Varying the degree of single-whisker stimulation differentially affects phases of intrinsic signals in rat barrel cortex.
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Using intrinsic signal optical imaging (ISI), we have shown previously that the point spread of evoked activity in the rat barrel cortex in response to single-whisker stimulation encompasses a surprisingly large area. Given that our typical stimulation consists of five deflections at 5 Hz, the large area of evoked activity might have resulted from repetitive stimulation. Thus in the present study, we use ISI through the thinned skull to determine whether decreasing the degree of single-whisker stimulation decreases the area of the cortical point spread. We additionally outline a protocol to quantify stimulus-related differences in the temporal characteristics of intrinsic signals at a fine spatial scale. In 10 adult rats, whisker C2 was stimulated randomly with either one or five deflections delivered in a rostral-to-caudal fashion. Each deflection consisted of a 0.5-mm displacement of the whisker as measured at the point of contact, 15 mm from the snout. The number of whisker deflections did not affect the area or peak magnitude of the cortical point spread based on the intrinsic signal activity occurring from 0.5 up to 1.5 s poststimulus onset. In contrast, the magnitude and time course of intrinsic signal activity collected after 1.5-s poststimulus onset did reflect the difference in the degree of stimulation. Thus decreasing the degree of stimulation differentially affected the early and late phases of the evoked intrinsic signal response. The implications of the present results are discussed in respect to probable differences in the signal source underlying the early versus later phases of evoked intrinsic signals. (+info)
C-fiber depletion alters response properties of neurons in trigeminal nucleus principalis.
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The effects of C-fiber depletion induced by neonatal capsaicin treatment on the functional properties of vibrissa-sensitive low-threshold mechanoreceptive (LTM) neurons in the rat trigeminal nucleus principalis were examined in adult rats. Neonatal rats were injected either with capsaicin or its vehicle within 48 h of birth. The depletion of unmyelinated afferents was confirmed by the significant decrease in plasma extravasation of Evan's blue dye induced in the hindlimb skin of capsaicin-treated rats by cutaneous application of mustard oil and by the significant decrease of unmyelinated fibers in both the sciatic and infraorbital nerves. The mechanoreceptive field (RF) and response properties of 31 vibrissa-sensitive neurons in capsaicin-treated rats were compared with those of 32 vibrissa-sensitive neurons in control (untreated or vehicle-treated) rats. The use of electronically controlled mechanical stimuli allowed quantitative analysis of response properties of vibrissa-sensitive neurons; these included the number of center- and surround-RF vibrissae within the RF (i.e., those vibrissae which when stimulated elicited >/=1 and <1 action potential per stimulus, respectively), the response magnitude and latency, and the selectivity of responses to stimulation of vibrissae in different directions with emphasis on combining both the response magnitude and direction of vibrissal deflection in a vector analysis. Neonatal capsaicin treatment was associated with significant increases in the total number of vibrissae, in the number of center-RF vibrissae per neuronal RF, and in the percentage of vibrissa-sensitive neurons that also responded to stimulation of other types of orofacial tissues. Compared with control rats, capsaicin-treated rats showed significant increases in the response magnitude to stimulation of surround-RF vibrissae as well as in response latency variability to stimulation of both center- and surround-RF vibrissae. C-fiber depletion also significantly altered the directional selectivity of responses to stimulation of vibrissae. For neurons with multiple center-RF vibrissae, the proportion of center-RF vibrissae with net vector responses oriented toward the same quadrant was significantly less in capsaicin-treated compared with control rats. These changes in the functional properties of principalis vibrissa-sensitive neurons associated with marked depletion of C-fiber afferents are consistent with similarly induced alterations in LTM neurons studied at other levels of the rodent somatosensory system, and indeed may contribute to alterations previously described in the somatosensory cortex of adult rodents. Furthermore, these results provide additional support to the view that C fibers may have an important role in shaping the functional properties of LTM neurons in central somatosensory pathways. (+info)
Intrinsic firing patterns and whisker-evoked synaptic responses of neurons in the rat barrel cortex.
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We have used whole cell recording in the anesthetized rat to study whisker-evoked synaptic and spiking responses of single neurons in the barrel cortex. On the basis of their intrinsic firing patterns, neurons could be classified as either regular-spiking (RS) cells, intrinsically burst-spiking (IB) cells, or fast-spiking (FS) cells. Some recordings responded to current injection with a complex spike pattern characteristic of apical dendrites. All cell types had high rates of spontaneous postsynaptic potentials, both excitatory (EPSPs) and inhibitory (IPSPs). Some spontaneous EPSPs reached threshold, and these typically elicited only single action potentials in RS cells, bursts of action potentials in FS cells and IB cells, and a small, fast spike or a complex spike in dendrites. Deflection of single whiskers evoked a fast initial EPSP, a prolonged IPSP, and delayed EPSPs in all cell types. The intrinsic firing pattern of cells predicted their short-latency whisker-evoked spiking patterns. All cell types responded best to one or, occasionally, two primary whiskers, but typically 6-15 surrounding whiskers also generated significant synaptic responses. The initial EPSP had a relatively fixed amplitude and latency, and its amplitude in response to first-order surrounding whiskers was approximately 55% of that induced by the primary whisker. Second- and third-order surrounding whiskers evoked responses of approximately 27 and 12%, respectively. The latency of the initial EPSP was shortest for the primary whiskers, longer for surrounding whiskers, and varied with the neurons' depth below the pia. EPSP latency was shortest in the granular layer, longer in supragranular layers, and longest in infragranular layers. The receptive field size, defined as the total number of fast EPSP-inducing whiskers, was independent of each cell's intrinsic firing type, its subpial depth, or the whisker stimulus parameters. On average, receptive fields included >10 whiskers. Our results show that single neurons integrate rapid synaptic responses from a large proportion of the mystacial vibrissae, and suggest that the whisker-evoked responses of barrel neurons are a function of both synaptic inputs and intrinsic membrane properties. (+info)
Dural vasodilation causes a sensitization of rat caudal trigeminal neurones in vivo that is blocked by a 5-HT1B/1D agonist.
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1. Migraine headache pain is thought to result from an abnormal distention of intracranial, extracerebral blood vessels and the consequent activation of the trigeminal nervous system. Migraine is also often accompanied by extracranial sensory disturbances from facial tissues. These experiments investigate whether meningeal dilation produces central sensitization of neurones that receive convergent input from the face. 2. Single unit extracellular activity was recorded from the trigeminal nucleus caudalis of anaesthetized rats in response to either noxious stimulation of the dura mater, innocuous stimulation of the vibrissae or to a transient dilation of the meningeal vascular bed. 3. Rat alpha-CGRP (calcitonin gene-related peptide; 1 microg kg(-1), i.v.) caused a dilation of the middle meningeal artery and facilitated vibrissal responses by 36+/-7%. 4. The 5-HT1B/1D agonist, L-741,604 (3 mg kg(-1), i.v.), inhibited responses to noxious stimulation of the dura mater (16+/-7% of control) and, in a separate group of animals, blocked the CGRP-evoked facilitation of vibrissal responses. 5. L-741,604 (3 mg kg(-1), i.v.) also inhibited responses to innocuous stimulation of the vibrissa (14+/-10% of control) with neurones that received convergent input from the face and from the dura mater, but not with cells that received input only from the face (70+/-12% of control). 6. These data show that dilation of meningeal blood vessels causes a sensitization of central trigeminal neurones and a facilitation of facial sensory processing which was blocked by activation of pre-synaptic 5-HT1B/1D receptors. 7. Sustained dural blood vessel dilation during migraine may cause a sensitization of trigeminal neurones. This may underlie some of the symptoms of migraine, such as the headache pain and the extracranial allodynia. Inhibition of this central sensitization may therefore offer a novel strategy for the development of acute and/or prophylactic anti-migraine therapies. (+info)
Medullary thyroid carcinomas in transgenic mice expressing a Polyoma carboxyl-terminal truncated middle-T and wild type small-T antigens.
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Medullary thyroid carcinoma (MTC) is a rare human tumor affecting the calcitonin-secreting c-cells of the thyroid. Here we report that two independent strains of transgenic mice expressing a Polyomavirus (Py) truncated middle-T antigen (deltaMT), consisting of the amino-terminal 304 amino acids, and the full length Py small-T antigen, developed multifocal bilateral MTCs with 100% penetrance. Occasionally one strain also developed mammary and bone tumors. Furthermore, offspring from both transgenic lines displayed pronounced waviness of the whiskers and fur, previously associated with defective epidermal growth factor receptor signaling. Transgene transcription, driven by the homologous early promoter/enhancer, and the corresponding translation products were detected in tumors and in many other organs which did not develop pathologies. The subcellular distribution of deltaMT and its interactions with the adapter proteins of the SHC family have also been analysed. Our study describes a novel murine model of MTC and provides evidence that the N-terminal 304 amino acid fragment of Py middle-T antigen, possibly in co-operation with small-T antigen, acts as a potent oncogene in c-cells of the thyroid. (+info)
Role of semaphorin III in the developing rodent trigeminal system.
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Semaphorins are a large family of secreted and transmembrane glycoproteins. Sema III, a member of the Class III semaphorins is a potent chemorepulsive signal for subsets of sensory axons and steers them away from tissue regions with high levels of expression. Previous studies in mutant mice lacking sema III gene showed various neural and nonneural abnormalities. In this study, we focused on the developing trigeminal pathway of sema III knockout mice. We show that the peripheral and central trigeminal projections are impaired during initial pathway formation when they develop into distinct nerves or tracts. These axons defasciculate and compromise the normal bundling of nerves and restricted alignment of the central tract. In contrast to trigeminal projections, thalamocortical projections to the barrel cortex appear normal. Furthermore, sema III receptor, neuropilin, is expressed during a short period of development when the tract is laid down, but not in the developing thalamocortical pathway. Peripherally, trigeminal axons express neuropilin for longer duration than their central counterparts. In spite of projection errors, whisker follicle innervation appears normal and whisker-related patterns form in the trigeminal nuclei and upstream thalamic and cortical centers. Our observations suggest that sema III plays a limited role during restriction of developing trigeminal axons to proper pathways and tracts. Other molecular and cellular mechanisms must act in concert with semaphorins in ensuring target recognition, topographic order of projections, and patterning of neural connections. (+info)
A rapid and dynamic regulation of GDNF-family ligands and receptors correlate with the developmental dependency of cutaneous sensory innervation.
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Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are members of the transforming growth factor-beta family and have been shown to elicit neurotrophic effects upon several classes of neurons including dopaminergic neurons, motoneurons, parasympathetic, sympathetic as well as primary sensory neurons. However, there is little information available on their roles in cutaneous innervation. Herein, we have studied the regulation of gdnf, ntn and the GDNF family receptors and examined their role in the development of facial cutaneous innervation in GDNF mutant mice. A dynamic spatial and temporal regulation of gdnf, ntn and their ligand binding receptors within the follicle-sinus complex correlate with development of distinct subclasses of sensory nerve endings. Furthermore, development of NGF-dependent myelinated mechanoreceptors, i.e. reticular and transverse lanceolate endings also require GDNF during ending formation and maintenance. In addition, ligand and receptor association seems to be intricately linked to a local Schwann cell-axon interaction essential for sensory terminal formation. Our results suggests that functionally specified nerve endings depend on different GDNF family members and that in contrast to neurotrophins, this family of neurotrophic factors may be acting at local sites of terminal Schwann cell-axon growth cone interactions and that they collaborate with neurotrophins by supporting the same populations of neurons but at different times in development. (+info)
Impaired experience-dependent plasticity in barrel cortex of mice lacking the alpha and delta isoforms of CREB.
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The transcription factor cyclic-AMP response element binding protein (CREB) has been implicated in long-term plasticity processes in vertebrate and invertebrate species. In the absence of the alpha/delta CREB isoforms, performance is impaired in long-term memory tasks and the long-term maintenance of long-term potentiation (LTP) is impaired in the hippocampus. However, it is not known whether CREB plays a role in neocortical plasticity. Antibodies to CREB revealed that CREB-immunoreactive nuclei are present in all cortical layers but are more numerous in layers II/III, where they composed at least two-thirds the total population of cells. CREB-immunopositive cells were therefore present and densest in the very cortical layers that exhibit experience-dependent plasticity at this age. In order to assess the role of CREB in neocortical plasticity, we studied the effect of vibrissae deprivation on receptive field plasticity in the barrel cortex of mutant mice lacking the alpha/delta isoforms of CREB. A single vibrissa was spared and the others removed for 18 days. In wild-types this caused potentiation of the spared vibrissa response. However, in adult mutants (>6 months) spared vibrissa responses from homozygotes were potentiated less than in any adolescent animals or in adult wild-type littermates. Surround receptive field responses were abnormally large in homozygotes and failed to increase by the same amount as they did in wild-types. In contrast, the alpha/delta CREB mutation had no discernible effect on plasticity in cortical layers II/III of the younger adolescent age group (1-2 months), suggesting that different plasticity processes may operate at this age. Further tests showed that the beta isoform of CREB was up-regulated in the barrel cortex of the alpha/delta CREB knock-outs, suggesting that this subunit may have compensated partly for the loss of the alpha/delta isoforms. These studies suggests that CREB plays a role in experience-dependent plasticity in the adult neocortex. (+info)