Direct activation of G-protein-gated inward rectifying K+ channels promotes nonrapid eye movement sleep.
Sleep
Zou, B., Cao, W. S., Guan, Z., Xiao, K., Pascual, C., Xie, J., Zhang, J., Xie, J., Kayser, F., Lindsley, C. W., Weaver, C. D., Fang, J., Xie, X. S.
2019; 42 (3)
Abstract
A major challenge in treating insomnia is to find effective medicines with fewer side effects. Activation of G-protein-gated inward rectifying K+ channels (GIRKs) by GABAB agonists baclofen or γ-hydroxybutyric acid (GHB) promotes nonrapid eye movement (NREM) sleep and consolidates sleep. However, baclofen has poor brain penetration, GHB possesses abuse liability, and in rodents both drugs cause spike-wave discharges (SWDs), an absence seizure activity. We tested the hypothesis that direct GIRK activation promotes sleep without inducing SWD using ML297, a potent and selective GIRK activator.Whole-cell patch-clamp recordings from hypocretin/orexin or hippocampal neurons in mouse brain slices were made to study neuronal excitability and synaptic activity; spontaneous activity, locomotion, contextual and tone-conditioned memory, and novel object recognition were assessed. Electroencephalogram/electromyogram (EEG/EMG) recordings were used to study GIRK modulation of sleep.ML297, like baclofen, caused membrane hyperpolarization, decreased input resistance, and blockade of spontaneous action potentials. Unlike baclofen, ML297 (5-10 µM) did not cause significant depression of postsynaptic excitatory and inhibitory currents (EPSCs-IPSCs), indicating preferential postsynaptic inhibition. ML297 (30 mg/kg, i.p.) inhibited wake activity and locomotion, and preferentially increased NREM sleep without altering EEG delta power, REM sleep, inducing SWDs, or impairing conditioned memory and novel object recognition.This study finds that direct activation of neuronal GIRK channels modulates postsynaptic membrane excitability and prolongs NREM sleep without changing sleep intensity, inducing SWDs, or impairing memory in rodents. These results suggest that direct GIRK activation with a selective compound may present an innovative approach for the treatment of chronic insomnia.
View details for DOI 10.1093/sleep/zsy244
View details for PubMedID 30535004
View details for PubMedCentralID PMC6424090
Abstract
Neuropathic pain caused by nerve injury is debilitating and difficult to treat. Current systemic pharmacological therapeutics for neuropathic pain produce limited pain relief and have undesirable side effects, while current local anesthetics tend to nonspecifically block both sensory and motor functions. Calcitonin gene related peptide (CGRP), a neuropeptide released from sensory nerve endings, appears to play a significant role in chronic neuropathic pain. In this study, an analgesic microneedle (AMN) patch was developed using dissolvable microneedles to transdermally deliver selective CGRP antagonist peptide in a painless manner for the treatment of localized neuropathic pain. Local analgesic effects were evaluated in rats by testing behavioral pain sensitivity in response to thermal and mechanical stimuli using neuropathic pain models such as spared-nerve injury and diabetic neuropathy pain, as well as neurogenic inflammatory pain model induced by ultraviolet B (UVB) radiation. Unlike several conventional therapies, the AMN patches produced effective analgesia on neuropathic pain without disturbing the normal nociception and motor function of the rat, resulting from the high specificity of the delivered peptide against CGRP receptors. The AMN patches did not cause skin irritation or systemic side effects. These results demonstrate that dissolvable microneedle patches delivering CGRP antagonist peptide provide an effective, safe, and simple approach to mitigate neuropathic pain with significant advantages over current treatments.
View details for DOI 10.1021/acsnano.6b06104
View details for Web of Science ID 000392886500040
View details for PubMedID 28001346
Abstract
Many national organizations call for medical students to receive more public health education in medical school. Nonetheless, limited evidence exists about successful servicelearning programs that administer preventive health services in nonclinical settings. The Flu Crew program, started in 2001 at the Stanford University School of Medicine, provides preclinical medical students with opportunities to administer influenza immunizations in the local community. Medical students consider Flu Crew to be an important part of their medical education that cannot be learned in the classroom. Through delivering vaccines to where people live, eat, work, and pray, Flu Crew teaches medical students about patient care, preventive medicine, and population health needs. Additionally, Flu Crew allows students to work with several partners in the community in order to understand how various stakeholders improve the delivery of population health services. Flu Crew teaches students how to address common vaccination myths and provides insights into implementing public health interventions. This article describes the Stanford Flu Crew curriculum, outlines the planning needed to organize immunization events, shares findings from medical students' attitudes about population health, highlights the program's outcomes, and summarizes the lessons learned. This article suggests that Flu Crew is an example of one viable service-learning modality that supports influenza vaccinations in nonclinical settings while simultaneously benefiting future clinicians.
View details for DOI 10.2147/AMEP.S70294
View details for PubMedID 26170731
View details for PubMedCentralID PMC4492543
Abstract
BACKGROUND: Clinic no shows (NS) create a lost opportunity for provider-patient interaction and impose a financial burden to the healthcare system and on society. We aimed to: (1) to determine the clinical and demographic factors associated with increased NS rates at a children's hospital's subsubspecialty clinics and (2) to estimate the direct institutional financial costs associated with NS events. METHODS: A comprehensive database was generated from all clinic encounters for 15 subspecialty outpatient clinics (five surgical and 10 medical) between September 12, 2005 and December 30, 2010. Multivariate logistic regressions were performed to identify the variables associated with NS events. Direct costs of NS events were estimated using annual revenue for each clinic. RESULTS: A total of 284,275 encounters and 17,024 NS events were available for analysis. Public insurance coverage (Medicaid and Title V), compared to private insurance or self-pay status, was associated with an increased likelihood NS (OR 2.19, 95% CI 2.10-2.28, p < 0.0005 for Medicaid; OR 1.56, 95% CI 1.50-1.62, p < 0.0005 for Title V). Compared to patients 21-30 years of age, patients <12 years (OR 2.08, 95% CI 1.77-2.45, p < 0.0005) had increased likelihood of NS. Scheduled visits with medical subspecialists were more likely than surgical subspecialty visits to result in a NS (OR 1.69, 95% CI 1.63-1.75, p < 0.0005). The predicted annualized lost revenue associated with NS visits was estimated at $730,000 from the 15 clinics analyzed, approximately $210 per NS event. CONCLUSION: Pediatric subspecialty NS events are common, costly, and potentially preventable.
View details for Web of Science ID 000348450800003
View details for PubMedID 23551280
Abstract
Hypocretin/orexin (Hcrt)-producing neurons in the lateral hypothalamus project throughout the brain, including to the hippocampus, where Hcrt receptors are widely expressed. Hcrt neurons activate these targets to orchestrate global arousal state, wake-sleep architecture, energy homeostasis, stress adaptation, and reward behaviors. Recently, Hcrt has been implicated in cognitive functions and social interaction. In the present study, we tested the hypothesis that Hcrt neurons are critical to social interaction, particularly social memory, using neurobehavioral assessment and electrophysiological approaches. The validated "two-enclosure homecage test" devices and procedure were used to test sociability, preference for social novelty (social novelty), and recognition memory. A conventional direct contact social test was conducted to corroborate the findings. We found that adult orexin/ataxin-3-transgenic (AT) mice, in which Hcrt neurons degenerate by 3 months of age, displayed normal sociability and social novelty with respect to their wild-type littermates. However, AT mice displayed deficits in long-term social memory. Nasal administration of exogenous Hcrt-1 restored social memory to an extent in AT mice. Hippocampal slices taken from AT mice exhibited decreases in degree of paired-pulse facilitation and magnitude of long-term potentiation, despite displaying normal basal synaptic neurotransmission in the CA1 area compared to wild-type hippocampal slices. AT hippocampi had lower levels of phosphorylated cAMP response element-binding protein (pCREB), an activity-dependent transcription factor important for synaptic plasticity and long-term memory storage. Our studies demonstrate that Hcrt neurons play an important role in the consolidation of social recognition memory, at least in part through enhancements of hippocampal synaptic plasticity and cAMP response element-binding protein phosphorylation.
View details for DOI 10.1523/JNEUROSCI.3200-12.2013
View details for Web of Science ID 000316553800020
View details for PubMedID 23516292
View details for PubMedCentralID PMC3640412
Abstract
1. To facilitate investigation of diverse rodent behaviours in rodents' home cages, we have developed an integrated modular platform, the SmartCage(™) system (AfaSci, Inc. Burlingame, CA, USA), which enables automated neurobehavioural phenotypic analysis and in vivo drug screening in a relatively higher-throughput and more objective manner. 2, The individual platform consists of an infrared array, a vibration floor sensor and a variety of modular devices. One computer can simultaneously operate up to 16 platforms via USB cables. 3. The SmartCage(™) detects drug-induced increases and decreases in activity levels, as well as changes in movement patterns. Wake and sleep states of mice can be detected using the vibration floor sensor. The arousal state classification achieved up to 98% accuracy compared with results obtained by electroencephalography and electromyography. More complex behaviours, including motor coordination, anxiety-related behaviours and social approach behaviour, can be assessed using appropriate modular devices and the results obtained are comparable with results obtained using conventional methods. 4. In conclusion, the SmartCage(™) system provides an automated and accurate tool to quantify various rodent behaviours in a 'stress-free' environment. This system, combined with the validated testing protocols, offers powerful a tool kit for transgenic phenotyping and in vivo drug screening.
View details for DOI 10.1111/j.1440-1681.2012.05719.x
View details for Web of Science ID 000305758200005
View details for PubMedID 22540540
Abstract
Electrophysiological measures can provide information that complements clinical assessments such as the American Spinal Injury Association sensory and motor scores in the evaluation of outcomes after spinal cord injury (SCI). The authors review and summarize the literature regarding tests that are most relevant to the study of SCI recovery--in particular, motor evoked potentials and somatosensory evoked potentials (SSEPs). In addition, they discuss the role of other tests, including F-wave nerve conductance tests and electromyography, sympathetic skin response, and the Hoffman reflex (H-reflex) test as well as the promise of dermatomal SSEPs and the electrical perceptual threshold test, newer quantitative tests of sensory function. It has been shown that motor evoked potential amplitudes improve with SCI recovery but latencies do not. Somatosensory evoked potentials are predictive of ambulatory capacity and hand function. Hoffman reflexes are present during spinal shock despite the loss of tendon reflexes, but their amplitudes increase with time after injury. Further, H-reflex modulation is reflective of changes in spinal excitability. While these tests have produced data that is congruent with clinical evaluations, they have yet to surpass clinical evaluations in predicting outcomes. Continuing research using these methodologies should yield a better understanding of the mechanisms behind SCI recovery and thus provide potentially greater predictive and evaluative power.
View details for DOI 10.3171/FOC.2008.25.11.E11
View details for Web of Science ID 000260566600011
View details for PubMedID 18980471
