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Adjacent sections through ventral posterior and adjacent nuclei of thalamus contralateral to rhizotomies. Section is stained for cytochrome oxidase (A). Loss or reduction of enzyme activity in area (outlined by dots) corresponds to representation of most ofthe upper limb. (B-D) Section is stained immunocytochemically for GABAA receptors (B), parvalbumin (C), or calbindin (D) and shows loss of receptor and parvalbumin immunoreactivity and increase in calbindin immunoreactivity in the same region (cf. Fig. 4). Arrows indicate position of the same blood vessel. A large part of affected region is continuous with regions of enhanced calbindin immunoreactivity in shell of VPM and in anterior pulvinar nucleus. Patches of enhanced calbindin immunoreactivity in affected zone of VPL are indicated by stars. CL, central lateral nucleus; CM, centre median nucleus; LP, lateral posterior nucleus; Pla, anterior pulvinar nucleus; R, reticular nucleus; VMb, basal ventral medial nucleus; VPI, ventral posterior inferior nucleus. (Bar = 1 mm.)
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Chronic deafferentation of skin and peripheral tissues is associated with plasticity of representational maps in cerebral cortex and with perturbations of sensory experience that include severe "central" pain. This study shows that in normal monkeys the nonnociceptive, lemniscal component of the somatosensory pathways at spinal, brainstem, and thal...
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Context 1
... the upper limb (24)(25)(26) shows a loss of large cells (20-40 ,um in diameter). Their density is reduced to 0-0.5 + 0.25 per 100 m2 n comparison with 2-3 ± 1 per 100 pum2 in the compa- rable region ofthe opposite side; the difference is statistically significant (t test, P < 0.05). There is an associated reduction in cytochrome oxidase activity (Fig. 3A) to levels consider- ably below that in the rest of VPL and in the adjoining VPM subnucleus that represents the face. The zone of reduced cytochrome oxidase activity contains some higher density patches but extends anteroposteriorly throughout VPL. In adjacent sections, this zone is exactly matched by an almost complete loss of ...
Context 2
... below that in the rest of VPL and in the adjoining VPM subnucleus that represents the face. The zone of reduced cytochrome oxidase activity contains some higher density patches but extends anteroposteriorly throughout VPL. In adjacent sections, this zone is exactly matched by an almost complete loss of parvalbumin-immunoreactive cell staining (Fig. 3C), a reduction in GABAA receptor immunoreactivity to background levels (Fig. 3B) affects small-to-medium (10-20 Am) neurons and the inter- vening neuropil, both of which stain more heavily than in other parts of VPL or VPM in normal or affected monkeys (Fig. 4). Calbindin-positive cells increase from 4-5 + 1 per 100 Xm2 in the ...
Context 3
... the face. The zone of reduced cytochrome oxidase activity contains some higher density patches but extends anteroposteriorly throughout VPL. In adjacent sections, this zone is exactly matched by an almost complete loss of parvalbumin-immunoreactive cell staining (Fig. 3C), a reduction in GABAA receptor immunoreactivity to background levels (Fig. 3B) affects small-to-medium (10-20 Am) neurons and the inter- vening neuropil, both of which stain more heavily than in other parts of VPL or VPM in normal or affected monkeys (Fig. 4). Calbindin-positive cells increase from 4-5 + 1 per 100 Xm2 in the symmetrical region of the normal side to 5-7 ± 1 per 100 Am2 on the affected side; this ...
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This study describes cytoarchitectonic criteria to define the prefrontal cortical areas in the mouse brain (C57BL/6 strain). Currently, well-illustrated mouse brain stereotaxic atlases are available, which, however, do not provide a description of the distinctive cytoarchitectonic characteristics of individual prefrontal areas. Such a description i...
Citations
... Spinal cord injury-induced loss of γ-aminobutyric acid GABAergic neurons -the principle inhibitory interneurons -in the superficial dorsal horn causes persistent pain [13,14,23,42]. Calciumbinding proteins, particularly those in GABAergic subpopulations, have received much attention due to their robust, developmentally regulated, and cell type-specific expression in the nervous system, and they have emerged as effective markers to identify neurons in pain networks [34]. These facts led us to postulate the existence of crosstalk between SBArelated pain complications and alteration in GABA ergic transmission in the spinal cord dorsal horn. ...
... Spinal cord injury-induced pain complications are due in part to neuronal dysfunction in the spinal cord, characterised by decreasing inhibitory controls [6,10,22,30]. In fact, loss of spinal cord dorsal horn inhibitory circuits, many of which involve interneurons that express GABA and its subpopulations, is a major contributor to persistent pain [13][14][15]23,34,42]. In this study, GABA-and PV-, CB-, and CR-expressing neurons were lost, and the expression levels of these factors were reduced in the exposed spinal cord dorsal horns of SBA chicks at the neonatal stage (Figs. ...
Spina bifida aperta (SBA), one of the most common congenital malformations, causes various neurological disorders. Pain is a common complaint of patients with SBA. However, little is known about the neuropathology of SBA-related pain. Because loss of g-aminobutyric acid GABAergic neurons in the spinal cord dorsal horn is associated with pain, we hypothesised the existence of crosstalk between SBA-related pain and alterations in GABAergic transmission in the spinal cord. Therefore, we investigated the kinetics of GABAergic transmission in the spinal cord dorsal horn in a chicken model of SBA. Neonatal chicks with SBA exhibited various pain-like behaviours, such as an increased number of vocalisations with elevated intensity (loudness) and frequency (pitch), reduced mobility, difficulty with locomotion, and escape reactions. Furthermore, the chicks with SBA did not respond to standard toe-pinching, indicating disruption of the spinal cord sensorimotor networks. These behavioural observations were concomitant with loss of GABAergic transmission in the spinal cord dorsal horn. We also found apoptosis of GABAergic neurons in the superficial dorsal horn in the early neonatal period, although cellular abnormalisation and propagation of neuro-degenerative signals were evident at middle to advanced gestational stages. In conclusion, ablation of GABAergic neurons induced alterations in spinal cord neuronal networks, providing novel insights into the pathophysiology of SBA-related pain-like complications.
... g-Aminobutyric acid (GABA)-mediated inhibition has been proposed to be crucial for the initiation and maintenance of somatotopic reorganization in the CNS induced by peripheral nerve injury. The protein and mRNA expression levels of the GABA A receptors (GABA A Rs), glutamate decarboxylase (GAD), and GABA in the CNS are altered after nerve injury (Castro-Lopes et al., 1993;Fukuoka et al., 1998;Jones and Pons, 1998;Moore et al., 2002;Mowery et al., 2013;Ralston and Ralston, 1994;Rausell et al., 1992;Vassias et al., 2005). Downregulation of GABA A Rs was linked to rapid somatotopic reorganization of the adult cortex after nerve injury, such as that underlying the unmasking of latent synaptic connections (Chen et al., 2002;Mowery et al., 2013;Ralston and Ralston, 1994;Rausell et al., 1992). ...
... The protein and mRNA expression levels of the GABA A receptors (GABA A Rs), glutamate decarboxylase (GAD), and GABA in the CNS are altered after nerve injury (Castro-Lopes et al., 1993;Fukuoka et al., 1998;Jones and Pons, 1998;Moore et al., 2002;Mowery et al., 2013;Ralston and Ralston, 1994;Rausell et al., 1992;Vassias et al., 2005). Downregulation of GABA A Rs was linked to rapid somatotopic reorganization of the adult cortex after nerve injury, such as that underlying the unmasking of latent synaptic connections (Chen et al., 2002;Mowery et al., 2013;Ralston and Ralston, 1994;Rausell et al., 1992). GABA A Rs produce two types of inhibition: phasic and tonic. ...
... Peripheral nerve injury or deafferentation leads to changes in the expression levels of GABA, GAD, and GABA A Rs in the spinal cord (Castro-Lopes et al., 1993;Fukuoka et al., 1998;Moore et al., 2002), brainstem (Vassias et al., 2005), thalamus (Ralston and Ralston, 1994;Rausell et al., 1992), and cerebral cortex (Garraghty et al., 1991;Hendry and Jones, 1986;Jones and Pons, 1998;Mowery et al., 2013;Welker et al., 1989). We previously reported that IONC induces remodeling of lemniscal fibers from POD5 . ...
Peripheral nerve injury induces functional and structural remodeling of neural circuits along the somatosensory pathways, forming the basis for somatotopic reorganization and ectopic sensations, such as referred phantom pain. However, the mechanisms underlying that remodeling remain largely unknown. Whisker sensory nerve injury drives functional remodeling in the somatosensory thalamus: the number of afferent inputs to each thalamic neuron increases from one to many. Here, we report that extrasynaptic γ-aminobutyric acid-type A receptor (GABAAR)-mediated tonic inhibition is necessary for that remodeling. Extrasynaptic GABAAR currents were potentiated rapidly after nerve injury in advance of remodeling. Pharmacological activation of the thalamic extrasynaptic GABAARs in intact mice induced similar remodeling. Notably, conditional deletion of extrasynaptic GABAARs in the thalamus rescued both the injury-induced remodeling and the ectopic mechanical hypersensitivity. Together, our results reveal a molecular basis for injury-induced remodeling of neural circuits and may provide a new pharmacological target for referred phantom sensations after peripheral nerve injury.
... Calbindin-D28K regulation of gamma-aminobutyric acid type A receptors [285]. ...
... Furthermore, it is also not possible to determine if this reduction in neural viability reflects changes in projection neurons from the somatosensory thalamus to S1 and the TRN, although the reduction in TRN and S1 blood flow associated with neuropathic pain means that this is a distinct possibility. It has been shown in the macaque, that peripheral nerve or somatosensory pathway lesions result in significant reductions (up to 50%) in somatosensory thalamus GABA-immunoreactive synapses (Rausell et al., 1992;Ralston, 2005). Though this inhibitory synapse loss may reflect a loss of local inhibitory neurons numbers, given the robust GABAergic projection from the TRN to the somatosensory thalamus, it likely represents a change in the function of this circuitry. ...
The transmission of noxious stimuli from peripheral receptors to the cortex involves multiple central ascending pathways. While projections to areas in the brainstem and diencephalon are likely involved in mediating the immediate behavioural responses to pain, the assessment of the sensory and emotional/motivational components of pain are likely processed in parallel ascending pathways that relay in the thalamus on their way to the cerebral cortex. In this review we discuss experimental animal and human findings that support the view that a lateral thalamocortical pathway is involved coding the sensory discriminative aspects of pain, whilst a medial thalamocortical pathway codes the emotional qualities of pain. In addition, we outline experimental animal and human evidence of functional, anatomical and biochemical alterations in thalamocortical circuits that may be responsible for altered thalamocortical rhythms and the persistent presence of pain following nervous system damage. Finally, we discuss advances in clinical and preclinical development of chronic pain treatments aimed at altering neural and glial function.
... Electrophysiologically, neuronal hyperexcitability or central sensitization is characterized by the enhanced spontaneous or evoked neuronal response properties to external stimuli applied to peripheral receptive fields with lowered activation thresholds, increased peripheral receptive field sizes, or that are increased after discharge activity [8]. Spinal hemisection results in the loss of endogenous GABAergic tone [19,32]. Further, this altered sensory perception to pathologic pain, which is linked to both spontaneous and evoked activities, is regulated by inhibitory input from the GABAergic nucleus ZI [29]. ...
Objective:
Suppression of the gamma-aminobutyric acid (GABA)ergic activity of the zona incerta (ZI) reportedly plays a role in neuropathic pain after spinal cord injury (SCI). A reduction in GABAergic signaling in the ZI of a thoracic hemisection-SCI rat model has been suggested, but not clearly demonstrated. Accordingly, our objective was to investigate whether GABAergic signals influence SCI-induced neuropathic pain.
Methods:
In vivo, we recorded and compared single-unit, neuronal activity between hemisection-SCI and sham-operated rat models. Furthermore, we analyzed neuronal activity in both models following treatment with either a GABAA receptor agonist (muscimol) or antagonist (bicuculline).
Results:
Rats that underwent hemisection SCI exhibited reduced hindpaw withdrawal thresholds, latencies, and decreased ZI neuronal activity compared with sham-operated controls. Importantly, muscimol treatment increased, whereas bicuculline decreased, the firing rates of the ZI neurons. The muscimol treated, hemisection-SCI rats also exhibited increased hindpaw withdrawal thresholds and latencies.
Conclusions:
These data provide evidence that neuropathic pain after SCI is caused by decreased GABAergic signaling in the ZI. Furthermore, our data demonstrate that infusion of a GABAergic drug into the ZI could restore its inhibitory action and improve neuropathic pain behaviors.
... , 1996b. These results demonstrate anatomical changes from healthy animals, including decreases in terminations of axons of the dorsal column nuclei, as indicated by thalamic CO staining (Rausell et al. 1992b). In healthy animals, neural elements of the lemniscal somatosensory pathway from the spinal cord (e.g., spinocervical tract; Willis and Coggeshall 2004) to the brain stem (e.g., dorsal column nuclei) and thalamus have different staining properties from those of the spinothalamic pathway. ...
... The rhizotomized monkeys display loss of parvalbumin cells in the brain stem and thalamus and downregulation of thalamic GABA A receptors (Rausell et al. 1992b). Inhibitory GABAergic inputs to thalamocortical "relay" neurons are integral to the mechanism of low-threshold calcium spikes crested by characteristic low-threshold spike (LTS) bursts of action potentials that occur in all mammalian species (Domich et al. 1986;Llinás 1984a, 1984b;Steriade et al. 1997b). ...
... This complex inhibitory circuitry is impacted by changes in GABAergic elements after the major injuries to the peripheral component of the somatic sensory system described above (Woods et al. 2000;Rausell et al. 1992b). Synapses and glomeruli are altered following injuries to the somatic sensory system and may be involved in the abnormal physiology that results (Ralston et al. 1996(Ralston et al. , 2000, including increased LTS bursting (Lenz et al. 1994a(Lenz et al. , 1998a and prolonged dystonia (Kobayashi et al. 2011). ...
The normal organization and plasticity of the cutaneous core of the thalamic principal somatosensory nucleus (ventral caudal, Vc) have been studied by single neuron recordings and microstimulation in patients undergoing awake stereotactic operations for essential tremor (ET) without apparent somatic sensory abnormality, and in patients with dystonia or chronic pain secondary to major nervous system injury. In patients with ET, most Vc neurons responded to one of the four stimuli, each of which optimally activates one mechanoreceptor type. Sensations evoked by microstimulation were similar to those evoked by the optimal stimulus only among rapidly adapting neurons. In patients with ET, Vc was highly segmented somatotopically and vibration, movement, pressure and sharp sensations were usually evoked by microstimulation at separate sites in Vc. In patients with conditions including spinal cord transection, amputation or dystonia, RFs were mismatched with projected fields more commonly than in patients with ET. The representation of the border of the anesthetic area (e.g. stump) or of the dystonic limb was much larger than that of the same part of the body in patients with ET. This review describes the organization and reorganization of human Vc neuronal activity in nervous system injury and dystonia and then proposes basic mechanisms.
... 29,30 Shoulder pain on the paretic side is common after stroke and is strongly associated with abnormal shoulder joint examination, ipsilateral sensory abnormalities, and arm weakness. 31 Deafferentation and sensory loss may also lead to the development of neuronal hypersensitivity, and eventually, chronic central pain [32][33][34] which is often difficult to treat. Pain can lead to learned nonuse, which may persist even after the pain has resolved. ...
Understanding poststroke upper limb impairment is essential to planning therapeutic efforts to restore function. However, determining which upper limb impairment to treat and how is complex because the impairments are not static and multiple impairments may be present simultaneously. How impairments contribute to upper limb dysfunction may be understood by examining them from the perspective of their functional consequences. There are 3 main functional consequences of impairments on upper limb function: (1) learned nonuse, (2) learned bad use, and (3) forgetting as determined by behavioral analysis of tasks. The impairments that contribute to each of these functional limitations are described.
... In calbinden staining zones, adjacent neurons and divergent fibers can project to more than one cortical area, such as the nuclei located posterior to Vc which project to S1 and to cortical areas in and around PS (Rausell and Jones 1991;Rausell et al. 1992a). The present results may have been recorded from calbinden compartments of thalamic nuclei, which may be involved in mechanisms of acute and chronic pain (Rausell et al. 1992a(Rausell et al. , 1992b. ...
Although the thalamus is an important module in 'pain networks', there are few studies of the effect of experimental pain upon thalamic oscillations. We have now examined the hypothesis that during a series of painful cutaneous laser stimuli thalamic signals will show stimulus-related gamma band spectral activity, which is modulated by attention to versus distraction from the painful stimulus. When the series of laser stimuli was presented, attention was focused by counting the laser stimuli (count laser task) while distraction was produced by counting backward (count back plus laser task). We have studied the effect of a cutaneous laser upon thalamic local field potentials (LFPs) and EEG activity during awake procedures (DBS implants) for the treatment of essential tremor. At different delays after the stimulus, three low gamma (30-50 Hz) and two high gamma band (70-90 Hz) activations were observed during the two tasks. Greater high gamma activation was found during the count laser task for the earlier Window, while greater high gamma activation was found during the count back plus laser task for the later Window. Thalamic signals were coherent with EEG signals in the beta band, which indicated significant synchrony. Thalamic cross frequency coupling analysis indicated that the phase of the lower frequency activity (theta to beta) modulated the amplitude of the higher frequency activity (low and high gamma) more strongly during the count laser task than during the count back plus laser task. This modulation might result in multiplexed signals each encoding a different aspect of pain.
Copyright © 2014, Journal of Neurophysiology.
... Although historically considered to serve as a marker for inhibitory neurons (DeFelipe 1997), calbindin D28k is also expressed by glutamatergic neurons, and this expression can be altered by excessive neuronal activity (Carter et al. 2008;Magloczky et al. 1997). Calbindin D28k is expressed at all levels of the pain axis, including the amygdala, thalamus, and spinal cord dorsal horn, and in primary sensory neurons (Craig et al. 2002;Fournet et al. 1986;Goncalves et al. 2008;Ichikawa and Sugimoto 2002;Li et al. 2005;Rausell et al. 1992). Calbindin D28k immunoreactivity has also been observed in a small population of enkephalin-positive neurons in the trigeminal subnucleus caudalis, a brainstem nucleus associated with nociception at the level of the head and thought to be the functional equivalent of the spinal cord dorsal horn (Huang et al. 2011). ...
Acute physiological pain, the unpleasant sensory response to a noxious stimulus, is essential for animals and humans to avoid potential injury. Pathological pain that persists after the original insult or injury has subsided, however, not only results in individual suffering but also imposes a significant cost on society. Improving treatments for long-lasting pathological pain requires a comprehensive understanding of the biological mechanisms underlying pain perception and the development of pain chronicity. In this review, we aim to highlight some of the major findings related to the involvement of neuronal calcium signaling in the processes that mediate chronic pain.
... This research was unexpectedly interrupted after the monkeys had been surgically prepared but before results could be obtained. It was these animals who 12 years later were subjects in the experiments by Pons and coworkers (1991) and from the laboratory of E. Jones (Rausell et al., 1992;Woods et al., 2000) reported on above. ...
For the nineteenth and the better part of the twentieth centuries two correlative beliefs were strongly held by almost all neuroscientists and practitioners in the field of neurorehabilitation. The first was that after maturity the adult CNS was hardwired and fixed, and second that in the chronic phase after CNS injury no substantial recovery of function could take place no matter what intervention was employed. However, in the last part of the twentieth century evidence began to accumulate that neither belief was correct. First, in the 1960s and 1970s, in research with primates given a surgical abolition of somatic sensation from a single forelimb, which rendered the extremity useless, it was found that behavioral techniques could convert the limb into an extremity that could be used extensively. Beginning in the late 1980s, the techniques employed with deafferented monkeys were translated into a rehabilitation treatment, termed Constraint Induced Movement therapy or CI therapy, for substantially improving the motor deficit in humans of the upper and lower extremities in the chronic phase after stroke. CI therapy has been applied successfully to other types of damage to the CNS such as traumatic brain injury, cerebral palsy, multiple sclerosis, and spinal cord injury, and it has also been used to improve function in focal hand dystonia and for aphasia after stroke. As this work was proceeding, it was being shown during the 1980s and 1990s that sustained modulation of afferent input could alter the structure of the CNS and that this topographic reorganization could have relevance to the function of the individual. The alteration in these once fundamental beliefs has given rise to important recent developments in neuroscience and neurorehabilitation and holds promise for further increasing our understanding of CNS function and extending the boundaries of what is possible in neurorehabilitation.
