious ocular stimulation. Animals had previously received injections of a retrograde tracer into either thalamic or parabrachial nuclei to identify projection neurons in the trigeminal dorsal horn. Noxious stimulation of the cornea induced c-Fos in neurons sending projections to parabrachial nuclei, but not thalamic nuclei. We also confirmed that corneal afferent fibers identified with cholera toxin B preferentially target trigeminal dorsal horn neurons projecting to the parabrachial nucleus. The parabrachial region sends ascending projections to brain regions involved in emotional and homeostatic responses. Activation of the ascending parabrachial system may explain the extraordinary salience of stimulation of corneal nociceptors.

Chemokine CCL2 up-regulated in the medullary dorsal horn astrocytes contributes to nocifensive behaviors induced by experimental tooth movement.

To test the hypothesis that the astrocytic chemokine (C-C motif) ligand 2 (CCL2) plays an important role in nocifensive behaviors after experimental tooth movement (ETM), the expression and cellular localization of CCL2 and astrocyte activation in the medullary dorsal horn (MDH) were determined by immunohistochemistry in rats. The dose-dependent effects of intrathecal C-C chemokine receptor type 2 (CCR2) antagonists on these changes in nocifensive behaviors were evaluated. Exogenous CCL2 was added to medullary dorsal horn slices to evaluate its contributory role in the induction of extracellular signal-regulated kinase (ERK) activation ex vivo. We found a significant increase in the expression of CCL2 and glial fibrillary acidic protein (GFAP), corresponding well to the nocifensive behaviors after ETM. In addition, application of recombinant CCL2 led to ERK activation, which could be attenuated effectively by pretreatment with CCL2-neutralizing antibody ex vivo. The magnitude of the nocifensive behavior could be reduced by medullary CCR2 antagonists in a dose-dependent manner. Therefore, the astrocytic CCL2 is actively involved in the development and maintenance of tooth-movement pain and thus may be a potential target for analgesics in orthodontic nocifensive responses control.

Trigeminal-rostral ventromedial medulla circuitry is involved in orofacial hyperalgesia contralateral to tissue injury.

BACKGROUND: Our previous studies have shown that complete Freund's adjuvant (CFA)-induced masseter inflammation and microinjection of the pro-inflammatory cytokine interleukin-1ß (IL-1ß) into the subnucleus interpolaris/subnucleus caudalis transition zone of the spinal trigeminal nucleus (Vi/Vc) can induce contralateral orofacial hyperalgesia in rat models. We have also shown that contralateral hyperalgesia is attenuated with a lesion of the rostral ventromedial medulla (RVM), a critical site of descending pain modulation. Here we investigated the involvement of the RVM-Vi/Vc circuitry in mediating contralateral orofacial hyperalgesia after an injection of CFA into the masseter muscle. RESULTS: Microinjection of the IL-1 receptor antagonist (5 nmol, n=6) into the ipsilateral Vi/Vc attenuated the CFA-induced contralateral hyperalgesia but not the ipsilateral hyperalgesia. Intra-RVM post-treatment injection of the NK1 receptor antagonists, RP67580 (0.5-11.4 nmol) and L-733,060 (0.5-11.4 nmol), attenuated CFA-induced bilateral hyperalgesia and IL-1ß induced bilateral hyperalgesia. Serotonin depletion in RVM neurons prior to intra-masseter CFA injection prevented the development of contralateral hyperalgesia 1-3 days after CFA injection. Inhibition of 5-HT(3) receptors in the contralateral Vi/Vc with direct microinjection of the select 5-HT(3) receptor antagonist, Y-25130 (2.6-12.9 nmol), attenuated CFA-induced contralateral hyperalgesia. Lesions to the ipsilateral Vc prevented the development of ipsilateral hyperalgesia but did not prevent the development of contralateral hyperalgesia. CONCLUSIONS: These results suggest that the development of CFA-induced contralateral orofacial hyperalgesia is mediated through descending facilitatory mechanisms of the RVM-Vi/Vc circuitry.

Trigeminocervical complex responses after lesioning dopaminergic A11 nucleus are modified by dopamine and serotonin mechanisms.

Both serotonergic and dopaminergic receptor modulation can alter trigeminal nociceptive processing, and descending A11 dopaminergic projections can affect trigeminal nociceptive transmission. Here we aimed to test the interaction between dopamine D(2) and serotonin 5-HT(1B/1D) receptors and their individual and combined effects in order to better understand the relationship of the descending influences of these systems on nociceptive trigeminovascular afferents. Extracellular recordings were made in the rat trigeminocervical complex in response to electrical stimulation of the dura mater and mechanical noxious and innocuous stimulation of the ipsilateral ophthalmic dermatome. The A11 nucleus was lesioned, and following the resultant facilitation of neuronal firing, one of a selective 5-HT(1B/1D) receptor agonist (naratriptan), selective 5-HT(1B/1D) receptor antagonist (GR127935), a selective D(2)-like receptor agonist (quinpirole), and a selective D(1)-like receptor agonist (dihydrexidine), or a combination of the above, were administered. Both quinpirole and quinpirole with naratriptan inhibited firing in the trigeminocervical complex evoked by noxious stimuli, reducing it below prelesion baseline, while the response to innocuous stimuli was reduced back to baseline. Both naratriptan alone, and quinpirole combined with GR127935, inhibited firing in the trigeminocervical complex evoked by noxious stimuli, returning it to prelesion baseline, while the response to innocuous stimuli remained facilitated. Immunohistochemical staining demonstrated D(2)-receptor and 5-HT(1B/1D)-receptor colocalization in the trigeminocervical complex. The data suggest that the serotonergic and dopaminergic antinociceptive pathways act simultaneously on neurons in the trigeminocervical complex, and both amine systems need to be functioning for trigeminal sensitization to be reversed.

The role of trigeminal interpolaris-caudalis transition zone in persistent orofacial pain.

Previous studies have established the role of the medullary dorsal horn or the subnucleus caudalis of the spinal trigeminal complex, a homolog of the dorsal horn of the spinal cord, in trigeminal pain processing. In addition to the medullary dorsal horn, recent studies have pointed out increased excitability and sensitization of trigeminal interpolaris and caudalis transition zone (Vi/Vc) following deep orofacial injury, involving neuron-glia-cytokine interactions. The Vi/Vc transition zone accesses rostral brain regions that are important for descending pain modulation, and somatovisceral and somatoautonomic processing and plays a unique role in coordinating trigeminal nocifensive responses.

Involvement of GluR2 and GluR3 subunit C-termini in the trigeminal spinal subnucleus caudalis and C1-C2 neurons in trigeminal neuropathic pain.

To clarify the involvement of GluR2 and GluR3 subunits of AMPA receptor in orofacial neuropathic pain, we studied changes in nocifensive behavior and extracellular-signal regulated kinase (ERK) phosphorylation followed by infraorbital nerve (ION)-partial transection model applied to GluR2 or GluR3 delta7 knock-in (KI) mice. In these animals, last seven amino acids of GluR2 or GluR3 subunit, the binding sites of interacting protein, are deleted in vivo. Head-withdrawal threshold to mechanical stimulation of the whisker pad skin ipsilateral to ION-partial transection was significantly reduced at 1, 3, 5, 7, 11 and 14 days after transection compared with that before transection in wild-type mice. In the GluR2 and GluR3 delta7 KI mice, the head-withdrawal threshold did not change following ION-partial transection. The number of pERK-LI cells examined in Vc and C1-C2 in wild-type mice after the non-noxious stimulation was larger than that of GluR2 and GluR3 delta7 KI mice. The present findings suggest that GluR2 and GluR3 subunits of AMPA receptor play roles in the trigeminal nerve injury-mediated enhancement of Vc and C1-C2 neuronal excitability, and hyperalgesia.

IL-1beta in the trigeminal subnucleus caudalis contributes to extra-territorial allodynia/hyperalgesia following a trigeminal nerve injury.

It has been reported that the whisker pad (WP) area, which is innervated by the second branch of the trigeminal nerve, shows allodynia/hyperalgesia following transection of the mental nerve (MN: the third branch of the trigeminal nerve). However, the mechanisms of this extra-territorial pain induction still remain unclear. Glia and cytokines are known to facilitate perception of noxious input, raising a possibility that these non-neuronal elements are involved in the induction and spread of allodynia/hyperalgesia at non-injured skin territory. One day after MN transection, tactile allodynia/hyperalgesia developed on the ipsilateral WP area, which is in the non-injured skin territory. The tactile allodynia/hyperalgesia lasted for more than 56 days. In response to MN transection, astrocytes and microglia appeared to be in an activated state, and interleukin (IL)-1beta was up-regulated in astrocytes in the trigeminal subnucleus caudalis (Vc). Allodynia/hyperalgesia at WP area induced by MN transection was attenuated dose-dependently by IL-1 receptor antagonist IL-1ra (i.t., 0.05, 0.5, and 5 pg/rat). Fos-like immunoreactive (Fos-Li) neurons were observed in the Vc after non-noxious mechanical stimulation of the WP area in the rats with MN transection. Administration of IL-1ra also attenuated the number of Fos-Li neurons dose-dependently. Administration of a noncompetitive antagonist of NMDA receptors MK-801 (i.t., 5 µg/rat) reversed allodynia/hyperalgesia. IL-1 receptor type I (IL-1RI) was localized in Fos- and phospho NR1-immunoreactive neurons. These results suggest that IL-1beta in the Vc plays an important role in the development of extra-territorial tactile allodynia/hyperalgesia after MN transection.

Homocysteine inhibits proliferation of neuronal precursors in the mouse adult brain by impairing the basic fibroblast growth factor signaling cascade and reducing extracellular regulated kinase 1/2-dependent cyclin E expression.

Hyperhomocysteinemia (HHcy)-abnormally elevated plasma levels of homocysteine (Hcy)-has been associated with the development of neurodegenerative dementia and mild cognitive impairment. This association suggests that HHcy might facilitate memory loss in the elderly. As memory loss can occur through a deteriorated neurogenic capacity, we have studied the effects of Hcy on neural progenitor cells (NPCs) both in vitro and in vivo. We show that Hcy exerts an antiproliferative effect on basic fibroblast growth factor (bFGF) -stimulated NPCs isolated from the postnatal subventricular zone (SVZ), accompanied by inactivation of the extracellular signal-regulated kinase (Erk1/2) and inhibition of Erk1/2-dependent expression of cyclin E. Using a mice model we show that, under normal folate conditions, HHcy exerts an inhibitory effect on adult brain neurogenesis. This inhibition occurs in the caudal areas of the dentate gyrus (DG) of the hippocampus, a neurogenic area mainly involved in learning and memory performance, and in the SVZ, recently implicated in olfactory learning performance. In both areas reduced number of proliferative neuroblasts were found. Since neuroblasts are primarily bFGF-responsive progenitors already committed to a neuronal phenotype, our results strongly suggest that excess Hcy inhibits neurogenesis in the DG and SVZ by inhibiting the bFGF-dependent activation of Erk1/2 in these cells.

Thoracic Vagal Ganglion and Referred Craniofacial Pain: a Case Report and Review / Ganglio Torácico Vagal y Dolor Craneofacial Referido: Reporte de Caso y Revisión

The presence of a ganglion-like tumefaction is reported in the mediastinal course of the right vagus nerve at Tl level in a cadaver in the Universidad Industrial de Santander's morphology laboratory. The vagal ganglion was located next to hyperplasic lymphoid nodes in para-tracheal and tracheal-bronchial levels, agglomerating in a large lymphoid mass in the carina and the pulmonary hilum. Anatomical-pathological study revealed a marked, diffusely distributed, predominantly histo-lymphocyte mixed inflammation, separating the epineurium, producing lysis of the vagus nerve fibers. This finding showed the degeneration of this cranial par by mediastinal pathology. This provided a possible explanation for the physiopathology of pain referring to the head and neck in inflammatory or neoplastic pathology involving compression and degeneration by inflammatory infiltration of the vagus nerve. Pons-medullar trigeminal afferent tracts and connectivity, supra-spinal pathways for processing somatic-visceral pain, possible somatic-vegetative responses and the integration of the trigeminal system in the physiology of pain concerning the vagus nerve are all discussed.

Se reporta la presencia de una tumefacción a manera de "ganglio" en el trayecto mediastínico del nervio vago derecho, a nivel de TI, en un cadáver en el Laboratorio de Morfología de la Universidad Industrial de Santander, Colombia. El "ganglio" vagal se encuentra adyacente a nodos linfoides hiperplásicos, en niveles para-traqueales y tráqueo-bronquiales que se aglomeran en una gran masa linfoide a la altura de la carina e hilio pulmonar. En el estudio anatomopatológico, se encontró marcado proceso inflamatorio mixto de predominio histo-linfocitario el cual se distribuye de manera difusa separando el epineuro y produciendo lisis de las fibras del nervio vago. Este hallazgo muestra la degeneración de este par craneal por patologías a nivel mediastínico. Esto brinda una posible explicación de la fisiopatología del dolor referido a cabeza y cuello, en patologías inflamatorias o neoplásicas que involucran la compresión y degeneración por infiltración inflamatoria del nervio vago. Se discute los tractos y la conectividad de las aferencias vagales a nivel ponto-medular, las vías supraespinales para el procesamiento del dolor sómato-visceral, las posibles respuestas sómato-vegetativas y la integración del sistema trigeminal en la fisiología del dolor en el nervio vago.

Morphological changes in the trigemino-rubral pathway in dystrophic (mdx) mice.

The lack of dystrophin that causes Duchenne muscle disease affects not only the muscles but also the central nervous system. Dystrophin-deficient mdx mice present changes in several brain fiber systems. We compared the projections from the trigeminal sensory nuclear complex to the red nucleus in control and mdx mice using retrograde tracers. Injection of 200 nL 2% fluorogold into the red nucleus caused labeling in the mesencephalic trigeminal nucleus, the principal sensory nucleus and the oral, interpolar, and caudal subnuclei of the spinal trigeminal nucleus in both control and mdx mice. Injection of latex microbeads labeled with rhodamine and fluorescein gave results similar to those seen with fluorogold. The number of labeled neurons in the trigeminal sensory nuclear complex was significantly reduced in mdx mice. In the oral subnucleus of the spinal trigeminal nucleus this reduction was 50%. These results indicate that the trigemino-rubral pathway is reduced in dystrophin-deficient mice.

Decreased caudal anterior cingulate gyrus volume and positive symptoms in schizophrenia.

The anterior cingulate gyrus is a heterogeneous region that has specialized subdivisions with respect to its cytoarchitecture, function and connectivity. The aim of this study was to examine the morphological changes of the caudal subdivision of the anterior cingulate gyrus in the context of the cortico-striatal-thalamo-cortical circuitry of schizophrenia and their relationship to clinical symptoms. Accordingly, we measured the volumes of the caudal and rostral anterior cingulate gyrus, the orbitofrontal cortex, the caudate and the thalamus by magnetic resonance imaging in age- and sex-matched groups, which consisted of 22 patients with schizophrenia and 22 normal volunteers. The clinical symptoms of schizophrenia patients were obtained using the Positive and Negative Syndrome Scale. Volumetric reduction of the right caudal anterior cingulate gyrus was observed in patients with schizophrenia as compared with the normal controls. Furthermore, a smaller volume of the caudal anterior cingulate gyrus was significantly correlated with more severe positive symptoms of schizophrenia. Thus, these findings suggest that a volumetric abnormality of the caudal anterior cingulate gyrus in schizophrenia may be related to positive symptoms and possibly involved in the pathophysiology of schizophrenia.