Showing papers on "Summation published in 2010"

Distinct FGFs promote differentiation of excitatory and inhibitory synapses

Abstract: The differential formation of excitatory (glutamate-mediated) and inhibitory (GABA-mediated) synapses is a critical step for the proper functioning of the brain. An imbalance in these synapses may lead to various neurological disorders such as autism, schizophrenia, Tourette's syndrome and epilepsy. Synapses are formed through communication between the appropriate synaptic partners. However, the molecular mechanisms that mediate the formation of specific synaptic types are not known. Here we show that two members of the fibroblast growth factor (FGF) family, FGF22 and FGF7, promote the organization of excitatory and inhibitory presynaptic terminals, respectively, as target-derived presynaptic organizers. FGF22 and FGF7 are expressed by CA3 pyramidal neurons in the hippocampus. The differentiation of excitatory or inhibitory nerve terminals on dendrites of CA3 pyramidal neurons is specifically impaired in mutants lacking FGF22 or FGF7. These presynaptic defects are rescued by postsynaptic expression of the appropriate FGF. FGF22-deficient mice are resistant to epileptic seizures, and FGF7-deficient mice are prone to them, as expected from the alterations in excitatory/inhibitory balance. Differential effects of FGF22 and FGF7 involve both their distinct synaptic localizations and their use of different signalling pathways. These results demonstrate that specific FGFs act as target-derived presynaptic organizers and help to organize specific presynaptic terminals in the mammalian brain.

Sensitivity loss in early glaucoma can be mapped to an enlargement of the area of complete spatial summation

Abstract: Purpose. The area of complete spatial summation (Ricco's area) is the largest stimulus size for which area × intensity is constant at threshold. The authors sought to investigate whether Ricco's area changes in early glaucoma to account for the decreased visual signal/noise ratio that may accompany retinal ganglion cell loss. Methods. Spatial summation functions were measured, and Ricco's area was determined at four 10° retinal locations in 24 patients with early glaucoma (total deviation at test locations, mean, −1.3 dB; range, +2 dB to −8 dB) and 26 age-similar healthy subjects under achromatic and S-cone isolation conditions. Achromatic grating resolution acuity was measured at the same locations to estimate functional ganglion cell density. Results. Ricco's area was enlarged in patients compared with controls for both achromatic (enlarged by: superior field, 0.57 log units, P < 0.01; inferior field, 0.72 log units, P < 0.01) and chromatic (enlarged by: superior field, 0.26 log units, P < 0.01; inferior field, 0.25 log units, P = 0.065) stimuli, with negligible vertical summation curve shifts along the intensity axis. Resolution acuity was significantly reduced in glaucoma patients in both hemifields (P < 0.001). There was a weak, but significant, relationship between Ricco's area and resolution acuity. Conclusions. Enlargement of Ricco's area completely compensates for reduced perimetric sensitivity in early glaucoma to maintain constant threshold at Ricco's area, suggesting an increase in signal pooling in response to ganglion cell loss. The rightward displacement of the spatial summation curve indicates that perimetric stimuli should be capable of modulating in size as well as/instead of contrast, which may boost the glaucoma signal within measurement noise.

Homeostatic Regulation of Synaptic Excitability: Tonic GABAA Receptor Currents Replace Ih in Cortical Pyramidal Neurons of HCN1 Knock-Out Mice

Abstract: Homeostatic control of synaptic efficacy is often mediated by dynamic regulation of excitatory synaptic receptors. Here, we report a novel form of homeostatic synaptic plasticity based on regulation of shunt currents that control dendritosomatic information transfer. In cortical pyramidal neurons from wild-type mice, HCN1 channels underlie a dendritic hyperpolarization-activated cationic current ( I h) that serves to limit temporal summation of synaptic inputs. In HCN1 knock-out mice, as expected, I h is reduced in pyramidal neurons and its effects on synaptic summation are strongly diminished. Unexpectedly, we found a markedly enhanced bicuculline- and L-655,708-sensitive background GABAA current in these cells that could be attributed to selective upregulation of GABAA α5 subunit expression in the cortex of HCN1 knock-out mice. Strikingly, despite diminished I h, baseline sublinear summation of evoked EPSPs was unchanged in pyramidal neurons from HCN1 knock-out mice; however, blocking tonic GABAA currents with bicuculline enhanced synaptic summation more strongly in pyramidal cells from HCN1 knock-out mice than in those cells from wild-type mice. Increasing tonic GABAA receptor conductance in the context of reduced I h, using computational or pharmacological approaches, restored normal baseline synaptic summation, as observed in neurons from HCN1 knock-out mice. These data indicate that upregulation of α5 subunit-mediated GABAA receptor tonic current compensates quantitatively for loss of dendritic I h in cortical pyramidal neurons from HCN1 knock-out mice to maintain normal synaptic summation; they further imply that dendritosomatic synaptic efficacy is a controlled variable for homeostatic regulation of cortical neuron excitability in vivo .

Dynamic spike thresholds during synaptic integration preserve and enhance temporal response properties in the avian cochlear nucleus.

Abstract: Neurons of the cochlear nuclei are anatomically and physiologically specialized to optimally encode temporal and spectral information about sound stimuli, in part for binaural auditory processing. The avian cochlear nucleus magnocellularis (NM) integrates excitatory eighth nerve inputs and depolarizing GABAergic inhibition such that temporal fidelity is enhanced across the synapse. The biophysical mechanisms of this depolarizing inhibition, and its role in temporal processing, are not fully understood. We used whole-cell electrophysiology and computational modeling to examine how subthreshold excitatory inputs are integrated and how depolarizing IPSPs affect spike thresholds and synaptic integration by chick NM neurons. We found that both depolarizing inhibition and subthreshold excitatory inputs cause voltage threshold accommodation, nonlinear temporal summation, and shunting. Inhibition caused such large changes in threshold that subthreshold excitatory inputs were followed by a refractory period. We hypothesize that these large shifts in threshold eliminate spikes to asynchronous inputs, providing a mechanism for the enhanced temporal fidelity seen across the eighth nerve/cochlear nucleus synapse. Thus, depolarizing inhibition and threshold shifting hone the temporal response properties of this system so as to enhance the temporal fidelity that is essential for auditory perception.

The interactions between spatial summation and DNIC: effect of the distance between two painful stimuli and attentional factors on pain perception.

Abstract: The ability of a painful stimulus to suppress pain in another, remote area (DNIC) has been intensely studied. However, the effect of the distance between the two painful stimuli and the attentional factors during the measurement of pain perception received minimal treatment. We evaluated the effect of these factors on DNIC and on the interaction between DNIC and spatial summation (SS) of pain. Subjects rated the intensity of a test stimulus (applied to one hand) alone and simultaneously with conditioning stimuli applied to four different locations; 5 and 30 cm from the test stimulus on the same hand, the contralateral hand and contralateral leg. In each location, ratings were performed under three different instructions: summation, attention to test stimulus, attention to conditioning stimulus. The distance between the conditioning and test stimulus significantly affected pain perception ( p p p

Supra-threshold scaling, temporal summation, and after-sensation: relationships to each other and anxiety/fear

Abstract: This study investigated the relationship of thermal pain testing from three types of quantitative sensory testing (ie, supra-threshold stimulus response scaling, temporal summation, and after-sensation) at three anatomical sites (ie, upper extremity, lower extremity, and trunk). Pain ratings from these procedures were also compared with common psychological measures previously shown to be related to experimental pain responses and consistent with fear-avoidance models of pain. Results indicated that supra-threshold stimulus response scaling, temporal summation, and after-sensation, were significantly related to each other. The site of stimulation was also an important factor, with the trunk site showing the highest sensitivity in all three quantitative sensory testing procedures. Supra-threshold response measures were highly related to measures of fear of pain and anxiety sensitivity for all stimulation sites. For temporal summation and after-sensation, only the trunk site was significantly related to anxiety sensitivity, and fear of pain, respectively. Results suggest the importance of considering site of stimulation when designing and comparing studies. Furthermore, psychological influence on quantitative sensory testing is also of importance when designing and comparing studies. Although there was some variation by site of stimulation, fear of pain and anxiety sensitivity had consistent influences on pain ratings.

The effect of age on the area of complete spatial summation for chromatic and achromatic stimuli

Abstract: Purpose. Previously, an association between the area of complete spatial summation (Ricco's area) and age under scotopic conditions had been found. The authors sought to determine whether Ricco's area is similarly associated with age under photopic achromatic and selective S-cone conditions in peripheral vision and whether any association relates to a loss of ganglion cell density as determined by measurements of peripheral grating resolution acuity. Methods. Achromatic spatial summation functions were plotted for 68 healthy subjects (aged 20–77 years) in four oblique meridians on a gray background field of 10 cd/m2. Similar functions were generated for the S-cone pathway (isolated using Stiles' two-color threshold method) for the same locations. Ricco's area was determined using two-phase regression analysis. Achromatic peripheral grating resolution acuity was measured at the same locations using high-contrast Gabor stimuli, as an estimate of localized functional ganglion cell density. Results. There was a notable decrease in overall contrast sensitivity with age for all stimulus sizes. However, there was no evidence of age-related change in Ricco's area for either achromatic (superior field, r2 = 0.05; inferior field, r2 = 0.0007; all P > 0.05) or chromatic (superior field, r2 = 0.01; inferior field, r2 = 0.006; all P > 0.05) stimuli, despite a significant decrease in peripheral grating resolution acuity with age (superior field, r2 = 0.15; inferior field, r2 = 0.17; both P < 0.05). Conclusions. An age-related decline in functional ganglion cell density is not accompanied by a significant change in Ricco's area for achromatic or chromatic stimuli.

Temporal summation of heat pain in humans: Evidence supporting thalamocortical modulation

Abstract: Noxious cutaneous contact heat stimuli (48 °C) are perceived as increasingly painful when the stimulus duration is extended from 5 to 10 s, reflecting the temporal summation of central neuronal activity mediating heat pain. However, the sensation of increasing heat pain disappears, reaching a plateau as stimulus duration increases from 10 to 20 s. We used functional magnetic resonance imaging (fMRI) in 10 healthy subjects to determine if active central mechanisms could contribute to this psychophysical plateau. During heat pain durations ranging from 5 to 20 s, activation intensities in the bilateral orbitofrontal cortices and the activation volume in the left primary (S1) somatosensory cortex correlated only with perceived stimulus intensity and not with stimulus duration. Activation volumes increased with both stimulus duration and perceived intensity in the left lateral thalamus, posterior insula, inferior parietal cortex, and hippocampus. In contrast, during the psychophysical plateau, both the intensity and volume of thalamic and cortical activations in the right medial thalamus, right posterior insula, and left secondary (S2) somatosensory cortex continued to increase with stimulus duration but not with perceived stimulus intensity. Activation volumes in the left medial and right lateral thalamus, and the bilateral mid-anterior cingulate, left orbitofrontal, and right S2 cortices also increased only with stimulus duration. The increased activity of specific thalamic and cortical structures as stimulus duration, but not perceived intensity, increases is consistent with the recruitment of a thalamocortical mechanism that participates in the modulation of pain-related cortical responses and the temporal summation of heat pain.

Role of ocular aberrations in photopic spatial summation in the fovea

Abstract: An adaptive optics vision simulator was used to measure the role of ocular aberrations in the photopic foveal spatial summation curve for three young subjects. After the correction of the ocular aberrations over a 6 mm pupil, the increment luminance threshold was lowered for small stimuli and the estimated area of complete summation (Ricco's area) was reduced by a factor of 2.6 on average. These results show that the image spread due to natural ocular aberrations partly accounts for the spatial summation observed in the fovea in the photopic light regime.

Area CA3 interneurons receive two spatially segregated mossy fiber inputs.

Abstract: Area CA3 receives two extrinsic excitatory inputs, the mossy fibers (MF) and the perforant path (PP). Interneurons with somata in str. lacunosum moleculare (L-M) of CA3 modulate the influence of the MF and PP on pyramidal cell activity by providing strong feed-forward inhibitory influence to pyramidal cells. Here we report that L-M interneurons receive two separate MF inputs, one to the dorsal dendrites from the suprapyramidal blade of the dentate gyrus (MFSDG), and a second to ventral dendrites from the str. lucidum (MFSL). Responses elicited from MFSDG and MFSL stimulation sites have strong paired-pulse facilitation, similar DCG-IV sensitivity, amplitude, and decay kinetics but target spatially segregated domains on the interneuron dendrites. These data demonstrate that certain interneuron subtypes are entrained by two convergent MF inputs to spatially separated regions of the dendritic tree. This anatomical arrangement could make these interneurons considerably more responsive to the excitatory drive from dentate granule cells. Furthermore, temporal summation is linear or slightly sublinear between PP and MFSL but supralinear between PP and MFSDG. This specific boosting of the excitatory drive to interneurons from the SDG location may indicate that L-M interneurons could be specifically involved in the processing of the associational component of the recognition memory.

In vivo patch-clamp analysis of response properties of rat primary somatosensory cortical neurons responding to noxious stimulation of the facial skin.

Abstract: Although it has been widely accepted that the primary somatosensory (SI) cortex plays an important role in pain perception, it still remains unclear how the nociceptive mechanisms of synaptic transmission occur at the single neuron level. The aim of the present study was to examine whether noxious stimulation applied to the orofacial area evokes the synaptic response of SI neurons in urethane-anesthetized rats using an in vivo patch-clamp technique. In vivo whole-cell current-clamp recordings were performed in rat SI neurons (layers III-IV). Twenty-seven out of 63 neurons were identified in the mechanical receptive field of the orofacial area (36 neurons showed no receptive field) and they were classified as non-nociceptive (low-threshold mechanoreceptive; 6/27, 22%) and nociceptive neurons. Nociceptive neurons were further divided into wide-dynamic range neurons (3/27, 11%) and nociceptive-specific neurons (18/27, 67%). In the majority of these neurons, a proportion of the excitatory postsynaptic potentials (EPSPs) reached the threshold, and then generated random discharges of action potentials. Noxious mechanical stimuli applied to the receptive field elicited a discharge of action potentials on the barrage of EPSPs. In the case of noxious chemical stimulation applied as mustard oil to the orofacial area, the membrane potential shifted depolarization and the rate of spontaneous discharges gradually increased as did the noxious pinch-evoked discharge rates, which were usually associated with potentiated EPSP amplitudes. The present study provides evidence that SI neurons in deep layers III-V respond to the temporal summation of EPSPs due to noxious mechanical and chemical stimulation applied to the orofacial area and that these neurons may contribute to the processing of nociceptive information, including hyperalgesia.

epeated nociceptive stimulation for detecting drug effects

Abstract: Early seminal studies have revealed that prolonged nociceptive timulation induceshyperexcitability andprolongedfiringof spinal ord nociceptive neurones, both phenomena persisting after cessaion of the peripheral stimulus [1,2] These observations provoked ubstantial changes in the understanding of pain pathophysiology hey demonstrated that activity of central pain pathwaysmay perist in the absence of a peripheral nociceptive input, and neural athways may undergo long-lasting sensitisation These findings ere mirrored by human studies showing that repeated periphral stimulation at constant intensity evokes an increase in pain ensation during the stimulation train, so that the last stimuli are erceived as painful [3,4] This phenomenon is known as temporal ummation and is believed to reflect aspects of central sensitisation nduced by the peripheral nociceptive input Due to the widely recognised importance of processes of entral sensitisation, the temporal summation model soon found pplication in human pain research Clinical studies have found hat the threshold to evoke temporal summation is lower in hronic pain patients, compared to pain-free subjects This has een observed in a variety of pain conditions, such as complex egional pain syndrome [5], whiplash [6] and fibromyalgia [7] The educed temporal summation threshold suggests that sensitisation rocesses can be induced in patients at low stimulation intensities his is expected to promote exaggerated pain even when nomajor issue damage is present The temporal summation model has also been used to assess rug efficacy Themain rationale for this application is the assumpion that certain drugs have a particular action on the mechanisms nderlying central sensitisation processes, which would make he temporal summation model suitable for detecting such drug ffects The paper by Enggaard et al [8] in the present issue of this ournal used amultimodal pain testing approach to investigate the nalgesic effect of gabapentin in healthy volunteers The investiators found a clear effect of gabapentin on temporal summation, quantitatively lower influence of the drug on pain after single lectrical stimulation, and no significant effect on pain ratings after he cold pressor test Similar findings were obtained by a previous tudy, in which gabapentin acted on part of the experimental tests mployed, including cutaneous temporal summation [9] Perhaps he most striking case of selective drug action is ketamine, which ffects the pain thresholds after repeated stimulation while being neffective on pain after single nociceptive stimulation [10]