Goshajinkigan attenuates paclitaxel-induced neuropathic pain via cortical astrocytes.

The anticancer agents platinum derivatives and taxanes such as paclitaxel (PCX) often cause neuropathy known as chemotherapy-induced peripheral neuropathy with high frequency. However, the cellular and molecular mechanisms underlying such neuropathy largely remain unknown. Here, we show new findings that the effect of Goshajinkigan (GJG), a Japanese KAMPO medicine, inhibits PCX-induced neuropathy by acting on astrocytes. The administration of PCX in mice caused the sustained neuropathy lasting at least 4 weeks, which included mechanical allodynia and thermal hyperalgesia but not cold allodynia. PCX-evoked pain behaviors were associated with the sensitization of all primary afferent fibers. PCX did not activate microglia or astrocytes in the spinal cord. However, it significantly activated astrocytes in the primary sensory (S1) cortex without affecting S1 microglial activation there. GJG significantly inhibited the PCX-induced mechanical allodynia by 50% and thermal hyperalgesia by 90%, which was in accordance with the abolishment of astrocytic activation in the S1 cortex. Finally, the inhibition of S1 astrocytes by an astrocyte-toxin L-alpha-aminoadipic acid abolished the PCX-induced neuropathy. Our findings suggest that astrocytes in the S1 cortex would play an important role in the pathogenesis of PCX-induced neuropathy and are a potential target for its treatment.

The effect of GABAergic neurotransmission on the seizure-related activity of the laterodorsal thalamic nuclei and the somatosensory cortex in a genetic model of absence epilepsy.

The present study aimed to investigate the alterations of the GABAergic system in the laterodorsal nucleus (LDN) of the thalamus and the somatosensory cortex (SC) in an experimental model of absence seizure. The effects of pharmacological manipulation of both GABAA and GABAB receptor subunits in the LDN on the generation of spike-wave discharges (SWD) were evaluated. The experiments were carried out in four groups of both WAG/Rij and Wistar rats with 2 and 6 months of age. The expressions of various GABA receptor subunits were studied in the LDN and SC. Furthermore, recordings of unit activity from the LDN and electrocorticography were simultaneously monitored before, during, and after the application of GABAA and GABAB antagonists in the LDN. The generation of SWD in the older WAG/Rij rats was associated with significant alterations in the expression of GABAARα1, GABAARß3, and GABABR2 subunits in the LDN as well as GABAARα1, GABAARß3, GABAARγ2, and GABABR2 subunits in the SC. Furthermore, the occurrence of SWD was associated with a significant reduction of gene expression of GABAARα1 and increase of GABAARß3 in the LDN as well as reduction of GABAARα1, GABAARß3, GABAARγ2, and GABABR2 in the SC. The microionthophoretic application of the GABAA antagonist bicuculline resulted in a significant increase in the population firing rate of LDN neurons as well as the mean number and duration of SWD. The application of the GABAB antagonist CGP35348 significantly increased the population firing rate of LDN neurons but decreased the mean number of SWD. Our data indicate the regulatory effect of the GABAergic system of the LDN and SC in absence seizures.

Polyherbal Formulation Enhancing Cerebral Slow Waves in Sleeping Rats.

Polyherbal medicines are composed of multiple herbs and have traditionally been used in East Asian countries for the remedy of physiological symptoms. Although the effects of polyherbal formulations have been investigated at the molecular and behavioral levels, less is known about whether and how medicinal herbs affect the central nervous system in terms of neurophysiology. We introduced a novel blended herbal formulation that consisted of 35% linden, 21% mulberry, 20% lavandin, 20% butterfly pea, and 4% tulsi. After intraperitoneal administration of this formulation or saline, we simultaneously recorded epidural electrocorticograms (ECoGs) from the olfactory bulb (OB), primary somatosensory cortex (S1), and primary motor cortex (M1), along with electromyograms (EMGs) and electrocardiograms (ECGs), of rats exploring an open field arena. Using the EMGs and OB ECoGs, we segmented the behavioral states of rats into active awake, quiet awake, and sleeping states. Compared to saline, herbal medicine significantly shortened the total sleep time. Moreover, we converted the ECoG signal into a frequency domain using a fast Fourier transform (FFT) and calculated the powers at various ECoG oscillation frequencies. In the sleeping state, a slow component (0.5-3 Hz) of S1 ECoGs was significantly enhanced following the administration of the formulation, which suggests a region- and frequency-specific modulation of extracellular field oscillations by the polyherbal medicine.

Effects of gabapentinoids on responses of primary cultures from rat dorsal root ganglia to inflammatory or somatosensory stimuli.

Background Gabapentinoids are known to reduce neuropathic pain. The aim of this experimental study was to investigate whether gabapentinoids exert anti-inflammatory and/or anti-nociceptive effects at the cellular level using primary cultures of rat dorsal root ganglia (DRG). Methods Cells from rat DRG were cultured in the presence of gabapentin or pregabalin, and we tested the effects of subsequent stimulation with lipopolysaccharide (LPS) on the expression of genes (real-time polymerase chain reaction) and production of tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) by specific bioassays. Using Ca2+ imaging, we further investigated in neurons the effects of gabapentinoids upon stimulation with the TRPV-1 agonist capsaicin. Results There is a small influence of gabapentinoids on the inflammatory response to LPS stimulation, namely, a significantly reduced expression of IL-6. Pregabalin and gabapentin further seem to exert a moderate inhibitory influence on capsaicin-induced Ca2+ signals in DRG neurons. Conclusions Although the single inhibitory effects of gabapentinoids on inflammatory and nociceptive responses are moderate, a combination of both effects might provide an explanation for the proposed function of these substances as an adjuvant for the reduction of neuropathic pain.

Medial Prefrontal Cortical Modulation of Whisker Thalamic Responses in Anesthetized Rats.

The medial prefrontal cortex (mPFC) has been implicated in novelty detection and attention. We studied the effect of mPFC electrical stimulation on whisker responses recorded in the ventroposterior medial thalamic nucleus (VPM), the posterior thalamic nucleus (POm) and the primary somatosensory (S1) cortex in urethane anesthetized rats. Field potentials and unit recordings were performed in the VPM or POm thalamic nuclei, in S1 cortex, and in the Zona Incerta (ZI). Somatosensory evoked potentials were elicited by whisker deflections. Current pulses were delivered by bipolar stimulating electrodes aimed at the prelimbic (PL) or infralimbic (IL) areas of mPFC. PL train stimulation (50 Hz, 500 ms) induced a facilitation of whisker responses in the VPM nucleus that lasted minutes and a short inhibition in the POm nucleus. IL stimulation induced a facilitation of whisker responses in both VPM and POm nuclei. Facilitation was due to corticofugal projections because it was reduced after S1 cortical inactivation with lidocaine, and by activation of NMDA glutamatergic receptors because it was blocked by APV. Paired stimulation of mPFC and whiskers revealed an inhibitory effect at short intervals (<100 ms), which was mediated by ZI inhibitory neurons since PL stimulation induced response facilitation in the majority of ZI neurons (42%) and muscimol injection into ZI nucleus reduced inhibitory effects, suggesting that the mPFC may inhibit the POm neurons by activation of GABAergic ZI neurons. In conclusion, the mPFC may control the flow of somatosensory information through the thalamus by activation of S1 and ZI neurons.

An Electroencephalography Bioassay for Preclinical Testing of Analgesic Efficacy.

We present a multimodal method combining quantitative electroencephalography (EEG), behavior and pharmacology for pre-clinical screening of analgesic efficacy in vivo. The method consists of an objective and non-invasive approach for realtime assessment of spontaneous nociceptive states based on EEG recordings of theta power over primary somatosensory cortex in awake rats. Three drugs were chosen: (1) pregabalin, a CNS-acting calcium channel inhibitor; (2) EMA 401, a PNS-acting angiotensin II type 2 receptor inhibitor; and (3) minocycline, a CNS-acting glial inhibitor. Optimal doses were determined based on pharmacokinetic studies and/or published data. The effects of these drugs at single or multiple doses were tested on the attenuation of theta power and paw withdrawal latency (PWL) in a rat model of neuropathic pain. We report mostly parallel trends in the reversal of theta power and PWL in response to administration of pregabalin and EMA 401, but not minocycline. We also note divergent trends at non-optimal doses and following prolonged drug administration, suggesting that EEG theta power can be used to detect false positive and false negative outcomes of the withdrawal reflex behavior, and yielding novel insights into the analgesic effects of these drugs on spontaneous nociceptive states in rats.

Secretory vesicle trafficking in awake and anaesthetized mice: differential speeds in axons versus synapses.

KEY POINTS: Despite their immense physiological and pathophysiological importance, we know very little about the biology of dense core vesicle (DCV) trafficking in the intact mammalian brain. DCVs are transported at similar average speeds in the anaesthetized and awake mouse brain compared to neurons in culture, yet maximal speed and pausing fraction of transport were higher. Microtubule plus (+)-end extension imaging visualized microtubular growth at 0.12 µm/s and revealed that DCVs were transported faster in the anterograde direction. DCV transport slowed down upon presynaptic bouton approach, possibly promoting synaptic localization and cargo release. Our work provides a basis to extrapolate DCV transport properties determined in cultured neurons to the intact mouse brain and reveals novel features such as slowing upon bouton approach and brain state-dependent trafficking directionality. ABSTRACT: Neuronal dense core vesicles (DCVs) transport many cargo molecules like neuropeptides and neurotrophins to their release sites in dendrites or axons. The transport properties of DCVs in axons of the intact mammalian brain are unknown. We used viral expression of a DCV cargo reporter (NPY-Venus/Cherry) in the thalamus and two-photon in vivo imaging to visualize axonal DCV trafficking in thalamocortical projections of anaesthetized and awake mice. We found an average speed of 1 µm/s, maximal speeds of up to 5 µm/s and a pausing fraction of ∼11%. Directionality of transport differed between anaesthetized and awake mice. In vivo microtubule +-end extension imaging using MACF18-GFP revealed microtubular growth at 0.12 µm/s and provided positive identification of antero- and retrograde axonal transport. Consistent with previous reports, anterograde transport was faster (∼2.1 µm/s) than retrograde transport (∼1.4 µm/s). In summary, DCVs are transported with faster maximal speeds and lower pausing fraction in vivo compared to previous results obtained in vitro. Finally, we found that DCVs slowed down upon presynaptic bouton approach. We propose that this mechanism promotes synaptic localization and cargo release.

Topiramate modulates trigeminal pain processing in thalamo-cortical networks in humans after single dose administration.

Migraine is the sixth most common cause of disability in the world. Preventive migraine treatment is used to reduce frequency, severity and duration of attacks and therefore lightens the burden on the patients' quality of life and reduces disability. Topiramate is one of the preventive migraine treatments of proven efficacy. The mechanism of action underlying the preventive effect of topiramate in migraine remains largely unknown. Using functional magnetic resonance imaging (fMRI) we examined the central effects of a single dose of topiramate (100mg) on trigeminal pain in humans, compared to placebo (mannitol). In this prospective, within subject, randomized, placebo-controlled and double-blind study, 23 healthy participants received a standardized nociceptive trigeminal stimulation and control stimuli whilst being in the scanner. No differences in the subjective intensity ratings of the painful stimuli were observed between topiramate and placebo sessions. In contrast, topiramate significantly decreased the activity in the thalamus and other pain processing areas. Additionally, topiramate increased functional coupling between the thalamus and several brain regions such as the bilateral precuneus, posterior cingulate cortex and secondary somatosensory cortex. These data suggest that topiramate exhibits modulating effects on nociceptive processing in thalamo-cortical networks during trigeminal pain and that the preventive effect of topiramate on frequent migraine is probably mediated by an effect on thalamo-cortical networks.

Developmental changes in Notch1 and NLE1 expression in a genetic model of absence epilepsy.

Childhood absence epilepsy (CAE) is an epilepsy syndrome with seizures occurring in the early childhood, highlighting that seizures susceptibility in CAE is dependent on brain development. The Notch 1 signalling pathway is important in brain development, yet the role of the Notch1 signalling pathway in CAE remains elusive. We here explored Notch1 and its modulator notchless homologue 1 (NLE1) expression in WAG/Rij and control rats using immunohistochemistry. Functional Notch 1 effects were assessed in WAG/Rij rats in vivo. WAG/Rij rats lack the developmental increase in cortical Notch1 and NLE 1 mRNA expression seen in controls, and Notch 1 and NLE1 mRNA and protein expression were lower in somatosensory cortices of WAG/Rij rats when compared to controls. This coincided with an overall decreased cortical GFAP expression in the early development in WAG/Rij rats. These effects were region-specific as they were not observed in thalamic tissues. Neuron-to-glia ratio as a marker of the impact of Notch signalling on differentiation was higher in layer 4 of somatosensory cortex of WAG/Rij rats. Acute application of Notch 1 agonist Jagged 1 suppressed, whereas DAPT, a Notch antagonist, facilitated spike and wave discharges (SWDs) in WAG/Rij rats. These findings point to Notch1 as an important signalling pathway in CAE which likely shapes architectural organization of the somatosensory cortex, a region critically involved in developmental epileptogenesis in CAE. More immediate effects of Notch 1 signalling are seen on in vivo SWDs in CAE, pointing to the Notch 1 pathway as a possible treatment target in CAE.

Effects of garlic extract on spreading depression: In vitro and in vivo investigations.

OBJECTIVES: The potential use of garlic for prevention and treatment of different types of headaches has been suggested by several medieval literatures. Cortical spreading depression (CSD), a propagating wave of neuroglial depolarization, was established as a target for anti-migraine drugs. This study was designed to investigate the effect of garlic extract on CSD in adult rats. METHODS: CSD was induced by KCl microinjection in the somatosensory cortex. The effects of five different concentrations of garlic oil (1-500 µl/l) were tested on different characteristic features of CSD in necocortical slices. In in vivo experiments, the effects of garlic oil on electrophysiological and morphological changes induced by CSD were investigated. RESULTS: Garlic oil in a dose-dependent manner decreased the amplitude of CSD but not its duration and velocity in neocortical brain slices. Garlic oil at concentration of 500 µl/l reversibly reduced the amplitude of the field excitatory post-synaptic potentials and inhibited induction of long-term potentiation in the third layer of neocortical slices. In in vivo studies, systemic application of garlic oil (1 ml/l) for three consecutive days reduced the amplitude and repetition rate of CSD. Garlic oil also prevented of CSD-induced reactive astrocytosis in the neocortex. DISCUSSION: Garlic oil suppresses CSD, likely via inhibition of synaptic plasticity, and prevents its harmful effects on astrocyte. Further studies are required to identify the exact active ingredient(s) of garlic oil that inhibit CSD and may have the potential to use in treatment of CSD-related disorders.

Cortex dynamically modulates responses of thalamic relay neurons through prolonged circuit-level disinhibition in rat thalamus in vivo.

Cortex actively modulates the responses of thalamic relay neurons through corticothalamic (CT) projections. Here we investigated the temporal precision of CT modulation on sensory responses of relay neurons in rat ventral posterior medial thalamus (VPM) to direction-specific whisker stimuli. CT feedback levels were either augmented by cortical electrical microstimulation or depressed by cortical application of muscimol, a potent agonist of γ-aminobutyric acid A-type (GABAA) receptors. To evaluate the temporal specificity of CT influence, we compared the early (3-10 ms after stimulus onset) and late (10-100 ms) response components of VPM single units to whisker deflections in preferred or nonpreferred directions before and after altering CT feedback levels under urethane anesthesia. The data showed that cortical feedback most strongly affected the late responses of single VPM units to whisker stimulation. That is, cortical stimulation consistently increased the late responses of VPM units in the corresponding (homologous) barreloids to the stimulus direction preferred by neurons in the cortical locus stimulated. However, cortical stimulation could either increase or decrease the early response, depending on whether or not cortical and thalamic loci were tuned to the same direction. Such bidirectional regulation of the early and late VPM responses is consistent with a mechanism of circuit-level disinhibition in vivo. The results support the theory that CT feedback on thalamic sensory responses is mediated by a time-dependent shift of the excitation-inhibition balance in the thalamo-cortico-thalamic loop, such as would occur during sensory feature integration, plasticity, and learning in the awake state.

Changes in effective connectivity of sensorimotor rhythms in thalamocortical circuits during the induction and recovery of anesthesia in mice.

The thalamocortical network serves a role in both consciousness and sensorimotor processing. However, little is known regarding how changes in conscious states, via induction of and recovery from anesthesia, affect the processing of sensorimotor information in the thalamocortical network. To address this, we investigated the dynamics of causal interactions among sensorimotor rhythms (SMR; frequency range of 3-12Hz) across the thalamocortical network during transitions into and out of ketamine-induced unconsciousness. Two local field potentials from the ventral lateral and ventrobasal thalamic nuclei, as well as two intracranial electroencephalography signals from the primary sensory and primary motor regions, were recorded in 10 mice. Spectral Granger causality analysis revealed two distinct frequency-specific patterns in sensorimotor rhythms. For the low-frequency (3-6.5Hz) SMR, loss of consciousness evoked causal influences directed from the cortex to the thalamus. For the high-frequency (6.5-12Hz) SMR, causal influences from the primary sensory cortex to other regions during the conscious period were abruptly altered by loss of consciousness and gradually regenerated following recovery of consciousness. The results of the present study indicate that anesthesia alters the flow of sensorimotor information in the thalamocortical network and may provide evidence of the neural basis of loss and recovery of sensorimotor function associated with anesthesia.

Altered excitatory-inhibitory balance within somatosensory cortex is associated with enhanced plasticity and pain sensitivity in a mouse model of multiple sclerosis.

BACKGROUND: Chronic neuropathic pain is a common symptom of multiple sclerosis (MS). MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) has been used as an animal model to investigate the mechanisms of pain in MS. Previous studies have implicated sensitization of spinal nociceptive networks in the pathogenesis of pain in EAE. However, the involvement of supraspinal sites of nociceptive integration, such as the primary somatosensory cortex (S1), has not been defined. We therefore examined functional, structural, and immunological alterations in S1 during the early stages of EAE, when pain behaviors first appear. We also assessed the effects of the antidepressant phenelzine (PLZ) on S1 alterations and nociceptive (mechanical) sensitivity in early EAE. PLZ has been shown to restore central nervous system (CNS) tissue concentrations of GABA and the monoamines (5-HT, NA) in EAE. We hypothesized that PLZ treatment would also normalize nociceptive sensitivity in EAE by restoring the balance of excitation and inhibition (E-I) in the CNS. METHODS: We used in vivo flavoprotein autofluorescence imaging (FAI) to assess neural ensemble responses in S1 to vibrotactile stimulation of the limbs in early EAE. We also used immunohistochemistry (IHC), and Golgi-Cox staining, to examine synaptic changes and neuroinflammation in S1. Mechanical sensitivity was assessed at the clinical onset of EAE with Von Frey hairs. RESULTS: Mice with early EAE exhibited significantly intensified and expanded FAI responses in S1 compared to controls. IHC revealed increased vesicular glutamate transporter (VGLUT1) expression and disrupted parvalbumin+ (PV+) interneuron connectivity in S1 of EAE mice. Furthermore, peri-neuronal nets (PNNs) were significantly reduced in S1. Morphological analysis of excitatory neurons in S1 revealed increased dendritic spine densities. Iba-1+ cortical microglia were significantly elevated early in the disease. Chronic PLZ treatment was found to normalize mechanical thresholds in EAE. PLZ also normalized S1 FAI responses, neuronal morphologies, and cortical microglia numbers and attenuated VGLUT1 reactivity-but did not significantly attenuate the loss of PNNs. CONCLUSIONS: These findings implicate a pro-excitatory shift in the E-I balance of the somatosensory CNS, arising early in the pathogenesis EAE and leading to large-scale functional and structural plasticity in S1. They also suggest a novel antinociceptive effect of PLZ treatment.

Corticothalamic Spike Transfer via the L5B-POm Pathway in vivo.

The cortex connects to the thalamus via extensive corticothalamic (CT) pathways, but their function in vivo is not well understood. We investigated "top-down" signaling from cortex to thalamus via the cortical layer 5B (L5B) to posterior medial nucleus (POm) pathway in the whisker system of the anesthetized mouse. While L5B CT inputs to POm are extremely strong in vitro, ongoing activity of L5 neurons in vivo might tonically depress these inputs and thereby block CT spike transfer. We find robust transfer of spikes from the cortex to the thalamus, mediated by few L5B-POm synapses. However, the gain of this pathway is not constant but instead is controlled by global cortical Up and Down states. We characterized in vivo CT spike transfer by analyzing unitary PSPs and found that a minority of PSPs drove POm spikes when CT gain peaked at the beginning of Up states. CT gain declined sharply during Up states due to frequency-dependent adaptation, resulting in periodic high gain-low gain oscillations. We estimate that POm neurons receive few (2-3) active L5B inputs. Thus, the L5B-POm pathway strongly amplifies the output of a few L5B neurons and locks thalamic POm sub-and suprathreshold activity to cortical L5B spiking.

Brain Mapping-Based Model of Δ(9)-Tetrahydrocannabinol Effects on Connectivity in the Pain Matrix.

Cannabinoids receive increasing interest as analgesic treatments. However, the clinical use of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) has progressed with justified caution, which also owes to the incomplete mechanistic understanding of its analgesic effects, in particular its interference with the processing of sensory or affective components of pain. The present placebo-controlled crossover study therefore focused on the effects of 20 mg oral THC on the connectivity between brain areas of the pain matrix following experimental stimulation of trigeminal nocisensors in 15 non-addicted healthy volunteers. A general linear model (GLM) analysis identified reduced activations in the hippocampus and the anterior insula following THC administration. However, assessment of psychophysiological interaction (PPI) revealed that the effects of THC first consisted in a weakening of the interaction between the thalamus and the secondary somatosensory cortex (S2). From there, dynamic causal modeling (DCM) was employed to infer that THC attenuated the connections to the hippocampus and to the anterior insula, suggesting that the reduced activations in these regions are secondary to a reduction of the connectivity from somatosensory regions by THC. These findings may have consequences for the way THC effects are currently interpreted: as cannabinoids are increasingly considered in pain treatment, present results provide relevant information about how THC interferes with the affective component of pain. Specifically, the present experiment suggests that THC does not selectively affect limbic regions, but rather interferes with sensory processing which in turn reduces sensory-limbic connectivity, leading to deactivation of affective regions.

In Vivo Voltage-Sensitive Dye Imaging of Subcortical Brain Function.

The whisker system of rodents is an excellent model to study peripherally evoked neural activity in the brain. Discrete neural modules represent each whisker in the somatosensory cortex ("barrels"), thalamus ("barreloids"), and brain stem ("barrelettes"). Stimulation of a single whisker evokes neural activity sequentially in its corresponding barrelette, barreloid, and barrel. Conventional optical imaging of functional activation in the brain is limited to surface structures such as the cerebral cortex. To access subcortical structures and image sensory-evoked neural activity, we designed a needle-based optical system using gradient-index (GRIN) rod lens. We performed voltage-sensitive dye imaging (VSDi) with GRIN rod lens to visualize neural activity evoked in the thalamic barreloids by deflection of whiskers in vivo. We stimulated several whiskers together to determine the sensitivity of our approach in differentiating between different barreloid responses. We also carried out stimulation of different whiskers at different times. Finally, we used muscimol in the barrel cortex to silence the corticothalamic inputs while imaging in the thalamus. Our results show that it is possible to obtain functional maps of the sensory periphery in deep brain structures such as the thalamic barreloids. Our approach can be broadly applicable to functional imaging of other core brain structures.

Anti-absence activity of mGlu1 and mGlu5 receptor enhancers and their interaction with a GABA reuptake inhibitor: Effect of local infusions in the somatosensory cortex and thalamus.

OBJECTIVE: Glutamate and γ-aminobutyric acid (GABA) are the key neurotransmitter systems in the cortical-thalamocortical network, involved in normal and pathologic oscillations such as spike-wave discharges (SWDs), which characterize different forms of absence epilepsy. Metabotropic glutamate (mGlu) and GABA receptors are widely expressed within this network. Herein, we examined the effects of two selective positive allosteric modulators (PAMs) of mGlu1 and mGlu5 receptors, the GABA reuptake inhibitor, tiagabine, and their interaction in the somatosensory cortex and thalamus on SWDs in WAG/Rij rats. METHODS: Male WAG/Rij rats were equipped with bilateral cannulas in the somatosensory cortex (S1po) or the ventrobasal (VB) thalamic nuclei, and with cortical electroencephalography (EEG) electrodes. Rats received a single dose of the mGlu1 receptor PAM, RO0711401, or the mGlu5 receptor PAM, VU0360172, various doses of tiagabine, or VU0360172 combined with tiagabine. RESULTS: Both PAMs suppressed SWDs regardless of the site of injection. Tiagabine enhanced SWDs when injected into the thalamus, but, unexpectedly, suppressed SWDs in a dose-dependent manner when injected into the cortex. Intracortical co-injection of VU0360172 and tiagabine produced slightly larger effects as compared to either VU0360172 or tiagabine alone. Intrathalamic co-injections of VU0360172 and subthreshold doses of tiagabine caused an antiabsence effect similar to that exhibited by VU0360172 alone in the first 10 min. At 30 min, however, the antiabsence effect of VU0360172 was prevented by subthreshold doses of tiagabine, and the combination produced a paradoxical proabsence effect at 40 and 50 min. SIGNIFICANCE: These data (1) show that mGlu1 and mGlu5 receptor PAMs reduce absence seizures acting at both thalamic and cortical levels; (2) demonstrate for the first time that tiagabine, despite its established absence-enhancing effect, reduces SWDs when injected into the somatosensory cortex; and (3) indicate that the efficacy of VU0360172 in the thalamus may be critically affected by the availability of (extra)synaptic GABA.

Ketamine-Induced Modulation of the Thalamo-Cortical Network in Healthy Volunteers As a Model for Schizophrenia.

BACKGROUND: Schizophrenia has been associated with disturbances of thalamic functioning. In light of recent evidence suggesting a significant impact of the glutamatergic system on key symptoms of schizophrenia, we assessed whether modulation of the glutamatergic system via blockage of the N-methyl-D-aspartate (NMDA)-receptor might lead to changes of thalamic functional connectivity. METHODS: Based on the ketamine model of psychosis, we investigated changes in cortico-thalamic functional connectivity by intravenous ketamine challenge during a 55-minute resting-state scan. Thirty healthy volunteers were measured with pharmacological functional magnetic resonance imaging using a double-blind, randomized, placebo-controlled, crossover design. RESULTS: Functional connectivity analysis revealed significant ketamine-specific changes within the thalamus hub network, more precisely, an increase of cortico-thalamic connectivity of the somatosensory and temporal cortex. CONCLUSIONS: Our results indicate that changes of thalamic functioning as described for schizophrenia can be partly mimicked by NMDA-receptor blockage. This adds substantial knowledge about the neurobiological mechanisms underlying the profound changes of perception and behavior during the application of NMDA-receptor antagonists.

Experience-Dependent, Layer-Specific Development of Divergent Thalamocortical Connectivity.

The main input to primary sensory cortex is via thalamocortical (TC) axons that form the greatest number of synapses in layer 4, but also synapse onto neurons in layer 6. The development of the TC input to layer 4 has been widely studied, but less is known about the development of the layer 6 input. Here, we show that, in neonates, the input to layer 6 is as strong as that to layer 4. Throughout the first postnatal week, there is an experience-dependent strengthening specific to layer 4, which correlates with the ability of synapses in layer 4, but not in layer 6, to undergo long-term potentiation (LTP). This strengthening consists of an increase in axon branching and the divergence of connectivity in layer 4 without a change in the strength of individual connections. We propose that experience-driven LTP stabilizes transient TC synapses in layer 4 to increase strength and divergence specifically in layer 4 over layer 6.

Opioid modulation of resting-state anterior cingulate cortex functional connectivity.

Individuals misuse oxycodone, a widely prescribed opioid analgesic, in part to self-medicate physical and emotional pain. Physical and emotional pain is thought to be represented in the brain by a 'pain matrix,' consisting of the insula, thalamus, and somatosensory cortices, with processing of the affective dimension of pain in the dorsal and rostral anterior cingulate cortex (ACC). The current study examined oxycodone's effects on resting-state functional connectivity between the dorsal ACC, rostral ACC, and other regions of the pain matrix using functional magnetic resonance imaging (fMRI). In a within-subjects, randomized, double-blind, placebo-controlled, dose-response design, 14 healthy subjects completed a resting-state scan following ingestion of placebo, 10 mg, or 20 mg of oxycodone. Functional correlations between the dorsal and rostral ACC seed regions and the pain matrix were examined and compared across sessions. Both doses of oxycodone reduced functional coupling between the dorsal ACC and bilateral anterior insula/putamen and the rostral ACC and right insula relative to placebo (no differences between doses). The findings do not withstand correction for multiple comparisons, and thus should be considered preliminary. However, they are consistent with the idea that oxycodone may produce its physical and emotional 'analgesic' effects through disruption of ACC-insula and ACC-putamen connectivity.