Carbachol increases locus coeruleus activation by targeting noradrenergic neurons, inhibitory interneurons and inhibitory synaptic transmission.

The locus coeruleus (LC) consists of noradrenergic (NA) neurons and plays an important role in controlling behaviours. Although much of the knowledge regarding LC functions comes from studying behavioural outcomes upon administration of muscarinic acetylcholine receptor (mAChR) agonists into the nucleus, the exact mechanisms remain unclear. Here, we report that the application of carbachol (CCh), an mAChR agonist, increased the spontaneous action potentials (sAPs) of both LC-NA neurons and local inhibitory interneurons (LC I-INs) in acute brain slices by activating M1/M3 mAChRs (m1/3 AChRs). Optogenetic activation of LC I-INs evoked inhibitory postsynaptic currents (IPSCs) in LC-NA neurons that were mediated by γ-aminobutyric acid type A (GABAA ) and glycine receptors, and CCh application decreased the IPSC amplitude through a presynaptic mechanism by activating M4 mAChRs (m4 AChRs). LC-NA neurons also exhibited spontaneous phasic-like activity (sPLA); CCh application increased the incidence of this activity. This effect of CCh application was not observed with blockade of GABAA and glycine receptors, suggesting that the sPLA enhancement occurred likely because of the decreased synaptic transmission of LC I-INs onto LC-NA neurons by the m4 AChR activation and/or increased spiking rate of LC I-INs by the m1/3 AChR activation, which could lead to fatigue of the synaptic transmission. In conclusion, we report that CCh application, while inhibiting their synaptic transmission, increases sAP rates of LC-NA neurons and LC I-INs. Collectively, these effects provide insight into the cellular mechanisms underlying the behaviour modulations following the administration of muscarinic receptor agonists into the LC reported by the previous studies.

Practitioner and Director Perceptions, Beliefs, and Practices Related to STEM and Inclusion in Early Childhood.

The importance of early science, technology, engineering, and math (STEM) learning opportunities for all young children has become increasingly documented by research and recommended practices. In addition, high quality inclusive settings where all children can access and benefit from learning activities continues to demonstrate optimal outcomes for all children. This manuscript reports findings from a survey broadly disseminated related to early childhood practitioners' and directors' perceptions related to STEM and inclusion and explores what practices related to STEM and inclusion are currently being used by early childhood practitioners and directors. While the majority of respondents supported the importance of both STEM and inclusion, there were varied responses related to relevance for infants and toddlers and inconsistent reports of specific practices being used. The findings suggest the need to emphasize and provide professional development opportunities focused on STEM and inclusion for our early childhood workforce more explicitly. Additional implications for research and practice are discussed. Supplementary Information: The online version contains supplementary material available at 10.1007/s10643-023-01476-w.

Exploring the Perspectives of Preschool Teachers on Implementing Structured Motor Programs in Inclusive Classrooms.

Children with disabilities (CWD) tend to participate in fewer physical activities than typically developing children. During motor play, CWD often depend on teachers to provide direct instruction and frequent opportunities to practice motor skills, to interact with their peers, and learn new skills. To promote participation in physical activities for CWD, it is necessary to understand (a) teachers' perceptions about the importance of structured motor programs and (b) teachers' thoughts and concerns about implementing structured motor programs. The aim of this study was to understand teachers' perceptions about structured motor programs (e.g., obstacle course, bowling) and factors that may influence their motivation to implement them. Semi-structured interviews were conducted with 17 teachers who taught in inclusive preschools. Interview data were transcribed and analyzed to identify key themes. The results show that the majority of participants valued structured motor programs and were aware of the benefits of implementing such programs with preschoolers. Several teachers expressed concerns about meeting the expectations of a motor program and preschoolers' challenging behaviors during such programs. Implications for practice from this study include the need to (a) provide professional development to help teachers support preschoolers with disabilities in learning motor skills and understanding how to arrange and scaffold opportunities for children to participate in physical activities and gross motor play with their typically developing peers, and (b) create quality structured motor programs to ensure that all children have access to motor learning opportunities in inclusive preschool settings.

Inhibitory interneurons regulate phasic activity of noradrenergic neurons in the mouse locus coeruleus and functional implications.

KEY POINTS: The locus coeruleus (LC) contains noradrenergic (NA) neurons that respond to novel stimuli in the environment with phasic activation to initiate an orienting response; phasic LC activation is also triggered by stimuli, representing the outcome of task-related decision processes, to facilitate ensuing behaviours and help optimize task performance. Here, we report that LC-NA neurons exhibit bursts of action potentials in vitro resembling phasic LC activation in vivo, and the activity is gated by inhibitory interneurons (I-INs) located in the peri-LC. We also observe that inhibition of peri-LC I-INs enhances prepulse inhibition and axons from cortical areas that play important roles in evaluating the cost/reward of a stimulus synapse on both peri-LC I-INs and LC-NA neurons. The results help us understand the cellular mechanisms underlying the generation and regulation of phasic LC activation with a focus on the role of peri-LC I-INs. ABSTRACT: Noradrenergic (NA) neurons in the locus coeruleus (LC) have global axonal projection to the brain. These neurons discharge action potentials phasically in response to either novel stimuli in the environment to initiate an orienting behaviour or stimuli representing the outcome of task-related decision processes to facilitate ensuing behaviours and help optimize task performance. Nevertheless, the cellular mechanisms underlying the generation and regulation of phasic LC activation remain unknown. We report here that LC-NA neurons recorded in brain slices exhibit bursts of action potentials that resembled the phasic activation-pause profile observed in animals. The activity was referred to as phasic-like activity (PLA) and was suppressed and enhanced by blocking excitatory and inhibitory synaptic transmissions, respectively. These results suggest the existence of a local circuit to drive PLA, and the activity could be regulated by the excitatory-inhibitory balance of the circuit. In support of this notion, we located a population of inhibitory interneurons (I-INs) in the medial part of the peri-LC that exerted feedforward inhibition of LC-NA neurons through GABAergic and glycinergic transmissions. Selective inhibition of peri-LC I-INs with chemogenetic methods could enhance PLA in brain slices and increase prepulse inhibition in animals. Moreover, axons from the orbitofrontal and prelimbic cortices, which play important roles in evaluating the cost/reward of a stimulus, synapse on both peri-LC I-INs and LC-NA neurons. These observations demonstrate functional roles of peri-LC I-INs in integrating inputs of the frontal cortex onto LC-NA neurons and gating the phasic LC output.

Carbodicarbene: geminal-Bimetallic Coordination in Selective Manner.

The reaction of Pd(OAc)2 with free carbodicarbene (CDC) generates a Pd acetate trinuclear complex 1 via intramolecular C(sp3 )-H bond activation at one of the CDC methyl side arms. The solid structure of 1 reveals the capability of CDC to facilitate a double dative bond with two palladium centers in geminal fashion. This is attributed to the chelating mode of CDC, which can frustrate π-conjugation within the CDC framework. Such effect maybe also amplified by ligand-ligand interaction. The formation of other gem-bimetallic Pd-Pd, Pd-Au, and Ni-Au provides further structural evidence for this proof-of-concept in selective installation. Structural analysis is supported by computational calculations based on state-of-the-art energy decomposition analysis (EDA) in conjunction with natural orbitals for chemical valence (NOCV) method.

GABAB receptor-mediated tonic inhibition regulates the spontaneous firing of locus coeruleus neurons in developing rats and in citalopram-treated rats.

KEY POINTS: Noradrenaline (NA)-releasing neurons in the locus coeruleus (LC) provide NA to the forebrain and play important roles in regulating many brain functions. LC neurons are subject to tonic inhibition mediated by GABAB receptors (GABAB Rs) and that the extent of the effect varies with ambient GABA levels. GABAB R-mediated tonic inhibition can effectively tune the spontaneous firing rate (SFR) of LC neurons; it is developmentally regulated and is responsible for maintaining a constant SFR of LC neurons during development. In male, but not female rats, chronic perinatal treatment with citalopram, a selective serotonin reuptake inhibitor, results in downregulation of GABAB R-mediated tonic inhibition of LC neurons that partially accounts for increased SFR in male, but not female, rats receiving such treatment. Our results show that GABAB R-mediated tonic inhibition could be an important player in the development of normal and abnormal behaviours/brain functions associated with the LC-NA system. Noradrenaline (NA)-releasing neurons in the locus coeruleus (LC) provide NA to the forebrain. Their activity is believed to be a key factor regulating the wakefulness/arousal level of the brain. In this study, we found that the activity of NA-releasing neurons in the LC (LC neurons) was subject to γ-aminobutyric acid (GABA) tonic inhibition through GABAB receptors (GABAB Rs), but not GABAA receptors. The intensity of GABAB R tonic inhibition was found to depend on ambient GABA levels, as it was dramatically increased by blockade of GABA reuptake. It also varied with the function of GABAB Rs. The GABAB R activity on LC neurons was found to increase with postnatal age up to postnatal days 8-10, resulting in increased tonic inhibition. Interestingly, there was no significant difference in the spontaneous activity of LC neurons at different postnatal ages unless GABAB R tonic inhibition was blocked. These results show that, during postnatal development, there is a continuous increase in GABAB R tonic inhibition that maintains the activity of LC neurons at a proper level. In male, but not female, rats, chronic perinatal treatment with citalopram, a selective serotonin reuptake inhibitor, reduced GABAB R activity and tonic inhibition, which might result in the significantly higher spontaneous activity of LC neurons seen in these animals. In conclusion, our results show that GABAB R-mediated tonic inhibition has a direct impact on the spontaneous activity of LC neurons and that the extent of the effect varies with ambient GABA levels and functionality of GABAB R signalling.

Morphological and physiological evidence of a synaptic connection between the lateral parabrachial nucleus and neurons in the A7 catecholamine cell group in rats.

BACKGROUND: The descending noradrenergic (NAergic) system is one of the important endogenous analgesia systems. It has been suggested that noxious stimuli could activate descending NAergic system; nevertheless, the underlying neuronal circuit remains unclear. As NAergic neurons in the A7 catecholamine cell group (A7) are a part of the descending NAergic system and the lateral parabrachial nucleus (LPB) is an important brainstem structure that relays ascending nociceptive signal, we aimed to test whether LPB neurons have direct synaptic contact with NAergic A7 neurons. RESULTS: Stereotaxic injections of an anterograde tracer, biotinylated dextran-amine (BDA), were administered to LPB in rats. The BDA-labeled axonal terminals that have physical contacts with tyrosine hydroxylase-positive (presumed noadrenergic) neurons were identified in A7. Consistent with these morphological observations, the excitatory synaptic currents (EPSCs) were readily evoked in NAergic A7 neurons by extracellular stimulation of LPB. The EPSCs evoked by LPB stimulation were blocked by CNQX, a non-NMDA receptor blocker, and AP5, a selective NMDA receptor blocker, showing that LPB-A7 synaptic transmission is glutamatergic. Moreover, the amplitude of LPB-A7 EPSCs was significantly attenuated by DAMGO, a selective µ-opioid receptor agonist, which was associated with an increase in paired-pulse ratio. CONCLUSIONS: Taken together, the above results showed direct synaptic connections between LPB and A7 catecholamine cell group, the function of which is subject to presynaptic modulation by µ-opioid receptors.

Characterization of poly(N-isopropylacrylamide)-nucleobase supramolecular complexes featuring bio-multiple hydrogen bonds.

In this study we employed poly(N-isopropylacrylamide) (PNIPAAm) as a matrix that we hybridized with five different nucleobase units (adenine, thymine, uracil, guanine, cytosine) to generate PNIPAAm-nucleobase supramolecular complexes (PNSCs) stabilized through bio-multiple hydrogen bonds (BMHBs). These nucleobase units interacted with PNIPAAm through BMHBs of various strengths, leading to competition between the BMHBs and the intramolecular hydrogen bonds (HBs) of PNIPAAm. The changes in morphology, crystalline structure, and thermoresponsive behavior of PNIPAAm were related to the strength of its BMHBs with the nucleobases. The strengths of the BMHBs followed the order guanine > adenine > thymine > cytosine > uracil, as verified through analyses of Fourier transform infrared spectra, lower critical solution temperatures, and inter-association equilibrium constants. The PNSCs also exhibited remarkable improvements in conductivity upon the formation of BMHBs, which facilitated proton transport. The neat PNIPAAm film was an insulator, but it transformed into a semiconductor after hybridizing with the nucleobases. In particular, the resistivity of the PNIPAAm-guanine supramolecular complex decreased to 1.35 × 10(5) ohm cm. The resistivity of the PNIPAAm-cytosine supramolecular complex increased significantly from 5.83 × 10(6) to 3 × 10(8) ohm cm upon increasing the temperature from 40 to 50 °C, suggesting that this material might have applicability in thermo-sensing. The ability to significantly improve the conductivity of hydrogels through such a simple approach involving BMHBs might facilitate their use as novel materials in bioelectronics.

Effect of mirror therapy combined with somatosensory stimulation on motor recovery and daily function in stroke patients: A pilot study.

BACKGROUND/PURPOSE: Mirror therapy (MT) has been recommended as a simple, inexpensive approach to treat motor dysfunction. The use of a mesh glove (MG) was suggested to normalize muscle tone that ameliorates motor impairment. Combining two efficient treatment protocols might maximize the benefits from training. This study investigated the effects of MT combined with MG (MG + MT) versus MT alone on motor performance and daily function after stroke. METHODS: Sixteen patients with chronic unilateral stroke were recruited. A randomized two-group pretest and posttest design was used to randomly assign participants to MG + MT or MT groups. MT involves repetitive bimanual, symmetrical movement practice in which the individual moves the affected limb as much as she/he could while watching the reflective illusion of the unaffected limb's movements from a mirror. The MG + MT group wore a MG on the affected hand during the MT. The Modified Ashworth scale of muscle spasticity (MAS), Action Research Arm Test (ARAT), Box and Block Test (BBT), and Functional Independence Measure (FIM) were administered to evaluate spasticity, and motor and daily function. RESULTS: The results for the BBT (p = 0.013), total scores (p = 0.031), grasping subscales (p = 0.036) of ARAT, and FIM transfer scores (p = 0.013) presented significantly large effects in favor of the MG + MT group. CONCLUSION: Combining MG with MT significantly improves manual dexterity, grasping, and transfer performance. Adding the MG component into the MT likely increased the richness of sensory input and improved the movement performance more than MT alone.

Prediction of partition coefficients of organic compounds between SPME/PDMS and aqueous solution.

Polydimethylsiloxane (PDMS) is commonly used as the coated polymer in the solid phase microextraction (SPME) technique. In this study, the partition coefficients of organic compounds between SPME/PDMS and the aqueous solution were compiled from the literature sources. The correlation analysis for partition coefficients was conducted to interpret the effect of their physicochemical properties and descriptors on the partitioning process. The PDMS-water partition coefficients were significantly correlated to the polarizability of organic compounds (r = 0.977, p < 0.05). An empirical model, consisting of the polarizability, the molecular connectivity index, and an indicator variable, was developed to appropriately predict the partition coefficients of 61 organic compounds for the training set. The predictive ability of the empirical model was demonstrated by using it on a test set of 26 chemicals not included in the training set. The empirical model, applying the straightforward calculated molecular descriptors, for estimating the PDMS-water partition coefficient will contribute to the practical applications of the SPME technique.

Effects of mirror therapy on motor and sensory recovery in chronic stroke: a randomized controlled trial.

OBJECTIVE: To compare the effects of mirror therapy (MT) versus control treatment (CT) on movement performance, motor control, sensory recovery, and performance of activities of daily living in people with chronic stroke. DESIGN: Single-blinded, randomized controlled trial. SETTING: Four hospitals. PARTICIPANTS: Outpatients with chronic stroke (N=33) with mild to moderate motor impairment. INTERVENTIONS: The MT group (n=16) received upper extremity training involving repetitive bimanual, symmetrical movement practice, in which the individual moves the affected limb while watching the reflective illusion of the unaffected limb's movements from a mirror. The CT group received task-oriented upper extremity training. The intensity for both groups was 1.5 hours/day, 5 days/week, for 4 weeks. MAIN OUTCOME MEASUREMENTS: The Fugl-Meyer Assessment; kinematic variables, including reaction time, normalized movement time, normalized total displacement, joint recruitment, and maximum shoulder-elbow cross-correlation; the Revised Nottingham Sensory Assessment; the Motor Activity Log; and the ABILHAND questionnaire. RESULTS: The MT group performed better in the overall (P=.01) and distal part (P=.04) Fugl-Meyer Assessment scores and demonstrated shorter reaction time (P=.04), shorter normalized total displacement (P=.04), and greater maximum shoulder-elbow cross-correlation (P=.03). The Revised Nottingham Sensory Assessment temperature scores improved significantly more in the MT group than in the CT group. No significant differences on the Motor Activity Log and the ABILHAND questionnaire were found immediately after MT or at follow-up. CONCLUSIONS: The application of MT after stroke might result in beneficial effects on movement performance, motor control, and temperature sense, but may not translate into daily functions in the population with chronic stroke.

Role of extracellular signal-regulated kinase in synaptic transmission and plasticity of a nociceptive input on capsular central amygdaloid neurons in normal and acid-induced muscle pain mice.

Application of phorbol 12,13-diacetate (PDA) caused marked enhancement of synaptic transmission of nociceptive parabrachio-amygdaloid (PBA) input onto neurons of the capsular central amygdaloid (CeAC) nucleus. The potentiation of PBA-CeAC EPSCs by PDA involved a presynaptic protein kinase C (PKC)-dependent component and a postsynaptic PKC-extracellular-regulated kinase (ERK)-dependent component. NMDA glutamatergic receptor (NMDAR)-dependent long-term potentiation (LTP) of PBA-CeAC EPSCs, which was also dependent on the PKC-ERK signaling pathway, was induced by tetanus stimulation at 100 Hz. In slices from mice subjected to acid-induced muscle pain (AIMP), phosphorylated ERK levels in the CeAC increased, and PBA-CeAC synaptic transmission was postsynaptically enhanced. The enhanced PBA-CeAC synaptic transmission in AIMP mice shared common mechanisms with the postsynaptic potentiation effect of PDA and induction of NMDAR-dependent LTP by high-frequency stimulation in normal slices, both of which required ERK activation. Since the CeAC plays an important role in the emotionality of pain, enhanced synaptic function of nociceptive (PBA) inputs onto CeAC neurons might partially account for the supraspinal mechanisms underlying central sensitization.

A requirement of low-threshold calcium spike for induction of spike-timing-dependent plasticity at corticothalamic synapses on relay neurons in the ventrobasal nucleus of rat thalamus.

Relay neurons in sensory thalamus transmit somatosensory information to cerebral cortex and receive sensory and feedback corticothalamic (CT) synaptic inputs. Their duality of firing modes, in bursts and continuous, underlies state dependence of thalamic information transfer, but the impact of different firing patterns on synaptic plasticity was rarely explored. To address this issue, we made whole-cell recording from relay neurons in the ventrobasal nucleus (VBN) of rat thalamus and compared synaptic plasticity induced by pairing CT-EPSP with two different types of burst spiking: low-threshold spike (LTS)-burst spiking triggered at Vm~-70 mV, and high-frequency spiking induced at Vm~-55 mV. The latter mimics natural burst spiking of relay neurons without activation of LTS. We found that, while backpropagating APs alone were not sufficient, low-threshold calcium spike was required for the induction of spike-timing-dependent LTP at CT synapses. Our results reveal a novel role of the calcium spike plays in the induction of long-term plasticity of CT synapse. Considering the dendritic origin of LTS, this study also implies potential physiological regulations over synaptic plasticity in thalamus. We propose that this form of synaptic plasticity may be involved in the dynamic fine-tuning of thalamocortical information relay.

GABAB receptor-mediated tonic inhibition of noradrenergic A7 neurons in the rat.

Noradrenergic (NAergic) A7 neurons that project axonal terminals to the dorsal horn of the spinal cord to modulate nociceptive signaling are suggested to receive tonic inhibition from local GABAergic interneurons, which are under the regulation of descending analgesic pathways. In support of this argument, we presently report GABA(B) receptor (GABA(B)R)-mediated tonic inhibition of NAergic A7 neurons. Bath application of baclofen induced an outward current (I(Bac)) in NAergic A7 neurons that was blocked by CGP 54626, a GABA(B)R blocker. The I(Bac) was reversed at about -99 mV, displayed inward rectification, and was blocked by Ba(2+) or Tertipian-Q, showing it was mediated by G protein-activated inward-rectifying K(+) (GIRK) channels. Single-cell RT-PCR results suggested that GIRK1/3 heterotetramers might dominate functional GIRK channels in NAergic A7 neurons. Under conditions in which GABA(A) and glycine receptors were blocked, bath application of GABA inhibited the spontaneous firing of NAergic A7 neurons in a dose-dependent manner. Interestingly, CGP 54626 application not only blocked the effect of GABA but also increased the firing rate to 126.9% of the control level, showing that GABA(B)Rs were constitutively active at an ambient GABA concentration of 2.8 µM and inhibited NAergic A7 neurons. GABA(B)Rs were also found at presynaptic excitatory and inhibitory axonal terminals in the A7 area. Pharmacological activation of these GABA(B)Rs inhibited the release of neurotransmitters. No physiological role was found for GABA(B)Rs on excitatory terminals, whereas those on the inhibitory terminals were found to exert autoregulatory control of GABA release.

Bidirectional synaptic plasticity induced by conditioned stimulations with different number of pulse at hippocampal CA1 synapses: roles of N-methyl-D-aspartate and metabotropic glutamate receptors.

In the mammalian brain, the hippocampus has been established as a principle structure for learning and memory processes, which involve synaptic plasticity. Although a relationship between synaptic plasticity and stimulation frequency has been reported in numerous studies, little is known about the importance of pulse number on synaptic plasticity. Here we investigated whether the pulse number can modulate bidirectional plasticity in hippocampal CA1 areas. When a CA1 area was induced by a paired-pulse (PP) with a 10-ms interval, the strength of the synapse was altered to form a long-term depression (LTD), with a 68 ± 4% decrease in expression. The PP-induced LTD (PP-LTD) was blocked by the metabotropic glutamate receptors subtype 5 (mGluR5) antagonist MPEP, suggesting that the PP-LTD relied on the activation of GluR5. In addition, this modulation of LTD was protein kinase C (PKC)- and Group II mGluR-independent. However, when increasing the pulse number to 4 and 6, potentiated synaptic strength was observed, which was N-methyl-D-aspartate receptor (NMDAR)-dependent but mGluR5-independent. Surprisingly, when blocking mGluR, the synaptic efficacy induced by triple-pulse stimulation was altered to form a long-term potentiation (LTP) with a 142 ± 7% enhancement, and was further blocked by NMDA antagonist APV. Following treatment with APV and PKC blocker chelerythrine, the LTP expression induced by 4- and 6-pulse stimulation was switched to LTD. We suggest that CA1 synaptic plasticity is regulated by the result of competition between NMDA and mGluR5 receptors. We suggest that the pulse number can bidirectionally modulate synaptic plasticity through the activation of NMDA and mGluR5 in hippocampal CA1 areas.

Acceptability of COVID-19 Vaccines and Protective Behavior among Adults in Taiwan: Associations between Risk Perception and Willingness to Vaccinate against COVID-19.

This study aims to evaluate acceptance of COVID-19 vaccines and the impact of risk perception on vaccine acceptance and personal health protective behaviors in Taiwan. A nationwide cross-sectional study was conducted from 19 to 30 October 2020; 1020 participants were included in the final analysis; chi-square and logistic regression analyses were conducted. In total, 52.7% of participants were willing to receive COVID-19 vaccines, 63.5% perceived the severity of COVID-19 in Taiwan as "not serious", and nearly 40% were worried about COVID-19 infection. Participants with higher perceived severity of COVID-19 had significantly higher odds of refusing the vaccine (OR = 1.546), while those worried about infection had lower odds of poor health protective behaviors (OR = 0.685). Vaccine refusal reasons included "the EUA process is not strict enough" (48.7%) and "side effects" (30.3%). Those who had previously refused other vaccinations were 2.44 times more likely to refuse the COVID-19 vaccines. Participants' age had an influence on COVID-19 vaccine acceptance. In general, the Taiwanese public's acceptance of the vaccine was lower than that in other high-income countries. Elderly participants and those with college-level education and above who had previously refused vaccines had lower willingness to receive a COVID-19 vaccine. Risk perception was positively associated with personal health protective behaviors but negatively associated with COVID-19 vaccine acceptance.

Comparison of synaptic transmission and plasticity between sensory and cortical synapses on relay neurons in the ventrobasal nucleus of the rat thalamus.

Relay neurons in the ventrobasal nucleus of the thalamus transmit somatosensory information to the cerebral cortex and receive sensory and cortical (feedback) synaptic inputs via, respectively, medial lemniscal (ML) and corticothalamic (CT) fibres. Here, we report that calcium-permeable AMPA receptors are expressed at CT synapses, but not ML synapses, and that the NMDA receptor (NMDAR)-mediated/non-NMDAR-mediated synaptic current ratio is significantly larger at CT synapses than at ML synapses. Moreover, NMDAR-dependent LTP and L-type voltage-gated calcium channel-dependent LTD are readily induced at CT synapses, but not ML synapses. In particular, LTD of CT synaptic transmission is induced by spiking of postsynaptic relay neurons in continuous mode, but not burst mode, in current-clamp recordings. These results show that the strength of the cortical input to thalamic relay neurons is selectively subjected to use-dependent modification, which could be a mechanism for regulation of thalamocortical-corticothalamic interactions and the underlying sensory processing.

Neurokinin 1 receptor activates transient receptor potential-like currents in noradrenergic A7 neurons in rats.

Noradrenergic (NAergic) A7 neurons are involved in modulating nociception by releasing noradrenaline in the dorsal spinal cord. Since NAergic A7 neurons receive dense Substance P (Sub-P) releasing terminals from ventromedial medulla, here we tested the effect of Sub-P on them. Bath application of Sub-P induced an inward current (I(Sub-P)) in NAergic neurons, which was significantly blocked by Neurokinin 1 (NK1) receptor antagonist. The I(Sub-P) was reversed at approximately -20 mV, blocked by several TRP channel blockers, enhanced by OAG and negatively regulated by PKC. Immunohistochemistry staining showed that NAergic A7 neurons express high level of TRPC6 channel proteins, which is consistent with pharmacological properties of I(Sub-P) shown above, as TRPC6 channel is shown to be augmented by OAG and inhibited by PKC. In conclusion, the above results provide mechanism underlying postsynaptic action of Sub-P on NAergic A7 neurons and a role for TRPC6 channel in NAergic pain modulation.

Extracellular Signal-Regulated Kinases Mediate an Autoregulation of GABAB-Receptor-Activated Whole-Cell Current in Locus Coeruleus Neurons.

The norepinephrine-releasing neurons in the locus coeruleus (LC) are well known to regulate wakefulness/arousal. They display active firing during wakefulness and a decreased discharge rate during sleep. We have previously reported that LC neurons express large numbers of GABAB receptors (GABABRs) located at peri-/extrasynaptic sites and are subject to tonic inhibition due to the continuous activation of GABABRs by ambient GABA, which is significantly higher during sleep than during wakefulness. In this study, we further showed using western blot analysis that the activation of GABABRs with baclofen could increase the level of phosphorylated extracellular signal-regulated kinase 1 (ERK1) in LC tissue. Recordings from LC neurons in brain slices showed that the inhibition of ERK1/2 with U0126 and FR180204 accelerated the decay of whole-cell membrane current induced by prolonged baclofen application. In addition, the inhibition of ERK1/2 also increased spontaneous firing and reduced tonic inhibition of LC neurons after prolonged exposure to baclofen. These results suggest a new role of GABABRs in mediating ERK1-dependent autoregulation of the stability of GABABR-activated whole-cell current, in addition to its well-known effect on gated potassium channels, to cause a tonic current in LC neurons.

Reduction of multitasking distractions underlies the higher adenoma detection rate of water exchange compared to air insufflation - blinded analysis of withdrawal phase videos.

Background: Experts have hypothesized that a reduction of multitasking distractions and improved bowel cleanliness can explain why insertion water exchange enhances adenoma detection rate. Objective: The purpose of this study was to test the role of both distractions during withdrawal and bowel cleanliness in enhancing adenoma detection rate using coded video records of colonoscopy. Methods: The withdrawal phase of videos of 299 consecutive colonoscopies from two randomized controlled trials comparing water exchange versus air insufflation at a regional hospital in Taiwan were coded. The primary outcome was distractions; activities that preclude full attention being paid to inspection of the mucosa for polyps. A single blinded reviewer collected the data. Results: There were significant agreements in inter-rater reliability indexes. Compared to air insufflation, water exchange had significantly fewer distractions; higher diagnostic yield (intervention time and number), adenoma detection rate, and Boston Bowel Preparation Scale score. Water exchange had a higher withdrawal technique score (predominantly adequacy of cleaning). The association between increased adenoma detection rate and water exchange was mediated by the number of distractions and withdrawal time, but not the Boston Bowel Preparation Scale score. Conclusion: The speculation by experts that a reduction of multitasking distractions underlies the significantly higher adenoma detection rate of water exchange is supported by the current study. Increased bowel cleanliness did not contribute to the increased adenoma detection rate by use of water exchange.