Long-lasting adverse effects of short-term stress during the suckling-mastication transition period on masticatory function and intraoral sensation in rats.

Early-life stress affects brain development, eventually resulting in adverse behavioral and physical health consequences in adulthood. The present study assessed the hypothesis that short-term early-life stress during infancy before weaning, a period for the maturation of mastication and sleep, poses long-lasting adverse effects on masticatory function and intraoral sensations later in life.Rat pups were exposed to either maternal separation (MS) or intermittent hypoxia (IH-Infancy) for 6 h/day in the light/sleep phase from postnatal day (P)17 to P20 to generate "neglect" and "pediatric obstructive sleep apnea" models, respectively. The remaining rats were exposed to IH during P45-P48 (IH-Adult). Masticatory ability was evaluated based on the rats' ability to chew pellets and bite pasta throughout the growth period (P21-P70). Intraoral chemical and mechanical sensitivities were assessed using two-bottle preference drinking tests, and hind paw pain thresholds were measured in adulthood (after P60).No differences were found in body weight, grip force, and hind paw sensitivity in MS, IH-Infancy, and IH-Adult rats compared with naïve rats. Masticatory ability was lower in MS and IH-Infancy rats from P28 to P70 than in naïve rats. MS and IH-Infancy rats exhibited intraoral hypersensitivity to capsaicin and mechanical stimulations in adulthood. The IH-Adult rats did not display inferior masticatory ability or intraoral hypersensitivity.In conclusion, short-term early-life stress during the suckling-mastication transition period potentially causes a persistent decrease in masticatory ability and intraoral hypersensitivity in adulthood. The period is a "critical window" for the maturation of oral motor and sensory functions.

Sleep architecture as a candidate for phenotyping sleep bruxism: A narrative physiological review.

BACKGROUND: Sleep bruxism (SB), an oral behaviour in otherwise healthy individuals, is characterised by frequent rhythmic masticatory muscle activity (RMMA) during sleep. RMMA/SB episodes occur over various sleep stages (N1-N3 and rapid eye movement (REM)), sleep cycles (non-REM to REM), and frequently with microarousals. It currently remains unclear whether these characteristics of sleep architecture are phenotype candidates for the genesis of RMMA/SB. OBJECTIVES: This narrative review investigated the relationship between sleep architecture and the occurrence of RMMA as a SB phenotype candidate. METHODS: PubMed research was performed using keywords related to RMMA/SB and sleep architecture. RESULTS: In non-SB and SB healthy individuals, RMMA episodes were most frequent in the light non-REM sleep stages N1 and N2, particularly during the ascending phase of sleep cycles. The onset of RMMA/SB episodes in healthy individuals was preceded by a physiological arousal sequence of autonomic cardiovascular to cortical activation. It was not possible to extract a consistent sleep architecture pattern in the presence of sleep comorbidities. The lack of standardisation and variability between subject complexified the search for specific sleep architecture phenotype(s). CONCLUSION: In otherwise healthy individuals, the genesis of RMMA/SB episodes is largely affected by oscillations in the sleep stage and cycle as well as the occurrence of microarousal. Furthermore, a specific sleep architecture pattern cannot be confirmed in the presence of sleep comorbidity. Further studies are needed to delineate sleep architecture phenotype candidate(s) that contribute to the more accurate diagnosis of SB and treatment approaches using standardised and innovative methodologies.

Reciprocal first night effect on rhythmic and non-rhythmic oromotor episodes in moderate to severe primary sleep bruxism: A retrospective physiological study.

BACKGROUND: Sleep on the first night in a sleep laboratory is characterized by a lower sleep quality and frequency of rhythmic masticatory muscle activity (RMMA) than that on the second night in moderate to severe sleep bruxism (SB) patients. OBJECTIVE: The aims of this study was to clarify the physiological factors contributing to the first night effect on oromotor activity during sleep and investigate whether physiological factors involved in the first night effect differed between rhythmic and non-rhythmic oromotor activities. METHODS: Polysomnographic data collected on two consecutive nights from 15 moderate to severe SB subjects (F 7: M 8; age: 23.2 ± 1.3 [mean ± SD] years) were retrospectively analysed. Sleep variables, RMMA and non-specific masticatory muscle activity (NSMA) were scored in relation to episode types (i.e. phasic or tonic and cluster or isolated), sleep architecture and transient arousals. The relationships between nightly differences in oromotor and sleep variables were assessed. The distribution of oromotor events, arousals, cortical electroencephalographic power, RR intervals and heart rate variability were examined in relation to sleep cycle changes. These variables were compared between the first and second nights and between RMMA and NSMA. RESULTS: Sleep variables showed a lower sleep quality on Night 1 than on Night 2. In comparisons with Night 1, the RMMA index increased by 18.8% (p < .001, the Wilcoxon signed-rank test) on Night 2, while the NSMA index decreased by 17.9% (p = .041). Changes in the RMMA index did not correlate with those in sleep variables, while changes in the NSMA index correlated with those in arousal-related variables (p < .001, Spearman's rank correlation). An increase in the RMMA index on Night 2 was found for the cluster type and stage N1 related to sleep cyclic fluctuations in cortical and cardiac activities. In contrast, the decrease in the NSMA index was associated with increases in the isolated type and the occurrence of stage N2 and wakefulness regardless of the sleep cycle. CONCLUSION: Discrepancies in first night effect on the occurrence of RMMA and NSMA represent unique sleep-related processes in the genesis of oromotor phenotypes in SB subjects.

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.

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.

Synaptic and Genetic Bases of Impaired Motor Learning Associated with Modified Experience-Dependent Cortical Plasticity in Heterozygous Reeler Mutants.

Patients with neurodevelopmental disorders show impaired motor skill learning. It is unclear how the effect of genetic variation on synaptic function and transcriptome profile may underlie experience-dependent cortical plasticity, which supports the development of fine motor skills. RELN (reelin) is one of the genes implicated in neurodevelopmental psychiatric vulnerability. Heterozygous reeler mutant (HRM) mice displayed impairments in reach-to-grasp learning, accompanied by less extensive cortical map reorganization compared with wild-type mice, examined after 10 days of training by intracortical microstimulation. Assessed by patch-clamp recordings after 3 days of training, the training induced synaptic potentiation and increased glutamatergic-transmission of cortical layer III pyramidal neurons in wild-type mice. In contrast, the basal excitatory and inhibitory synaptic functions were depressed, affected both by presynaptic and postsynaptic impairments in HRM mice; and thus, no further training-induced synaptic plasticity occurred. HRM exhibited downregulations of cortical synaptophysin, immediate-early gene expressions, and gene enrichment, in response to 3 days of training compared with trained wild-type mice, shown using quantitative reverse transcription polymerase chain reaction, immunohistochemisty, and RNA-sequencing. We demonstrated that motor learning impairments associated with modified experience-dependent cortical plasticity are at least partially attributed by the basal synaptic alternation as well as the aberrant early experience-induced gene enrichment in HRM.

Long-term changes in oral feeding behaviors of growing rats.

Oral feeding is critical for survival in both humans and animals. However, few studies have reported quantitative behavioral measures associated with the development of oral feeding behaviors. Therefore, the present study investigated developmental changes in the oral feeding behaviors of rats by quantitatively assessing pasta eating and licking behaviors. In the pasta eating test, the time to finish pasta sticks of three different thicknesses (Φ = 0.9, 1.4, and 1.9 mm, 4 cm long) was recorded between postnatal day 29 (P29) and P49, because all rats were able to finish eating these pasta sticks on P29. A developmental decrease in the time to finish pasta sticks of all thicknesses was observed during the initial period of recordings and plateaued before P35. The extent of this decrease was dependent on the thickness of pasta sticks. In the licking test, the number of licks per 10 s and the total intake volume during the test were recorded between P19 and P49, because all rats were able to access and lick the solution on P19. The time courses of developmental increases in the number of licks and the total intake volume were similar to the results obtained in the pasta eating test. Collectively, these results suggest that developmental changes in pasta eating and licking behaviors markedly differed between the weanling and periadolescent periods. The present study also demonstrated the applicability of the pasta eating and licking tests to the quantification of developmental changes in the oral feeding behaviors of rats.

After-effects of acute footshock stress on sleep states and rhythmic masticatory muscle activity during sleep in guinea pigs.

This study investigated the effects of acute footshock stress (FS) on the occurrence of rhythmic masticatory muscle activity (RMMA) during sleep in guinea pigs. Animals were prepared for chronic recordings from electroencephalogram, electrooculogram and electromyograms of neck and masseter muscles. The signals were recorded for six hours on the two successive days: the first day with stress-free condition (non-FS condition) and the second day with acute FS (FS condition). Sleep/wake states and RMMA were scored visually. Sleep variables and the frequency of RMMA occurring during non-rapid eye movement (NREM) sleep were compared during 6-h periods between the two conditions. Compared to non-FS condition, the amount of total sleep and NREM sleep significantly reduced during 2 h following the acute FS in the FS condition. Similarly, the frequency of RMMA significantly increased during 2 h following the acute FS for the FS condition compared to non-FS condition. During 2-6 h after FS in the FS condition, sleep variables and the frequency of RMMA did not differ from those without FS in the non-FS condition. These results suggest that acute experimental stress can induce transient changes in sleep-wake states and the occurrence of RMMA in experimental animals.

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.

Changes in cortical, cardiac, and respiratory activities in relation to spontaneous rhythmic jaw movements in ketamine-anesthetized guinea pigs.

It has been reported that rhythmic jaw movements (RJMs) spontaneously occur in ketamine-anesthetized animals. The present study investigated the physiological processes that occur during the cortical, cardiac, and respiratory events which contribute to the genesis of RJMs in animals after supplemental ketamine injections. Fourteen guinea pigs were prepared to allow electroencephalographic, electrocardiographic, and electromyographic activities to be recorded from the digastric muscle, measurement of jaw movements, and nasal expiratory airflow under ketamine-xylazine anesthesia. Rhythmic jaw movements spontaneously occurred with rhythmic digastric muscle contractions, 23-29 minutes after injection of supplemental ketamine (12.5 and 25.0 mg kg-1 , intravenously). The cycle length of RJMs did not differ significantly between the two doses of ketamine (mean±SD: 12.5 mg kg-1 , 326.5 ± 60.0 ms; 25 mg kg-1 , 278.5 ± 45.1 ms). Following injection of ketamine, digastric muscle activity, heart and respiratory rates, and cortical beta power significantly decreased, while cortical delta and theta power significantly increased. These changes were significantly larger in animals given 25.0 mg kg-1 of ketamine than in those given 12.5 mg kg-1 . With the onset of RJMs, the levels of these variables returned to pre-injection levels, regardless of the dose of ketamine administered. These results suggest that, following supplemental ketamine injections, spontaneous RJMs occur during a specific period when the pharmacological effects of ketamine wear off, and that these RJMs are characterized by stereotypical changes in cardiac, respiratory, and cortical activities.

Nicotine Exposure during Adolescence Leads to Changes of Synaptic Plasticity and Intrinsic Excitability of Mice Insular Pyramidal Cells at Later Life.

To find satisfactory treatment for nicotine addiction, synaptic and cellular mechanisms should be investigated comprehensively. Synaptic transmission, plasticity and intrinsic excitability in various brain regions are known to be altered by acute nicotine exposure. However, it has not been addressed whether and how nicotine exposure during adolescence alters these synaptic events and intrinsic excitability in the insular cortex in adulthood. To address this question, we performed whole-cell patch-clamp recordings to examine the effects of adolescent nicotine exposure on synaptic transmission, plasticity and intrinsic excitability in layer V pyramidal neurons (PNs) of the mice insular cortex five weeks after the treatment. We found that excitatory synaptic transmission and potentiation were enhanced in these neurons. Following adolescent nicotine exposure, insular layer V PNs displayed enhanced intrinsic excitability, which was reflected in changes in relationship between current strength and spike number, inter-spike interval, spike current threshold and refractory period. In addition, spike-timing precision evaluated by standard deviation of spike timing was decreased following nicotine exposure. Our data indicate that adolescent nicotine exposure enhances synaptic transmission, plasticity and intrinsic excitability in layer V PNs of the mice insular cortex at later life, which might contribute to severe nicotine dependence in adulthood.

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.

Intranasal Administration of Rotenone Reduces GABAergic Inhibition in the Mouse Insular Cortex Leading to Impairment of LTD and Conditioned Taste Aversion Memory.

The pesticide rotenone inhibits mitochondrial complex I and is thought to cause neurological disorders such as Parkinson's disease and cognitive disorders. However, little is known about the effects of rotenone on conditioned taste aversion memory. In the present study, we investigated whether intranasal administration of rotenone affects conditioned taste aversion memory in mice. We also examined how the intranasal administration of rotenone modulates synaptic transmission and plasticity in layer V pyramidal neurons of the mouse insular cortex that is critical for conditioned taste aversion memory. We found that the intranasal administration of rotenone impaired conditioned taste aversion memory to bitter taste. Regarding its cellular mechanisms, long-term depression (LTD) but not long-term potentiation (LTP) was impaired in rotenone-treated mice. Furthermore, spontaneous inhibitory synaptic currents and tonic GABA currents were decreased in layer V pyramidal neurons of rotenone-treated mice compared to the control mice. The impaired LTD observed in pyramidal neurons of rotenone-treated mice was restored by a GABAA receptor agonist muscimol. These results suggest that intranasal administration of rotenone decreases GABAergic synaptic transmission in layer V pyramidal neurons of the mouse insular cortex, the result of which leads to impairment of LTD and conditioned taste aversion memory.

Nicotinic activity layer specifically modulates synaptic potentiation in the mouse insular cortex.

Nicotinic acetylcholine receptors (nAChRs) in the insular cortex play an important role in nicotine addiction, but its cellular and synaptic mechanisms underlying nicotine addiction still remain unresolved. In layer 5 pyramidal neurons of the mouse insular cortex, activation of nAChRs suppresses synaptic potentiation through enhancing GABAergic synaptic transmission via activation of ß2-containing nAChRs in non-fast-spiking (non-FS) interneurons. However, it has not been addressed whether and how activation of nAChRs modulates synaptic plasticity in layers 3 and 6 pyramidal neurons of the insular cortex. In this study, I demonstrate that activation of nAChRs oppositely modulates synaptic potentiation in layers 3 and 6 pyramidal neurons of the insular cortex. In layer 3 pyramidal neurons, activation of nAChRs depressed synaptic potentiation induced by combination of presynaptic stimulation with postsynaptic depolarization (paired training) through enhancing GABAergic synaptic transmission via activation of ß2-containing nAChRs in non-FS interneurons. By contrast, in layer 6 pyramidal neurons, activation of nAChRs enhanced synaptic potentiation through activating postsynaptic ß2-containing nAChRs. These results indicate, in different layers of the mouse insular cortex, paired training-induced synaptic potentiation is oppositely regulated by activation of nAChRs which are located on GABAergic interneurons (layer 3) and on pyramidal neurons (layer 6). Thus, layer-specific modulation of synaptic potentiation may be involved in cellular and synaptic mechanisms of insular cortical changes in nicotine addiction.

Interaction of nicotinic acetylcholine receptors with dopamine receptors in synaptic plasticity of the mouse insular cortex.

The insular cortex plays essential roles in nicotine addiction. However, much is still unknown about its cellular and synaptic mechanisms responsible for nicotine addiction. We have previously shown that in layer 5 pyramidal neurons of the mouse insular cortex, activation of the nicotinic acetylcholine receptors (nAChRs) suppresses synaptic potentiation through enhancing GABAergic synaptic transmission, although it enhances both glutamatergic and GABAergic synaptic transmission. In the present study, we examined whether dopamine receptors might contribute to the nicotine-induced inhibition of synaptic potentiation. The nicotine-induced inhibition of synaptic potentiation was decreased in the presence of a D1 dopamine receptor antagonist SCH23390 irrespective of the presence of a D2 dopamine receptor antagonist sulpiride, suggesting that D1 dopamine receptors are involved in nicotine-induced inhibition. We also investigated how dopamine receptors might contribute to the nAChR-induced enhancement of glutamatergic and GABAergic synaptic transmission. The nAChR-induced enhancement of GABAergic synaptic transmission was decreased in the presence of SCH23390 irrespective of the presence of sulpiride, whereas that of glutamatergic synaptic transmission was not altered in the presence of SCH23390 and sulpiride. These results suggest that D1 dopamine receptors are involved in the nAChR-induced enhancement of GABAergic synaptic transmission while dopamine receptors are not involved in that of glutamatergic synaptic transmission. These observations indicate that the interaction between nAChRs and D1 dopamine receptors plays critical roles in synaptic activities in layer 5 pyramidal neurons of the mouse insular cortex. These insular synaptic changes might be associated with nicotine addiction.

Experimentally induced rhythmic jaw muscle activities during non-rapid eye movement sleep in freely moving guinea pigs.

Rhythmic jaw muscle activities frequently occur during non-rapid eye movement sleep in patients with sleep bruxism. The present study aimed to investigate the response characteristics of the masticatory rhythm generation during non-rapid eye movement sleep in animals. Eleven guinea pigs were surgically prepared for polygraphic recordings by electromyography, electrooculography, electroencephalography and electrocardiography with the implantation of a stimulating electrode. Repetitive electrical microstimulations at three intensities were applied to the corticobulbar tract under freely moving conditions. The rhythmic electro-myographic responses of the digastric and masseter muscles were scored and analysed. Changes in cortical electro-encephalographic power and heart rate in association with these stimulations were quantified. Microstimulations to the corticobulbar tract induced rhythmic jaw muscle activities in digastric muscles, occasionally with masseter activities during wakefulness and non-rapid eye movement sleep. The response rate of rhythmic jaw muscle activities was significantly lower (p < 0.01) and the response latency was significantly longer (p < 0.01) during non-rapid eye movement sleep than during wakefulness. At higher stimulus intensities, the response rate increased and response latency decreased. The mean burst intervals of the digastric and masseter muscles were similar regardless of vigilance states and stimulus intensities. Induced rhythmic jaw muscle activities during non-rapid eye movement sleep were followed by a transient decrease in delta power and increases in beta power and heart rate. During non-rapid eye movement sleep, the masticatory motor system is able to generate rhythmic outputs to the jaw muscles in response to facilitatory inputs although the responsiveness was decreased from wakefulness.

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.

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.

Search for unknown neural link between the masticatory and cognitive brain systems to clarify the involvement of its impairment in the pathogenesis of Alzheimer's disease.

Brain degenerations in sporadic Alzheimer's disease (AD) are observed earliest in the locus coeruleus (LC), a population of noradrenergic neurons, in which hyperphosphorylated tau protein expression and ß-amyloid (Aß) accumulation begin. Along with this, similar changes occur in the basal forebrain cholinergic neurons, such as the nucleus basalis of Meynert. Neuronal degeneration of the two neuronal nuclei leads to a decrease in neurotrophic factors such as brain-derived neurotrophic factor (BDNF) in the hippocampus and cerebral cortex, which results in the accumulation of Aß and hyperphosphorylated tau protein and ultimately causes neuronal cell death in those cortices. On the other hand, a large number of epidemiological studies have shown that tooth loss or masticatory dysfunction is a risk factor for dementia including AD, and numerous studies using experimental animals have also shown that masticatory dysfunction causes brain degeneration in the basal forebrain, hippocampus, and cerebral cortex similar to those observed in human AD, and that learning and memory functions are impaired accordingly. However, it remains unclear how masticatory dysfunction can induce such brain degeneration similar to AD, and the neural mechanism linking the trigeminal nervous system responsible for mastication and the cognitive and memory brain system remains unknown. In this review paper, we provide clues to the search for such "missing link" by discussing the embryological, anatomical, and physiological relationship between LC and its laterally adjoining mesencephalic trigeminal nucleus which plays a central role in the masticatory functions.