Discovering the Intriguing Properties of Extrasynaptic γ-Aminobutyric Acid Type A Receptors.

Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by α5 subunit-containing γ-aminobutyric acid type A receptors. By Caraiscos VB, Elliott EM, You-Ten KE, Cheng VY, Belelli D, Newell JG, Jackson MF, Lambert JJ, Rosahl TW, Wafford KA, MacDonald JF, Orser BA. Proc Natl Acad Sci U S A 2004; 101:3662-7. Reprinted with permission. In this Classic Paper Revisited, the author recounts the scientific journey leading to a report published in the Proceedings of the National Academy of Sciences (PNAS) and shares several personal stories from her formative years and "research truths" that she has learned along the way. Briefly, the principal inhibitory neurotransmitter in the brain, γ-aminobutyric acid (GABA), was conventionally thought to regulate cognitive processes by activating synaptic GABA type A (GABAA) receptors and generating transient inhibitory synaptic currents. However, the author's laboratory team discovered a novel nonsynaptic form of tonic inhibition in hippocampal pyramidal neurons, mediated by extrasynaptic GABAA receptors that are pharmacologically distinct from synaptic GABAA receptors. This tonic current is highly sensitive to most general anesthetics, including sevoflurane and propofol, and likely contributes to the memory-blocking properties of these drugs. Before the publication in PNAS, the subunit composition of GABAA receptors that generate the tonic current was unknown. The team's research showed that GABAA receptors containing the α5 subunit (α5GABAARs) generated the tonic inhibitory current in hippocampal neurons. α5GABAARs are highly sensitive to GABA, desensitize slowly, and are thus well suited for detecting low, persistent, ambient concentrations of GABA in the extracellular space. Interest in α5GABAARs has surged since the PNAS report, driven by their pivotal roles in cognitive processes and their potential as therapeutic targets for treating various neurologic disorders.

Repurposing General Anesthetic Drugs to Treat Depression: A New Frontier for Anesthesiologists in Neuropsychiatric Care.

During the last 100 years, the role of anesthesiologists in psychiatry has focused primarily on facilitating electroconvulsive therapy and mitigating postoperative delirium and other perioperative neurocognitive disorders. The discovery of the rapid and sustained antidepressant properties of ketamine, and early results suggesting that other general anesthetic drugs (including nitrous oxide, propofol, and isoflurane) have antidepressant properties, has positioned anesthesiologists at a new frontier in the treatment of neuropsychiatric disorders. Moreover, shared interest in understanding the biologic underpinnings of anesthetic drugs as psychotropic agents is eroding traditional academic boundaries between anesthesiology and psychiatry. This article presents a brief overview of anesthetic drugs as novel antidepressants and identifies promising future candidates for the treatment of depression. The authors issue a call to action and outline strategies to foster collaborations between anesthesiologists and psychiatrists as they work toward the common goals of repurposing anesthetic drugs as antidepressants and addressing mood disorders in surgical patients.

The evolution and formalization of anesthesia assistant roles across Canada.

PURPOSE: The purpose of this Special Article is to document the evolution of the anesthesia assistant (AA) profession in Canada and summarize AA practice at Canadian institutions as it exists today, five decades after Quebec and 15 years after most other provinces formalized AA practice. SOURCE: Through the Management Committee of the Association of Canadian University Departments of Anesthesia (ACUDA), we conducted a purposeful sampling of all ACUDA chairs or their delegates. We requested the following data: history of AAs becoming a reality in their particular province or region; potential recruitment pools; training programs and curricula; pathway to credentialing; funding, pay, retention, recruitment, and status of union representation; and metrics. PRINCIPAL FINDINGS: Data were provided by 19 institutions in 8 provinces: Newfoundland and Labrador, Nova Scotia, Quebec, Ontario, Manitoba, Saskatchewan, Alberta, and British Columbia. Given the different health care governance structures across the provinces, AA roles vary in terms of its associated technical, clinical, and educational responsibilities. The role of AAs in supporting anesthesia care through equipment maintenance and assistance with airway management, resuscitation, and administration of regional anesthesia seems to be well established, as is their role in providing brief intraoperative relief for anesthesiologists during a stable period of anesthesia. Anesthesia assistant duties continue to evolve, becoming more aligned with the specific institution and less dependent on the supervising anesthesiologist. Apart from the initial metrics collected during the Ontario ACT implementation pilot projects, we are not aware of any formal metrics, current or ongoing, being collected across Canada, related to either patient safety events or perioperative efficiency. CONCLUSIONS: This compilation of pan-Canadian AA data shows diverse models of practice and highlights the value to patients and the health care system as a whole of incorporating these allied professionals into the anesthesia care team (ACT). The present findings allow us to offer suggestions for consideration during discussions of retention, recruitment, program expansion, and cross-country collection of metrics and other data. We conclude by making six recommendations: 1. recognize that implementation of ACTs is a key element in solving the challenge of an increasing surgical backlog; 2. develop, or facilitate the development of, metrics and increase data-sharing nationally to enable health care authorities to better understand the importance of AAs in patient safety and perioperative efficiency; 3. develop and implement funding strategies to lower the barriers to AA training such as hospital-sponsored positions, ongoing salary support, and return-of-service arrangements; 4. ensure that salaries appropriately reflect the increased level of training and added levels of responsibility of certified AAs; 5. develop long-term strategies to ensure stable funding, recruitment and retention, and a better match between the number of AA training positions and the need for newly certified AAs; and 6. engage all stakeholders to acknowledge that AAs, as knowledgeable and specifically trained assistants, not only fulfill their defined clinical role but also contribute significantly to patient safety and clinical efficiency by assuming nondirect patient care tasks.

RéSUMé: OBJECTIF: Le but de cet article spécial est de documenter l'évolution de la profession d'assistant·e en anesthésie (AA) au Canada et de résumer la pratique des AA dans les établissements canadiens telle qu'elle existe aujourd'hui, cinquante ans après que le Québec et quinze ans après que la plupart des autres provinces ont officialisé la pratique des AA. SOURCES: Par l'entremise du Comité de gestion de l'Association canadienne universitaire des départements d'anesthésie (ACUDA), nous avons réalisé un échantillonnage ciblé de tou·tes les président·es de l'ACUDA ou de leurs délégué·es. Nous avons demandé les données suivantes : historique de la concrétisation de la profession d'AA dans leur province ou région; bassins de recrutement potentiels; programmes de formation et programmes d'études; voie d'accès à l'accréditation; financement, rémunération, rétention, recrutement et état de la représentation syndicale; et données métriques. CONSTATATIONS PRINCIPALES: Des données ont été fournies par 19 institutions dans 8 provinces : Terre-Neuve-et-Labrador, Nouvelle-Écosse, Québec, Ontario, Manitoba, Saskatchewan, Alberta et Colombie-Britannique. Compte tenu des différentes structures de gouvernance des soins de santé dans les provinces, les rôles des AA varient en termes de responsabilités techniques, cliniques et éducatives connexes. Le rôle des AA dans le soutien des soins d'anesthésie par l'entretien du matériel et l'aide à la prise en charge des voies aériennes, à la réanimation et à l'administration de l'anesthésie régionale semble bien établi, tout comme leur rôle dans la fourniture d'un bref soulagement peropératoire aux anesthésiologistes pendant une période stable d'anesthésie. Les tâches des assistant·es en anesthésie continuent d'évoluer, devenant plus alignées sur l'établissement spécifique et moins dépendantes de l'anesthésiologiste superviseur·e. À l'exception des mesures initiales recueillies dans le cadre des projets pilotes de mise en œuvre des ESA (équipes de soins en anesthésie) en Ontario, nous ne sommes au courant d'aucune mesure officielle, actuelle ou en cours, recueillie dans l'ensemble du Canada, concernant les événements liés à la sécurité des patient·es ou à l'efficacité périopératoire. CONCLUSION: Cette compilation de données pancanadiennes sur les AA présente divers modèles de pratique et souligne l'importance pour les patient·es et le système de soins de santé dans son ensemble d'intégrer ces professionnel·les connexes à l'équipe de soins d'anesthésie (ESA). Les résultats actuels nous permettent d'avancer des suggestions à prendre en compte lors des discussions sur le maintien en poste, le recrutement, l'expansion des programmes et la collecte de mesures et d'autres données à l'échelle du pays. Nous concluons en formulant six recommandations : 1. reconnaître que la mise en œuvre des ESA constitue un élément clé pour résoudre le problème de l'augmentation de l'arriéré chirurgical; 2. élaborer ou faciliter l'élaboration de mesures et accroître le partage des données à l'échelle nationale pour permettre aux autorités sanitaires de mieux comprendre l'importance des AA pour la sécurité des patient·es et l'efficacité périopératoire; 3. élaborer et mettre en œuvre des stratégies de financement pour réduire les obstacles à la formation des AA, comme les postes parrainés par les hôpitaux, le soutien salarial continu et les ententes de retour de service; 4. veiller à ce que les salaires reflètent de manière appropriée le niveau accru de formation et les niveaux de responsabilité accrus des AA certifié·es; 5. élaborer des stratégies à long terme pour assurer un financement, un recrutement et une rétention stables, ainsi qu'une meilleure adéquation entre le nombre de postes de formation des AA et le besoin de nouveaux et nouvelles AA certifié·es; et 6. inciter toutes les personnes impliquées à reconnaître que les AA, en tant qu'assistant·es compétent·es et spécialement formé·es, non seulement remplissent leur rôle clinique défini, mais contribuent également de manière significative à la sécurité des patient·es et à l'efficacité clinique en assumant des tâches de soins non directs aux patient·es.

Proof-of-concept randomized controlled trial of single-session nitrous oxide treatment for refractory bipolar depression: Focus on cerebrovascular target engagement.

BACKGROUND: There remain few efficacious treatments for bipolar depression, which dominates the course of bipolar disorder (BD). Despite multiple studies reporting associations between depression and cerebral blood flow (CBF), little is known regarding CBF as a treatment target, or predictor and/or indicator of treatment response, in BD. Nitrous oxide, an anesthetic gas with vasoactive and putative antidepressant properties, has a long history as a neuroimaging probe. We undertook an experimental medicine paradigm, coupling in-scanner single-session nitrous oxide treatment of bipolar depression with repeated measures of CBF. METHODS: In this double-blind randomized controlled trial, 25 adults with BD I/II and current treatment-refractory depression received either: (1) nitrous oxide (20 min at 25% concentration) plus intravenous saline (n = 12), or (2) medical air plus intravenous midazolam (2 mg total; n = 13). Study outcomes included changes in depression severity (Montgomery-Asberg Depression Rating Scale scores, primary) and changes in CBF (via arterial spin labeling magnetic resonance imaging). RESULTS: There were no significant between-group differences in 24-h post-treatment MADRS change or treatment response. However, the nitrous oxide group had significantly greater same-day reductions in depression severity. Lower baseline regional CBF predicted greater 24-h post-treatment MADRS reductions with nitrous oxide but not midazolam. In region-of-interest and voxel-wise analyses, there was a pattern of regional CBF reductions following treatment with midazolam versus nitrous oxide. CONCLUSIONS: Present findings, while tentative and based on secondary endpoints, suggest differential associations of nitrous oxide versus midazolam with bipolar depression severity and cerebral hemodynamics. Larger studies integrating neuroimaging targets and repeated nitrous oxide treatment sessions are warranted.

Cognitive deficits after general anaesthesia in animal models: a scoping review.

BACKGROUND: It remains controversial whether general anaesthetic drugs contribute to perioperative neurocognitive disorders in adult patients. Preclinical studies have generated conflicting results, likely because of differing animal models, study protocols, and measured outcomes. This scoping review of preclinical studies addressed the question: 'Do general anaesthetic drugs cause cognitive deficits in adult animals that persist after the drugs have been eliminated from the brain?' METHODS: Reports of preclinical studies in the MEDLINE database published from 1953 to 2021 were examined. A structured review process was used to assess original studies of cognitive behaviours, which were measured after treatment (≥24 h) with commonly used general anaesthetic drugs in adult animals. RESULTS: The initial search yielded 380 articles, of which 106 were fully analysed. The most frequently studied animal model was male (81%; n=86/106) rodents (n=106/106) between 2-3 months or 18-20 months of age. Volatile anaesthetic drugs were more frequently studied than injected drugs, and common outcomes were memory behaviours assessed using the Morris water maze and fear conditioning assays. Cognitive deficits were detected in 77% of studies (n=82/106) and were more frequent in studies of older animals (89%), after inhaled anaesthetics, and longer drug treatments. Limitations of the studies included a lack of physiological monitoring, mortality data, and risk of bias attributable to the absence of randomisation and blinding. CONCLUSIONS: Most studies reported cognitive deficits after general anaesthesia, with age, use of volatile anaesthetic drugs, and duration of anaesthesia as risk factors. Recommendations to improve study design and guide future research are presented.

Effect of inhaled anaesthetics on cognitive and psychiatric outcomes in critically ill adults: a systematic review and meta-analysis.

BACKGROUND: Sedation of critically ill patients with inhaled anaesthetics may reduce lung inflammation, time to extubation, and ICU length of stay compared with intravenous (i.v.) sedatives. However, the impact of inhaled anaesthetics on cognitive and psychiatric outcomes in this population is unclear. In this systematic review, we aimed to summarise the effect of inhaled anaesthetics on cognitive and psychiatric outcomes in critically ill adults. METHODS: We searched MEDLINE, EMBASE, and PsycINFO for case series, retrospective, and prospective studies in critically ill adults sedated with inhaled anaesthetics. Outcomes included delirium, psychomotor and neurological recovery, long-term cognitive dysfunction, ICU memories, anxiety, depression, post-traumatic stress disorder (PTSD), and instruments used for assessment. RESULTS: Thirteen studies were included in distinct populations of post-cardiac arrest survivors (n=4), postoperative noncardiac patients (n=3), postoperative cardiac patients (n=2), and mixed medical-surgical patients (n=4). Eight studies reported delirium incidence, two neurological recovery, and two ICU memories. One study reported on psychomotor recovery, long-term cognitive dysfunction, anxiety, depression, and PTSD. A meta-analysis of five trials found no difference in delirium incidence between inhaled and i.v. sedatives (relative risk 0.95 [95% confidence interval: 0.59-1.54]). Compared with i.v. sedatives, inhaled anaesthetics were associated with fewer hallucinations and faster psychomotor recovery but no differences in other outcomes. There was heterogeneity in the instruments used and timing of these assessments. CONCLUSIONS: Based on the limited evidence available, there is no difference in cognitive and psychiatric outcomes between adults exposed to volatile sedation or intravenous sedation in the ICU. Future studies should incorporate outcome assessment with validated tools during and after hospital stay. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42021236455.

The Impact of Inflammation and General Anesthesia on Memory and Executive Function in Mice.

BACKGROUND: Perioperative neurocognitive disorders (PNDs) are complex, multifactorial conditions that are associated with poor long-term outcomes. Inflammation and exposure to general anesthetic drugs are likely contributing factors; however, the relative impact of each factor alone versus the combination of these factors remains poorly understood. The goal of this study was to compare the relative impact of inflammation, general anesthesia, and the combination of both factors on memory and executive function. METHODS: To induce neuroinflammation at the time of exposure to an anesthetic drug, adult male mice were treated with lipopolysaccharide (LPS) or vehicle. One day later, they were anesthetized with etomidate (or vehicle). Levels of proinflammatory cytokines were measured in the hippocampus and cortex 24 hours after LPS treatment. Recognition memory and executive function were assessed starting 24 hours after anesthesia using the novel object recognition assay and the puzzle box, respectively. Data are expressed as mean (or median) differences (95% confidence interval). RESULTS: LPS induced neuroinflammation, as indicated by elevated levels of proinflammatory cytokines, including interleukin-1ß (LPS versus control, hippocampus: 3.49 pg/mg [2.06-4.92], P < .001; cortex: 2.60 pg/mg [0.83-4.40], P = .010) and tumor necrosis factor-α (hippocampus: 3.50 pg/mg [0.83-11.82], P = .002; cortex: 2.38 pg/mg [0.44-4.31], P = .021). Recognition memory was impaired in mice treated with LPS, as evinced by a lack of preference for the novel object (novel versus familiar: 1.03 seconds [-1.25 to 3.30], P = .689), but not in mice treated with etomidate alone (novel versus familiar: 2.38 seconds [0.15-4.60], P = .031). Mice cotreated with both LPS and etomidate also exhibited memory deficits (novel versus familiar: 1.40 seconds [-0.83 to 3.62], P = .383). In the puzzle box, mice treated with either LPS or etomidate alone showed no deficits. However, the combination of LPS and etomidate caused deficits in problem-solving tasks (door open task: -0.21 seconds [-0.40 to -0.01], P = .037; plug task: -0.30 seconds [-0.50 to -0.10], P < .001; log values versus control), indicating impaired executive function. CONCLUSIONS: Impairments in recognition memory were driven by inflammation. Deficits in executive function were only observed in mice cotreated with LPS and etomidate. Thus, an interplay between inflammation and etomidate anesthesia led to cognitive deficits that were not observed with either factor alone. These findings suggest that inflammation and anesthetic drugs may interact synergistically, or their combination may unmask covert or latent deficits induced by each factor alone, leading to PNDs.

The Physician Anesthesia Workforce in Canada From 1996 to 2018: A Longitudinal Analysis of Health Administrative Data.

BACKGROUND: A robust anesthesia workforce is essential to the provision of safe surgical, obstetrical, and critical care but information describing the physician anesthesia workforce and volume of clinical services delivered in Canada is limited. This study examines the Canadian physician anesthesia workforce, exploring trends in physician characteristics and activity levels over time. Practice patterns of specialist anesthesiologists and family physician anesthetists (FPAs) working in urban and rural communities were of particular interest. METHODS: Physicians who provided anesthesia care between 1996 and 2018 were identified using health administrative data from the Canadian Institute of Health Information (CIHI). In addition, data from the Canadian Post-MD Education Registry (CAPER) were used to characterize physicians pursuing postgraduate anesthesia training (1996-2019). Descriptive analyses of physician demographics, training, location, specialty designations, and volume of clinical services were undertaken. RESULTS: Between 1996 and 2018, the anesthesia workforce grew 1.8-fold to 3681 physicians, including 536 FPAs. Over the same time, nerve block services increased 7-fold, and payments for other anesthesia services increased 5-fold. The average age of the anesthesiology workforce increased by 2.3 years and the annual retirement rate was 3%. The workforce has become more gender balanced but remains predominantly male (73% in 2018). The proportion of physicians who were trained internationally (about 30%; 38% in rural areas) remained stable (and higher than that in the overall physician workforce). FPAs provided most anesthesia care in rural Canada and their attrition rate was generally 2- to 3-fold higher than specialists. Physicians in the rural anesthesia workforce provided anesthesia services more intensively over time. Relatively few FPAs who left the anesthesia workforce entered full retirement and they instead contributed other medical services to their communities. CONCLUSIONS: This study provides foundational information regarding anesthesia workforce capacity over a 22-year period, including insights into demographics, locations of practice, and clinical volumes. The results do not quantify the gap between service capacity and need; however, they support the need for a national workforce strategy to achieve equitable access to sustainable anesthesia services in Canada, particularly for rural communities.

The anesthesia workforce in Canada: a methodology to identify physician anesthesia providers using health administrative data.

BACKGROUND: Safe and timely anesthesia services are an integral component of modern health care systems. There are, however, increasing concerns about the availability of anesthesia services in Canada. Thus, a comprehensive approach to assess the capacity of the anesthesia workforce to provide service is a critical need. Data regarding the anesthesia services provided by specialists and family physicians are available through the Canadian Institute for Health Information (CIHI) but collating the data across delivery jurisdictions has proven challenging. As a result, information related to the activity of physician anesthesia providers is routinely excluded from annual physician workforce reports. Our goal was to develop a novel approach to identifying and characterizing the anesthesia workforce on a pan-Canadian scale. METHODS: The study was approved by the University of Ottawa Office of Research Ethics and Integrity. We developed a methodology to identify physicians who provided anesthesia services in Canada between 1996 and 2018 using data elements from the CIHI National Physician Database. We iteratively consulted with expert advisors and compared the results with Scott's Medical Database, the Canadian Medical Association (CMA) Masterfile, and the College of Family Physicians of Canada membership database. RESULTS: The methodology identified providers of anesthesia services using data elements from the CIHI National Physician Database, including categories of the National Grouping System, specialty designations, activity levels and participation thresholds. Physicians who provided anesthesia services only sporadically and medical residents-in-training were excluded. This methodology produced estimates of anesthesia providers that aligned with other sources. The process we followed was sequential, transparent, and intuitive, and was strengthened by collaboration and iterative consultation with experts and stakeholders. CONCLUSIONS: Using physician activity patterns, this novel methodology allows stakeholders to identify which physician provide anesthesia services in Canada. It is an essential step in developing a pan-Canadian anesthesia workforce strategy that can be used to examine patterns and trends related to the workforce and support evidence-informed workforce decision-making. It also establishes a foundation for assessing the effectiveness of a variety of interventions aimed at optimizing physician anesthesia services in Canada.

Anesthesia and Developing Brains: Unanswered Questions and Proposed Paths Forward.

Anesthetic agents disrupt neurodevelopment in animal models, but evidence in humans is mixed. The morphologic and behavioral changes observed across many species predicted that deficits should be seen in humans, but identifying a phenotype of injury in children has been challenging. It is increasingly clear that in children, a brief or single early anesthetic exposure is not associated with deficits in a range of neurodevelopmental outcomes including broad measures of intelligence. Deficits in other domains including behavior, however, are more consistently reported in humans and also reflect findings from nonhuman primates. The possibility that behavioral deficits are a phenotype, as well as the entire concept of anesthetic neurotoxicity in children, remains a source of intense debate. The purpose of this report is to describe consensus and disagreement among experts, summarize preclinical and clinical evidence, suggest pathways for future clinical research, and compare studies of anesthetic agents to other suspected neurotoxins.

Consensus statement on networks for high-quality rural anesthesia, surgery, and obstetric care in Canada.

OBJECTIVE: To describe the essential components of well-resourced and high-functioning multidisciplinary networks that support high-quality anesthesia, surgery, and maternity care for rural Canadians, delivered as close to home as possible. COMPOSITION OF THE COMMITTEE: A volunteer Writers' Group was drawn from the Society of Obstetricians and Gynaecologists of Canada, the Society of Rural Physicians of Canada, the Royal College of Physicians and Surgeons of Canada, the Canadian Association of General Surgeons, the College of Family Physicians of Canada, and the Association of Canadian University Departments of Anesthesia. METHODS: A collaborative effort over the past several years among the professional stakeholders has culminated in this consensus statement on networked care designed to integrate and support a specialist and non-specialist, urban and rural, anesthesia, surgery, and maternity work force into high-functioning networks based on the best available evidence. REPORT: Surgical and maternity triage needs to be embedded within networks to address the tensions between sustainable regional programs and local access to care. Safety and quality must be demonstrated to be equivalent across similar patients and procedures, regardless of network site. Triage of patients across multiple sites is a quality outcome metric requiring continuous iterative scrutiny. Clinical coaching between rural and regional centres can be helpful in building and sustaining high-functioning networks. Maintenance of quality and the provision of continuing professional development in low-volume settings represent a mutual value proposition. CONCLUSION: The trusting relationships that are foundational to successful networks are built through clinical coaching, continuing professional development, and quality improvement. Currently, a collaborative effort in British Columbia is delivering a provincial program-Rural Surgical Obstetrical Networks-built on the principles and supporting evidence described in this consensus statement.

Anesthesiology: Resetting Our Sights on Long-term Outcomes: The 2020 John W. Severinghaus Lecture on Translational Science.

Anesthesiologists have worked relentlessly to improve intraoperative anesthesia care. They are now well positioned to expand their horizons and address many of the longer-term adverse consequences of anesthesia and surgery. Perioperative neurocognitive disorders, chronic postoperative pain, and opioid misuse are not inevitable adverse outcomes; rather, they are preventable and treatable conditions that deserve attention. The author's research team has investigated why patients experience new cognitive deficits after anesthesia and surgery. Their animal studies have shown that anesthetic drugs trigger overactivity of "memory-blocking receptors" that persists after the drugs are eliminated, and they have discovered new strategies to preserve brain function by repurposing available drugs and developing novel therapeutics that inhibit these receptors. Clinical trials are in progress to examine the cognitive outcomes of such strategies. This work is just one example of how anesthesiologists are advancing science with the goal of improving the lives of patients.

Inhibition of a tonic inhibitory conductance in mouse hippocampal neurones by negative allosteric modulators of α5 subunit-containing γ-aminobutyric acid type A receptors: implications for treating cognitive deficits.

BACKGROUND: Multiple cognitive and psychiatric disorders are associated with an increased tonic inhibitory conductance that is generated by α5 subunit-containing γ-aminobutyric acid type A (α5 GABAA) receptors. Negative allosteric modulators that inhibit α5 GABAA receptors (α5-NAMs) are being developed as treatments for these disorders. The effects of α5-NAMs have been studied on recombinant GABAA receptors expressed in non-neuronal cells; however, no study has compared drug effects on the tonic conductance generated by native GABAA receptors in neurones, which was the goal of this study. METHODS: The effects of five α5-NAMs (basmisanil, Ono-160, L-655,708, α5IA, and MRK-016) on tonic current evoked by a low concentration of GABA were studied using whole-cell recordings in cultured mouse hippocampal neurones. Drug effects on current evoked by a saturating concentration of GABA and on miniature inhibitory postsynaptic currents (mIPSCs) were also examined. RESULTS: The α5-NAMs caused a concentration-dependent decrease in tonic current. The potencies varied as the inhibitory concentration for 50% inhibition (IC50) of basmisanil (127 nM) was significantly higher than those of the other compounds (0.4-0.8 nM). In contrast, the maximal efficacies of the drugs were similar (35.5-51.3% inhibition). The α5-NAMs did not modify current evoked by a saturating GABA concentration or mIPSCs. CONCLUSIONS: Basmisanil was markedly less potent than the other α5-NAMs, an unexpected result based on studies of recombinant α5 GABAA receptors. Studying the effects of α5 GABAA receptor-selective drugs on the tonic inhibitory current in neurones could inform the selection of compounds for future clinical trials.

Inhibiting α5 Subunit-Containing γ-Aminobutyric Acid Type A Receptors Attenuates Cognitive Deficits After Traumatic Brain Injury.

OBJECTIVES: Cognitive deficits after traumatic brain injury are a leading cause of disability worldwide, yet no effective pharmacologic treatments exist to improve cognition. Traumatic brain injury increases proinflammatory cytokines, which trigger excess function of α5 subunit-containing γ-aminobutyric acid type A receptors. In several models of brain injury, drugs that inhibit α5 subunit-containing γ-aminobutyric acid type A receptor function improve cognitive performance. Thus, we postulated that inhibiting α5 subunit-containing γ-aminobutyric acid type A receptors would improve cognitive performance after traumatic brain injury. In addition, because traumatic brain injury reduces long-term potentiation in the hippocampus, a cellular correlate of memory, we studied whether inhibition of α5 subunit-containing γ-aminobutyric acid type A receptors attenuated deficits in long-term potentiation after traumatic brain injury. DESIGN: Experimental animal study. SETTING: Research laboratory. SUBJECTS: Adult male mice and hippocampal brain slices. INTERVENTIONS: Anesthetized mice were subjected to traumatic brain injury with a closed-head, free-weight drop method. One week later, the mice were treated with L-655,708 (0.5 mg/kg), an inhibitor that is selective for α5 subunit-containing γ-aminobutyric acid type A receptors, 30 minutes before undergoing behavioral testing. Problem-solving abilities were assessed using the puzzle box assay, and memory performance was studied with novel object recognition and object place recognition assays. In addition, hippocampal slices were prepared 1 week after traumatic brain injury, and long-term potentiation was studied using field recordings in the cornu Ammonis 1 region of slices that were perfused with L-655,708 (100 nM). MEASUREMENTS AND MAIN RESULTS: Traumatic brain injury increased the time required to solve difficult but not simple tasks in the puzzle box assay and impaired memory in the novel object recognition and object place recognition assays. L-655,708 improved both problem solving and memory in the traumatic brain injury mice. Traumatic brain injury reduced long-term potentiation in the hippocampal slices, and L-655,708 attenuated this reduction. CONCLUSIONS: Pharmacologic inhibition of α5 subunit-containing γ-aminobutyric acid type A receptors attenuated cognitive deficits after traumatic brain injury and enhanced synaptic plasticity in hippocampal slices. Collectively, these results suggest that α5 subunit-containing γ-aminobutyric acid type A receptors are novel targets for pharmacologic treatment of traumatic brain injury-induced persistent cognitive deficits.

GABA promotes ß-cell proliferation, but does not overcome impaired glucose homeostasis associated with diet-induced obesity.

γ-Aminobutyric acid (GABA) administration has been shown to increase ß-cell mass, leading to a reversal of type 1 diabetes in mice. Whether GABA has any effect on ß cells of healthy and prediabetic/glucose-intolerant obese mice remains unknown. In the present study, we show that oral GABA administration ( ad libitum) to mice indeed increased pancreatic ß-cell mass, which led to a modest enhancement in insulin secretion and glucose tolerance. However, GABA treatment did not further increase insulin-positive islet area in high fat diet-fed mice and was unable to prevent or reverse glucose intolerance and insulin resistance. Mechanistically, whether in vivo or in vitro, GABA treatment increased ß-cell proliferation. In vitro, the effect was shown to be mediated via the GABAA receptor. Single-cell RNA sequencing analysis revealed that GABA preferentially up-regulated pathways linked to ß-cell proliferation and simultaneously down-regulated those networks required for other processes, including insulin biosynthesis and metabolism. Interestingly, single-cell differential expression analysis revealed GABA treatment gave rise to a distinct subpopulation of ß cells with a unique transcriptional signature, including urocortin 3 ( ucn3), wnt4, and hepacam2. Taken together, this study provides new mechanistic insight into the proliferative nature of GABA but suggests that ß-cell compensation associated with prediabetes overlaps with, and negates, its proliferative effects.-Untereiner, A., Abdo, S., Bhattacharjee, A., Gohil, H., Pourasgari, F., Ibeh, N., Lai, M., Batchuluun, B., Wong, A., Khuu, N., Liu, Y., Al Rijjal, D., Winegarden, N., Virtanen, C., Orser, B. A., Cabrera, O., Varga, G., Rocheleau, J., Dai, F. F., Wheeler, M. B. GABA promotes ß-cell proliferation, but does not overcome impaired glucose homeostasis associated with diet-induced obesity.

Perioperative Neurocognitive Disorder: State of the Preclinical Science.

The purpose of this article is to provide a succinct summary of the different experimental approaches that have been used in preclinical postoperative cognitive dysfunction research, and an overview of the knowledge that has accrued. This is not intended to be a comprehensive review, but rather is intended to highlight how the many different approaches have contributed to our understanding of postoperative cognitive dysfunction, and to identify knowledge gaps to be filled by further research. The authors have organized this report by the level of experimental and systems complexity, starting with molecular and cellular approaches, then moving to intact invertebrates and vertebrate animal models. In addition, the authors' goal is to improve the quality and consistency of postoperative cognitive dysfunction and perioperative neurocognitive disorder research by promoting optimal study design, enhanced transparency, and "best practices" in experimental design and reporting to increase the likelihood of corroborating results. Thus, the authors conclude with general guidelines for designing, conducting and reporting perioperative neurocognitive disorder rodent research.

Musings from an Unlikely Clinician-Scientist: 2018 American Society of Anesthesiologists Excellence in Research Award.

This article, which stems from the 2018 American Society of Anesthesiologists Excellence in Research Award Lecture, aims to encourage young investigators, offer advice, and share several early life experiences that have influenced the author's career as an anesthesiologist and clinician-scientist. The article also describes key discoveries that have increased understanding of the role of γ-aminobutyric acid type A (GABAA) receptors in health and disease. The author's research team identified the unique pharmacologic properties of extrasynaptic GABAA receptors and their role in the anesthetic state. The author's team also showed that extrasynaptic GABAA receptors expressed in neuronal and nonneuronal cells contribute to a variety of disorders and are novel drug targets. The author's overarching message is that young investigators must create their own unique narratives, train hard, be relentless in their studies and-most important-enjoy the journey of discovering new truths that will ultimately benefit patients.

Improving Access to Safe Anesthetic Care in Rural and Remote Communities in Affluent Countries.

Inadequate access to anesthesia and surgical services is often considered to be a problem of low- and middle-income countries. However, affluent nations, including Canada, Australia, and the United States, also face shortages of anesthesia and surgical care in rural and remote communities. Inadequate services often disproportionately affect indigenous populations. A lack of anesthesia care providers has been identified as a major contributing factor to the shortfall of surgical and obstetrical care in rural and remote areas of these countries. This report summarizes the challenges facing the provision of anesthesia services in rural and remote regions. The current landscape of anesthesia providers and their training is described. We also explore innovative strategies and emerging technologies that could better support physician-led anesthesia care teams working in rural and remote areas. Ultimately, we believe that it is the responsibility of specialist anesthesiologists and academic health sciences centers to facilitate access to high-quality care through partnership with other stakeholders. Professional medical organizations also play an important role in ensuring the quality of care and continuing professional development. Enhanced collaboration between academic anesthesiologists and other stakeholders is required to meet the challenge issued by the World Health Organization to ensure access to essential anesthesia and surgical services for all.