Molecular, Morphological and Electrophysiological Differences between Alpha and Gamma Motoneurons with Special Reference to the Trigeminal Motor Nucleus of Rat.

The muscle contraction during voluntary movement is controlled by activities of alpha- and gamma-motoneurons (αMNs and γMNs, respectively). In spite of the recent advances in research on molecular markers that can distinguish between αMNs and γMNs, electrophysiological membrane properties and firing patterns of γMNs have remained unknown, while those of αMNs have been clarified in detail. Because of the larger size of αMNs compared to γMNs, blindly or even visually recorded MNs were mostly αMNs, as demonstrated with molecular markers recently. Subsequently, the research on αMNs has made great progress in classifying their subtypes based on the molecular markers and electrophysiological membrane properties, whereas only a few studies demonstrated the electrophysiological membrane properties of γMNs. In this review article, we provide an overview of the recent advances in research on the classification of αMNs and γMNs based on molecular markers and electrophysiological membrane properties, and discuss their functional implication and significance in motor control.

Associations between measured masticatory function and cognitive status: A systematic review.

OBJECTIVE: This systematic review aimed to provide an overview of the most recent evidence on the association between measured masticatory function and cognitive status. MATERIALS AND METHODS: Literature and manual searches were conducted using three electronic databases (PubMed, Web of Science and CINAHL). Observational studies published between 2011 and 2021 investigating the association between masticatory function, dementia and cognitive status in adult humans were abstracted and reviewed by three reviewers. Studies that assessed participants' masticatory function using objective and subjective measurements and that individually examined its association with cognitive function were included. The included studies were divided into cross-sectional and cohort studies, and the quality of each study was analysed using critical appraisal skills checklists. Additionally, the main conclusions and strength of the evidence were assessed for each article. RESULTS: A total of 21 studies (11 cross-sectional studies that objectively evaluated masticatory function, 9 cross-sectional studies that subjectively evaluated masticatory function and 1 prospective cohort study) were evaluated. The poorer masticatory function was associated with lower cognitive status even after adjusting for potential risk factors of dementia in four of 11 and six of nine cross-sectional studies where the masticatory function was respectively evaluated objectively and subjectively. One prospective cohort study also demonstrated that masticatory function, as evaluated based on measurements of occlusal force, predicted cognitive decline during the follow-up period. CONCLUSION: Several studies demonstrated a positive association between masticatory function and cognitive status. However, further studies, particularly longitudinal studies, are required to determine whether the association is causal.

DO ORAL CARE AND REHABILITATION IMPROVE COGNITIVE FUNCTION? A SYSTEMATIC REVIEW OF CLINICAL STUDIES.

OBJECTIVES: An increasing number of studies have identified an association between oral health status and cognitive function. However, the effect of oral interventions, including oral health care, dental treatment and oral motor exercises, on cognitive function remains unclear. This systematic review examined whether oral interventions contribute to the long-term improvement of cognitive status. METHODS: Four databases were searched (MEDLINE, Web of Science, Cochrane Library, and ICHUSHI Web) to identify randomized and nonrandomized controlled trial studies and prospective cohort studies from inception until 1 September 2023, published in English or Japanese. The Cochrane risk of bias tool for randomized controlled trials and the risk of bias assessment tool for nonrandomized studies were used to assess bias risk. RESULTS: A total of 20 articles were included in the qualitative analysis; 13 articles were published in English, and 7 were published in Japanese. The implemented interventions were oral care in 8 studies, dental treatment in 8 studies, and oral motor exercise in 4 studies. One study found a significant effect on attention following oral care intervention. Some dental treatments influenced cognitive function, although a clear positive effect was not determined. In 1 study, attention and working memory improved in the chewing exercise group. CONCLUSIONS: Several studies verified the improvement effects of oral interventions, such as oral care, dental treatment, and oral motor exercise, on cognitive function or impairment. However, there was still a lack of conclusive evidence that such an intervention clearly improved cognitive function. To clarify the effects of oral interventions on cognitive function, it is necessary to examine participants, interventions, and outcome measures in detail.

The mechanism for regulating the isometric contraction of masseter muscles is involved in determining the vertical dimension of occlusion.

We previously demonstrated that accurate regulation of isometric contraction (IC) of jaw-closing muscles to counteract the ramp load applied to the jaw in the jaw-opening direction is achieved through the calibration between the two sensations arising from muscle spindles (MSs) and periodontal mechanoreceptors (PMRs). However, it remains unclear whether this calibration mechanism accurately works at any jaw positions, i.e., any vertical dimensions of occlusion (VDO). In the present study, we examined the effects of altering VDO on the IC of the masseter muscles in complete dentulous and edentulous subjects. At a VDO higher than the original VDO (O-VDO), the root mean square (RMS) of masseter EMG activity increased more steeply with a load increase, resulting in an over-counteraction. The regression coefficient of the load-RMS relationship significantly increased as the VDO was increased, suggesting that the overestimation became more pronounced with the VDO increases. Consistently also in the edentulous subjects, at a higher VDO than the O-VDO, a steeper increase in the RMS emerged with a delay in response to the same ramp load whereas a similar steeper increase was seen surprisingly even at a lower VDO. Thus, the edentulous subjects displayed a delayed overestimation of the ramp load presumably due to less and slowly sensitive mucous membrane mechanoreceptor (MMR) in alveolar ridge compared with the PMR. Taken together, the accurate calibration between the two sensations arising from MSs and PMRs/MMRs can be done only at the O-VDO, suggesting that the O-VDO is the best calibration point for performing accurate IC.NEW & NOTEWORTHY Since 1934, the vertical dimension of occlusion (VDO) in edentulous individuals has been anatomically determined mostly by referring to the resting jaw position. However, such a static method is not always accurate. Considering the dynamic nature of clenching/mastication, it is desirable to determine VDO dynamically. We demonstrate that VDO can be accurately determined by measuring masseter EMG during the voluntary isometric contraction of jaw-closing muscles exerted against the ramp load in the jaw-opening direction.

Predicting vertebral compression fracture prior to spinal SBRT using radiomics from planning CT.

PURPOSE: The purpose of the study was to develop a predictive model for vertebral compression fracture (VCF) prior to spinal stereotactic body radiation therapy (SBRT) using radiomics features extracted from pre-treatment planning CT images. METHODS: A retrospective analysis was conducted on 85 patients (114 spinal lesions) who underwent spinal SBRT. Radiomics features were extracted from pre-treatment planning CT images and used to develop a predictive model using a classification algorithm selected from nine different machine learning algorithms. Four different models were trained, including clinical features only, clinical and radiomics features, radiomics and dosimetric features, and all features. Model performance was evaluated using accuracy, precision, recall, F1-score, and area under the curve (AUC). RESULTS: The model that used all features (radiomics, clinical, and dosimetric) showed the highest performance with an AUC of 0.871. The radiomics and dosimetric features model had the superior performance in terms of accuracy, precision, recall, and F1-score. CONCLUSION: The developed predictive model based on radiomics features extracted from pre-treatment planning CT images can accurately predict the likelihood of VCF prior to spinal SBRT. This model has significant implications for treatment planning and preventive measures for patients undergoing spinal SBRT. Future research can focus on improving model performance by incorporating new data and external validation using independent data sets.

Subcellular Localization of Homomeric TASK3 Channels and Its Presumed Functional Significances in Trigeminal Motoneurons.

Somatic expressions of either heteromeric TASK1/3 or homomeric TASK1/1 channels have been reported in various neurons, while expression of homomeric TASK3/3 channels has been re-ported only in dendrites. However, it is not known why homomeric TASK3/3 channels are hardly seen in somata of CNS neurons. Given the absence of somatic TASK3/3 channels, it should be clarified why dendritic expression of TASK3/3 channels is inevitable and necessary and how differentially distributed TASK1/1 and TASK3/3 channels play roles in soma-to-dendritic integration. Here, we addressed these questions. We found that TASK3-transfected HEK293 cells showed decreases in cell volume after being transferred from the cultured medium to HEPES Ringer, suggesting that expressions of TASK3 channels in cell bodies cause an osmolarity problem. Using TASK1- and TASK3-transfected oocytes, we also found that cGMP application slightly suppressed TASK3 currents while it largely enhanced TASK1 currents, alleviating the difference between TASK1 and TASK3 currents at physiological pH. As larger motoneurons have extensive dendritic trees while smaller motoneurons have poor ones, cGMP could integrate Ia-EPSPs to recruit small and large motoneurons synchronously by differentially modulating TASKI and TASK3 channels which were complementary distributed in soma and dendrites of motoneurons in the dorsolateral part of the trigeminal motor nucleus.

Intra-Operative Bioprinting of Hard, Soft, and Hard/Soft Composite Tissues for Craniomaxillofacial Reconstruction.

Reconstruction of complex craniomaxillofacial (CMF) defects is challenging due to the highly organized layering of multiple tissue types. Such compartmentalization necessitates the precise and effective use of cells and other biologics to recapitulate the native tissue anatomy. In this study, intra-operative bioprinting (IOB) of different CMF tissues, including bone, skin, and composite (hard/soft) tissues, is demonstrated directly on rats in a surgical setting. A novel extrudable osteogenic hard tissue ink is introduced, which induced substantial bone regeneration, with ≈80% bone coverage area of calvarial defects in 6 weeks. Using droplet-based bioprinting, the soft tissue ink accelerated the reconstruction of full-thickness skin defects and facilitated up to 60% wound closure in 6 days. Most importantly, the use of a hybrid IOB approach is unveiled to reconstitute hard/soft composite tissues in a stratified arrangement with controlled spatial bioink deposition conforming the shape of a new composite defect model, which resulted in ≈80% skin wound closure in 10 days and 50% bone coverage area at Week 6. The presented approach will be absolutely unique in the clinical realm of CMF defects and will have a significant impact on translating bioprinting technologies into the clinic in the future.

Molecular and Regulatory Mechanisms of Desensitization and Resensitization of GABAA Receptors with a Special Reference to Propofol/Barbiturate.

It is known that desensitization of GABAA receptor (GABAAR)-mediated currents is paradoxically correlated with the slowdown of their deactivation, i.e., resensitization. It has been shown that an upregulation of calcineurin enhances the desensitization of GABAAR-mediated currents but paradoxically prolongs the decay phase of inhibitory postsynaptic currents/potentials without appreciable diminution of their amplitudes. The paradoxical correlation between desensitization and resensitization of GABAAR-mediated currents can be more clearly seen in response to a prolonged application of GABA to allow more desensitization, instead of brief pulse used in previous studies. Indeed, hump-like GABAAR currents were produced after a strong desensitization at the offset of a prolonged puff application of GABA in pyramidal cells of the barrel cortex, in which calcineurin activity was enhanced by deleting phospholipase C-related catalytically inactive proteins to enhance the desensitization/resensitization of GABAAR-mediated currents. Hump-like GABAAR currents were also evoked at the offset of propofol or barbiturate applications in hippocampal or sensory neurons, but not GABA applications. Propofol and barbiturate are useful to treat benzodiazepine/alcohol withdrawal syndrome, suggesting that regulatory mechanisms of desensitization/resensitization of GABAAR-mediated currents are important in understanding benzodiazepine/alcohol withdrawal syndrome. In this review, we will discuss the molecular and regulatory mechanisms underlying the desensitization and resensitization of GABAAR-mediated currents and their functional significances.

Supramolecular Phthalocyanine Assemblies for Improved Photoacoustic Imaging and Photothermal Therapy.

Phototheranostic nanoplatforms are of particular interest for cancer diagnosis and imaging-guided therapy. Herein, we develop a supramolecular approach to fabricate a nanostructured phototheranostic agent through the direct self-assembly of two water-soluble phthalocyanine derivatives, PcS4 and PcN4. The nature of the molecular recognition between PcS4 and PcN4 facilitates the formation of nanostructure (PcS4-PcN4) and consequently enables the fabrication of PcS4-PcN4 with completely quenched fluorescence and reduced singlet oxygen generation, leading to the high photoacoustic and photothermal activity of PcS4-PcN4. In vivo evaluations suggest that PcS4-PcN4 could not only efficiently visualize a tumor with high contrast through whole-body photoacoustic imaging but also enable excellent photothermal therapy for cancer.

Oxytocin produces thermal analgesia via vasopressin-1a receptor by modulating TRPV1 and potassium conductance in the dorsal root ganglion neurons.

Recent studies have provided several lines of evidence that peripheral administration of oxytocin induces analgesia in human and rodents. However, the exact underlying mechanism of analgesia still remains elusive. In the present study, we aimed to identify which receptor could mediate the analgesic effect of intraperitoneal injection of oxytocin and its cellular mechanisms in thermal pain behavior. We found that oxytocin-induced analgesia could be reversed by d(CH2)5[Tyr(Me)2,Dab5] AVP, a vasopressin-1a (V1a) receptor antagonist, but not by desGly-NH2-d(CH2)5[DTyr2, Thr4]OVT, an oxytocin receptor antagonist. Single cell RT-PCR analysis revealed that V1a receptor, compared to oxytocin, vasopressin-1b and vasopressin-2 receptors, was more profoundly expressed in dorsal root ganglion (DRG) neurons and the expression of V1a receptor was predominant in transient receptor potential vanilloid 1 (TRPV1)-expressing DRG neurons. Fura-2 based calcium imaging experiments showed that capsaicin-induced calcium transient was significantly inhibited by oxytocin and that such inhibition was reversed by V1a receptor antagonist. Additionally, whole cell patch clamp recording demonstrated that oxytocin significantly increased potassium conductance via V1a receptor in DRG neurons. Taken together, our findings suggest that analgesic effects produced by peripheral administration of oxytocin were attributable to the activation of V1a receptor, resulting in reduction of TRPV1 activity and enhancement of potassium conductance in DRG neurons.

General anesthetic actions on GABAA receptors in vivo are reduced in phospholipase C-related catalytically inactive protein knockout mice.

PURPOSE: The aim of this study was to investigate the action of general anesthetics in phospholipase C-related catalytically inactive protein (PRIP)-knockout (KO) mice that alter GABAA receptor signaling. METHODS: PRIP regulates the intracellular trafficking of ß subunit-containing GABAA receptors in vitro. In this study, we examined the effects of intravenous anesthetics, propofol and etomidate that act via ß subunit-containing GABAA receptors, in wild-type and Prip-KO mice. Mice were intraperitoneally injected with a drug, and a loss of righting reflex (LORR) assay and an electroencephalogram analysis were performed. RESULTS: The cell surface expression of GABAA receptor ß3 subunit detected by immunoblotting was decreased in Prip-knockout brain compared with that in wild-type brain without changing the expression of other GABAA receptor subunits. Propofol-treated Prip-KO mice exhibited significantly shorter duration of LORR and had lower total anesthetic score than wild-type mice in the LORR assay. The average duration of sleep time in an electroencephalogram analysis was shorter in propofol-treated Prip-KO mice than in wild-type mice. The hypnotic action of etomidate was also reduced in Prip-KO mice. However, ketamine, an NMDA receptor antagonist, had similar effects in the two genotypes. CONCLUSION: PRIP regulates the cell surface expression of the GABAA receptor ß3 subunit and modulates general anesthetic action in vivo. Elucidation of the involved regulatory mechanisms of GABAA receptor-dependent signaling would inform the development of safer anesthetic therapies for clinical applications.

Enhanced lateral inhibition in the barrel cortex by deletion of phospholipase C-related catalytically inactive protein-1/2 in mice.

We previously demonstrated that the deletion of phospholipase C-related catalytically inactive protein-1/2 (PRIP-1/2) enhances the desensitization of GABAA receptors (GABAARs), while it facilitates their resensitization at the offset of GABA puff, causing a hump-like tail current (tail-I) in layer 3 (L3) pyramidal cells (PCs) of the barrel cortex. In the present study, we investigated whether inhibitory synaptic transmission in L3 PCs in the barrel cortex is altered in the PRIP-1/2 double-knockout (PRIP-DKO) mice, and if so, how the interaction between excitation and inhibition is subsequently modified. PRIP-1/2 deletion resulted in the prolongation of the decay phase of inhibitory postsynaptic currents/potentials (IPSCs/IPSPs) in L3 PCs evoked by stimulation of L3, leaving the overall features of miniature IPSCs unchanged. An optical imaging revealed that the spatiotemporal profile of a horizontal excitation spread across columns in L2/3 caused by L4 stimulation in the barrel cortex was more restricted in PRIP-DKO mice compared to the wild type, while those obtained in the presence of bicuculline were almost identical between the two genotypes. These findings suggest that PRIP-1/2 deletion enhances the lateral inhibition by prolonging inhibitory synaptic actions to limit the intercolumnar integration in the barrel cortex. Considering the present findings together with our previous study including a mathematical simulation, the prolongation of inhibitory synaptic actions is likely to result from an enhancement of desensitization followed by an enhanced resensitization in GABAARs.

Enhanced desensitization followed by unusual resensitization in GABAA receptors in phospholipase C-related catalytically inactive protein-1/2 double-knockout mice.

Phospholipase C-related catalytically inactive proteins (PRIP-1/2) are previously reported to be involved in the membrane trafficking of GABAA receptor (GABAAR) and the regulation of intracellular Ca(2+) stores. GABAAR-mediated currents can be regulated by the intracellular Ca(2+). However, in PRIP-1/2 double-knockout (PRIP-DKO) mice, it remains unclear whether the kinetic properties of GABAARs are modulated by the altered regulation of intracellular Ca(2+) stores. Here, we investigated whether GABAAR currents (IGABA) evoked by GABA puff in layer 3 (L3) pyramidal cells (PCs) of the barrel cortex are altered in PRIP-DKO mice. The deletion of PRIP-1/2 enhanced the desensitization of IGABA but induced a hump-like tail current (tail-I) at the GABA puff offset. IGABA and the hump-like tail-I were suppressed by GABAAR antagonists. The enhanced desensitization of IGABA and the hump-like tail-I in PRIP-DKO PCs were mediated by increases in the intracellular Ca(2+) concentration and were largely abolished by a calcineurin inhibitor and ruthenium red. Calcium imaging revealed that Ca(2+)-induced Ca(2+) release (CICR) and subsequent store-operated Ca(2+) entry (SOCE) are more potent in PRIP-DKO PCs than in wild-type PCs. A mathematical model revealed that a slowdown of GABA-unbinding rate and an acceleration of fast desensitization rate by enhancing its GABA concentration dependency are involved in the generation of hump-like tail-Is. These results suggest that in L3 PCs of the barrel cortex in PRIP-DKO mice, the increased calcineurin activity due to the potentiated CICR and SOCE enhances the desensitization of GABAARs and slows the GABA-unbinding rate, resulting in their unusual resensitization following removal of GABA.

Generation of resonance-dependent oscillation by mGluR-I activation switches single spiking to bursting in mesencephalic trigeminal sensory neurons.

The primary sensory neurons supplying muscle spindles of jaw-closing muscles are unique in that they have their somata in the mesencephalic trigeminal nucleus (MTN) in the brainstem, thereby receiving various synaptic inputs. MTN neurons display bursting upon activation of glutamatergic synaptic inputs while they faithfully relay respective impulses arising from peripheral sensory organs. The persistent sodium current (IN aP ) is reported to be responsible for both the generation of bursts and the relay of impulses. We addressed how IN aP is controlled either to trigger bursts or to relay respective impulses as single spikes in MTN neurons. Protein kinase C (PKC) activation enhanced IN aP only at low voltages. Spike generation was facilitated by PKC activation at membrane potentials more depolarized than the resting potential. By injection of a ramp current pulse, a burst of spikes was triggered from a depolarized membrane potential whereas its instantaneous spike frequency remained almost constant despite the ramp increases in the current intensity beyond the threshold. A puff application of glutamate preceding the ramp pulse lowered the threshold for evoking bursts by ramp pulses while chelerythrine abolished such effects of glutamate. Dihydroxyphenylglycine, an agonist of mGluR1/5, also caused similar effects, and increased both the frequency and impedance of membrane resonance. Immunohistochemistry revealed that glutamatergic synapses are made onto the stem axons, and that mGluR1/5 and Nav1.6 are co-localized in the stem axon. Taken together, glutamatergic synaptic inputs onto the stem axon may be able to switch the relaying to the bursting mode.

Teeth clenching reduces arm abduction force.

It has been reported that the 90° arm abduction force counteracting external adduction loads appeared to be smaller under teeth clenching condition than under non-clenching condition. To elucidate the physiological mechanism underlying the possible inhibitory effect of teeth clenching on the arm abduction, we have attempted to quantify the difference in the force induced against the fast and slow ramp load between the arm abductions under teeth non-clenching and clenching conditions. When the load of adduction moment was linearly increased, the abductor force increased to a maximal isometric contraction force (MICF) and further increased to a maximal eccentric contraction force (MECF) with forced adduction. The MICF measured under teeth clenching was significantly lower than that under non-clenching, despite no significant difference in the MECF between the two conditions. The reduction in MICF caused by teeth clenching was enhanced by increasing the velocity of the load. These results suggest that clenching inhibits abduction force only during isometric contraction phase. The invariability of MECF would indicate the lack of involvement of fatigue in such inhibitory effects of clenching. To discover the source of the inhibition, we have examined the effects of teeth clenching on the stretch reflex in the deltoid muscle. The stretch reflex of deltoid muscles was inhibited during clenching, contrary to what was expected from the Jendrassik maneuver. Taken together, our results suggest that the teeth clenching reduced the MICF by depressing the recruitment of deltoid motoneurones presumably via the presynaptic inhibition of spindle afferent inputs onto those motoneurones.

Correlating Material Properties to Osteoprotegerin Expression on Nanoparticulate Mineralized Collagen Glycosaminoglycan Scaffolds.

Precision material design directed by cell biological processes represents a frontier in developing clinically translatable regenerative technologies. While understanding cell-material interactions on multipotent progenitor cells yields insights on target tissue differentiation, equally if not more important is the quantification of indirect multicellular interactions. In this work, the relationship of two material properties, phosphate content and stiffness, of a nanoparticulate mineralized collagen glycosaminoglycan scaffold (MC-GAG) in the expression of an endogenous anti-osteoclastogenic secreted protein, osteoprotegerin (OPG) by primary human mesenchymal stem cells (hMSCs) is evaluated. The phosphate content of MC-GAG requires the type III sodium phosphate symporter PiT-1/SLC20A1 for OPG expression, correlating with ß-catenin downregulation, but is independent of the effects of phosphate ion on osteogenic differentiation. Using three stiffness MC-GAG variants that do not differ significantly by osteogenic differentiation, it is observed that the softest material elicited ≈1.6-2 times higher OPG expression than the stiffer materials. Knockdown of the mechanosensitive signaling axis of YAP, TAZ, ß-catenin and combinations thereof in hMSCs on MC-GAG demonstrates that ß-catenin downregulation increases OPG expression by 1.5-fold. Taken together, these data constitute a roadmap for material properties that can used to suppress osteoclast activation via osteoprotegerin expression separately from the anabolic processes of osteogenesis.

Intraoperative bioprinting of human adipose-derived stem cells and extra-cellular matrix induces hair follicle-like downgrowths and adipose tissue formation during full-thickness craniomaxillofacial skin reconstruction.

Craniomaxillofacial (CMF) reconstruction is a challenging clinical dilemma. It often necessitates skin replacement in the form of autologous graft or flap surgery, which differ from one another based on hypodermal/dermal content. Unfortunately, both approaches are plagued by scarring, poor cosmesis, inadequate restoration of native anatomy and hair, alopecia, donor site morbidity, and potential for failure. Therefore, new reconstructive approaches are warranted, and tissue engineered skin represents an exciting alternative. In this study, we demonstrated the reconstruction of CMF full-thickness skin defects using intraoperative bioprinting (IOB), which enabled the repair of defects via direct bioprinting of multiple layers of skin on immunodeficient rats in a surgical setting. Using a newly formulated patient-sourced allogenic bioink consisting of both human adipose-derived extracellular matrix (adECM) and stem cells (ADSCs), skin loss was reconstructed by precise deposition of the hypodermal and dermal components under three different sets of animal studies. adECM, even at a very low concentration such as 2 % or less, has shown to be bioprintable via droplet-based bioprinting and exhibited de novo adipogenic capabilities both in vitro and in vivo. Our findings demonstrate that the combinatorial delivery of adECM and ADSCs facilitated the reconstruction of three full-thickness skin defects, accomplishing near-complete wound closure within two weeks. More importantly, both hypodermal adipogenesis and downgrowth of hair follicle-like structures were achieved in this two-week time frame. Our approach illustrates the translational potential of using human-derived materials and IOB technologies for full-thickness skin loss.

Capsaicin induces theta-band synchronization between gustatory and autonomic insular cortices.

In the insular cortex, the primary gustatory area caudally adjoins the primary autonomic area that is involved in visceral sensory-motor integration. However, it has not been addressed whether neural activity in the gustatory insula (Gu-I) is coordinated with that in the autonomic insula (Au-I). We have demonstrated that TRPV1 activation in Gu-I induces theta-band synchronization between Gu-I and Au-I in rat slice preparations. Electron-microscopic immunohistochemistry revealed that TRPV1 immunoreactivity was much higher in Gu-I than in Au-I, and was mostly detected in dendritic spines receiving asymmetrical synapses. Whole-cell voltage-clamp recordings revealed that, in Gu-I, capsaicin-induced currents in layer 3 (L3) pyramidal cells (PCs) displayed no apparent desensitization, while those in layer 5 (L5) PCs displayed Ca(2+)-dependent desensitization, suggesting that L3 and L5 PCs respond differentially to TRPV1 activation. Voltage-sensitive dye imaging demonstrated that TRPV1 activation in Gu-I can alter an optical response with a monophasic and columnar temporospatial pattern evoked within Gu-I into an oscillatory one extending over Gu-I and Au-I. Power and cross-power spectral analyses of optical responses revealed theta-band synchronization between Gu-I and Au-I. Whole-cell current-clamp recordings demonstrated that such theta-band waves were mediated by sustained rhythmic firings at 4 and 8 Hz in L3 and L5 PCs, respectively. These results strongly suggested that theta-band oscillatory neural coordination between Gu-I and Au-I was induced by two distinct TRPV1-mediated theta-rhythm firings in L3 and L5 PCs in Gu-I. This network coordination induced by TRPV1 activation could be responsible for autonomic responses to tasting and ingesting spicy foods.

A mathematical model of negative covariability of inter-columnar excitatory synaptic actions caused by presynaptic inhibition.

We previously showed that a positive covariability between intracortical excitatory synaptic actions onto the two layer three pyramidal cells (PCs) located in mutually adjacent columns is changed into a negative covariability by column-wise presynaptic inhibition of intracortical inputs, implicated as a basis for the desynchronization of inter-columnar synaptic actions. Here we investigated how the inter-columnar desynchronization is modulated by the strength of presynaptic inhibition or other factors, by using a mathematical model. Based on our previous findings on the paired-pulse depression (PPD) of intracortical excitatory postsynaptic currents (EPSCs) evoked in PCs located in the stimulated home column (HC) but no PPD in PCs located in the adjacent column (AC), a mathematical model of synaptic connections between PCs and inhibitory interneurons was constructed. When the paired-pulse ratio (PPR) was decreased beyond 0.80, the correlation coefficient between the two second EPSC amplitudes in the paired PCs located in the HC and AC and that in the paired PCs located in the same HC exhibited opposite changes, and reached a global negative maximum and local positive maximum, respectively, at almost the same PPR (0.40). At this PPR, the desynchronization between the two cell assemblies in mutually adjacent columns would be maximized. These positive and negative covariabilities were not produced without background oscillatory synchronization across columns and were enhanced by increasing the synchronization magnitude, indicating that the synchronization leads to the desynchronization. We propose that a slow oscillatory synchronization across columns may emerge following the liberation from the column-wise presynaptic inhibition of inter-columnar synaptic inputs.

GABA(B) receptor-mediated presynaptic inhibition reverses inter-columnar covariability of synaptic actions by intracortical axons in the rat barrel cortex.

Intracortical axons originating from pyramidal cells in layer 3 of the rat somatosensory cortex are shared between adjacent columns, and receive the presynaptic inhibition that is mediated by the GABA(B) receptor. Synaptic actions by intracortical axons of single layer 3 pyramidal cells covary between the two adjacent columns in response to stimulation of layer 3 of either column. We examined whether GABA(B) receptor-mediated presynaptic inhibition affects the covariability of synaptic actions by intracortical axons between adjacent columns in slice preparations of the rat barrel cortex. Paired stimulations of superficial layer 3 evoked first and second excitatory postsynaptic currents (EPSCs) of varying amplitudes, yielding varying paired-pulse depression of EPSCs in layer 3 pyramidal cells that were located in the stimulated column, but not in its adjacent column. The amplitude of the second EPSC was inversely proportional to that of the first EPSC in layer 3 pyramidal cells in the stimulated column, yielding a negative correlation coefficient between the first and second EPSCs. Baclofen and CGP55845 attenuated paired-pulse depression and abolished the inverse relationship. Simultaneous recordings from two layer 3 pyramidal cells in the stimulated and adjacent columns revealed a positive correlation between the paired first EPSC amplitudes and a negative correlation between the paired second EPSC amplitudes, which, respectively, indicate the positive and negative covariability of synaptic actions by intracortical axons between the two adjacent columns. These results suggest that GABA(B) receptor-mediated presynaptic inhibition can reverse the positive covariability of inter-columnar synaptic actions, which may serve as a basis for inter-columnar desynchronisation.