Threshold Neurons Research Articles

2-Hydroxypropyl-β-cyclodextrin Promotes Transcription Factor EB-mediated Activation of Autophagy

2-Hydroxypropyl-β-cyclodextrin (HPβCD) is a Food and Drug Administration-approved excipient used to improve the stability and bioavailability of drugs. Despite its wide use as a drug delivery vehicle and the recent approval of a clinical trial to evaluate its potential for the treatment of a cholesterol storage disorder, the cellular pathways involved in the adaptive response that is activated upon exposure to HPβCD are still poorly defined. Here, we show that cell treatment with HPβCD results in the activation of the transcription factor EB, a master regulator of lysosomal function and autophagy, and in enhancement of the cellular autophagic clearance capacity. HPβCD administration promotes transcription factor EB-mediated clearance of proteolipid aggregates that accumulate due to inefficient activity of the lysosome-autophagy system in cells derived from a patient with a lysosomal storage disorder. Interestingly, HPβCD-mediated activation of autophagy was found not to be associated with activation of apoptotic pathways. This study provides a mechanistic understanding of the cellular response to HPβCD treatment, which will inform the development of safe HPβCD-based therapeutic modalities and may enable engineering HPβCD as a platform technology to reduce the accumulation of lysosomal storage material.

GABAergic neurons in the ventral tegmental area receive dual GABA/enkephalin‐mediated inhibitory inputs from the bed nucleus of the stria terminalis

Activation of mu-opioid receptor (MOR) disinhibits dopaminergic neurons in the ventral tegmental area (VTA) through inhibition of γ-aminobutyric acid (GABA)ergic neurons. This mechanism is thought to play a pivotal role in mediating reward behaviors. Here, we characterised VTA-projecting enkephalinergic neurons in the anterior division of the bed nucleus of the stria terminalis (BST) and investigated their targets by examining MOR expression in the VTA. In the BST, neurons expressing preproenkephalin mRNA were exclusively GABAergic, and constituted 37.2% of the total GABAergic neurons. Using retrograde tracer injected into the VTA, 21.6% of VTA-projecting BST neurons were shown to express preproenkephalin mRNA. Enkephalinergic projections from the BST exclusively formed symmetrical synapses onto the dendrites of VTA neurons. In the VTA, 74.1% of MOR mRNA-expressing neurons were GABAergic, with the rest being glutamatergic neurons expressing type-2 vesicular glutamate transporter mRNA. However, MOR mRNA was below the detection threshold in dopaminergic neurons. By immunohistochemistry, MOR was highly expressed on the extrasynaptic membranes of dendrites in GABAergic VTA neurons, including dendrites innervated by BST-VTA projection terminals. MOR was also expressed weakly on GABAergic and glutamatergic terminals in the VTA. Given that GABAA α1 is expressed at GABAergic BST-VTA synapses on dendrites of GABAergic neurons [T. Kudo etal. (2012) J. Neurosci., 32, 18035-18046], our results collectively indicate that the BST sends dual inhibitory outputs targeting GABAergic VTA neurons; GABAergic inhibition via 'wired' transmission, and enkephalinergic inhibition via 'volume' transmission. This dual inhibitory system provides the neural substrate underlying the potent disinhibitory control over dopaminergic VTA neurons exerted by the BST.

Neuronal detection thresholds during vestibular compensation: contributions of response variability and sensory substitution

The vestibular system is responsible for processing self-motion, allowing normal subjects to discriminate the direction of rotational movements as slow as 1-2degs(-1). After unilateral vestibular injury patients' direction-discrimination thresholds worsen to ∼20degs(-1), and despite some improvement thresholds remain substantially elevated following compensation. To date, however, the underlying neural mechanisms of this recovery have not been addressed. Here, we recorded from first-order central neurons in the macaque monkey that provide vestibular information to higher brain areas for self-motion perception. Immediately following unilateral labyrinthectomy, neuronal detection thresholds increased by more than two-fold (from 14 to 30degs(-1)). While thresholds showed slight improvement by week 3 (25degs(-1)), they never recovered to control values - a trend mirroring the time course of perceptual thresholds in patients. We further discovered that changes in neuronal response variability paralleled changes in sensitivity for vestibular stimulation during compensation, thereby causing detection thresholds to remain elevated over time. However, we found that in a subset of neurons, the emergence of neck proprioceptive responses combined with residual vestibular modulation during head-on-body motion led to better neuronal detection thresholds. Taken together, our results emphasize that increases in response variability to vestibular inputs ultimately constrain neural thresholds and provide evidence that sensory substitution with extravestibular (i.e. proprioceptive) inputs at the first central stage of vestibular processing is a neural substrate for improvements in self-motion perception following vestibular loss. Thus, our results provide a neural correlate for the patient benefits provided by rehabilitative strategies that take advantage of the convergence of these multisensory cues.

Dynamic-clamp analysis of wild-type human Nav1.7 and erythromelalgia mutant channel L858H

The link between sodium channel Nav1.7 and pain has been strengthened by identification of gain-of-function mutations in patients with inherited erythromelalgia (IEM), a genetic model of neuropathic pain in humans. A firm mechanistic link to nociceptor dysfunction has been precluded because assessments of the effect of the mutations on nociceptor function have thus far depended on electrophysiological recordings from dorsal root ganglia (DRG) neurons transfected with wild-type (WT) or mutant Nav1.7 channels, which do not permit accurate calibration of the level of Nav1.7 channel expression. Here, we report an analysis of the function of WT Nav1.7 and IEM L858H mutation within small DRG neurons using dynamic-clamp. We describe the functional relationship between current threshold for action potential generation and the level of WT Nav1.7 conductance in primary nociceptive neurons and demonstrate the basis for hyperexcitability at physiologically relevant levels of L858H channel conductance. We demonstrate that the L858H mutation, when modeled using dynamic-clamp at physiological levels within DRG neurons, produces a dramatically enhanced persistent current, resulting in 27-fold amplification of net sodium influx during subthreshold depolarizations and even greater amplification during interspike intervals, which provide a mechanistic basis for reduced current threshold and enhanced action potential firing probability. These results show, for the first time, a linear correlation between the level of Nav1.7 conductance and current threshold in DRG neurons. Our observations demonstrate changes in sodium influx that provide a mechanistic link between the altered biophysical properties of a mutant Nav1.7 channel and nociceptor hyperexcitability underlying the pain phenotype in IEM.

Neuronal detection thresholds during vestibular compensation: contributions of response variability and sensory substitution

Key points Unilateral vestibular injury impairs our ability to detect motion. However, before this study the neural mechanisms underlying this impairment had not yet been established. We found that the detection thresholds of neurons at the first central stage of vestibular processing (i.e. vestibular nuclei) dramatically increase immediately post-lesion, and despite some recovery remain elevated even after 1 month, following the trend reported for vestibular patients’ perception. After the lesion, parallel changes in neuronal trial-to-trial variability and sensitivity account for consistently elevated thresholds, thus providing a neural correlate for impaired behavioural performance. In a subset of neurons, sensory substitution with extravestibular (i.e. proprioceptive) inputs after the lesion combined with residual vestibular information serves to improve neuronal detection thresholds for head-on-body motion. Our results provide a neural correlate for rehabilitation approaches that take advantage of the convergence of proprioceptive and vestibular inputs to improve patient outcomes. Abstract The vestibular system is responsible for processing self-motion, allowing normal subjects to discriminate the direction of rotational movements as slow as 1–2 deg s−1. After unilateral vestibular injury patients’ direction–discrimination thresholds worsen to ∼20 deg s−1, and despite some improvement thresholds remain substantially elevated following compensation. To date, however, the underlying neural mechanisms of this recovery have not been addressed. Here, we recorded from first-order central neurons in the macaque monkey that provide vestibular information to higher brain areas for self-motion perception. Immediately following unilateral labyrinthectomy, neuronal detection thresholds increased by more than two-fold (from 14 to 30 deg s−1). While thresholds showed slight improvement by week 3 (25 deg s−1), they never recovered to control values – a trend mirroring the time course of perceptual thresholds in patients. We further discovered that changes in neuronal response variability paralleled changes in sensitivity for vestibular stimulation during compensation, thereby causing detection thresholds to remain elevated over time. However, we found that in a subset of neurons, the emergence of neck proprioceptive responses combined with residual vestibular modulation during head-on-body motion led to better neuronal detection thresholds. Taken together, our results emphasize that increases in response variability to vestibular inputs ultimately constrain neural thresholds and provide evidence that sensory substitution with extravestibular (i.e. proprioceptive) inputs at the first central stage of vestibular processing is a neural substrate for improvements in self-motion perception following vestibular loss. Thus, our results provide a neural correlate for the patient benefits provided by rehabilitative strategies that take advantage of the convergence of these multisensory cues.

The relationship between iron deficiency anemia and simple febrile convulsion in children.

Background:Simple febrile convulsion is the most common disease of the nervous system in children. There are hypotheses that iron deficiency may affect febrile convulsion and the threshold of neuron excitation.Aims:This study was conducted with the objective of finding the effects of iron deficiency anemia on simple febrile convulsion episodes.Settings and Design:The study was conducted at AmirKabir Hospital of Arak Medical Sciences University, Arak, Iran. This is a case-control study.Materials and Methods:In this study, 382 children who were selected according to our inclusion and exclusion factors, were divided into two groups of case (febrile convulsion) and control (other factors causing fever) by their cause of hospitalization. After fever subsided, 5 ml blood sample was taken from each child and complete blood count and iron profile tests were performed.Statistical Analysis:The results were interpreted using descriptive statistics and independent t-test. Results: The prevalence of anemia in the group with febrile convulsion was significantly less than that in the control group: 22.5% of the children in the group with febrile convulsion and 34% in the control group exhibited anemia (P < 0.001). Moreover, the group with febrile convulsion had significantly higher blood indices, such as Hb, Hct, MCV, MCH, and MCHC, compared to the control group (P < 0.001).Conclusions:Iron deficiency can prevent febrile convulsion in children and probably increases the threshold of neuron excitation in fever.

Enhancing K–Cl co-transport restores normal spinothalamic sensory coding in a neuropathic pain model

Neuropathic pain is a widespread and highly debilitating condition commonly resulting from injury to the nervous system, one main sequela of which is tactile allodynia, a pain induced by innocuous mechanical stimulation of the skin. Yet, the cellular mechanisms and neuronal substrates underlying this pathology have remained elusive. We studied this by quantifying and manipulating behavioural and neuronal nociceptive thresholds in normal and pathological pain conditions. We found that, in both control rats and those with pain hypersensitivity induced by nerve injury, the nociceptive paw withdrawal threshold matches the response threshold of nociceptive-specific deep spinothalamic tract neurons. In contrast, wide dynamic range or multimodal spinothalamic tract neurons showed no such correlation nor any change in properties after nerve injury. Disrupting Cl(-) homeostasis by blocking K(+)-Cl(-) co-transporter 2 replicated the decrease in threshold of nociceptive-specific spinothalamic tract neurons without affecting wide dynamic range spinothalamic tract cells. Accordingly, only combined blockade of both GABAA- and glycine-gated Cl(-) channels replicated the effects of nerve injury or K(+)-Cl(-) co-transporter 2 blockade to their full extent. Conversely, rescuing K(+)-Cl(-) co-transporter 2 function restored the threshold of nociceptive-specific spinothalamic tract neurons to normal values in animals with nerve injury. Thus, we unveil a tight association between tactile allodynia and abnormal sensory coding within the normally nociceptive-specific spinothalamic tract. Thus allodynia appears to result from a switch in modality specificity within normally nociceptive-specific spinal relay neurons rather than a change in gain within a multimodal ascending tract. Our findings identify a neuronal substrate and a novel cellular mechanism as targets for the treatment of pathological pain.

Mouse Primary Visual Cortex Is Used to Detect Both Orientation and Contrast Changes

In mammals, the lateral geniculate nucleus (LGN) and the superior colliculus (SC) are the major targets of visual inputs from the retina. The LGN projects mainly to primary visual cortex (V1) while the SC targets the thalamus and brainstem, providing two potential pathways for processing visual inputs. Indeed, cortical lesion experiments in rodents have yielded mixed results, leading to the hypothesis that performance of simple visual behaviors may involve computations performed entirely by this subcortical pathway through the SC. However, these previous experiments have been limited by both their assays of behavioral performance and their use of lesions to change cortical activity. To determine the contribution of V1 to these tasks, we trained mice to perform threshold detection tasks in which they reported changes in either the contrast or orientation of visual stimuli. We then reversibly inhibited V1 by optogenetically activating parvalbumin-expressing inhibitory neurons with channelrhodopsin-2. We found that suppressing activity in V1 substantially impaired performance in visual detection tasks. The behavioral deficit depended on the retinotopic position of the visual stimulus, confirming that the effect was due to the specific suppression of the visually driven V1 neurons. Behavioral effects were seen with only moderate changes in neuronal activity, as inactivation that raised neuronal contrast thresholds by a median of only 14% was associated with a doubling of behavioral contrast detection threshold. Thus, detection of changes in either orientation or contrast is dependent on, and highly sensitive to, the activity of neurons in V1.

Multitasking attractor networks with neuronal threshold noise

We consider the multitasking associative network in the low-storage limit and we study its phase diagram with respect to the noise level T and the degree d of dilution in pattern entries. We find that the system is characterized by a rich variety of stable states, including pure states, parallel retrieval states, hierarchically organized states and symmetric mixtures (remarkably, both even and odd), whose complexity increases as the number of patterns P grows. The analysis is performed both analytically and numerically: Exploiting techniques based on partial differential equations, we are able to get the self-consistencies for the order parameters. Such self-consistency equations are then solved and the solutions are further checked through stability theory to catalog their organizations into the phase diagram, which is outlined at the end. This is a further step towards the understanding of spontaneous parallel processing in associative networks.

Unipolar Sigmoid neural network classifier based on weights and structure determination method

A neural network classifier with the hidden neurons activated by unipolar Sigmoid function was constructed and investigated in this paper.The thresholds of hidden neurons and weights between the input layer and the hidden layer of the neural network were randomly generated.The psedoinverse-type Weights Direct Determination(WDD) method was applied to determining the weights between the hidden layer and the output layer.Moreover,a Structure Automatic Determination(SAD) algorithm with pruning-while-growing and twice-pruning policies was proposed to determine the optimal structure of the neural network.The numerical experimental results demonstrate that the SAD algorithm can determine the optimal structure of the neural network quickly and effectively and the neural network classifier has a satisfactory performance.

Effects of Cellular Homeostatic Intrinsic Plasticity on Dynamical and Computational Properties of Biological Recurrent Neural Networks

Homeostatic intrinsic plasticity (HIP) is a ubiquitous cellular mechanism regulating neuronal activity, cardinal for the proper functioning of nervous systems. In invertebrates, HIP is critical for orchestrating stereotyped activity patterns. The functional impact of HIP remains more obscure in vertebrate networks, where higher order cognitive processes rely on complex neural dynamics. The hypothesis has emerged that HIP might control the complexity of activity dynamics in recurrent networks, with important computational consequences. However, conflicting results about the causal relationships between cellular HIP, network dynamics, and computational performance have arisen from machine-learning studies. Here, we assess how cellular HIP effects translate into collective dynamics and computational properties in biological recurrent networks. We develop a realistic multiscale model including a generic HIP rule regulating the neuronal threshold with actual molecular signaling pathways kinetics, Dale's principle, sparse connectivity, synaptic balance, and Hebbian synaptic plasticity (SP). Dynamic mean-field analysis and simulations unravel that HIP sets a working point at which inputs are transduced by large derivative ranges of the transfer function. This cellular mechanism ensures increased network dynamics complexity, robust balance with SP at the edge of chaos, and improved input separability. Although critically dependent upon balanced excitatory and inhibitory drives, these effects display striking robustness to changes in network architecture, learning rates, and input features. Thus, the mechanism we unveil might represent a ubiquitous cellular basis for complex dynamics in neural networks. Understanding this robustness is an important challenge to unraveling principles underlying self-organization around criticality in biological recurrent neural networks.

A Modeling Framework for Deriving the Structural and Functional Architecture of a Short-Term Memory Microcircuit

Although many studies have identified neural correlates of memory, relatively little is known about the circuit properties connecting single-neuron physiology to behavior. Here we developed a modeling framework to bridge this gap and identify circuit interactions capable of maintaining short-term memory. Unlike typical studies that construct a phenomenological model and test whether it reproduces select aspects of neuronal data, we directly fit the synaptic connectivity of an oculomotor memory circuit to a broad range of anatomical, electrophysiological, and behavioral data. Simultaneous fits to all data, combined with sensitivity analyses, revealed complementary roles of synaptic and neuronal recruitment thresholds in providing the nonlinear interactions required to generate the observed circuit behavior. This work provides a methodology for identifying the cellular and synaptic mechanisms underlying short-term memory and demonstrates how the anatomical structure of a circuit may belie its functional organization.

Effects of Core Auditory Cortex Deactivation on Neuronal Response to Simple and Complex Acoustic Signals in the Contralateral Anterior Auditory Field

Interhemispheric communication has been implicated in various functions of sensory signal processing and perception. Despite ample evidence demonstrating this phenomenon in the visual and somatosensory systems, to date, limited functional assessment of transcallosal transmission during periods of acoustic signal exposure has hindered our understanding of the role of interhemispheric connections between auditory cortical fields. Consequently, the present investigation examines the impact of core auditory cortical field deactivation on response properties of contralateral anterior auditory field (AAF) neurons in the felis catus. Single-unit responses to simple and complex acoustic signals were measured across AAF before, during, and after individual and combined cooling deactivation of contralateral primary auditory cortex (A1) and AAF neurons. Data analyses revealed that on average: 1) interhemispheric projections from core auditory areas to contralateral AAF neurons are predominantly excitatory, 2) changes in response strength vary based on acoustic features, 3) A1 and AAF projections can modulate AAF activity differently, 4) decreases in response strength are not specific to particular cortical laminae, and 5) contralateral inputs modulate AAF neuronal response thresholds. Collectively, these observations demonstrate that A1 and AAF neurons predominantly modulate AAF response properties via excitatory projections.

The role of the coreceptor Orco in insect olfactory transduction

Insects sense odorants with specialized odorant receptors (ORs). Each antennal olfactory receptor neuron expresses one OR with an odorant binding site together with a conserved coreceptor called Orco which does not bind odorants. Orco is necessary for localization of ORs to dendritic membranes and, thus, is essential for odorant detection. It forms a spontaneously opening cation channel, activated via phosphorylation by protein kinase C. Thereafter, Orco is also activated via cyclic adenosine monophosphate (cAMP). Orco forms homo-as well as heteromers with ORs with unknown stoichiometry. Contradictory publications suggest different mechanisms of olfactory transduction. On the one hand, evidence accumulates for the employment of more than one G protein-coupled olfactory transduction cascade in different insects. On the other hand, results from other studies suggest that the OR-Orco complex functions as an odorant-gated cation channel mediating ionotropic signal transduction. This review analyzes conflicting hypotheses concerning the role of Orco in insect olfactory transduction. In conclusion, in situ studies in hawkmoths falsify the hypothesis that Orco underlies odorant-induced ionotropic signal transduction in all insect species. Instead, Orco forms a metabotropically gated, slow cation channel which controls odorant response threshold and kinetics of the sensory neuron.

Strong Correlations between Sensitivity and Variability Give Rise to Constant Discrimination Thresholds across the Otolith Afferent Population

The vestibular system is vital for our sense of linear self-motion. At the earliest processing stages, the otolith afferents of the vestibular nerve encode linear motion. Their resting discharge regularity has long been known to span a wide range, suggesting an important role in sensory coding, yet to date, the question of how this regularity alters the coding of translational motion is not fully understood. Here, we recorded from single otolith afferents in macaque monkeys during linear motion along the preferred directional axis of each afferent over a wide range of frequencies (0.5-16 Hz) corresponding to physiologically relevant stimulation. We used signal-detection theory to directly measure neuronal thresholds and found that values for single afferents were substantially higher than those observed for human perception even when a Kaiser filter was used to provide an estimate of firing rate. Surprisingly, we further found that neuronal thresholds were independent of both stimulus frequency and resting discharge regularity. This was because increases in trial-to-trial variability were matched by increases in sensitivity such that their ratio remains constant: a coding strategy that markedly differs from that used by semicircular canal vestibular afferents to encode rotations. Finally, using Fisher information, we show that pooling the activities of multiple otolith afferents gives rise to neural thresholds comparable with those measured for perception. Together, our results strongly suggest that higher-order structures integrate inputs across afferent populations to provide our sense of linear motion and provide unexpected insight into the influence of variability on sensory encoding.

The Auxiliary Subunit KChIP2 Is an Essential Regulator of Homeostatic Excitability

The necessity for, or redundancy of, distinctive KChIP proteins is not known. Deletion of KChIP2 leads to increased susceptibility to epilepsy and to a reduction in IA and increased excitability in pyramidal hippocampal neurons. KChIP2 is essential for homeostasis in hippocampal neurons. Mutations in K(A) channel auxiliary subunits may be loci for epilepsy. The somatodendritic IA (A-type) K(+) current underlies neuronal excitability, and loss of IA has been associated with the development of epilepsy. Whether any one of the four auxiliary potassium channel interacting proteins (KChIPs), KChIP1-KChIP4, in specific neuronal populations is critical for IA is not known. Here we show that KChIP2, which is abundantly expressed in hippocampal pyramidal cells, is essential for IA regulation in hippocampal neurons and that deletion of Kchip2 affects susceptibility to limbic seizures. The specific effects of Kchip2 deletion on IA recorded from isolated hippocampal pyramidal neurons were a reduction in amplitude and shift in the V½ for steady-state inactivation to hyperpolarized potentials when compared with WT neurons. Consistent with the relative loss of IA, hippocampal neurons from Kchip2(-/-) mice showed increased excitability. WT cultured neurons fired only occasional single action potentials, but the average spontaneous firing rate (spikes/s) was almost 10-fold greater in Kchip2(-/-) neurons. In slice preparations, spontaneous firing was detected in CA1 pyramidal neurons from Kchip2(-/-) mice but not from WT. Additionally, when seizures were induced by kindling, the number of stimulations required to evoke an initial class 4 or 5 seizure was decreased, and the average duration of electrographic seizures was longer in Kchip2(-/-) mice compared with WT controls. Together, these data demonstrate that the KChIP2 is essential for physiologic IA modulation and homeostatic stability and that there is a lack of functional redundancy among the different KChIPs in hippocampal neurons.

Central α-adrenoceptors contribute to mustard oil-induced central sensitization in the rat medullary dorsal horn

Our previous studies have demonstrated that application of the inflammatory irritant mustard oil (MO) to the tooth pulp produces trigeminal central sensitization that includes increases in mechanoreceptive field size and responses to noxious stimuli and decrease in activation threshold in brainstem nociceptive neurons of trigeminal subnucleus caudalis (the medullary dorsal horn, MDH). The aim of the present study was to test if central noradrenergic processes are involved in the central sensitization of MDH neurons and if α1-adrenoceptors or α2-adrenoceptors or both are involved. In urethane/α-chloralose-anesthetized rats, the activity of extracellularly recorded and functionally identified single nociceptive neurons in the MDH was studied. Continuous intrathecal (i.t.) superfusion of the adrenergic modulator guanethidine and α-adrenoceptor blocker phentolamine or selective α1-adrenoceptor antagonist prazosin over the medulla strongly attenuated all three MO-induced parameters of central sensitization in the MDH nociceptive neurons, compared to phosphate-buffered saline (as vehicle control). In contrast, i.t. superfusion of the selective α2-adrenoceptor antagonist yohimbine had little effect on the mechanoreceptive field expansion and the decreased mechanical activation threshold, and indeed facilitated responses to noxious stimuli of sensitized nociceptive neurons. Superfusion of each of the four chemicals alone did not affect baseline nociceptive neuronal properties. These findings provide the first documentation of the involvement of central noradrenergic processes in MDH in the development of the central sensitization, and that α1- and α2-adrenoceptors may be differentially involved.

Establishment of a central post-stroke pain model using global cerebral ischaemic mice

Stroke is the leading cause of disability in the world. Central post-stroke pain (CPSP), an intractable secondary disease, is a serious problem that occurs following cerebral stroke. However, the detailed mechanisms underlying CPSP and standard treatments for it are not well established. Therefore, we examined the nociceptive threshold and alterations in the current stimulus threshold of primary afferent neurons in bilateral carotid artery occlusion (BCAO) mice. Male ddY mice were subjected to 30 min of BCAO. The development of mechanical and thermal hyperalgesia and changes in current stimulus threshold in the hind paws were measured after BCAO using the von Frey test, plantar test and a Neurometer, respectively. The threshold for mechanical and thermal hyperalgesia in both hind paws was significantly decreased on day 3 after BCAO as compared with pre-BCAO treatment. Furthermore, the sensitivity of C and Aβ fibres (at stimulation of 5 and 2000 Hz, respectively) was increased on day 3 after BCAO as compared with pre-BCAO treatment, while that of Aδ fibres was not altered. Our data show the development of bilateral hyperalgesia in this model. Potentially, C and Aβ fibre-specific hypersensitization after stroke may have contributed to these symptoms.

Activation of metabotropic glutamate receptors improves the accuracy of coincidence detection by presynaptic mechanisms in the nucleus laminaris of the chick

Interaural time difference (ITD) is a major cue for localizing a sound source and is processed in the nucleus laminaris (NL) in birds. Coincidence detection (CD) is a crucial step for processing ITD and critically depends on the size and time course of excitatory postsynaptic potentials (EPSPs). Here, we investigated a role of metabotropic glutamate receptors (mGluRs) in the regulation of EPSP amplitude and CD in the NL of chicks. A non-specific agonist of mGluRs ((±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid; t-ACPD) reduced the amplitude and extent of depression of excitatory postsynaptic currents (EPSCs) during a stimulus train, while the paired pulse ratio and coefficient of variation of EPSC amplitude were increased. In contrast, the amplitudes of spontaneous EPSCs were not affected, but the frequency was reduced. Thus, the effects of t-ACPD were presynaptic and reduced the release of neurotransmitter from terminals in the NL. Expression of group II mGluRs was graded along the tonotopic axis and was stronger towards the low frequency region in the NL. Both group II (DCG-IV) and group III (l-AP4) specific agonists reduced EPSC amplitude by presynaptic mechanisms, and the reduction was larger in the low frequency region; however, we could not find any effects of group I-specific agonists on EPSCs. The reduced EPSP amplitude in DCG-IV improved CD. A specific antagonist of group II mGluRs (LY341495) increased the amplitude of both EPSCs and EPSPs and enhanced the depression during a stimulus train, indicating constitutive activation of mGluRs in the NL. These observations indicate that mGluRs may work as autoreceptors and regulate EPSP size to improve CD in the NL.

Relationship between electrophysiological signature and defined sensory modality of trigeminal ganglion neurons in vivo

The trigeminal ganglia (TG) innervate a heterogeneous set of highly sensitive and exposed tissues. Weak, innocuous stimuli can evoke pain as a normal response in some areas such as the cornea. This observation implies, however, the capability of low-threshold mechanoreceptors, inducing pain in the normal condition. To clarify this matter, the present study correlates the electrical signature (both fiber conduction velocity and somatic electrical properties) with receptor field, mechanical threshold, and temperature responsiveness of sensory afferents innervating tissues with dissimilar sensitivity (skin vs. cornea) in the trigeminal domain. Intracellular recordings were obtained in vivo from 148 neurons of the left TG of 62 mice. In 111 of these neurons, the peripheral receptor field was successfully localized: 96 of them innervated the hairy skin, while the remaining 15 innervated the cornea. The electrical signature was defined and peripheral responses correlated with tissue target. No high threshold neurons were found in the cornea. Moreover, the electrical signature of corneal afferents resembles nociceptive neurons in the skin. TG skin afferents showed similar membrane electrical signature and sensory modality as skin afferents from dorsal root ganglion, although TG afferents exhibited a shorter duration of afterhyperpolarization then those previously described in dorsal root ganglion. These data suggest than new or different ways to classify and study TG sensory neurons may be required.