GABABR Modulation of Electrical Synapses and Plasticity in the Thalamic Reticular Nucleus.

Two distinct types of neuronal activity result in long-term depression (LTD) of electrical synapses, with overlapping biochemical intracellular signaling pathways that link activity to synaptic strength, in electrically coupled neurons of the thalamic reticular nucleus (TRN). Because components of both signaling pathways can also be modulated by GABAB receptor activity, here we examined the impact of GABAB receptor activation on the two established inductors of LTD in electrical synapses. Recording from patched pairs of coupled rat neurons in vitro, we show that GABAB receptor inactivation itself induces a modest depression of electrical synapses and occludes LTD induction by either paired bursting or metabotropic glutamate receptor (mGluR) activation. GABAB activation also occludes LTD from either paired bursting or mGluR activation. Together, these results indicate that afferent sources of GABA, such as those from the forebrain or substantia nigra to the reticular nucleus, gate the induction of LTD from either neuronal activity or afferent glutamatergic receptor activation. These results add to a growing body of evidence that the regulation of thalamocortical transmission and sensory attention by TRN is modulated and controlled by other brain regions. Significance: We show that electrical synapse plasticity is gated by GABAB receptors in the thalamic reticular nucleus. This effect is a novel way for afferent GABAergic input from the basal ganglia to modulate thalamocortical relay and is a possible mediator of intra-TRN inhibitory effects.

Excitatory neuronal CHD8 in the regulation of neocortical development and sensory-motor behaviors.

CHD8 (chromodomain helicase DNA-binding protein 8) is a chromatin remodeler associated with autism spectrum disorders. Homozygous Chd8 deletion in mice leads to embryonic lethality, making it difficult to assess whether CHD8 regulates brain development and whether CHD8 haploinsufficiency-related macrocephaly reflects normal CHD8 functions. Here, we report that homozygous conditional knockout of Chd8 restricted to neocortical glutamatergic neurons causes apoptosis-dependent near-complete elimination of neocortical structures. These mice, however, display normal survival and hyperactivity, anxiolytic-like behavior, and increased social interaction. They also show largely normal auditory function and moderately impaired visual and motor functions but enhanced whisker-related somatosensory function. These changes accompany thalamic hyperactivity, revealed by 15.2-Tesla fMRI, and increased intrinsic excitability and decreased inhibitory synaptic transmission in thalamic ventral posterior medial (VPM) neurons involved in somatosensation. These results suggest that excitatory neuronal CHD8 critically regulates neocortical development through anti-apoptotic mechanisms, neocortical elimination distinctly affects cognitive behaviors and sensory-motor functions in mice, and Chd8 haploinsufficiency-related macrocephaly might represent compensatory responses.

Ventromedial hypothalamic primary cilia control energy and skeletal homeostasis.

Dysfunction of primary cilia is related to dyshomeostasis, leading to a wide range of disorders. The ventromedial hypothalamus (VMH) is known to regulate several homeostatic processes, but those modulated specifically by VMH primary cilia are not yet known. In this study, we identify VMH primary cilia as an important organelle that maintains energy and skeletal homeostasis by modulating the autonomic nervous system. We established loss-of-function models of primary cilia in the VMH by either targeting IFT88 (IFT88-KOSF-1) using steroidogenic factor 1-Cre (SF-1-Cre) or injecting an adeno-associated virus Cre (AAV-Cre) directly into the VMH. Functional impairments of VMH primary cilia were linked to decreased sympathetic activation and central leptin resistance, which led to marked obesity and bone-density accrual. Obesity was caused by hyperphagia, decreased energy expenditure, and blunted brown fat function and was also associated with insulin and leptin resistance. The effect of bone-density accrual was independent of obesity, as it was caused by decreased sympathetic tone resulting in increased osteoblastic and decreased osteoclastic activities in the IFT88-KOSF-1 and VMH primary cilia knockdown mice. Overall, our current study identifies VMH primary cilia as a critical hypothalamic organelle that maintains energy and skeletal homeostasis.

Barrel cortex VIP/ChAT interneurons suppress sensory responses in vivo.

Cortical interneurons expressing vasoactive intestinal polypeptide (VIP) and choline acetyltransferase (ChAT) are sparsely distributed throughout the neocortex, constituting only 0.5% of its neuronal population. The co-expression of VIP and ChAT suggests that these VIP/ChAT interneurons (VChIs) can release both γ-aminobutyric acid (GABA) and acetylcholine (ACh). In vitro physiological studies quantified the response properties and local connectivity patterns of the VChIs; however, the function of VChIs has not been explored in vivo. To study the role of VChIs in cortical network dynamics and their long-range connectivity pattern, we used in vivo electrophysiology and rabies virus tracing in the barrel cortex of mice. We found that VChIs have a low spontaneous spiking rate (approximately 1 spike/s) in the barrel cortex of anesthetized mice; nevertheless, they responded with higher fidelity to whisker stimulation than the neighboring layer 2/3 pyramidal neurons (Pyrs). Analysis of long-range inputs to VChIs with monosynaptic rabies virus tracing revealed that direct thalamic projections are a significant input source to these cells. Optogenetic activation of VChIs in the barrel cortex of awake mice suppresses the sensory responses of excitatory neurons in intermediate amplitudes of whisker deflections while increasing the evoked spike latency. The effect of VChI activation on the response was similar for both high-whisking (HW) and low-whisking (LW) conditions. Our findings demonstrate that, despite their sparsity, VChIs can effectively modulate sensory processing in the cortical microcircuit.

Neuropeptide S-initiated sequential cascade mediated by OX1, NK1, mGlu5 and CB1 receptors: a pivotal role in stress-induced analgesia.

BACKGROUND: Stress-induced analgesia (SIA) is an evolutionarily conserved phenomenon during stress. Neuropeptide S (NPS), orexins, substance P, glutamate and endocannabinoids are known to be involved in stress and/or SIA, however their causal links remain unclear. Here, we reveal an unprecedented sequential cascade involving these mediators in the lateral hypothalamus (LH) and ventrolateral periaqueductal gray (vlPAG) using a restraint stress-induced SIA model. METHODS: Male C57BL/6 mice of 8-12 week-old were subjected to intra-cerebroventricular (i.c.v.) and/or intra-vlPAG (i.pag.) microinjection of NPS, orexin-A or substance P alone or in combination with selective antagonists of NPS receptors (NPSRs), OX1 receptors (OX1Rs), NK1 receptors (NK1Rs), mGlu5 receptors (mGlu5Rs) and CB1 receptors (CB1Rs), respectively. Antinociceptive effects of these mediators were evaluated via the hot-plate test. SIA in mice was induced by a 30-min restraint stress. NPS levels in the LH and substance P levels in vlPAG homogenates were compared in restrained and unrestrained mice. RESULTS: NPS (i.c.v., but not i.pag.) induced antinociception. This effect was prevented by i.c.v. blockade of NPSRs. Substance P (i.pag.) and orexin-A (i.pag.) also induced antinociception. Substance P (i.pag.)-induced antinociception was prevented by i.pag. Blockade of NK1Rs, mGlu5Rs or CB1Rs. Orexin-A (i.pag.)-induced antinociception has been shown previously to be prevented by i.pag. blockade of OX1Rs or CB1Rs, and here was prevented by NK1R or mGlu5R antagonist (i.pag.). NPS (i.c.v.)-induced antinociception was prevented by i.pag. blockade of OX1Rs, NK1Rs, mGlu5Rs or CB1Rs. SIA has been previously shown to be prevented by i.pag. blockade of OX1Rs or CB1Rs. Here, we found that SIA was also prevented by i.c.v. blockade of NPSRs or i.pag. blockade of NK1Rs or mGlu5Rs. Restrained mice had higher levels of NPS in the LH and substance P in the vlPAG than unrestrained mice. CONCLUSIONS: These results suggest that, during stress, NPS is released and activates LH orexin neurons via NPSRs, releasing orexins in the vlPAG. Orexins then activate OX1Rs on substance P-containing neurons in the vlPAG to release substance P that subsequently. Activates NK1Rs on glutamatergic neurons to release glutamate. Glutamate then activates perisynaptic mGlu5Rs to initiate the endocannabinoid retrograde inhibition of GABAergic transmission in the vlPAG, leading to analgesia.

Attenuation of secondary damage and Aß deposits in the ipsilateral thalamus of dMCAO rats through reduction of cathepsin B by bis(propyl)-cognitin, a multifunctional dimer.

Delayed secondary degeneration in the non-ischemic sites such as ipsilateral thalamus would occur after cortical infarction. Hence, alleviating secondary damage is considered to be a promising novel target for acute stroke therapy. In the current study, the neuroprotective effects of bis(propyl)-cognitin (B3C), a multifunctional dimer, against secondary damage in the VPN of ipsilateral thalamus were investigated in a distal middle cerebral artery occlusion (dMCAO) stroke model in adult rats. It was found that B3C (0.5 and 1 mg/kg, ip) effectively improved neurological function of rats at day 7 and day 14 after dMCAO. Additionally, the treatment with B3C alleviated neuronal loss and gliosis in ipsilateral VPN after dMCAO, as evidenced by the higher immunoreactivity of neuron-specific nuclear-binding protein (NeuN) as well as lower immunostaining intensity of glial fibrillary acidic protein (GFAP) and cluster of differentiation 68 (CD68). Most encouragingly, immunohistochemistry and western blotting further revealed that B3C treatment greatly reduced Aß deposits and cathepsin B expression in the VPN of ipsilateral thalamus at day 7 and day 14 after dMCAO. In parallel, we demonstrated herein that the neuroprotective effects of B3C in dMCAO model were similar to L-3-trans-(Propyl-carbamoyloxirane-2-carbonyl)- L-isoleucyl-l-proline methyl ester (CA-074Me), a specific inhibitor of cathepsin B, suggesting that B3C attenuated secondary damage and Aß deposits in the VPN of ipsilateral thalamus after dMCAO possibly through the reduction of cathepsin B. These findings taken together provide novel molecular sights into the potential application of B3C for the treatment of secondary degeneration after cortical infarction.

Recruitment of GABAergic Interneurons in the Barrel Cortex during Active Tactile Behavior.

Neural computation involves diverse types of GABAergic inhibitory interneurons that are integrated with excitatory (E) neurons into precisely structured circuits. To understand how each neuron type shapes sensory representations, we measured firing patterns of defined types of neurons in the barrel cortex while mice performed an active, whisker-dependent object localization task. Touch excited fast-spiking (FS) interneurons at short latency, followed by activation of E neurons and somatostatin-expressing (SST) interneurons. Touch only weakly modulated vasoactive intestinal polypeptide-expressing (VIP) interneurons. Voluntary whisker movement activated FS neurons in the ventral posteromedial nucleus (VPM) target layers, a subset of SST neurons and a majority of VIP neurons. Together, FS neurons track thalamic input, mediating feedforward inhibition. SST neurons monitor local excitation, providing feedback inhibition. VIP neurons are activated by non-sensory inputs, disinhibiting E and FS neurons. Our data reveal rules of recruitment for interneuron types during behavior, providing foundations for understanding computation in cortical microcircuits.

Ratbot navigation using deep brain stimulation in ventral posteromedial nucleus.

Deep Brain Stimulation (DBS) is a medical-practical method and has been applied to solve many medical complications. Animal usage as sensors and actuators, mind-controlled machines, and animal navigation are some of the non-medical DBS applications. One of the brain areas used in ratbot navigation is the Ventral Posteromedial Nucleus (VPM), which creates non-volunteer head rotation. Rat training by water/food restriction can be used to create forward movement. In this study, a combination of VPM stimulation and water/food restriction has been employed to establish a complete navigation system. Five rats responded to VPM stimulations. However, with three of them, rats rotated to the same direction after the stimulations of either VPM side of the brain. Two rats rotated bilaterally, proportionate to the VPM stimulation side. These two rats were trained in a T-shape maze and became ratbots. The results of the 3-session test showed that their navigation performances were 96% and 86%, respectively. These ratbots are suitable for navigational purposes and are ready to complete the missions that are dangerous or impossible for humans.

Sweet and bitter taste stimuli activate VTA projection neurons in the parabrachial nucleus.

This study investigated neural projections from the parabrachial nucleus (PBN), a gustatory and visceral processing area in the brainstem, to the ventral tegmental area (VTA) in the midbrain. The VTA contains a large population of dopaminergic neurons that have been shown to play a role in reward processing. Anterograde neural tracing methods were first used to confirm that a robust projection from the caudal PBN terminates in the dorsal VTA; this projection was larger on the contralateral side. In the next experiment, we combined dual retrograde tracing from the VTA and the gustatory ventral posteromedial thalamus (VPMpc) with taste-evoked Fos protein expression, which labels activated neurons. Mice were stimulated through an intraoral cannula with sucrose, quinine, or water, and PBN sections were processed for immunofluorescent detection of Fos and retrograde tracers. The distribution of tracer-labeled PBN neurons demonstrated that the populations of cells projecting to the VTA or VPMpc are largely independent. Quantification of cells double labeled for Fos and either tracer demonstrated that sucrose and quinine were effective in activating both pathways. These results indicate that information about both appetitive and aversive tastes is delivered to a key midbrain reward interface via direct projections from the PBN.

Experience-dependent structural plasticity targets dynamic filopodia in regulating dendrite maturation and synaptogenesis.

Highly motile dendritic protrusions are hallmarks of developing neurons. These exploratory filopodia sample the environment and initiate contacts with potential synaptic partners. To understand the role for dynamic filopodia in dendrite morphogenesis and experience-dependent structural plasticity, we analyzed dendrite dynamics, synapse formation, and dendrite volume expansion in developing ventral lateral neurons (LNvs) of the Drosophila larval visual circuit. Our findings reveal the temporal coordination between heightened dendrite dynamics with synaptogenesis in LNvs and illustrate the strong influence imposed by sensory experience on the prevalence of dendritic filopodia, which regulate the formation of synapses and the expansion of dendritic arbors. Using genetic analyses, we further identified Amphiphysin (Amph), a BAR (Bin/Amphiphysin/Rvs) domain-containing protein as a required component for tuning the dynamic state of LNv dendrites and promoting dendrite maturation. Taken together, our study establishes dynamic filopodia as the key cellular target for experience-dependent regulation of dendrite development.

Suppression of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function in Thalamocortical Neurons Prevents Genetically Determined and Pharmacologically Induced Absence Seizures.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and the Ih current they generate contribute to the pathophysiological mechanisms of absence seizures (ASs), but their precise role in neocortical and thalamic neuronal populations, the main components of the network underlying AS generation, remains controversial. In diverse genetic AS models, Ih amplitude is smaller in neocortical neurons and either larger or unchanged in thalamocortical (TC) neurons compared with nonepileptic strains. A lower expression of neocortical HCN subtype 1 channels is present in genetic AS-prone rats, and HCN subtype 2 knock-out mice exhibit ASs. Furthermore, whereas many studies have characterized Ih contribution to "absence-like" paroxysmal activity in vitro, no data are available on the specific role of cortical and thalamic HCN channels in behavioral seizures. Here, we show that the pharmacological block of HCN channels with the antagonist ZD7288 applied via reverse microdialysis in the ventrobasal thalamus (VB) of freely moving male Genetic Absence Epilepsy Rats from Strasbourg decreases TC neuron firing and abolishes spontaneous ASs. A similar effect is observed on γ-hydroxybutyric acid-elicited ASs in normal male Wistar rats. Moreover, thalamic knockdown of HCN channels via virally delivered shRNA into the VB of male Stargazer mice, another genetic AS model, decreases spontaneous ASs and Ih-dependent electrophysiological properties of VB TC neurons. These findings provide the first evidence that block of TC neuron HCN channels prevents ASs and suggest that any potential anti-absence therapy that targets HCN channels should carefully consider the opposite role for cortical and thalamic Ih in the modulation of absence seizures.SIGNIFICANCE STATEMENT Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play critical roles in the fine-tuning of cellular and network excitability and have been suggested to be a key element of the pathophysiological mechanism underlying absence seizures. However, the precise contribution of HCN channels in neocortical and thalamic neuronal populations to these nonconvulsive seizures is still controversial. In the present study, pharmacological block and genetic suppression of HCN channels in thalamocortical neurons in the ventrobasal thalamic nucleus leads to a marked reduction in absence seizures in one pharmacological and two genetic rodent models of absence seizures. These results provide the first evidence that block of TC neuron HCN channels prevents absence seizures.

Selective downregulation of vesicular glutamate transporter2 in ventral posterolateral nucleus of thalamus attenuates neuropathic mechanical allodynia in mice.

Vesicular glutamate transporters (VGLUTs) transport glutamate into synaptic vesicles prior to exocytotic release. The expression pattern of VGLUT2 and studies of genetically modified mice have revealed that VGLUT2 contributes to neuropathic pain. We previously showed that VGLUT2 is upregulated in supraspinal regions including the thalamus in mice following spared nerve injury (SNI), and blocking VGLUTs using the VGLUT inhibitor CSB6B attenuated mechanical allodynia. To further evaluate the role of VGLUT2 in neuropathic pain, in this study, we developed a lentiviral vector expressing small hairpin RNAs (shRNAs) against mouse VGLUT2, which was injected into the ventral posterolateral (VPL) nucleus of the thalamus in the presence or absence of SNI. The administration of VGLUT2 shRNAs result in downregulation of VGLUT2 mRNA and protein expression, and decreased extracellular glutamate release in primary cultured neurons. We also showed that VGLUT2 shRNAs attenuated SNI-induced mechanical allodynia, in accordance with knockdown of VGLUT2 in the VPL nucleus in mice. Accordingly, our study supports the essential role of supraspinal VGLUT2 in neuropathic pain in adult mice and, thereby, validates VGLUT2 as a potential target for neuropathic pain therapy.

Role of thalamic ventral posterolateral nucleus histamine H2 and opiate receptors in modulation of formalin-induced muscle pain in rats.

BACKGROUND: Histamine and opiate systems contribute to supraspinal processing of pain. In the present study, we investigated the effects of microinjection of histamine and agonists and antagonists of histamine H2 and opiate receptors into the thalamic ventral posterolateral nucleus on muscle pain in rats. METHODS: The thalamic ventral posterolateral nuclei were bilaterally implanted with two guide cannulas. Muscle pain was induced by intramuscular injection of a diluted formalin solution (2.5%, 50µl) into the belly of gastrocnemius muscle, and pain-related behaviors including paw licking duration and paw flinching number were recorded at five-min blocks for 60min. RESULTS: Formalin produced a biphasic pattern of pain-related behaviors. Ranitidine (a histamine H2 receptor antagonist) alone did not affect pain intensity, whereas it prevented the antinociceptive activities of histamine, dimaprit (a histamine H2 receptor agonist) and morphine (an opiate receptor agonist). Naloxone (an opiate receptor antagonist) alone increased pain, and inhibited histamine-, dimaprit-, and morphine-induced antinociception. Locomotor activity was not changed with these chemicals. CONCLUSIONS: Our results showed an interaction between histamine H2 and opiate receptors at the thalamic ventral posterolateral nucleus in modulation of muscle pain.

[Effect of Electroacupuncture Intervention on Expressions of Nerve Growth Factor and Growth Arrest-specific Protein 7 in Ventral Posterolateral Thalamic Nucleus in Cerebral Ischemia Rats].

OBJECTIVE: To observe the effect of electroacupuncture(EA) on expressions of nerve growth factor(NGF) and growth arrest-specific protein 7(Gas 7) in the right ventral posterolateral nucleus(VPL) in the focal cerebral ischemia (FCI) rats, so as to explore its possible mechanism underlying improvement of secondary injury of FCI. METHODS: Forty-eight Sprague-Dawley rats were randomly divided into normal group, sham operation group, model group and electroacupuncture (EA) group (n=12 in each group) by random number table.The FCI model was made by occlusion of the right middle cerebral artery (MCAO) with thread embolus.One week after MCAO, EA(2 Hz,2 V) was performed on "Baihui"(GV 20) and left "Zusanli"(ST 36) for 30 min,once daily for successively 21 days.The expressions of NGF and Gas 7 in the right VPL were detected by immunohistochemistry (n=6 in each group) and Western blot (n=6 in each group), respectively;meanwhile Nissl staining was conducted to show VPL neurons. RESULTS: Nissl staining showed that the structure of right VPL was clear and complete,and the nuclei were centered and clear in the normal group and sham operation group;the VPL neurons were deeply stained, and the nuclei were pyknotic in the model group;the morphology of neurons in the EA group was similar to that of the normal group. The results of immunohistochemistry and Western blot were consistent. Expressions of NGF and Gas 7 proteins in the right VPL were not of significant differences between the sham operation group and the normal group (P>0.05). Compared with the normal group, the expressions of NGF and Gas 7 proteins in the VPL of the ischemic side were significantly increased in the model group(P<0.05). After treatment,the expression levels of NGF and Gas 7 proteins were further up-regulated in the EA group in comparison with the model group(P<0.05). CONCLUSIONS: The enhanced expressions of NGF and Gas 7 in the ischemic VPL of FCI rats may be involved in the neuroprotection and repairing; EA can significantly up-regulate the expressions of NGF and Gas 7 in VPL of the ischemic side, which may contribute to its effect in improving secondary thalamic impairment of FCI.

Ablation of IB4 non-peptidergic afferents in the rat facet joint prevents injury-induced pain and thalamic hyperexcitability via supraspinal glutamate transporters.

The facet joint is a common source of neck pain, particularly after excessive stretch of its capsular ligament. Peptidergic afferents have been shown to have an important role in the development and maintenance of mechanical hyperalgesia, dysregulated nociceptive signaling, and spinal hyperexcitability that develop after mechanical injury to the facet joint. However, the role of non-peptidergic isolectin-B4 (IB4) cells in mediating joint pain is unknown. Isolectin-B4 saporin (IB4-SAP) was injected into the facet joint to ablate non-peptidergic cells, and the facet joint later underwent a ligament stretch known to induce pain. Behavioral sensitivity, thalamic glutamate transporter expression, and thalamic hyperexcitability were evaluated up to and at day 7. Administering IB4-SAP prior to a painful injury prevented the development of mechanical hyperalgesia that is typically present. Intra-articular IB4-SAP also prevented the upregulation of the glutamate transporters GLT-1 and EAAC1 in the ventral posterolateral nucleus of the thalamus and reduced thalamic neuronal hyperexcitability at day 7. These findings suggest that a painful facet injury induces changes extending to supraspinal structures and that IB4-positive afferents in the facet joint may be critical for the development and maintenance of sensitization in the thalamus after a painful facet joint injury.

Prenatal thalamic waves regulate cortical area size prior to sensory processing.

The cerebral cortex is organized into specialized sensory areas, whose initial territory is determined by intracortical molecular determinants. Yet, sensory cortical area size appears to be fine tuned during development to respond to functional adaptations. Here we demonstrate the existence of a prenatal sub-cortical mechanism that regulates the cortical areas size in mice. This mechanism is mediated by spontaneous thalamic calcium waves that propagate among sensory-modality thalamic nuclei up to the cortex and that provide a means of communication among sensory systems. Wave pattern alterations in one nucleus lead to changes in the pattern of the remaining ones, triggering changes in thalamic gene expression and cortical area size. Thus, silencing calcium waves in the auditory thalamus induces Rorß upregulation in a neighbouring somatosensory nucleus preluding the enlargement of the barrel-field. These findings reveal that embryonic thalamic calcium waves coordinate cortical sensory area patterning and plasticity prior to sensory information processing.

Sub-synaptic localization of Cav3.1 T-type calcium channels in the thalamus of normal and parkinsonian monkeys.

T-type calcium channels (Cav3) are key mediators of thalamic bursting activity, but also regulate single cells excitability, dendritic integration, synaptic strength and transmitter release. These functions are strongly influenced by the subcellular and subsynaptic localization of Cav3 channels along the somatodendritic domain of thalamic cells. In Parkinson's disease, T-type calcium channels dysfunction in the basal ganglia-receiving thalamic nuclei likely contributes to pathological thalamic bursting activity. In this study, we analyzed the cellular, subcellular, and subsynaptic localization of the Cav3.1 channel in the ventral anterior (VA) and centromedian/parafascicular (CM/Pf) thalamic nuclei, the main thalamic targets of basal ganglia output, in normal and parkinsonian monkeys. All thalamic nuclei displayed strong Cav3.1 neuropil immunoreactivity, although the intensity of immunolabeling in CM/Pf was significantly lower than in VA. Ultrastructurally, 70-80 % of the Cav3.1-immunoreactive structures were dendritic shafts. Using immunogold labeling, Cav3.1 was commonly found perisynaptic to asymmetric and symmetric axo-dendritic synapses, suggesting a role of Cav3.1 in regulating excitatory and inhibitory neurotransmission. Significant labeling was also found at non-synaptic sites along the plasma membrane of thalamic neurons. There was no difference in the overall pattern and intensity of immunostaining between normal and parkinsonian monkeys, suggesting that the increased rebound bursting in the parkinsonian state is not driven by changes in Cav3.1 expression. Thus, T-type calcium channels are located to subserve neuronal bursting, but also regulate glutamatergic and non-glutamatergic transmission along the whole somatodendritic domain of basal ganglia-receiving neurons of the primate thalamus.

The role of histamine H1, H2 and H3 receptors of ventral posteromedial nucleus of thalamus in modulation of trigeminal pain.

Histamine receptors are involved in supraspinal modulation of pain. In the present study, we investigated the effects of microinjection of histamine H1, H2 and H3 receptor antagonists and agonists into the ventral posteromedial (VPM) nucleus of the thalamus on two models of trigeminal pain. Right and left sides of VPM were implanted with two guide cannulas. Corneal pain was induced by local corneal surface application of hypertonic saline and the number of eye wipes was recorded. The duration of face rubbing, as an orofacial pain measure, was recorded after subcutaneous (s.c.) injection of capsaicin into the vibrissa pad. 2-pyridylethylamine (2-PEA, a histamine H1 receptor agonist, 4µg/site) and dimaprit (a histamine H2 receptor agonist, 1 and 4µg/site) suppressed corneal and orofacial pains. Mepyramine (a histamine H1 receptor antagonist) and ranitidine (a histamine H2 receptor antagonist) at the similar doses of 0.5, 2 and 8µg/site alone had no effects on trigeminal pain. Prior microinjection of mepyramine and ranitidine at a similar dose of 8µg/site inhibited the antinociceptive effects of 2-PEA (4µg/site) and dimaprit (4µg/site), respectively. Immepip (a histamine H3 receptor agonist, 1 and 4µg/site) increased, and thioperamide (a histamine H3 receptor antagonist, 2 and 8µg/site) attenuated nociceptive responses. Prior microinjection of thioperamide (8µg/site) prevented immepip (4µg/site)-induced nociception. These chemicals did not change locomotor behavior. It is concluded that post-synaptic histamine H2, and to a lesser extent H1, receptors and pre-synaptic histamine H3 receptor may be involved in VPM modulation of trigeminal pain.

Metabolic demands of neural-hemodynamic associated and disassociated areas in brain.

Interpretation of regional blood oxygenation level-dependent (BOLD) responses in functional magnetic resonance imaging (fMRI) is contingent on whether local field potential (LFP) and multi-unit activity (MUA) is either dissociated or associated. To examine whether neural-hemodynamic associated and dissociated areas have different metabolic demands, we recorded sensory-evoked responses of BOLD signal, blood flow (CBF), and blood volume (CBV), which with calibrated fMRI provided oxidative metabolism (CMRO2) from rat's ventral posterolateral thalamic nucleus (VPL) and somatosensory forelimb cortex (S1FL) and compared these neuroimaging signals to neurophysiological recordings. MUA faithfully recorded evoked latency differences between VPL and S1FL because evoked MUA in these regions were similar in magnitude. Since evoked LFP was significantly attenuated in VPL, we extracted the time courses of the weaker thalamic LFP to compare with the stronger cortical LFP using wavelet transform. BOLD and CBV responses were greater in S1FL than in VPL, similar to LFP regional differences. CBF and CMRO2 responses were both comparably larger in S1FL and VPL. Despite different levels of CBF-CMRO2 and LFP-MUA couplings in VPL and S1FL, the CMRO2 was well matched with MUA in both regions. These results suggest that neural-hemodynamic associated and dissociated areas in VPL and S1FL can have similar metabolic demands.

Central Nervous System-Toxic Lidocaine Concentrations Unmask L-Type Ca²âº Current-Mediated Action Potentials in Rat Thalamocortical Neurons: An In Vitro Mechanism of Action Study.

BACKGROUND: High systemic lidocaine concentrations exert well-known toxic effects on the central nervous system (CNS), including seizures, coma, and death. The underlying mechanisms are still largely obscure, and the actions of lidocaine on supraspinal neurons have received comparatively little study. We recently found that lidocaine at clinically neurotoxic concentrations increases excitability mediated by Na-independent, high-threshold (HT) action potential spikes in rat thalamocortical neurons. Our goal in this study was to characterize these spikes and test the hypothesis that they are generated by HT Ca currents, previously implicated in neurotoxicity. We also sought to identify and isolate the specific underlying subtype of Ca current. METHODS: We investigated the actions of lidocaine in the CNS-toxic concentration range (100 µM-1 mM) on ventrobasal thalamocortical neurons in rat brain slices in vitro, using whole-cell patch-clamp recordings aided by differential interference contrast infrared videomicroscopy. Drugs were bath applied; action potentials were generated using current clamp protocols, and underlying currents were identified and isolated with ion channel blockers and electrolyte substitution. RESULTS: Lidocaine (100 µM-1 mM) abolished Na-dependent tonic firing in all neurons tested (n = 46). However, in 39 of 46 (85%) neurons, lidocaine unmasked evoked HT action potentials with lower amplitudes and rates of de-/repolarization compared with control. These HT action potentials remained during the application of tetrodotoxin (600 nM), were blocked by Cd (50 µM), and disappeared after superfusion with an extracellular solution deprived of Ca. These features implied that the unmasked potentials were generated by high-voltage-activated Ca channels and not by Na channels. Application of the L-type Ca channel blocker, nifedipine (5 µM), completely blocked the HT potentials, whereas the N-type Ca channel blocker, ω-conotoxin GVIA (1 µM), had little effect. CONCLUSIONS: At clinically CNS-toxic concentrations, lidocaine unmasked in thalamocortical neurons evoked HT action potentials mediated by the L-type Ca current while substantially suppressing Na-dependent excitability. On the basis of the known role of an increase in intracellular Ca in the pathogenesis of local anesthetic neurotoxicity, this novel action represents a plausible contributing candidate mechanism for lidocaine's CNS toxicity in vivo.