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.

Reduced menthol sensitivity in a prodromal Parkinson's disease model induced by intranasal rotenone treatment.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms, and it is associated with several prodromal non-motor symptoms, including an impaired sense of smell, taste and touch. We previously reported that bitter taste impairments occur independently of olfactory impairments in an early-stage PD animal model using short-term intranasal rotenone-treated mice. Cool temperatures also affect bitter taste perception, but it remains unclear whether or not bitter taste impairments result from an altered sensitivity for intraoral cool stimuli. We examined disturbances in the intraoral menthol sensitivity, such as coolness at low concentrations of menthol, using a brief-access test. Once a day, one solution from the 7-concentration series of (-)-menthol (0-2.3 mM) or the bitter taste quinine-HCl (0.3 mM) was randomly presented 20 times for 10 s to water-deprived mice before and 1 week after rotenone treatment. The total number of licks within 20 times was significantly decreased with the presentation of 2.3 mM menthol and quinine-HCl, compared to distilled water in untreated mice, but not in rotenone-treated mice. The correlation between the licks for quinine-HCl and that for menthol was increased after rotenone treatment. In contrast, the 2-bottle choice test for 48 h clarified that menthol sensitivity was increased after rotenone treatment. Furthermore, a thermal place preference test revealed that seeking behavior toward a cold-floored room was increased in the rotenone-treated mice despite the unchanged plantar cutaneous cold sensitivity. These results suggest that taste impairments in this model mice are at least partly due to intraoral somatosensory impairments, accompanied by peripheral/central malfunction.

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.

Increased vertical dimension of occlusion for varying periods differentially impairs learning and memory in guinea pigs.

There is an increasing number of studies showing that occlusal dysfunction impairs learning and memory. We previously demonstrated that the brain has a mechanism to calibrate between the activities of spindle afferents and periodontal-mechanoreceptor afferents for controlling the chewing movement, and the accurate calibration can be done only at the proper vertical dimension of occlusion (VDO). Then, the chewing at an inappropriate VDO may induce a severe mental stress due to a mal-calibration. However, it is not clear how the impairment of learning/memory progresses over the period of stress induced by occlusal dysfunction. We investigated by passive avoidance test how the behavior and learning/memory are altered in guinea pigs in which the VDO was raised by 2-3 mm over the period up to 8 weeks. We found that the guinea pigs reared under the raised occlusal-condition (ROC) for 1 week showed a very high sensitivity to electrical stimulation whereas this did not cause the memory consolidation in the 1st-day retention trial, suggesting that such hypersensitivity rather hampered the fear learning. In the guinea pigs reared under the ROC for 2 and 8 weeks, the learning ability was not largely affected and memory consolidation occurred similarly whereas the memory retention deteriorated more severely in the latter guinea pigs than in the former ones. In the guinea pigs reared under the ROC for 3 and 4 weeks, learning was severely impaired, and memory consolidation did not occur. These results suggest that the occlusal dysfunction for varying periods differentially impairs learning and memory.

Understanding the pathophysiology of sleep bruxism based on human and animal studies: A narrative review.

BACKGROUND: Sleep bruxism (SB) is a common sleep disorder that affects approximately 20% of children and 10% of adults. It may cause orodental problems, such as tooth wear, jaw pain, and temporal headaches. However, the pathophysiological mechanisms underlying SB remain largely unknown, and a definitive treatment has not yet been established. HIGHLIGHT: Human studies involving polysomnography have shown that rhythmic masticatory muscle activity (RMMA) is more frequent in otherwise healthy individuals with SB than in normal individuals. RMMA occurs during light non-rapid eye movement (non-REM) sleep in association with transient arousals and cyclic sleep processes. To further elucidate the neurophysiological mechanisms of SB, jaw motor activities have been investigated in naturally sleeping animals. These animals exhibit various contractions of masticatory muscles, including episodes of rhythmic and repetitive masticatory muscle bursts that occurred during non-REM sleep in association with cortical and cardiac activation, similar to those found in humans. Electrical microstimulation of corticobulbar tracts may also induce rhythmic masticatory muscle contractions during non-REM sleep, suggesting that the masticatory motor system is activated during non-REM sleep by excitatory inputs to the masticatory central pattern generator. CONCLUSION: This review article summarizes the pathophysiology of SB based on the findings from human and animal studies. Physiological factors contributing to RMMA in SB have been identified in human studies and may also be present in animal models. Further research is required to integrate the findings between human and animal studies to better understand the mechanisms underlying SB.

Longitudinal electromyographic analysis of jaw-closing muscle activities during ingestive behaviors from pre-weaning to juvenile periods in rats.

This longitudinal study investigated developmental changes in jaw-closing muscle activities during ingestive behaviors in rats. On postnatal day (P) 10, electromyography (EMG) electrodes were inserted into the masseter and temporalis muscles of rat pups. EMG activities were recorded for the following ingestive behaviors between P14 and P49: for suckling, including nipple attachment and rhythmic sucking on P14 and for pasta biting, pellet chewing, and milk licking between P21 and P49. Burst rhythms and muscle coordination (i.e., the correlation and time lag) between masseter and temporalis activities were assessed for each behavior. The burst rhythms of nipple attachment and rhythmic sucking on P14 were significantly slower than those of pasta biting, pellet chewing, and milk licking on P21. Muscle coordination differed between suckling on P14 and mastication and licking on P21. Between P21 and P49, increases were observed in burst rhythms for pasta biting and pellet chewing. The rate of increases in burst rhythms was higher for pasta biting than for pellet chewing. Muscle coordination between the two muscle activities for pasta biting did not significantly change between P21 and P49, whereas that for pellet chewing significantly changed between P21 and P24 and stabilized after P24. Burst rhythms for milk licking did not significantly change over time, while muscle coordination between the two muscle activities changed from agonist to antagonist muscle-like activity on approximately P35. The present results demonstrate that distinct patterns of rhythmic jaw-closing muscle activities emerge before weaning, they continue to change over time, and they exhibit unique developmental dynamics for each behavior after weaning.

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.

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.

Taste Impairments in a Parkinson's Disease Model Featuring Intranasal Rotenone Administration in Mice.

BACKGROUND: Taste impairments are often accompanied by olfactory impairments in the early stage of Parkinson's disease (PD). The development of animal models is required to elucidate the mechanisms underlying taste impairments in PD. OBJECTIVE: This study was conducted to clarify whether the intranasal administration of rotenone causes taste impairments prior to motor deficits in mice. METHODS: Rotenone was administrated to the right nose of mice once a day for 1 or 4 week(s). In the 1-week group, taste, olfactory, and motor function was assessed before and after a 1-week recovery period following the rotenone administration. Motor function was also continuously examined in the 4-weeks group from 0 to 5 weeks. After a behavioral test, the number of catecholamine neurons (CA-Nos) was counted in the regions responsible for taste, olfactory, and motor function. RESULTS: taste and olfactory impairments were simultaneously observed without locomotor impairments in the 1-week group. The CA-Nos was significantly reduced in the olfactory bulb and nucleus of the solitary tract. In the 4-week group, locomotor impairments were observed from the third week, and a significant reduction in the CA-Nos was observed in the substantia nigra (SN) and ventral tegmental area (VTA) at the fifth week along with the weight loss. CONCLUSION: The intranasal administration of rotenone caused chemosensory and motor impairments in an administration time-period dependent manner. Since chemosensory impairments were expressed prior to the locomotor impairments followed by SN/VTA CA neurons loss, this rotenone administration model may contribute to the clarification of the prodromal symptoms of PD.

The Nature of Noradrenergic Volume Transmission From Locus Coeruleus to Brainstem Mesencephalic Trigeminal Sensory Neurons.

Noradrenergic neurons in the locus coeruleus (LC) release noradrenaline (NA) that acts via volume transmission to activate extrasynaptic G-protein coupled receptors (GPCRs) in target cells throughout the brain. As the closest projection, the dorsal LC laterally adjoins the mesencephalic trigeminal nucleus (MTN), in which proprioceptive primary sensory neurons innervating muscle spindles of jaw-closing muscles are exceptionally located. MTN neurons express α2-adrenergic receptors (α2-ARs) and display hyperpolarization-activated cyclic nucleotide-gated (HCN) currents (Ihs), which is downregulated by α2-AR activation. To quantify the activity-dependent outcome of volume transmission of NA from LC to MTN, we investigated how direct LC activation inhibits Ih in MTN neurons by performing dual whole-cell recordings from LC and MTN neurons. Repetition of 20 Hz spike-train evoked with 1-s current-pulse in LC neurons every 30 s resulted in a gradual decrease in Ih evoked every 30 s, revealing a Hill-type relationship between the number of spike-trains in LC neurons and the degree of Ih inhibition in MTN neurons. On the other hand, when microstimulation was applied in LC every 30 s, an LC neuron repeatedly displayed a transient higher-frequency firing followed by a tonic firing at 5-10 Hz for 30 s. This subsequently caused a similar Hill-type inhibition of Ih in the simultaneously recorded MTN neuron, but with a smaller Hill coefficient, suggesting a lower signal transduction efficacy. In contrast, 20 Hz activity induced by a 1-s pulse applied every 5-10 s caused only a transient facilitation of Ih inhibition followed by a forced termination of Ih inhibition. Thus, the three modes of LC activities modulated the volume transmission to activate α2-adrenergic GPCR to differentially inhibit Ih in MTN neurons.

Motor representation of rhythmic jaw movements in the amygdala of guinea pigs.

OBJECTIVE: The areas of the amygdala contributing to rhythmic jaw movements and the movement patterns induced remain unknown. Therefore, the present study investigated the areas of the amygdala contributing to rhythmic jaw movements using repetitive electrical microstimulation techniques. DESIGN: Experiments were performed on head-restrained guinea pigs under ketamine-xylazine anesthesia. EMG activities in the masseter and digastric muscles and jaw movements were recorded. Short- and long-train electrical microstimulations of the amygdala were performed and the patterns of jaw movements induced were analyzed quantitatively. RESULT: The short-train stimulation induced short-latency EMG responses in the masseter and/or digastric muscles. The stimulation sites inducing short-latency EMG responses were distributed within the ventral part of the amygdala, which covered the medial, basal, and cortical nuclei. The long-train stimulation induced tonic jaw opening and two types of rhythmic jaw movements: those with or without lateral jaw shifts, which were characterized by a larger jaw gape and ipsilateral jaw excursion, respectively. Rhythmic jaw movements with lateral jaw shifts were characterized by overlapping masseter and digastric EMG activities. However, rhythmic patterns did not differ between the two types of rhythmic jaw movements. The stimulation sites that induced rhythmic jaw movements were more localized to the cortical nucleus. CONCLUSIONS: The present results suggest that the ventral part of the amygdala is involved in the induction of rhythmic jaw movements in guinea pigs. The putative roles of the limbic system in the genesis of functional (e.g., chewing) and non-functional (e.g., bruxism) rhythmic oromotor movements warrant further study.

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.

Sleep stage-dependent changes in tonic masseter and cortical activities in young subjects with primary sleep bruxism.

STUDY OBJECTIVES: The present study investigated the hypothesis that subjects with primary sleep bruxism (SB) exhibit masseter and cortical hyperactivities during quiet sleep periods that are associated with a high frequency of rhythmic masticatory muscle activity (RMMA). METHODS: Fifteen SB and ten control participants underwent polysomnographic recordings. The frequencies of oromotor events and arousals and the percentage of arousals with oromotor events were assessed. Masseter muscle tone during sleep was quantified using a cluster analysis. Electroencephalography power and heart rate variability were quantified and then compared between the two groups and among sleep stages. RESULTS: The frequency of RMMA and percentage of arousals with RMMA were significantly higher in SB subjects than in controls in all stages, while these variables for nonrhythmic oromotor events did not significantly differ between the groups. In SB subjects, the frequency of RMMA was the highest in stage N1 and the lowest in stages N3 and R, while the percentage of arousals with RMMA was higher in stage N3 than stages N1 and R. The cluster analysis classified masseter activity during sleep into two clusters for masseter tone and contractions. Masseter muscle tone showed typical stage-dependent changes in both groups but did not significantly differ between the groups. Furthermore, no significant differences were observed in electroencephalography power or heart rate variability between the groups. CONCLUSION: Young SB subjects exhibited sleep stage-dependent increases in the responsiveness of RMMA to transient arousals, but did not show masseter or cortical hyperactivity during sleep.

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.

Enhanced Ocular Surface and Intraoral Nociception via a Transient Receptor Potential Vanilloid 1 Mechanism in a Rat Model of Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA), characterized by low arterial oxygen saturation during sleep, is associated with an increased risk of orofacial pain. In this study, we simulated chronic intermittent hypoxia (CIH) during the sleep/rest phase (light phase) to determine the role of transient receptor potential vanilloid 1 (TRPV1) in mediating enhanced orofacial nocifensive behavior and trigeminal spinal subnucleus caudalis (Vc) neuronal responses to capsaicin (a TRPV1 agonist) stimulation in a rat model of OSA. Rats were subjected to CIH (nadir O2, 5%) during the light phase for 8 or 16 consecutive days. CIH yielded enhanced behavioral responses to capsaicin after application to the ocular surface and intraoral mucosa, which was reversed under normoxic conditions. The percentage of TRPV1-immunoreactive trigeminal ganglion neurons was greater in CIH rats than in normoxic rats and recovered under normoxic conditions after CIH. The ratio of large-sized TRPV1-immunoreactive trigeminal ganglion neurons increased in CIH rats. The density of TRPV1 positive primary afferent terminals in the superficial laminae of Vc was higher in CIH rats. Phosphorylated extracellular signal-regulated kinase (pERK)-immunoreactive cells intermingled with the central terminal of TRPV1-positive afferents in the Vc. The number of pERK-immunoreactive cells following low-dose capsaicin (0.33 µM) application to the tongue was significantly greater in the middle portion of the Vc of CIH rats than of normoxic rats and recovered under normoxic conditions after CIH. These data suggest that CIH during the sleep (light) phase is sufficient to transiently enhance pain on the ocular surface and intraoral mucosa via TRPV1-dependent mechanisms.

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.

Cellular mechanisms underlying the rapid depolarization caused by oxygen and glucose deprivation in layer III pyramidal cells of the somatosensory cortex.

Cortical pyramidal neurons show rapid and irreversible membrane depolarization in response to oxygen-glucose depolarization (OGD). In this study, we investigated cellular mechanisms responsible for rapid depolarization caused by OGD in layer III pyramidal neurons of the mouse somatosensory cortex. When OGD solution was perfused in the presence of Ca2+ chelator and inhibitors of ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs) in the pipette solution or in the presence of inhibitors of NMDA receptors (NMDARs), voltage-gated Ca2+ channels (VGCCs), and canonical transient receptor potential (TRPC) channels in the perfusion solution, the latency of the rapid depolarization was significantly prolonged compared to the control. In addition, when OGD solution was perfused in the presence of scavengers of nitric oxide and reactive oxygen species in the perfusion solution or in the presence of calcineurin inhibitors in the pipette solution, the latency of the rapid depolarization was significantly prolonged compared to the control. These data indicate that OGD-induced intracellular Ca2+ increases mediated by Ca2+ influx through NMDARs, VGCCs and TRPC channels as well as by Ca2+ release from RyRs and IP3Rs lead to mitochondrial impairment, which may facilitate the generation of the rapid depolarization via dysfunction of Na+-K+-ATPase due to decreased ATP production.