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Abstract Background Widespread neuropathic pain usually affects a wide range of body areas and inflicts huge suffering on patients. However, little is known about how it happens and effective therapeutic interventions are lacking. Methods Widespread neuropathic pain was induced by partial infraorbital nerve transection (p-IONX) and evaluated by measuring nociceptive thresholds. In vivo/vitro electrophysiology were used to evaluate neuronal activity. Virus tracing strategies, combined with optogenetics and chemogenetics, were used to clarify the role of remodeling circuit in widespread neuropathic pain. Results We found that in mice receiving p-IONX, along with pain sensitization spreading from the orofacial area to distal body parts, glutamatergic neurons in the ventral posteromedial nucleus of the thalamus (VPMGlu) were hyperactive and more responsive to stimulations applied to the hind paw or tail. Tracing experiments revealed that a remodeling was induced by p-IONX in the afferent circuitry of VPMGlu, notably evidenced by more projections from glutamatergic neurons in the dorsal column nuclei (DCNGlu). Moreover, VPMGlu receiving afferents from the DCN extended projections further to glutamatergic neurons in the posterior insular cortex (pIC). Selective inhibition of the terminals of DCNGlu in the VPM, the soma of VPMGlu or the terminals of VPMGlu in the pIC all alleviated trigeminal and widespread neuropathic pain. Conclusion These results demonstrate that hyperactive VPMGlu recruit new afferents from the DCN and relay the extra-cephalic input to the pIC after p-IONX, thus hold a key position in trigeminal neuropathic pain and its spreading. This study provides novel insights into the circuit mechanism and preclinical evidence for potential therapeutic targets of widespread neuropathic pain.

Background: Widespread neuropathic pain usually affects a wide range of body areas and inflicts huge suffering on patients. However, little is known about how it happens and effective therapeutic interventions are lacking. Methods: Widespread neuropathic pain was induced by partial infraorbital nerve transection (p-IONX) and evaluated by measuring nociceptive thresholds. In vivo/vitro electrophysiology were used to evaluate neuronal activity. Virus tracing strategies, combined with optogenetics and chemogenetics, were used to clarify the role of remodeling circuit in widespread neuropathic pain. Results: We found that in mice receiving p-IONX, along with pain sensitization spreading from the orofacial area to distal body parts, glutamatergic neurons in the ventral posteromedial nucleus of the thalamus (VPMGlu) were hyperactive and more responsive to stimulations applied to the hind paw or tail. Tracing experiments revealed that a remodeling was induced by p-IONX in the afferent circuitry of VPMGlu, notably evidenced by more projections from glutamatergic neurons in the dorsal column nuclei (DCNGlu). Moreover, VPMGlu receiving afferents from the DCN extended projections further to glutamatergic neurons in the posterior insular cortex (pIC). Selective inhibition of the terminals of DCNGlu in the VPM, the soma of VPMGlu or the terminals of VPMGlu in the pIC all alleviated trigeminal and widespread neuropathic pain. Conclusion: These results demonstrate that hyperactive VPMGlu recruit new afferents from the DCN and relay the extra-cephalic input to the pIC after p-IONX, thus hold a key position in trigeminal neuropathic pain and its spreading. This study provides novel insights into the circuit mechanism and preclinical evidence for potential therapeutic targets of widespread neuropathic pain. [ABSTRACT FROM AUTHOR]

The generation of an internal body model and its continuous update is essential in sensorimotor control. Although known to rely on proprioceptive sensory feedback, the underlying mechanism that transforms this sensory feedback into a dynamic body percept remains poorly understood. However, advances in the development of genetic tools for proprioceptive circuit elements, including the sensory receptors, are beginning to offer new and unprecedented leverage to dissect the central pathways responsible for proprioceptive encoding. Simultaneously, new data derived through emerging bionic neural machine–interface technologies reveal clues regarding the relative importance of kinesthetic sensory feedback and insights into the functional proprioceptive substrates that underlie natural motor behaviors. [ABSTRACT FROM AUTHOR]

Proprioceptive signals from body muscles have historically been considered to project to the rostrodorsal shell of the ventrobasal thalamic complex [the ventral posterolateral nucleus (VPL) and ventral posteromedial nucleus (VPM)]. However, we have recently found that proprioception from rat jaw-closing muscle spindles (JCMSs) is conveyed via the supratrigeminal nucleus to the caudo-ventromedial edge of the VPM, but not to the rostrodorsal shell of the VPM. Therefore, proprioception from other body muscles may also project to thalamic regions other than the rostrodorsal shell of the VPL. We thus examined the thalamic projection from the rat external cuneate nucleus (ECu), which receives proprioceptive inputs from forelimb and neck muscles. After injection of anterograde tracer into the ECu, axon terminals were contralaterally labeled in the ventromedial part (VPLvm) of the VPL, but not in the rostrodorsal shell of the VPL. After anterograde tracer injection into the cuneate nucleus (Cu), axon terminals were widely labeled in the contralateral VPL including the VPLvm. In the VPLvm, we electrophysiologically confirmed the proprioceptive inputs responsive to electrical stimulation of the ECu or median nerve and to the pressure of forelimb/neck muscles or wrist flexion. After retrograde tracer injection into the VPLvm, neurons were contralaterally labeled in the ECu and Cu. After retrograde tracer injection into the VPL where no such proprioceptive inputs were recorded, no ECu neurons were labeled. These findings indicate that proprioception from forelimb/neck muscle spindles and JCMSs is somatotopically transmitted to the ventromedial floor of the ventrobasal thalamic complex, but not to its rostrodorsal shell. [ABSTRACT FROM AUTHOR]

A wealth of mechanical information from the body generates various forms of sensory experience during touch or kinesthesia. Dorsal column nuclei (DCN) in the medulla are the first relay station for somatosensory inputs from peripheral receptors. These nuclei integrate somatosensory information and send the output to higher-order centers; therefore, investigating the firing patterns of DCN neurons should elucidate coding principles within the somatosensory system. In this study, we quantified the firing patterns of DCN neurons and examined whether the firing patterns of particular neurons are altered when moving tactile stimuli are applied in different directions. The activities of 17 neurons in the DCN of anesthetized rats were selected and their firing patterns were analyzed using LvR, which refers to the local variation of intervals of action potentials (i.e., the cross-correlation between consecutive intervals of action potentials) compensated by the refractoriness constant, R. The LvR of the 17 neurons ranged widely from 0.35 to 2.28. Of the 17 neurons, 12 responded to hair deflection (hair neurons), whereas five responded specifically to movement of forelimb joints. In 11 of 12 hair neurons, moving stimuli were applied in two to four different directions, which yielded 25 pairs of comparisons. Of these, 14 pairs (56%) showed significant differences in LvR. Among these 14 pairs, the range of LvR fluctuation was 0.13 ± 0.06 (mean ± standard deviation) and its effect size (Cohen's d) was 0.6 ± 0.2. These results suggest that the firing pattern of individual DCN neurons may contribute to somatosensory discrimination. [ABSTRACT FROM AUTHOR]

The presence of transient receptor potential vanilloid type-1 receptor (TRPV1)-like immunoreactivity (LI), in the form of nerve fibres and terminals, is shown in a set of discrete gray matter subregions placed in the territory of the human cuneate nucleus. We showed previously that those subregions share neurochemical and structural features with the protopathic nuclei and, after the ancient name of our town, collectively call them Locus Karalis, and briefly Locus K. TRPV1-LI in the Locus K is codistributed, though not perfectly overlapped, with that of the neuropeptides calcitonin gene-related peptide and substance P, the topography of the elements immunoreactive to the three markers, in relation to each other, reflecting that previously described in the caudal spinal trigeminal nucleus. Myelin stainings show that myelinated fibres, abundant in the cuneate, gracile and trigeminal magnocellular nuclei, are scarce in the Locus K as in the trigeminal substantia gelatinosa. Morphometric analysis shows that cell size and density of Locus K neurons are consistent with those of the trigeminal substantia gelatinosa and significantly different from those of the magnocellular trigeminal, solitary and dorsal column nuclei. We propose that Locus K is a special component of the human dorsal column nuclei. Its functional role remains to be determined, but TRPV1 appears to play a part in it.

Over the past half a century, many experimental animal investigations have explored the role of various brainstem regions in a variety of conditions. Despite the accumulation of a considerable body of knowledge in primarily anaesthetized preparations, relatively few investigations have explored brainstem function in awake humans. It is important that human brainstem function is explored given that many neurological conditions, from obstructive sleep apnea, chronic pain and hypertension, likely involve significant changes in the processing of information within the brainstem. Recent advances in the collection and processing of magnetic resonance images, has resulted in the possibility of exploring brainstem activity changes in awake healthy individuals and in those with various clinical conditions. We and others have begun to explore changes in brainstem activity in humans during a number of challenges, including during cutaneous and muscle pain, as well as during challenges that evoke increases in sympathetic activity. More recently we have successfully recorded sympathetic nerve activity concurrently with fMRI of the brainstem, which will allow us, for the first time to explore brainstem sites directly responsible for conditions such as hypertension. Since many conditions will involve changes in brainstem function and structure, defining brainstem changes will likely result in a greater ability to develop more effective treatment regimes.

The present paper is aimed at defining distinctive subdivisions of the human cuneate nucleus (Cu), evident from prenatal to old life, whose occurrence has never been clearly formalized in the human brain, or described in other species so far. It extends our early observations on the presence of gray matter areas that host strong substance P (SP) immunoreactivity in the territory of the human Cu and adjacent cuneate fascicle. Here we provide a three-dimensional reconstruction of the Cu fields rich in SP and further identify those areas by means of their immunoreactivity to the neuropeptides SP, calcitonin gene-related peptide, methionine- and leucine-enkephalin, peptide histidine-isoleucine, somatostatin and galanin, to the trophins glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor, and to the neuroplasticity proteins polysialylated neural cell adhesion molecule and growth-associated protein-43. The presence, density and distribution of immunoreactivity for each of these molecules closely resemble those occurring in the superficial layers of the caudal spinal trigeminal nucleus (Sp5C). Myelin and Nissl stainings suggest that those Cu subregions and the Sp5C superficial layers share a similar histological aspect. This work establishes the existence of definite subregions, localized within the Cu territory, that bear the neurochemical and histological features of sensory nuclei committed to the neurotransmission of protopathic stimuli, including pain. These findings appear of particular interest when considering that functional, preclinical and clinical studies show that the dorsal column nuclei, classical relay station of fine somatic tactile and proprioceptive sensory stimuli, are also involved in pain neurotransmission. [ABSTRACT FROM AUTHOR]

In this study, we examined the role of the ventral posterior lateral nucleus (VPL) as a possible substrate for large-scale cortical reorganization in the forepaw barrel subfield (FBS) of primary somatosensory cortex (SI) that follows forelimb amputation. Previously, we reported that, 6 weeks after forelimb amputation in young adult rats, new input from the shoulder becomes expressed throughout the FBS that quite likely has a subcortical origin. Subsequent examination of the cuneate nucleus (CN) 1 to 30 weeks following forelimb amputation showed that CN played an insignificant role in cortical reorganization and led to the present investigation of VPL. As a first step, we used electrophysiological recordings in forelimb intact adult rats ( n =8) to map the body representation in VPL with particular emphasis on the forepaw and shoulder representations and showed that VPL was somatotopically organized. We next used stimulation and recording techniques in forelimb intact rats ( n =5) and examined the pattern of projection (a) from the forelimb and shoulder to SI, (b) from the forepaw and shoulder to VPL, and (c) from sites in the forepaw and shoulder representation in VPL to forelimb and shoulder sites in SI. The results showed that the projections were narrowly focused and homotopic. Electrophysiological recordings were then used to map the former forepaw representation in forelimb amputated young adult rats ( n =5) at 7 to 24 weeks after amputation. At each time period, new input from the shoulder was observed in the deafferented forepaw region in VPL. To determine whether the new shoulder input in the deafferented forepaw VPL projected to a new shoulder site in the deafferented FBS, we examined the thalamocortical pathway in 2 forelimb-amputated rats. Stimulation of a new shoulder site in deafferented FBS antidromically-activated a cell in the former forepaw territory in VPL; however, similar stimulation from a site in the original shoulder representation, outside the deafferented region, in SI did not activate cells in the former forepaw VPL. These results suggest that the new shoulder input in deafferented FBS is relayed from cells in the former forepaw region in VPL. In the last step, we used anatomical tracing and stimulation and recording techniques in forelimb intact rats ( n =9) to examine the cuneothalamic pathway from shoulder and forepaw receptive field zones in CN to determine whether projections from the shoulder zone might provide a possible source of shoulder input to forepaw VPL. Injection of biotinylated dextran amine (BDA) into physiologically identified shoulder responsive sites in CN densely labeled axon terminals in the shoulder representation in VPL, but also gave off small collateral branches into forepaw VPL. In addition, microstimulation delivered to forepaw VPL antidromically-activated cells in shoulder receptive field sites in CN. These results suggest that forepaw VPL also receives input from shoulder receptive sites in CN that are latent or subthreshold in forelimb intact rats. However, we speculate that following amputation these latent shoulder inputs become expressed, possibly as a down-regulation of GABA inhibition from the reticular nucleus (RTN). These results, taken together, suggest that VPL provides a substrate for large-scale cortical reorganization that follows forelimb amputation. [ABSTRACT FROM AUTHOR]

Over the past half a century, many investigations in experimental animal have explored the functional roles of specific regions in the brainstem. Despite the accumulation of a considerable body of knowledge in, primarily, anesthetized preparations, relatively few studies have explored brainstem function in awake humans. It is important that human brainstem function is explored given that many neurological conditions, from obstructive sleep apnea, chronic pain, and hypertension, likely involve significant changes in the processing of information within the brainstem. Recent advances in the collection and processing of magnetic resonance images have resulted in the possibility of exploring brainstem activity changes in awake healthy individuals and in those with various clinical conditions.We and others have begun to explore changes in brainstem activity in humans during a number of challenges, including cutaneous and muscle pain, as well as during maneuvers that evoke increases in sympathetic nerve activity. More recently we have successfully recorded sympathetic nerve activity concurrently with functional magnetic resonance imaging of the brainstem, which will allow us, for the first time to explore brainstem sites directly responsible for conditions such as hypertension. Since many pathophysiological conditions no doubt involve changes in brainstem function and structure, defining these changes will likely result in a greater ability to develop more effective treatment regimens. [ABSTRACT FROM AUTHOR]

Abstract: We examined the physiological representation of the forelimb in the cuneate nucleus (CN) of forelimb-intact young adult rats (n=38) as the first part in a series of studies aimed at understanding the possible role that CN plays in delayed cortical reorganization that follows forelimb amputation. Metabolic labeling with cytochrome oxidase (CO) and electrophysiological mapping were used to examine the relationship between the structural and functional organization of CN. CN is a cylinder-shaped structure that lies bilaterally in the brainstem and extends nearly 4mm in the rostrocaudal direction. The forelimb is represented along the rostrocaudal extent. CN contains three zones; the rostral and caudal zones receive input largely from deep muscle and joint receptors and a middle zone, in the vicinity of the obex, receives input primarily from cutaneous receptors in the skin. The middle zone is somatotopically organized with the glabrous digits represented centrally, bordered on the medial side by ulnar wrist, ulnar forearm, and posterior upper arm representations; on the lateral side by radial wrist, radial forearm, and anterior upper arm representations; and on dorsal side by the dorsal digits and dorsal hand. The middle zone also contains well-defined CO-filled glomerular structures, called barrelettes, which are located within a homogenously stained field. The barrelettes are associated with the representation of the glabrous digits, with D5 represented most dorsal followed sequentially in a ventral-to-lateral direction by the representation of D4, D3, D2, and D1. The digit representations are topographically organized with the distal digit surface represented laterally with respect to the more medially lying proximal digit surface. The digit and palmar pads are also represented by barrelettes located on the medial side of CN. In contrast, the dorsal digit surfaces are represented dorsally and the dorsal hand is represented directly beneath the cuneate fasciculus, in a region devoid of barrelettes. The representations of the ulnar and radial wrist, forearm, and upper arm also lie within the homogeneously stained field in CN. The forelimb representation is bordered on the medial side by representation of trunk and hindlimb, and on the lateral side by representation of shoulder, ear, and head. While the present findings support and extend previous electrophysiological and anatomical studies of CN in the rat, they also provide a detailed physiological description of the functional organization of CN that is necessary for subsequent understanding of the functional reorganization of CN that may result following forelimb amputation. [Copyright &y& Elsevier]

The organization of the projection from the dorsal column nuclei (DCN) to the lobules of the cerebellar caudal vermis was studied in the rabbit. Following unilateral injections of the retrograde fluorescent tracers fast blue (FB) and diamidino yellow (DY) into the pyramis (Pr) and uvula (Uv), respectively, a great number of single FB- (40%) and DY-labeled (60%) neurons were observed in the ipsilateral (79%) and contralateral (21%) DCN subdivisions. These neurons, as parents for the DCN-Pr and DCN-Uv projections, were numerous in the lateral cuneate nucleus (CuL; 84 and 74%, respectively) and in the complex of the gracile (Gr) and medial cuneate nuclei (CuM; Gr+CuM; 14 and 25%, respectively). A small percentage of the Pr projecting neurons was found in the CuM and Gr nuclei (2% in total). As regards the Uv, a rare and only ipsilateral projection arose from the CuM (1%), and no connection originated from the Gr. The distribution pattern of labeled neurons within individual subnuclei indicates that there are both separate regions and, to a great extent, common regions of the DCN-Pr and DCN-Uv projections. In these common regions, a small population of double FB+DY-labeled neurons (1.2%) was identified. Such neurons, present exclusively in the ipsilateral CuL and Gr+CuM, were the source of projection by way of axonal collaterals to the Pr and Uv simultaneously. It is suggested that the described connections may play a role in coordination of the axial and proximal forelimb muscles. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Glutamate neurotransmission plays critical roles in normal central nervous system (CNS) function, neurodegenerative diseases, and neurotrauma. We determined whether glutamate signaling could be evoked within the anesthetized normal adult rat CNS with clinically relevant peripheral stimulation and recorded (at >1Hz) with glutamate-sensitive, ceramic microelectrode arrays (MEAs). Basal glutamate levels and both forelimb cutaneous and electrical stimulation-evoked glutamate release were measured within the cuneate nucleus, a relay of the mammalian dorsal columns somatosensory system. The MEAs with triangular, sharp-point tips were more effective at tissue penetration than the flat, blunt tips. Basal glutamate levels of 2.1±4.4μM (mean±SD, n =10 animals) were detected from 150μm to 1200μm below the brainstem dorsal surface. Cutaneous evoked glutamate signals showed an amplitude of 1.1±1.1μM and a duration of 7.3±6.5s (26 signals, n =6). Electrically evoked signals, like cutaneous ones, were both rapid and slowly rising. Electrically evoked signals, especially those evoked by stimulation trains, were more reproducible and had an amplitude of 1.2±1.4μM, duration of 19.4±17.3s, and latency from stimulus onset of 21.3±21.5s (25 signals, n =4). In contrast to cutaneous stimulation, glutamate signals evoked by electrical stimulation had longer durations and were recorded primarily in the middle and ventral cuneate nuclei. Importantly, both cutaneous and electrical stimulation of the contralateral forelimb and hindlimbs did not evoke glutamate signaling. With the use of MEAs, these results show, for the first time, somatosensory-pathway specific changes in glutamate levels during peripheral cutaneous and electrical stimulation. [Copyright &y& Elsevier]

The cerebellum receives sensory signals from spinocerebellar (lower limbs) and dorsal column nuclei (upper limbs) mossy fibers. In the cerebellum, mossy fibers terminate in bands that are topographically aligned with stripes of Purkinje cells. While much is known about the molecular heterogeneity of Purkinje cell stripes, little is known about whether mossy fiber compartments have distinct molecular profiles. Here, we show that the vesicular glutamate transporters VGLUT1 and VGLUT2, which mediate glutamate uptake into synaptic vesicles of excitatory neurons, are expressed in complementary bands of mossy fibers in the adult mouse cerebellum. Using a combination of immunohistochemistry and anterograde tracing, we found heavy VGLUT2 and weak VGLUT1 expression in bands of spinocerebellar mossy fibers. The adjacent bands, which are in part comprised of dorsal column nuclei mossy fibers, strongly express VGLUT1 and weakly express VGLUT2. Simultaneous injections of fluorescent tracers into the dorsal column nuclei and lower thoracic-upper lumbar spinal cord revealed that upper and lower limb sensory pathways innervate adjacent VGLUT1/VGLUT2 parasagittal bands. In summary, we demonstrate that VGLUT1 and VGLUT2 are differentially expressed by dorsal column nuclei and spinocerebellar mossy fibers, which project to complementary cerebellar bands and respect common compartmental boundaries in the adult mouse cerebellum. [ABSTRACT FROM AUTHOR]

The cochlear nucleus, the first central auditory structure, performs initial stimulus processing and segregation of information into parallel ascending pathways. It also receives nonauditory inputs. Here we show in vivo that responses of dorsal cochlear nucleus (DCN) principal neurons to sounds can change significantly depending on the presence or absence of inputs from the somatosensory dorsal column nucleus occurring before the onset of auditory stimuli. The effects range from short-term suppression of spikes lasting a few milliseconds at the onset of the stimulus to long-term increases or decreases in spike rate that last throughout the duration of an acoustic stimulus (up to several hundred milliseconds). The long-term effect requires only a single electrical stimulus pulse to initiate and seems to be similar to persistent activity reported in other parts of the brain. Among the DCN inhibitory interneurons, only the cartwheel cells show a long-term rate decrease that could account for the rate increases (but not the decreases) of DCN principal cells. Thus even at the earliest stages of auditory processing, the represented information is dependent on nonauditory context, in this case somatosensory events. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate the effect of the voluntary movement on the amplitude of the somatosensory evoked potentials (SEPs) recorded by an epidural electrode at level of the dorsal column nuclei (DCN). Methods: Five patients, suffering from chronic pain resistant to pharmacological treatment, underwent an epidural electrode implant at high cervical spinal cord level (C2) for neuromodulation. After tibial nerve stimulation, SEPs were recorded from the epidural electrode contacts, from a Cz lead, and from two electrodes placed over the 12th dorsal vertebra and 4th lumbar vertebra, respectively. SEPs were recorded at rest and during a voluntary flexo-extension movement of the stimulated foot. Beyond the low-frequency SEPs, also the high-frequency oscillations (HFOs), obtained by filtering the recorded traces by means of a 1000–2000Hz bandpass offline, were analysed. Results: The epidural electrode contacts recorded a triphasic potential (P1–N1–P2), whose negative peak showed a latency similar to that of the P30 far-field response obtained from the scalp. The epidural potential amplitude was significantly decreased by the voluntary movement, as compared to the rest (p <0.01). A main HFO peak, identifiable at around 1200Hz, was significantly lower in amplitude during movement than at rest (p =0.008). Conclusions: Our findings suggest that the epidural C2 triphasic wave is a potential arising from DCN. The low-frequency epidural SEP component is subtended by a 1200Hz HFO, probably generated by post-synaptic events. Significance: The amplitude reduction of the DCN response during movement is possibly due to decreased excitability of the DCN neurons receiving the somatosensory ascending input. [Copyright &y& Elsevier]

Abstract: Protein kinase C gamma (PKCγ) is widely distributed throughout the CNS and is thought to play a role in long term hyper-excitability in nociceptive neurones. Here, we provide the first report of PKCγ cells in the dorsal column nuclei of the adult rat. Retrograde labeling of PKCγ cells from the thalamus with choleragenoid revealed that 25% of the PKCγ positive gracile cells projected to the thalamus. Further, we have characterized the distribution of PKCγ within gracile nucleus in terms of colocalization with various neurotransmitter receptors or enzymes and calcium binding proteins, and compared this with PKCγ colocalization in cells of laminae I–III of the spinal cord. We show that approximately 90% of the PKCγ cells in the gracile nucleus and 60% in the dorsal horn were immuno-positive for the AMPA receptor subunit glutamate 2/3 (GluR2/3). Little coexpression was seen with neurokinin 1 receptor, nitric oxide synthase (NOS) and the AMPA receptor subunit GluR1, markers of distinct neuronal subpopulations. In the spinal cord, a quarter of PKCγ cells expressed calbindin, but very few cells did so in the gracile nucleus. Electrical stimulation at c-fiber strength of the normal or injured sciatic nerve was used to induce c-fos as a marker of postsynaptic activation in the spinal cord and gracile nucleus. Quantitative analysis of the number of PKCγ positive gracile cells that expressed also c-fos increased from none to 24% after injury, indicating an alteration in the sensory activation pattern in these neurones after injury. C-fos was not induced in inner lamina II following c-fiber electrical stimulation of the intact or axotomized sciatic nerve, indicating no such plasticity at the spinal cord level. As dorsal column nuclei cells may contribute to allodynia after peripheral nerve injury, pharmacological modulation of PKCγ activity may therefore be a possible way to ameliorate neuropathic pain after peripheral nerve injury. [Copyright &y& Elsevier]

Abstract: Increased chondroitin sulfate proteoglycan (CSPG) expression in the vicinity of a spinal cord injury (SCI) is a primary participant in axonal regeneration failure. However, the presence of similar increases of CSPG expression in denervated synaptic targets well away from the primary lesion and the subsequent impact on regenerating axons attempting to approach deafferented neurons have not been studied. Constitutively expressed CSPGs within the extracellular matrix and perineuronal nets of the adult rat dorsal column nuclei (DCN) were characterized using real-time PCR, Western blot analysis and immunohistochemistry. We show for the first time that by 2 days and through 3 weeks following SCI, the levels of NG2, neurocan and brevican associated with reactive glia throughout the DCN were dramatically increased throughout the DCN despite being well beyond areas of trauma-induced blood brain barrier breakdown. Importantly, regenerating axons from adult sensory neurons microtransplanted 2 weeks following SCI between the injury site and the DCN were able to regenerate rapidly within white matter (as shown previously by Davies et al. [Davies, S.J., Goucher, D.R., Doller, C., Silver, J., 1999. Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. J. Neurosci. 19, 5810–5822]) but were unable to enter the denervated DCN. Application of chondroitinase ABC or neurotrophin-3-expressing lentivirus in the DCN partially overcame this inhibition. When the treatments were combined, entrance by regenerating axons into the DCN was significantly augmented. These results demonstrate both an additional challenge and potential treatment strategy for successful functional pathway reconstruction after SCI. [Copyright &y& Elsevier]

Abstract: Spontaneous and rhythmic neuronal activity in dorsal column nuclei has long been identified in anesthetized cats. Here, we have studied the spontaneous behavior of cuneate cells in anesthetized rats through extracellular recording, showing that most cuneate neurones recorded (155 of 185) fired spontaneously. Overall, 74% of these spontaneously firing neurones were single-spiking and 26% were bursting. Cells were considered “bursting” when more than 50% of the spontaneous spikes belonged to bursts. Nevertheless, occasional bursts were seen in 33% of spontaneous cuneate cells which were classified as single-spiking. Rhythmic firing was observed in about 14% of both spontaneously bursting and single-spiking cells, and these cells were located close to the obex (±0.5 mm). Although the spike-frequency was mostly in the range 0–15 spikes/s, spontaneous rhythmic activity was circumscribed mainly to the alpha/beta-like range, both in single-spiking (26.1±3.6 Hz, n=16) and bursting cells (19.5±4.1 Hz, n=6). Lemniscal stimulation often activated several antidromic units with the same latency. About 65% of cuneolemniscal cells were spontaneously active and of these, 83% were single-spiking and 11% rhythmic (all single-spiking). In cells that were not antidromically activated from the medial lemniscus, short latency orthodromic responses consistent with excitation by recurrent lemniscal collaterals were often observed following lemniscal activation. Interestingly, only cells completely unresponsive to lemniscal stimulation showed rhythmic bursting. Most spontaneous cells responded with a burst to natural receptive field stimulation, while rhythmic cells became temporally arrhythmic. These results demonstrate, for the first time, that rat cuneate neurones can fire bursts spontaneously. Besides, this bursting activity can be rhythmic. These two properties, and the fact that groups of cuneolemniscal cells share the same conduction velocity, probably imply the reinforcement of temporal and spatial summation at their targets when they are synchronously recruited by the stimulation of overlapping receptive fields. [Copyright &y& Elsevier]

Abstract: The dorsal column nuclei, cuneatus and gracilis, receive somesthetic information impinging on projection cells and local inhibitory interneurons. The presence of these interneurons allows spatio-temporal progressive coding of information that can be modeled [E. Sánchez, J. Aguilar, C. Rivadulla, A. Canedo, The role of Glycinergic Interneurons in the Dorsal Column Nuclei, Neurocomputing 58–60 (2004) 1049–1055 ] using their known synaptic connections with projection cells [J. Aguilar, C. Rivadulla, C. Soto, A. Canedo, New corticocuneate cellular mechanisms underlying the modulation of cutaneous ascending transmission in anesthetized cats, J. Neurophysiol. 89 (2003) 3328–3339 , J. Aguilar, C. Soto, C. Rivadulla, A. Canedo, The lemniscal-cuneate recurrent excitation is suppressed by strychnine and enhancedd by GABAA antagonists in the anesthetized cat, Eur. J. Neurosci. 16 (2002) 1697–1704 , J. Mariño, L. Martinez, A. Canedo, Sensorimotor integration at the dorsal column nuclei, NIPS 14 (1999) 231–237 . Here we explore the dependency of the processing time required to complete the progressive coding with regard to cutaneous stimuli varying in size and regularity of the intensity profile. [Copyright &y& Elsevier]

Abstract: Cortical contributions to brainstem plasticity in the somatosensory system are poorly understood. Tactile receptive fields (RFs) of brainstem dorsal column nuclei (DCN) neurons rapidly enlarge when peripheral inputs are disrupted by local anesthetic blocks with lidocaine (LID). Cortical inputs appear to influence this plasticity because enlargements have been shown to be greater when cortical inputs are disrupted. Like disruptions of peripheral inputs, disruptions of DCN inhibition by DCN administration of the GABAA receptor antagonist bicuculline methiodide (BMI) also cause rapid enlargements of DCN RFs when cortical inputs are intact. These findings leave questions about interactions between cortical inputs, DCN inhibition, and DCN RF plasticity. To study potential interactions, the present experiments evaluated RF sizes of DCN tactilely responsive neurons in anesthetized rats following DCN microinjection of BMI when cortical inputs were acutely disrupted or intact. These tests were also supplemented by subsequent LID tests to directly compare post-BMI and post-LID effects on the same RF. BMI caused DCN RF enlargements when cortical inputs were disrupted or intact; however, enlargements after cortical input disruption were greater than when cortical inputs were intact. Following RF enlargement and retraction after BMI, LID often caused a second enlargement of the same RF, across skin that partially matched skin involved in the enlargement after BMI. This occurred when cortical inputs were disrupted or intact. We hypothesize that cortical inputs are not required for BMI and LID to initiate partially matching enlargements in individual DCN tactile RFs, however, cortical inputs constrain magnitudes of these enlargements. [Copyright &y& Elsevier]

Abstract: This study examined the modulatory influence exerted by GABAB receptors on the transmission of cutaneous afferent input to cuneate nucleus neurons in anesthetized cats. Electrical stimulation at the center of a receptive field activated cuneate nucleus cells at latencies of ≤7 ms whereas stimulation at neighboring sites (receptive field edge) increased the response latency. Extracellular recording combined with microiontophoresis demonstrated that GABAB receptors are tonically active. Blockade of GABAB receptors prolonged sensory-evoked response durations and decreased times of occurrence of successive bursts whereas the agonist baclofen suppressed both these effects. Ejection of baclofen delayed the evoked response from the receptive field edge with respect to the receptive field center response and inhibited responses from the receptive field edge more effectively than responses from the receptive field center. From these results it is concluded that activation of GABAB receptors precludes cuneate cells from reaching firing threshold when afferent inputs are weak, spatially modulate cuneate nucleus excitability, play a major role in temporal pattern of discharges, and shape cutaneous receptive fields. [Copyright &y& Elsevier]

Abstract: After scientific successes in the study of synaptic activation and inhibition of motoneurons and unraveling mechanisms underlying presynaptic inhibition, Sir John Eccles was interested in studying synaptic mechanisms governing the activity of neurons in the brain stem, cerebellum, and various cortical areas. In this new arena, his group discovered several principles, which have later been shown to generalize across brain structures and have substantial functional significance. Among these were the first identification and location of inhibitory synapses in the cerebral cortex and recurrent inhibitory systems in the hippocampus, cerebellum, and thalamus. [Copyright &y& Elsevier]

Abstract: Prior experiments have shown that a region of the medial and inferior vestibular nuclei contributes to cardiovascular and respiratory regulation. In addition to labyrinthine inputs, the majority of neurons in this region of the vestibular nuclei receive signals from the skin, muscle, and viscera, although the pathways conveying these nonlabyrinthine inputs to the vestibular nucleus neurons are unknown. To gain further insight into the afferent pathways to this functionally distinct subdivision of the vestibular complex, we combined monosynaptic mapping with viral transneuronal tracing in the ferret. First order afferent projections were defined by retrograde transport of the β-subunit of cholera toxin (CTβ), and the extended polysynaptic circuitry was defined in the same animals by injection of a recombinant of pseudorabies virus Bartha (PRV) into the contralateral vestibular nuclei. Neurons containing CTβ or infected by retrograde transneuronal transport and replication of PRV were distributed throughout the spinal cord, but were 10 times more prevalent in the cervical cord than the lumbar cord. The labeled spinal neurons were most commonly observed in Rexed''s laminae IV–VI and the dorsal portions of laminae VII–VIII. Both the CTβ and PRV injections also resulted in labeling of neurons in all four vestibular nuclei, the prepositus hypoglossi, the reticular formation, the inferior olivary nucleus, the medullary raphe nuclei, the spinal and principal trigeminal nuclei, the facial nucleus, and the lateral reticular nucleus. Following survival times ≥3 days, PRV-infected neurons were additionally present in nucleus solitarius and the gracile and cuneate nuclei. These data show that an anatomical substrate is present for somatosensory and visceral inputs to influence the activity of cells in the autonomic region of the vestibular nuclei and suggest that these signals are primarily transmitted through brainstem relay neurons. [Copyright &y& Elsevier]

Abstract: Repairing upper extremity function would significantly enhance the quality of life for persons with cervical spinal cord injury (SCI). Repair strategy development requires investigations of the deficits and the spontaneous recovery that occurs when cervical spinal cord axonal pathways are damaged. The present study revealed that both anatomically and electrophysiologically complete myelotomies of the C4 spinal cord dorsal columns significantly increased the adult rat''s averaged times to first attend to adhesive stickers placed on the palms of their forepaws at 1 week. Complete bilateral myelotomies of the dorsal funiculi and dorsal hemisection, but not bilateral dorsolateral funiculi injuries, also similarly increased these times at 1 week. These data extend a previous finding by showing that a forepaw tactile sensory deficit that occurred in the adult rat after bilateral C4 spinal cord dorsal funiculi injury is due to damage of the dorsal columns. Averaged times to first attend to the stickers also decreased to those of sham-operated rats at 3 and 4 weeks post-dorsal hemisection with weekly testing. In contrast, a separate group of rats with dorsal hemisections had significantly increased times when tested only at 4 weeks. These data indicate that frequent assessment of this particular behavior in rats with dorsal hemisections extinguishes it and/or engenders a learned response in the absence of sensory axons in the dorsal columns and dorsolateral funiculi. This finding contrasted with weekly testing of grid walking where increased forelimb footfall numbers persisted for 4 weeks post-dorsal hemisection. [Copyright &y& Elsevier]

The aim of this paper is to provide new insights about the circuitry and the role of the dorsal column nuclei (DCN) in processing somatosensory information. The presence of glycinergic cells, a second type of DCN interneurons in addition to well-known GABAergic interneurons, opens the door to more complex interactions between cuneate cells as well as to a new hypothesis about the computational implications of such interactions. The research posed here fits in a broader context in the field of the sensory systems and deals with the general issue on the role of subcortical structures (i.e the thalamus) in processing sensory information. [Copyright &y& Elsevier]

Recent studies have revealed that noxious visceral inputs travel in the dorsal column pathway, and interactions between colorectal noxious and tactile inputs occur in the ventrobasal thalamus. This investigation was to test whether the somatovisceral interactions also take place at a lower level in the dorsal column nuclei. Extracellular single neuron recordings were carried out in nucleus gracilus of anesthetized rats. Forty-three neurons responsive to colorectal distension (CRD) all had excitatory responses to tactile stimuli, and their tactile responses were predominantly (31/43 units) enhanced by preceding CRD. In contrast, the neuronal responses to CRD were reduced in 22/43 units when preceded by tactile stimulation but in two units there was an enhancement. The similarity and differences in the gracile response features in comparison with the thalamic recordings suggest that somatovisceral interactions take place at multiple levels in the dorsal column-medial lemniscus system. [Copyright &y& Elsevier]

Corticofugal influences from the primary somatosensory cortex to the gracilis nuclei were studied with single unit recordings performed in urethane-anaesthetized rats. Two types of neurons were identified: low firing rate (LF) neurons, which could be activated antidromically by medial lemniscus stimulation; and high firing rate (HF) neurons. The effects of electrically stimulating the contralateral primary somatosensory cortex were studied in two situations: when the stimulated cortical area and specific gracilis cells had overlapping receptive fields and when the receptive fields of the cells and primary somatosensory cortex did not overlap. Cortical stimulation facilitated cortical and tactile responses in most gracilis neurons (68% and 58% for LF and HF neurons, respectively) with overlapping receptive fields. When receptive fields were different, cortical stimulation inhibited tactile response in most LF neurons (58%) and some HF neurons (20%). Trains of cortical shocks during sensory stimulation demonstrated that the facilitatory and inhibitory effects outlasted the stimulation period by 5 min. The facilitatory effect was decreased by iontophoretic application of the N-methyl-D-aspartate (NMDA) receptor antagonist APV (50 m m). However, APV did not modify the intensity of the tactile response inhibition in cells with nonoverlapping receptive fields, although, its duration was decreased (<5 min). Iontophoretic application of the γ-aminobutyric acid (GABA)A antagonist bicuculline (20 m m) blocked the cortically evoked inhibition in cells with nonoverlapping receptive fields. The results indicate that the somatosensory cortex precisely controls somatosensory transmission throughout the gracilis nucleus by means of NMDA and GABAA receptor activation. [ABSTRACT FROM AUTHOR]

Cells in the main cuneate nucleus (MCN) are known to provide a direct projection to the cerebellum, but the precise nature of the information these cells transmit to the cerebellum is unknown. The present study employed anatomical and electrophysiological procedures to determine the location of cuneocerebellar cells in the MCN, and their somatosensory properties in the rat. The location of neurones projecting to the cerebellum was determined with injections of the retrograde tracers, horseradish peroxidase or Fluoro-Gold in vermal and paravermal regions of the cerebellum. Topographically, the majority of retrogradely labelled cells in the MCN were found to lie primarily ventrolateral in the nucleus and rostral to the level of the obex. Single unit recordings from 69 well characterized MCN cells, identified as projection cells by antidromic activation from stimulation of the inferior cerebellar peduncle, were classified according to their responses to cutaneous stimulation and manipulation of joints and muscles. A slight majority of cells (37.7%) responded only to manipulation/stimulation of joints, and 30.4% of cells responded only to cutaneous stimulation. The remaining cells received convergent input from joint and cutaneous receptors. Cutaneous responsive cells all rapidly adapted to maintained stimuli, and had large receptive fields (RFs) that were generally located over the joints. These cells could be activated by passive movements of the forelimb that deformed the RF. They only discharged during movements and were silent during maintained limb positions. Cells responsive to punctate mechanical stimuli applied to the joint capsules, responded to passive movements of the forelimb, but typically only discharged towards the limits of joint movement, and adapted within a few seconds. Once adapted, small perturbations of joint position resulted in vigorous dynamic responses. The results indicate that the neurones in the MCN of the rat which project directly to the cerebellum are localized in the rostral half of the nucleus. They transmit predominantly dynamic information from joint and cutaneous receptors that are likely to be normally activated as a result of limb movements. These cells could signal information about evolving movements or disturbances of forelimb posture or stance. [ABSTRACT FROM AUTHOR]

Selective activation of single tactile or kinaesthetic afferent nerve fibers in conscious human subjects by means of the intraneural microstimulation procedure reveals quite marked differences among the different classes in their capacity for eliciting perceptual responses. This work, conducted largely by Swedish researchers, suggests that there may be differential transmission security for different fiber classes across synaptic linkages in the central tactile and kinaesthetic sensory pathways. In order to test this hypothesis we have developed an experimental paradigm in the anaesthetized cat, based upon paired, simultaneous recording from an individual afferent fiber in an intact peripheral nerve fascicle, and from the central target neurone of that afferent fiber within the dorsal column nuclei (DCN). Our results demonstrate, for all tactile and kinaesthetic fiber classes examined, that the minimum sensory input, a single impulse in one sensory fiber, can generate spike output from DCN target neurones. This remarkable security of transmission has been demonstrated for single Pacinian corpuscle (PC) fibers (associated with Pacinian Corpuscle receptors); single SAI and SAII fibers (the slowly adapting Type I and II tactile fibers associated, respectively, with Merkel and Ruffini receptor endings); the Hair Follicle Afferent fibers (HFA fibers); and kinaesthetic afferent fibers of both joint and muscle origin. The results demonstrate that the differential capacities of various tactile and kinaesthetic fiber classes to generate perceptual responses when activated singly in microneurography experiments do not appear to be explicable in terms of systematic differences in DCN transmission characteristics. [Copyright &y& Elsevier]