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Chameau, Pascal; Qin, Yongjun; Spijker, Sabine; Smit, Guus; Joëls, Marian
doi: 10.1152/jn.00821.2006pmid: 17021021
Previous studies have shown that corticosterone enhances whole cell calcium currents in CA1 pyramidal neurons, through a pathway involving binding of glucocorticoid receptor homodimers to the DNA. We examined whether glucocorticoids show selectivity for L- over N-type of calcium currents. Moreover, we addressed the putative gene targets that eventually lead to the enhanced calcium currents. Electrophysiological recordings were performed in nucleated patches that allow excellent voltage control. Calcium currents in these patches almost exclusively involve N- and L-type channels. We found that L- but not N-type calcium currents were largely enhanced after treatment with a high dose of corticosterone sufficient to activate glucocorticoid receptors. Voltage dependency and kinetic properties of the currents were unaffected by the hormone. Nonstationary noise analysis suggests that the increased current is not caused by a larger unitary conductance, but rather to a doubling of the number of functional channels. Quantitative real-time PCR revealed that transcripts of the Ca v 1 subunits encoding for the N- or L-type calcium channels are not upregulated in the mouse CA1 area; instead, a strong, direct, and consistent upregulation of the 4 subunit was observed. This indicates that the corticosteroid-induced increase in number of L-type calcium channels is not caused by a simple transcriptional regulation of the pore-forming subunit of the channels. Address for reprint requests and other correspondence: P. Chameau, SILS-CNS, Univ. of Amsterdam, Kruislaan 320, 1098 SM Amsterdam, The Netherlands (E-mail: [email protected] )
Zheng, Ji-Hong; Walters, Edgar T.; Song, Xue-Jun
doi: 10.1152/jn.00559.2006pmid: 17021029
Injury or inflammation affecting sensory neurons in dorsal root ganglia (DRG) causes hyperexcitability of DRG neurons that can lead to spontaneous firing and neuropathic pain. Recent results indicate that after chronic compression of DRG (CCD treatment), both hyperexcitability of neurons in intact DRG and behaviorally expressed hyperalgesia are maintained by concurrent activity in cAMP-protein kinase A (PKA) and cGMP-protein kinase G (PKG) signaling pathways. We report here that when tested under identical conditions, dissociation produces a pattern of hyperexcitability in small DRG neurons similar to that produced by CCD treatment, manifest as decreased action potential (AP) current threshold, increased AP duration, increased repetitive firing to depolarizing pulses, increased spontaneous firing and resting depolarization. A novel feature of this hyperexcitability is its early expression—as soon as testing can be conducted after dissociation (∼2 h). Both forms of injury increase the electrophysiological responsiveness of the neurons to activation of cAMP-PKA and cGMP-PKG pathways as indicated by enhancement of hyperexcitability by agonists of these pathways in dissociated or CCD-treated neurons but not in control neurons. Although inflammatory signals are known to activate cAMP-PKA pathways, dissociation-induced hyperexcitability is unlikely to be triggered by signals released from inflammatory cells recruited to the DRG because of insufficient time for recruitment during the dissociation procedure. Inhibition by specific antagonists indicates that continuing activation of cAMP-PKA and cGMP-PKG pathways is required to maintain hyperexcitability after dissociation. The reduction of hyperexcitability by blockers of adenylyl cyclase and soluble guanylyl cyclase after dissociation suggests a continuing release of autocrine and/or paracrine factors from dissociated neurons and/or satellite cells, which activate both cyclases and help to maintain acute, injury-induced hyperexcitability of DRG neurons. Address for reprint requests and other correspondence: X.-J. Song, Dept. of Neurobiology, Parker College Research Institute, 2500 Walnut Hill Ln., Dallas, TX 75229 (E-mail: [email protected] )
Malhotra, Shveta; Lomber, Stephen G.
doi: 10.1152/jn.00720.2006pmid: 17035367
Although the contributions of primary auditory cortex (AI) to sound localization have been extensively studied in a large number of mammals, little is known of the contributions of nonprimary auditory cortex to sound localization. Therefore the purpose of this study was to examine the contributions of both primary and all the recognized regions of acoustically responsive nonprimary auditory cortex to sound localization during both bilateral and unilateral reversible deactivation. The cats learned to make an orienting response (head movement and approach) to a 100-ms broad-band noise stimulus emitted from a central speaker or one of 12 peripheral sites (located in front of the animal, from left 90° to right 90°, at 15° intervals) along the horizontal plane after attending to a central visual stimulus. Twenty-one cats had one or two bilateral pairs of cryoloops chronically implanted over one of ten regions of auditory cortex. We examined AI which included the dorsal zone (DZ), the three other tonotopic fields anterior auditory field (AAF), posterior auditory field (PAF), ventral posterior auditory field (VPAF), as well as six nontonotopic regions that included second auditory cortex (AII), the anterior ectosylvian sulcus (AES), the insular (IN) region, the temporal (T) region which included the ventral auditory field (VAF), the dorsal posterior ectosylvian (dPE) gyrus which included the intermediate posterior ectosylvian (iPE) gyrus, and the ventral posterior ectosylvian (vPE) gyrus. In accord with earlier studies, unilateral deactivation of AI/DZ caused sound localization deficits in the contralateral field. Bilateral deactivation of AI/DZ resulted in bilateral sound localization deficits throughout the 180° field examined. Of the three other tonotopically organized fields, only deactivation of PAF resulted in sound localization deficits. These deficits were virtually identical to the unilateral and bilateral deactivation results obtained during AI/DZ deactivation. Of the six nontonotopic regions examined, only deactivation of AES resulted in sound localization deficits in the contralateral hemifield during unilateral deactivation. Although bilateral deactivation of AI/DZ, PAF, or AES resulted in profound sound localization deficits throughout the entire field, the cats were generally able to orient toward the hemifield that contained the acoustic stimulus, but not accurately identify the location of the stimulus. Neither unilateral nor bilateral deactivation of areas AAF, VPAF, AII, IN, T, dPE, nor vPE had any effect on the sound localization task. Finally, bilateral heterotopic deactivations of AI/DZ, PAF, or AES yielded deficits that were as profound as bilateral homotopic cooling of any of these sites. The fact that deactivation of any one region (AI/DZ, PAF, or AES) was sufficient to produce a deficit indicated that normal function of all three regions was necessary for normal sound localization. Neither unilateral nor bilateral deactivation of AI/DZ, PAF, or AES affected the accurate localization of a visual target. The results suggest that hemispheric deactivations contribute independently to sound localization deficits. Address for reprint requests and other correspondence: S. G. Lomber, Centre for Brain and Mind, Robarts Research Institute, University of Western Ontario, 100 Perth Drive, London, Ontario N6A 5K8, Canada (E-mail: [email protected] )
doi: 10.1152/jn.00717.2006pmid: 17021027
Variability is increasingly recognized as a characteristic feature of cellular, synaptic, and network properties. While studies have traditionally focused on mean values, significant effects can result from changes in variance. This study has examined cellular and synaptic variability in the lamprey spinal cord and its modulation by the neuropeptide substance P. Cellular and synaptic variability differed in different types of cell and synapse. Substance P reduced the variability of subthreshold locomotor-related depolarizations and spiking in motor neurons during network activity. These effects were associated with a reduction in the variability of spiking in glutamatergic excitatory network interneurons and with a reduction in the variance of excitatory interneuron-evoked excitatory postsynaptic potentials (EPSPs). Substance P also reduced the variance of postsynpatic potentials (PSPs) from crossing inhibitory and excitatory interneurons, but it increased the variance of inhibitory postsynpatic potentials (IPSPs) from ipsilateral inhibitory interneurons. The effects on the variance of different PSPs could occur with or without changes in the PSP amplitude. The reduction in the variance of excitatory interneuron-evoked EPSPs was protein kinase A, calcium, and N -methyl- D -aspartate (NMDA) dependent. The NMDA dependence suggested that substance P was acting postsynaptically. This was supported by the reduced variability of postsynaptic responses to glutamate by substance P. However, ultrastructural analyses suggested that there may also be a presynaptic component to the modulation, because substance P reduced the variability of synaptic vesicle diameters in putative glutamatergic terminals. These results suggest that cellular and synaptic variability can be targeted for modulation, making it an additional source of spinal cord plasticity. Address for reprint requests and other correspondence: D. Parker, Dept. of Physiology, Development, and Neuroscience, Univ. of Cambridge, Downing St., Cambridge CB2 3EJ, UK (E-mail [email protected] )
doi: 10.1152/jn.00902.2006pmid: 17021019
Time and expected outcome are two ubiquitous factors contributing to decision-making. However, it is unclear how they interact to influence motor responses. When two differential reward outcomes are expected at the end of a waiting period, behavioral bias is consistently induced, manifested as shorter latencies for motor responses associated with the preferred reward. To examine how this bias develops in time during the waiting period, we manipulated the duration of the waiting period in an asymmetric reward saccade task in monkeys. We found that the bias increases with the duration of waiting period. Surprisingly, the bias resulted from gradual suppression of saccades to nonpreferred targets rather than from facilitation of saccades to preferred targets. These results have important implications on the neural correlates of reward-induced bias. Address for reprint requests and other correspondence: L. Ding, Lab. of Sensorimotor Research, National Eye Inst., National Inst. of Health, Bldg. 49, Rm. 2A50, Bethesda, MD 20892 (E-mail: [email protected] )
Sun, X.; Zhou, D.; Zhang, P.; Moczydlowski, E. G.; Haddad, G. G.
doi: 10.1152/jn.00700.2006pmid: 17021030
In this study, we examined the effect of arachidonic acid (AA) on the BK α-subunit with or without -subunits expressed in Xenopus oocytes. In excised patches, AA potentiated the hSlo -α current and slowed inactivation only when 2/3 subunit was co-expressed. The 2-subunit–dependent modulation by AA persisted in the presence of either superoxide dismutase or inhibitors of AA metabolism such as nordihydroguaiaretic acid and eicosatetraynoic acid, suggesting that AA acts directly rather than through its metabolites. Other cis unsaturated fatty acids (docosahexaenoic and oleic acid) also enhanced hSlo- α + 2 currents and slowed inactivation, whereas saturated fatty acids (palmitic, stearic, and caprylic acid) were without effect. Pretreatment with trypsin to remove the cytosolic inactivation domain largely occluded AA action. Intracellularly applied free synthetic 2-ball peptide induced inactivation of the hSlo -α current, and AA failed to enhance this current and slow the inactivation. These results suggest that AA removes inactivation by interacting, possibly through conformational changes, with 2 to prevent the inactivation ball from reaching its receptor. Our data reveal a novel mechanism of -subunit–dependent modulation of BK channels by AA. In freshly dissociated mouse neocortical neurons, AA eliminated a transient component of whole cell K + currents. BK channel inactivation may be a specific mechanism by which AA and other unsaturated fatty acids influence neuronal death/survival in neuropathological conditions. Address for reprint requests and other correspondence: G. G. Haddad, Dept. of Pediatrics, Univ. of California San Diego, 9500 Gilman Dr., La Jolla, CA 92037-0735 (E-mail: [email protected] )
Schieber, Marc H.; Rivlis, Gil
doi: 10.1152/jn.00544.2006pmid: 17035361
Primary motor cortex (M1) neurons traditionally have been viewed as "upper motor neurons" that directly drive spinal motoneuron pools, particularly during finger movements. We used spike-triggered averages (SpikeTAs) of electromyographic (EMG) activity to select M1 neurons whose spikes signaled the arrival of input in motoneuron pools, and examined the degree of similarity between the activity patterns of these M1 neurons and their target muscles during 12 individuated finger and wrist movements. Neuron–EMG similarity generally was low. Similarity was unrelated to the strength of the SpikeTA effect, to whether the effect was pure versus synchrony, or to the number of muscles influenced by the neuron. Nevertheless, the sum of M1 neuron activity patterns, each weighted by the sign and strength of its SpikeTA effect, could be more similar to the EMG than the average similarity of individual neurons. Significant correlations between the weighted sum of M1 neuron activity patterns and EMG were obtained in six of 17 muscles, but showed R 2 values ranging from only 0.26 to 0.42. These observations suggest that additional factors—including inputs from sources other than M1 and nonlinear summation of inputs to motoneuron pools—also contributed substantially to EMG activity patterns. Furthermore, although each of these M1 neurons produced SpikeTA effects with a significant peak or trough 6–16 ms after the triggering spike, shifting the weighted sum of neuron activity to lead the EMG by 40–60 ms increased their similarity, suggesting that the influence of M1 neurons that produce SpikeTA effects includes substantial synaptic integration that in part may reach the motoneuron pools over less-direct pathways. Address for reprint requests and other correspondence: M. H. Schieber, University of Rochester Medical Center, Department of Neurology, 601 Elmwood Avenue, Box 673, Rochester, NY 14642 (E-mail: [email protected] )
Guo, Xiaochuan; Lester, Robin A. J.
doi: 10.1152/jn.01046.2005pmid: 17050826
The fraction of inward current carried by Ca 2+ ( F Ca 2+ ) through nicotinic acetylcholine receptors (nAChRs) on acutely isolated rat medial habenula (MHb) neurons was calculated from experiments that simultaneously monitored agonist-induced membrane currents and intracellular Ca 2+ , measured with patch-clamp and indo-1 fluorescence, respectively. In physiological concentrations of extracellular Ca 2+ (2 mM) at –50 mV, the percentage of current carried by Ca 2+ was determined to be roughly 3–4%, which is in close agreement with measurements from other heteromeric nicotinic receptors expressed in peripheral tissue. Among factors that may have affected this measurement, such as Ca 2+ influx through voltage-gated Ca 2+ channels, the concentration of intracellular Ca 2+ buffer, and Ca 2+ sequestration and release from intracellular stores, only Ca 2+ uptake by mitochondria was shown to confound the analysis. Furthermore, we find that because of the high density of nAChRs on MHb cells, low concentrations of ACh (10 µM) and its hydrolysis product, choline (1 mM), can significantly elevate intracellular Ca 2+ . Moreover, during persistent activation of nAChRs, the level of intracellular Ca 2+ is proportional to its extracellular concentration in the physiological range. Together, these findings support the suggestion that nAChRs may be capable of sensing low concentrations of diffusely released neurotransmitter and, in addition, transfer information about ongoing local synaptic activity by changes in extracellular Ca 2+ . Address for reprint requests and other correspondence: R.A.J. Lester, Department of Neurobiology, SHEL1006, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham AL 35294-2182 (E-mail: [email protected] )
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