Time is of the essence : Coupling sleep-wake and circadian neurobiology to the antidepressant effects of ketamine

Several studies have demonstrated the effectiveness of ketamine in rapidly alleviating depression and suicidal ideation. Intense research efforts have been undertaken to expose the precise mechanism underlying the antidepressant action of ketamine; however, the translation of findings into new clinical treatments has been slow. This translational gap is partially explained by a lack of understanding of the function of time and circadian timing in the complex neurobiology around ketamine. Indeed, the acute pharmacological effects of a single ketamine treatment last for only a few hours, whereas the antidepressant effects peak at around 24 hours and are sustained for the following few days. Numerous studies have investigated the acute and long-lasting neurobiological changes induced by ketamine; however, the most dramatic and fundamental change that the brain undergoes each day is rarely taken into consideration. Here, we explore the link between sleep and circadian regulation and rapid-acting antidepressant effects and summarize how diverse phenomena associated with ketamine’s antidepressant actions – such as cortical excitation, synaptogenesis, and involved molecular determinants – are intimately connected with the neurobiology of wake, sleep, and circadian rhythms. We review several recently proposed hypotheses about rapid antidepressant actions, which focus on sleep or circadian regulation, and discuss their implications for ongoing research. Considering these aspects may be the last piece of the puzzle necessary to gain a more comprehensive understanding of the effects of rapid-acting antidepressants on the brain.Several studies have demonstrated the effectiveness of ketamine in rapidly alleviating depression and suicidal ideation. Intense research efforts have been undertaken to expose the precise mechanism underlying the antidepressant action of ketamine; however, the translation of findings into new clinical treatments has been slow. This translational gap is partially explained by a lack of understanding of the function of time and circadian timing in the complex neurobiology around ketamine. Indeed, the acute pharmacological effects of a single ketamine treatment last for only a few hours, whereas the antidepressant effects peak at around 24 hours and are sustained for the following few days. Numerous studies have investigated the acute and long-lasting neurobiological changes induced by ketamine; however, the most dramatic and fundamental change that the brain undergoes each day is rarely taken into consideration. Here, we explore the link between sleep and circadian regulation and rapid -acting antidepressant effects and summarize how diverse phenomena associated with ketamine's antidepressant actions - such as cortical excitation, synaptogenesis, and involved molecular determinants - are intimately connected with the neurobiology of wake, sleep, and circadian rhythms. We review several recently proposed hypotheses about rapid antidepressant actions, which focus on sleep or circadian regulation, and discuss their implications for ongoing research. Considering these aspects may be the last piece of the puzzle necessary to gain a more comprehensive understanding of the effects of rapid-acting antidepressants on the brain. (c) 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).Peer reviewe

Linguistic validation of cystic fibrosis quality of life questionnaires

OBJECTIVE: The purpose of this study was to validate the Portuguese translations of four cystic fibrosis quality of life questionnaires (CFQ). The first three were developed for patients with cystic fibrosis aged from 6 to 11 years, from 12 to 13 years and 14 years or more, while the fourth was developed for the parents of patients aged 6 to 13 years. MATERIAL AND METHODS: The four CFQ translations contained from 35 to 50 questions covering nine domains and were validated as follows: translation from English to Portuguese, pilot application, back translation and then approval by the author of the English versions. The four translations were applied to 90 stable patients (30 from each age group) and the parents of patients aged 6-13 years (n = 60), on two occasions with a 13 to 17 day interval. Intraclass Correlation Coefficients (ICC) were used to measure reproducibility. This study was approved by the Commission for Ethics in Research at the institution. RESULTS:Reproducibility was good (ICC = 0.62 to 0.99) for the four translations in all domains, with the exceptions of the Digestion domain for the 6 to 11 and 12 to 13 years age groups with ICC = 0.59 and 0.47, respectively and the Social Role domain for the 14 and over age group (ICC = -0.19 ) CONCLUSION: The translation and cultural adaptation for Brazil resulted in four CFQ versions that are easy to understand and offer good reproducibility.OBJETIVO: O propósito deste estudo foi validar em português as quatro versões de questionários de qualidade de vida em fibrose cística, desenvolvidos para pacientes com fibrose cística de 6 a 11 anos, de 12 a 13 e mais de 14 anos, e para os pais de pacientes de 6 a 13 anos. MATERIAL E MÉTODOS: A validação das quatro versões de questionários de qualidade de vida em fibrose cística (de 35 e 50 questões, abrangendo nove domínios) constou de: versão inglês-português, aplicação-piloto, tradução retrógrada e aprovação da autora da versão inglesa. As quatro versões foram aplicadas a 90 pacientes estáveis (30 de cada grupo etário) e aos pais de doentes de 6-13 anos (n = 60), em duas entrevistas, com intervalo de 13-17 dias. Foi avaliada a reprodutibilidade pelo coeficiente de correlação intraclasse (CCI). O estudo foi aprovado pela comissão de ética em pesquisa da instituição. RESULTADOS: A reprodutibilidade foi boa (CCI = 0,62 a 0,99) para as quatro versões, em todos os domínios, exceto o digestivo (CCI = 0,59 e CCI = 0,47) para os grupos etários de 6 a 11 e 12 a 13 anos, respectivamente, e domínio papel social (CCI = -0,19 ) para o grupo acima de 14 anos. CONCLUSÃO: A tradução e a adaptação à língua e à cultura brasileiras das quatro versões de questionários de qualidade de vida em fibrose cística mostraram-se de fácil entendimento e boa reprodutibilidade.Universidade de São Paulo Faculdade de Medicina Departamento de PediatriaUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de MedicinaFaculdade de Medicina do ABCUNIFESP-EPM Centro de Reabilitação PulmonarUniversidade de São Paulo Faculdade de Medicina Hospital das ClínicasUniversity of Miami Department of PsychologyUNIFESP, EPM, Centro de Reabilitação PulmonarSciEL

Actin/alpha-actinin-dependent transport of AMPA receptors in dendritic spines: role of the PDZ-LIM protein RIL

The efficacy of excitatory transmission in the brain depends to a large extent on synaptic AMPA receptors, hence the importance of understanding the delivery and recycling of the receptors at the synaptic sites. Here we report a novel regulation of the AMPA receptor transport by a PDZ (postsynaptic density-95/Drosophila disc large tumor suppressor zona occludens 1) and LIM (Lin11/rat Isl-1/Mec3) domain-containing protein, RIL (reversion-induced LIM protein). We show that RIL binds to the AMPA glutamate receptor subunit GluR-A C-terminal peptide via its LIM domain and to alpha-actinin via its PDZ domain. RIL is enriched in the postsynaptic density fraction isolated from rat forebrain, strongly localizes to dendritic spines in cultured neurons, and coprecipitates, together with alpha-actinin, in a protein complex isolated by immunoprecipitation of AMPA receptors from forebrain synaptosomes. Functionally, in heterologous cells, RIL links AMPA receptors to the alpha-actinin/actin cytoskeleton, an effect that appears to apply selectively to the endosomal surface-internalized population of the receptors. In cultured neurons, an overexpression of recombinant RIL increases the accumulation of AMPA receptors in dendritic spines, both at the total level, as assessed by immunodetection of endogenous GluR-A-containing receptors, and at the synaptic surface, as assessed by recording of miniature EPSCs. Our results thus indicate that RIL directs the transport of GluR-A-containing AMPA receptors to and/or within dendritic spines, in an alpha-actinin/actin-dependent manner, and that such trafficking function promotes the synaptic accumulation of the receptors

Select Overexpression of Homer1a in Dorsal Hippocampus Impairs Spatial Working Memory

Long Homer proteins forge assemblies of signaling components involved in glutamate receptor signaling in postsynaptic excitatory neurons, including those underlying synaptic transmission and plasticity. The short immediate-early gene (IEG) Homer1a can dynamically uncouple these physical associations by functional competition with long Homer isoforms. To examine the consequences of Homer1a-mediated “uncoupling” for synaptic plasticity and behavior, we generated forebrain-specific tetracycline (tet) controlled expression of Venus-tagged Homer1a (H1aV) in mice. We report that sustained overexpression of H1aV impaired spatial working but not reference memory. Most notably, a similar impairment was observed when H1aV expression was restricted to the dorsal hippocampus (HP), which identifies this structure as the principal cortical area for spatial working memory. Interestingly, H1aV overexpression also abolished maintenance of CA3-CA1 long-term potentiation (LTP). These impairments, generated by sustained high Homer1a levels, identify a requirement for long Homer forms in synaptic plasticity and temporal encoding of spatial memory

Genetically altered AMPA-type glutamate receptor kinetics in interneurons disrupt long-range synchrony of gamma oscillation

Gamma oscillations synchronized between distant neuronal populations may be critical for binding together brain regions devoted to common processing tasks. Network modeling predicts that such synchrony depends in part on the fast time course of excitatory postsynaptic potentials (EPSPs) in interneurons, and that even moderate slowing of this time course will disrupt synchrony. We generated mice with slowed interneuron EPSPs by gene targeting, in which the gene encoding the 67-kDa form of glutamic acid decarboxylase (GAD67) was altered to drive expression of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor subunit GluR-B. GluR-B is a determinant of the relatively slow EPSPs in excitatory neurons and is normally expressed at low levels in γ-aminobutyric acid (GABA)ergic interneurons, but at high levels in the GAD-GluR-B mice. In both wild-type and GAD-GluR-B mice, tetanic stimuli evoked gamma oscillations that were indistinguishable in local field potential recordings. Remarkably, however, oscillation synchrony between spatially separated sites was severely disrupted in the mutant, in association with changes in interneuron firing patterns. The congruence between mouse and model suggests that the rapid time course of AMPA receptor-mediated EPSPs in interneurons might serve to allow gamma oscillations to synchronize over distance

Опыт применения данных дистанционного зондирования Земли при производстве судебных экологических экспертиз

The opportunity of remote sensing Earth data application in performing of environmental forensics is contemplated. Using examples from expert practice, the progress of soil and vegetation mantle examination on the remote sensing materials is analyzed. It is demonstrated that existing methods of data interpretation enable the non-contact reconnaissance of environmental objects on an immense territory signifcantly reducing the time and expense of the expertise. With the help of this method an expert gets an opportunity to perform backcasting of landscape changes and the features of the modern image software make both visual and automated ways of analysis possible. The latest enables subjectivity elimination from interpretation of the images which is essential in getting reasonable expert conclusions.Рассмотрена возможность использования данных дистанционного зондирования Земли при производстве судебно-экологических экспертиз. На примерах из экспертной практики анализируется ход изучения почвенного и растительного покрова по материалам дистанционного зондирования. Показано, что существующие методики их дешифрирования позволяют осуществлять бесконтактное обследование объектов окружающей среды на обширной территории, что существенно сокращает сроки и затраты на производство экспертизы. С помощью данного метода эксперт имеет возможность провести ретроспективный анализ ландшафтных изменений, причем возможности современных программных средств обработки изображений позволяют проводить анализ как визуальным, так и автоматизированным способом. Последний позволяет устранить субъективизм в дешифрировании изображений, что немаловажно для получения обоснованных экспертных выводов

Factors associated with smoking in pregnancy

The aim of this cross-sectional study was to identify factors related to smoking during pregnancy. The sample included 267 puerperae hospitalized in the maternity unit of a university hospital in Porto Alegre/RS. The data were collected through a self-applied instrument and statistically analyzed. The majority of the puerperae (51.3%) were between 18 and 25 years old, 55.4% were nonsmokers, 25.5% were smokers, 19.1% had recently ceased smoking (in abstinence). The nonsmokers had more consultations than the smokers and the abstinent smokers (p=0.025). The number of women who had more than one child was higher among smokers than among nonsmokers and abstinent smokers (p=0.002). Women were more likely to stop smoking before pregnancy when they had a partner who was a nonsmoker (p=0.007). Several factors influence smoking and smoking cessation and these are important in prenatal interventions aimed at pregnant women and their partners

Somatic Accumulation of GluA1-AMPA Receptors Leads to Selective Cognitive Impairments in Mice

© 2018 Bannerman, Borchardt, Jensen, Rozov, Haj-Yasein, Burnashev, Zamanillo, Bus, Grube, Adelmann, Rawlins and Sprengel. The GluA1 subunit of the L-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) plays a crucial, but highly selective, role in cognitive function. Here we analyzed AMPAR expression, AMPAR distribution and spatial learning in mice (Gria1R/R), expressing the “trafficking compromised” GluA1(Q600R) point mutation. Our analysis revealed somatic accumulation and reduction of GluA1(Q600R) and GluA2, but only slightly reduced CA1 synaptic localization in hippocampi of adult Gria1R/R mice. These immunohistological changes were accompanied by a strong reduction of somatic AMPAR currents in CA1, and a reduction of plasticity (short-term and long-term potentiation, STP and LTP, respectively) in the CA1 subfield following tetanic and theta-burst stimulation. Nevertheless, spatial reference memory acquisition in the Morris water-maze and on an appetitive Y-maze task was unaffected in Gria1R/R mice. In contrast, spatial working/short-term memory during both spontaneous and rewarded alternation tasks was dramatically impaired. These findings identify the GluA1(Q600R) mutation as a loss of function mutation that provides independent evidence for the selective role of GluA1 in the expression of short-term memory

Axion searches with the EDELWEISS-II experiment

We present new constraints on the couplings of axions and more generic axion-like particles using data from the EDELWEISS-II experiment. The EDELWEISS experiment, located at the Underground Laboratory of Modane, primarily aims at the direct detection of WIMPs using germanium bolometers. It is also sensitive to the low-energy electron recoils that would be induced by solar or dark matter axions. Using a total exposure of up to 448 kg.d, we searched for axion-induced electron recoils down to 2.5 keV within four scenarios involving different hypotheses on the origin and couplings of axions. We set a 95% CL limit on the coupling to photons $g_{A\gamma}<2.13\times 10^{-9}$ GeV$^{-1}$ in a mass range not fully covered by axion helioscopes. We also constrain the coupling to electrons, $g_{Ae} < 2.56\times 10^{-11}$, similar to the more indirect solar neutrino bound. Finally we place a limit on $g_{Ae}\times g_{AN}^{\rm eff}<4.70 \times 10^{-17}$, where $g_{AN}^{\rm eff}$ is the effective axion-nucleon coupling for $^{57}$Fe. Combining these results we fully exclude the mass range $0.91\,{\rm eV}<m_A<80$ keV for DFSZ axions and $5.73\,{\rm eV}<m_A<40$ keV for KSVZ axions