PAK3 activation promotes the tangential to radial migration switch of cortical interneurons by increasing leading process dynamics and disrupting cell polarity.

Mutations of PAK3, a p21-activated kinase, are associated in humans with cognitive deficits suggestive of defective cortical circuits and with frequent brain structural abnormalities. Most human variants no longer exhibit kinase activity. Since GABAergic interneurons express PAK3 as they migrate within the cortex, we here examined the role of PAK3 kinase activity in the regulation of cortical interneuron migration. During the embryonic development, cortical interneurons migrate a long distance tangentially and then re-orient radially to settle in the cortical plate, where they contribute to cortical circuits. We showed that interneurons expressing a constitutively kinase active PAK3 variant (PAK3-ca) extended shorter leading processes and exhibited unstable polarity. In the upper cortical layers, they entered the cortical plate and extended radially oriented processes. In the deep cortical layers, they exhibited erratic non-processive migration movements and accumulated in the deep pathway. Pharmacological inhibition of PAK3 kinase inhibited the radial migration switch of interneurons to the cortical plate and reduced their accumulation in the deep cortical layers. Interneurons expressing a kinase dead PAK3 variant (PAK3-kd) developed branched leading processes, maintained the same polarity during migration and exhibited processive and tangentially oriented movements in the cortex. These results reveal that PAK3 kinase activity, by promoting leading process shortening and cell polarity changes, inhibits the tangential processive migration of interneurons and favors their radial re- orientation and targeting to the cortical plate. They suggest that patients expressing PAK3 variants with impaired kinase activity likely present alterations in the cortical targeting of their GABAergic interneurons.

The nightmare severity index (NSI): A short new multidimensional tool for assessing nightmares.

This psychometric pilot study aims to evaluate a new multidimensional simple scale, named the nightmare severity index (NSI) - close to the existing insomnia (ISI) and hypersomnia (HSI) severity indexes. The NSI encompasses all main dimensions of nightmare disorder, evaluating four subdimensions: frequency, emotional impact, diurnal impact, and nocturnal impact of nightmares. The NSI was completed by a total of 102 patients. The majority of the population consisted of women (64%) and outpatient individuals (76%) diagnosed with mood disorders such as depression (31%) and bipolar disorder (41%). Comorbidity with post-traumatic stress disorder (PTSD) was prevalent (44%), and psychotropic medications were commonly used (47%). Internal validity analyses indicated that the NSI was well suited for exploratory factor analysis. All items demonstrated satisfactory correlations with the factors, and the questionnaire exhibited good internal consistency (Cronbach's alpha >0.7). Higher NSI scores were observed among individuals experiencing nightmare symptoms considering the DSM-5/ICSD-3 criteria. In summary, the NSI proves to be a promising and valuable tool for clinical practice, demonstrating good acceptability, internal validity, and the ability to assess nightmare severity.

Factors associated with insomnia symptoms: A cross-sectional study during a Covid-19 fully restrictive lockdown.

Insomnia is the most frequent sleep disorder and a public health concern that increased during the Covid 19 pandemic. Fully restrictive lockdowns during Covid are interesting periods to examine the impact of environmental and behavioural changes on the emergence of insomnia symptoms. In this cross-sectional study we aimed to (1) determine the main factors associated with insomnia symptoms during a Covid-19 fully restrictive lockdown examining the associated daily life alterations and (2) create a predictive model of insomnia symptoms. We used the data drawn from the "Covid-RythmE" study that reached volunteers from the general French population through an online survey during the last 2 weeks of the 2 month full lockdown. Associations with insomnia symptoms were tested and significant associations were entered in a Backward Stepwise Logistic Regression (BSLR) to assess the best combination to classify individuals with or without insomnia symptoms. From the 1624 participants, 50.64% suffered from mild to severe insomnia symptoms as assessed by the ISI. The best combination for explaining insomnia symptoms with 74.26% of accuracy included: age (OR = 1.15), females (OR = 1.26), smaller home sizes (OR = 0.77), environmental noises (OR = 1.59), anxiety symptoms (OR = 1.24), depressive symptoms (OR = 1.15), regularity of sleep-wake schedules (OR = 1.25), exposure to screen during the morning (OR = 1.13), and LED light during the evening (OR = 1.17). Thus, lifestyle schedule and exposure to natural synchronizers such as light, are primordial in considering in insomnia physiopathology, prevention and treatment, as well as the associated mental health status.

Continuous positive airway pressure as an accurate marker for non-24-hour sleep-wake rhythm disorder.

Non-24-h sleep-wake rhythm disorder is quite rare in sighted patients and frequently associated with psychiatric disorders. We report the case of a 46-year-old man with autism spectrum disorder (ASD) and agoraphobia who had been referred for a suspicion of obstructive sleep apnea syndrome (OSAS). Polysomnography and arterial blood gas confirmed moderate OSAS associated with hypoventilation. Continuous positive airway pressure (CPAP) was started on fixed mode with excellent results. At follow-up, his CPAP report data revealed an irregular sleep-wake rhythm with a progressive offset of sleep schedule and wake time delayed from 1 h from day to day. Melatonin (or agonist) is efficacious and safe for long-term treatment in ASD and circadian rhythm sleep-wake disorder (CRSWD) with light therapy and wakefulness promoting medication. This case underlines the importance to sensitise psychiatrists to sleep and CRSWD, and also that CPAP data offer a possible objective alternative to sleep diary.

Blood fibrocytes are associated with severity and prognosis in COVID-19 pneumonia.

Increased blood fibrocytes are associated with a poor prognosis in fibrotic lung diseases. We aimed to determine whether the percentage of circulating fibrocytes could be predictive of severity and prognosis during coronavirus disease 2019 (COVID-19) pneumonia. Blood fibrocytes were quantified by flow cytometry as CD45+/CD15-/CD34+/collagen-1+ cells in patients hospitalized for COVID-19 pneumonia. In a subgroup of patients admitted in an intensive care unit (ICU), fibrocytes were quantified in blood and bronchoalveolar lavage (BAL). Serum amyloid P (SAP), transforming growth factor-ß1 (TGF-ß1), CXCL12, CCL2, and FGF2 concentrations were measured. We included 57 patients in the hospitalized group (median age = 59 yr [23-87]) and 16 individuals as healthy controls. The median percentage of circulating fibrocytes was higher in the patients compared with the controls (3.6% [0.2-9.2] vs. 2.1% [0.9-5.1], P = 0.04). Blood fibrocyte count was lower in the six patients who died compared with the survivors (1.6% [0.2-4.4] vs. 3.7% [0.6-9.2], P = 0.02). Initial fibrocyte count was higher in patients showing a complete lung computed tomography (CT) resolution at 3 mo. Circulating fibrocyte count was decreased in the ICU group (0.8% [0.1-2.0]), whereas BAL fibrocyte count was 6.7% (2.2-15.4). Serum SAP and TGF-ß1 concentrations were increased in hospitalized patients. SAP was also increased in ICU patients. CXCL12 and CCL2 were increased in ICU patients and negatively correlated with circulating fibrocyte count. We conclude that circulating fibrocytes were increased in patients hospitalized for COVID-19 pneumonia, and a lower fibrocyte count was associated with an increased risk of death and a slower resolution of lung CT opacities.

YIF1B mutations cause a post-natal neurodevelopmental syndrome associated with Golgi and primary cilium alterations.

Human post-natal neurodevelopmental delay is often associated with cerebral alterations that can lead, by themselves or associated with peripheral deficits, to premature death. Here, we report the clinical features of 10 patients from six independent families with mutations in the autosomal YIF1B gene encoding a ubiquitous protein involved in anterograde traffic from the endoplasmic reticulum to the cell membrane, and in Golgi apparatus morphology. The patients displayed global developmental delay, motor delay, visual deficits with brain MRI evidence of ventricle enlargement, myelination alterations and cerebellar atrophy. A similar profile was observed in the Yif1b knockout (KO) mouse model developed to identify the cellular alterations involved in the clinical defects. In the CNS, mice lacking Yif1b displayed neuronal reduction, altered myelination of the motor cortex, cerebellar atrophy, enlargement of the ventricles, and subcellular alterations of endoplasmic reticulum and Golgi apparatus compartments. Remarkably, although YIF1B was not detected in primary cilia, biallelic YIF1B mutations caused primary cilia abnormalities in skin fibroblasts from both patients and Yif1b-KO mice, and in ciliary architectural components in the Yif1b-KO brain. Consequently, our findings identify YIF1B as an essential gene in early post-natal development in human, and provide a new genetic target that should be tested in patients developing a neurodevelopmental delay during the first year of life. Thus, our work is the first description of a functional deficit linking Golgipathies and ciliopathies, diseases so far associated exclusively to mutations in genes coding for proteins expressed within the primary cilium or related ultrastructures. We therefore propose that these pathologies should be considered as belonging to a larger class of neurodevelopmental diseases depending on proteins involved in the trafficking of proteins towards specific cell membrane compartments.

Key role of the 5-HT1A receptor addressing protein Yif1B in serotonin neurotransmission and SSRI treatment.

Background: Altered function of serotonin receptor 1A (5-HT1AR) has been consistently implicated in anxiety, major depressive disorder and resistance to antidepressants. Mechanisms by which the function of 5-HT1AR (expressed as an autoreceptor in serotonergic raphe neurons and as a heteroreceptor in serotonin [5-HT] projection areas) is altered include regulation of its expression, but 5-HT1AR trafficking may also be involved. Methods: We investigated the consequences of the lack of Yif1B (the 5-HT1AR trafficking protein) on 5-HT neurotransmission in mice, and whether Yif1B expression might be affected under conditions known to alter 5-HT neurotransmission, such as anxious or depressive states or following treatment with fluoxetine (a selective serotonin reuptake inhibitor) in humans, monkeys and mice. Results: Compared with wild-type mice, Yif1B-knockout mice showed a significant decrease in the forebrain density of 5-HT projection fibres and a hypofunctionality of 5-HT1A autoreceptors expressed on raphe 5-HT neurons. In addition, social interaction was less in Yif1B-knockout mice, which did not respond to the antidepressant-like effect of acute fluoxetine injection. In wild-type mice, social defeat was associated with downregulated Yif1B mRNA in the prefrontal cortex, and chronic fluoxetine treatment increased Yif1B expression. The expression of Yif1B was also downregulated in the postmortem prefrontal cortex of people with major depressive disorder and upregulated after chronic treatment with a selective serotonin reuptake inhibitor in monkeys. Limitations: We found sex differences in Yif1B expression in humans and monkeys, but not in mice under the tested conditions. Conclusion: These data support the concept that Yif1B plays a critical role in 5-HT1AR functioning and brain 5-HT homeostasis. The opposite changes in its expression observed in anxious or depressive states and after therapeutic fluoxetine treatment suggest that Yif1B might be involved in vulnerability to anxiety and depression, and fluoxetine efficacy.

Knowledge self-monitoring, efficiency, and determinants of self-confidence statement in multiple choice questions in medical students.

BACKGROUND: Multiple-choice question (MCQ) tests are commonly used to evaluate medical students, but they do not assess self-confidence nor penalize lucky guess or harmful behaviors. Based on a scoring method according to the appropriateness of confidence in answers, the study aimed at assessing knowledge self-monitoring and efficiency, and the determinants of self-confidence. METHODS: A cross-sectional study of 842 s- and third-year medical students who were asked to state their level of confidence (A: very confident, B: moderately confident and C: not confident) during 12 tests (106,806 events). A bonus was applied if the level of confidence matched with the correctness of the answer, and a penalty was applied in the case of inappropriate confidence. RESULTS: Level A was selected more appropriately by the top 20% students whereas level C was selected more appropriately by the lower 20% students. Efficiency of higher-performing students was higher when correct (among correct answers, rate of A statement), but worse when incorrect compared to the bottom 20% students (among incorrect answers, rate of C statement). B and C statements were independently associated with female and male gender, respectively (OR for male vs female = 0.89 [0.82-0.96], p = 0.004, for level B and 1.15 [1.01-1.32], p = 0.047, for level C). CONCLUSION: While both addressing the gender confidence gap, knowledge self-monitoring might improve awareness of students' knowledge whereas efficiency might evaluate appropriate behavior in clinical practice. These results suggest differential feedback during training in higher versus lower-performing students, and potentially harmful behavior in decision-making during clinical practice in higher-performing students.

Yif1B Is Involved in the Anterograde Traffic Pathway and the Golgi Architecture.

Yif1B is an intracellular membrane-bound protein belonging to the Yip family, shown previously to control serotonin 5-HT1A receptor targeting to dendrites. Because some Yip proteins are involved in the intracellular traffic between the ER and the Golgi, here we investigated the precise localization of Yif1B in HeLa cells. We found that Yif1B is not resident into the Golgi, but rather belongs to the IC compartment. After analyzing the role of Yif1B in protein transport, we showed that the traffic of the VSVG protein marker was accelerated in Yif1B depleted HeLa cells, as well as in hippocampal neurons from Yif1B KO mice. Conversely, Yif1B depletion in HeLa cells did not change the retrograde traffic of ShTx. Interestingly, in long term depletion of Yif1B as in Yif1B KO mice, we observed a disorganized Golgi architecture in CA1 pyramidal hippocampal neurons, which was confirmed by electron microscopy. However, because short term depletion of Yif1B did not change Golgi structure, it is likely that the implication of Yif1B in anterograde traffic does not rely on its role in structural organization of the Golgi apparatus, but rather on its shuttling between the ER, the IC and the Golgi compartments.

A New Mechanism of Receptor Targeting by Interaction between Two Classes of Ligand-Gated Ion Channels.

The 5-HT3 receptors are serotonin-gated ion channels that physically couple with purinergic P2X2 receptors to trigger a functional cross-inhibition leading to reciprocal channel occlusion. Although this functional receptor-receptor coupling seems to serve a modulatory role on both channels, this might not be its main physiological purpose. Using primary cultures of rat hippocampal neurons as a quantitative model of polarized targeting, we show here a novel function for this interaction. In this model, 5-HT3A receptors did not exhibit by themselves the capability of distal targeting in dendrites and axons but required the presence of P2X2R for their proper subcellular localization. 5-HT3AR distal targeting occurred with a delayed time course and exhibited a neuron phenotype dependency. In the subpopulation of neurons expressing endogenous P2X2R, 5-HT3AR distal neuritic localization correlated with P2X2R expression and could be selectively inhibited by P2X2R RNA interference. Cotransfection of both receptors revealed a specific colocalization, cotrafficking in common surface clusters, and the axonal rerouting of 5-HT3AR. The physical association between the two receptors was dependent on the second intracellular loop of the 5-HT3A subunit, but not on the P2X2R C-terminal tail that triggers the functional cross-inhibition with the 5-HT3AR. Together, these data establish that 5-HT3AR distal targeting in axons and dendrites primarily depends on P2X2R expression. Because several P2XR have now been shown to functionally interact with several other members of the 4-TMD family of receptor channels, we propose to reconsider the real functional role for this receptor family, as trafficking partner proteins dynamically involved in other receptors targeting. SIGNIFICANCE STATEMENT: So far, receptor targeting mechanisms were found to involve intracellular partner proteins or supramolecular complexes that couple receptors to cytoskeletal elements and recruit them into cargo vesicles. In this paper, we describe a new trafficking mechanism for the neuronal serotonin 5-HT3A ionotropic channel receptor, in which the role of routing partner is endowed by a functionally interacting purinergic receptor: the P2X2 receptor. This work not only unveils the mechanism by which 5-HT3 receptors can reach their axonal localization required for the control of neurotransmitter release, but also suggests that, in addition to their modulatory role, the family of P2X receptors could have a previously undescribed functional role of trafficking partner proteins dynamically involved in the targeting of other receptors.

Clinical characteristics, functional respiratory decline and follow-up in adult patients with primary ciliary dyskinesia.

INTRODUCTION: Primary ciliary dyskinesia (PCD) is a genetic disease characterised by abnormalities in ciliary function, responsible for chronic pulmonary and sinonasal diseases. Adult clinical features and outcome are poorly described. OBJECTIVES: To assess the clinical characteristics and disease progression in adults with PCD. METHODS: Bicentric retrospective study, focusing on adults (≥18 years) with an asserted diagnosis of PCD based on the presence of bronchiectasis with typical ultrastructural defect of cilia and/or situs inversus (SI). Clinical symptoms, respiratory function, extent of bronchiectasis, microbiology and molecular analysis were assessed. Results are expressed as median (25th; 75th centile). RESULTS: 78 patients were included with a median follow-up of 8.1 years. 91% of patients had respiratory symptoms and 95% had chronic rhinosinusitis. Half of ultrastructural defects concerned dynein arms. Respiratory function was significantly lower in women (FEV1=60% predicted (50; 76), vs 77% (62; 95), p=0.009) and in patients with chronic airway Pseudomonas aeruginosa (PA, n=21) infection (FEV1=60% (48; 71) vs 75% (55; 89), p=0.04). FEV1 was associated with gender (regression coefficient for men =13.8, p=0.009), chest CT score (r=-0.42, p<0.001) but not with age at diagnosis, SI or body mass index. FEV1 decline was -13.4 mL/year (-42.8; +11.9) and was greater in women (-29.3 mL/year, (-59.7; -11.9), vs -2.0 mL/year (-26.9; +25.4), p=0.002). Three patients had severe respiratory failure. CONCLUSIONS: Alteration of respiratory function in adults with PCD is heterogeneous and usually moderate but appears more severe in women and in patients with chronic PA infection. Only 4% of patients develop chronic respiratory failure.

Bacteria-driven peribronchial lymphoid neogenesis in bronchiectasis and cystic fibrosis.

We aimed to characterise lymphoid neogenesis in bronchiectasis and cystic fibrosis (CF) lungs and to examine the role of bacterial infection.Lymphoid aggregates were examined using immunohistochemical staining and morphometric analysis in surgical lung sections obtained from nonsmokers and patients with bronchiectasis or CF. Sterile, Pseudomonas aeruginosa- or Staphylococcus aureus-coated agarose beads were instilled intratracheally in mice. Kinetics of lymphoid neogenesis and chemokine expression were examined over 14 days.Lymphoid aggregates were scarce in human lungs of nonsmokers, but numerous peribronchial lymphoid aggregates containing B-lymphocytes, T-lymphocytes, germinal centres and high endothelial venules were found in bronchiectasis and CF. Mouse lungs contained no lymphoid aggregate at baseline. During persistent P. aeruginosa or S. aureus airway infection peribronchial lymphoid neogenesis occurred. At day 14 after instillation, lymphoid aggregates expressed markers of tertiary lymphoid organs and the chemokines CXCL12 and CXCL13. The airway epithelium was an important site of CXCL12, CXCL13 and interleukin-17A expression, which began at day 1 after instillation.Peribronchial tertiary lymphoid organs are present in bronchiectasis and in CF, and persistent bacterial infection triggered peribronchial lymphoid neogenesis in mice. Peribronchial localisation of tertiary lymphoid organs and epithelial expression of chemokines suggest roles for airway epithelium in lymphoid neogenesis.

Neuronal phenotype dependency of agonist-induced internalization of the 5-HT(1A) serotonin receptor.

Selective serotonin reuptake inhibitors (SSRI) are aimed at increasing brain 5-HT tone; however, this expected effect has a slow onset after starting SSRI treatment because of initial activation of 5-HT(1A) autoreceptor-mediated negative feedback of 5-HT release. After chronic SSRI treatment, 5-HT(1A) autoreceptors desensitize, which allows 5-HT tone elevation. Because 5-HT(1A) receptor (5-HT(1A)R) internalization has been proposed as a possible mechanism underlying 5-HT(1A) autoreceptor desensitization, we examined whether this receptor could internalize under well controlled in vitro conditions in the LLC-CPK1 cell line and in raphe or hippocampal neurons from rat embryos. To this goal, cells were transfected with recombinant lentiviral vectors encoding N-terminal tagged 5-HT(1A)R, and exposed to various pharmacological conditions. Constitutive endocytosis and plasma membrane recycling of tagged-5-HT(1A)R was observed in LLC-PK1 cells as well as in neurons. Acute exposure (for 1 h) to the full 5-HT(1A)R agonists, 5-HT and 5-carboxamido-tryptamine, but not the partial agonist 8-OH-DPAT, triggered internalization of tagged 5-HT(1A)R in serotonergic neurons only. In contrast, sustained exposure (for 24 h) to all agonists induced tagged-5-HT(1A)R endocytosis in raphe serotonergic neurons and a portion of hippocampal neurons, but not LLC-PK1 cells and partial agonist displayed an effect only in serotonergic neurons. In all cases, agonist-induced tagged 5-HT(1A)R endocytosis was prevented by the 5-HT(1A)R antagonist, WAY-100635, which was inactive on its own. These data showed that agonist-induced 5-HT(1A)R internalization does exist in neurons and depends on agonist efficacy and neuronal phenotype. Its differential occurrence in serotonergic neurons supports the idea that 5-HT(1A)R internalization might underlie 5-HT(1A) autoreceptor desensitization under SSRI antidepressant therapy.

Images: "Too much heat for my non-24-hour sleep-wake disorder!" A case report.

The non-24-hour sleep-wake disorder (N24SWD) is a rare condition, sometimes associated with blindness or with suprachiasmatic nuclei lesions, resulting in a free-running rhythm or hypernycthemeral syndrome. Synchronizers, such as light, when light perception remains, melatonin, food intakes, physical activity, social interactions, and temperature, play a key role in the treatment of N24SWD. In this report, we describe a case illustrating the impact of outdoor temperature in a 34-year-old man with N24SWD effectively treated through a combination of chronotherapy interventions. During 3 consecutive heat waves, he experienced a recurrence of his natural 25.5-hour free-running rhythm, with a consistent bedtime phase delay caused by temperature, resulting in the discontinuation of chronotherapy. After these heat waves, he was able again to resynchronize his rhythms with the combination of chronotherapeutics. This case report highlights that patients with N24SWD may be particularly at risk of relapse during heat waves, with direct implications for monitoring and reinforcing chronotherapies. CITATION: Garrivet J, d'Ortho M-P, Frija-Masson J, et al. "Too much heat for my non-24-hour sleep-wake disorder!" A case report. J Clin Sleep Med. 2024;20(2):329-333.

Major depressive disorder with hypersomnolence complaint: A comparison study with non-depressed individuals examining objective biomarkers.

BACKGROUND: Hypersomnolence is common in major depressive disorder (MDD), associated with more severe episodes, suicide and antidepressant resistance. Nevertheless, few studies used polysomnography (PSG) and multiple sleep latency test (MSLT) to characterize these patients. In this context, we compared patients visiting a sleep center for hypersomnolence complaint with MDD (HSC/MDD+) and without MDD (HSC/MDD-). METHODS: HSC/MDD+ and HSC/MDD- groups were defined according to DSM-5 criteria and CES-D scale, and had a 30 h-PSG with ad libitum-sleep and PSG followed by MLST. RESULTS: HSC/MDD+ had an increased self-declared total sleep time (sTST) of about 10 h30 similar to HSC/MDD- (630.8 ± 17.3 min-vs-616.5 ± 18.1 min, respectively, p = 0.39). Nevertheless, their objective TST (oTST) on ad libitum PSG was significantly longer and about 10 h50 (648.6 ± 23.9 min-vs-587.4 ± 19.0 min, respectively, p = 0.038). HSC/MDD+ also significantly better estimated their sleep duration, with a lower difference between their sTST and oTST compared to HSC/MDD- (10.0 ± 1.7 %-vs-17.4 ± 2.1 %, respectively, p = 0.009) and confirmed significantly more frequently the hypersomnia diagnosis -i.e. oTST>10H- (82.6 ± 8.1 %-vs-54.6 ± 10.9 %, respectively, p = 0.046). Using the Kupfer index (KI), we confirmed a reduced REM sleep latency in patients MDD/HSC+ (15.2 ± 10.0 %-vs-2.3 ± 2.3 %, respectively, p = 0.039). Both groups had comparable increased diurnal sleepiness assessed with the Epworth scale (14.1 ± 1.1-vs-14.8 ± 1.1, respectively, p = 0.65). HSC/MDD+ had less MSLT sleep latency <8 min (9.1 ± 5.1 %-vs-27.3 ± 6.8 %, respectively, p = 0.048). LIMITATIONS: Retrospective cross-sectional study. CONCLUSIONS: HSC/MDD+ accurately estimated their sleep duration, objectively confirmed hypersomnia and may specifically had a decreased Kupfer index.

A new vesicular scaffolding complex mediates the G-protein-coupled 5-HT1A receptor targeting to neuronal dendrites.

Although essential for their neuronal function, the molecular mechanisms underlying the dendritic targeting of serotonin G-protein-coupled receptors are poorly understood. Here, we characterized a Yif1B-dependent vesicular scaffolding complex mediating the intracellular traffic of the rat 5-HT(1A) receptor (5-HT(1A)R) toward dendrites. By combining directed mutagenesis, GST-pull down, and surface plasmon resonance, we identified a tribasic motif in the C-tail of the 5-HT(1A)R on which Yif1B binds directly with high affinity (K(D) ≈ 37 nM). Moreover, we identified Yip1A, Rab6, and Kif5B as new partners of the 5-HT(1A)R/Yif1B complex, and showed that their expression in neurons is also crucial for the dendritic targeting of the 5-HT(1A)R. Live videomicroscopy revealed that 5-HT(1A)R, Yif1B, Yip1A, and Rab6 traffic in vesicles exiting the soma toward the dendritic tree, and also exhibit bidirectional motions, sustaining their role in 5-HT(1A)R dendritic targeting. Hence, we propose a new trafficking pathway model in which Yif1B is the scaffold protein recruiting the 5-HT(1A)R in a complex including Yip1A and Rab6, with Kif5B and dynein as two opposite molecular motors coordinating the traffic of vesicles along dendritic microtubules. This targeting pathway opens new insights for G-protein-coupled receptors trafficking in neurons.

Effects of smoking on sleep architecture and ventilatory parameters including apneas: Results of the Tab-OSA study.

Background: The interaction between smoking and sleep seems appears to be bidirectional, but few studies evaluated the impact of smoking and its cessation on objective sleep parameters. In this context, this new study aimed to assess the impact of smoking and its cessation on sleep architecture and on ventilatory sleep parameters, particularly the presence of sleep apnea syndrome (apnea-hypopnea index (AHI)≥15). Methods: Patients hospitalized for polysomnographic sleep exploration were compared according to their smoking status: active smokers (AS), former smokers (FS), non-smokers (NoNi). Psychiatric and non-psychiatric co-morbidities and treatment or substance use were taken into account in the analyses. Results: A total of 170 participants were included (N = 37 FS, 39 AS, 86 NoNi). A significant decrease in the mean nocturnal O2 saturation was observed for FS and AS compared to NoNi. No differences were found regarding AHI. Regarding sleep architecture, we observed a significant decrease in the slow wave sleep duration for AS compared to NoNi, and interestingly not between FS and NoNi. Conclusion: This study suggests that current smokers suffer from alterations in both sleep architecture and ventilatory parameters, the later appears to persist even after smoking cessation.

Effect of lockdown on sleep-wake rhythm and alcohol use.

The global covid-19 pandemic has imposed radical changes in daily lives. This study reflects upon sociodemographic and clinical characteristics (sleep-wake rhythm, psychiatric symptoms, and alcohol use behavior) during the full lockdown, comparing individuals who increased their alcohol use (iAU), those who maintained a stable use (sAU), and those who did not consume alcohol (AnoU). Participants were recruited via e-mails and they were required to complete an online survey that included questionnaires, during the last week of the full lockdown. The iAU group, compared to the sAU group, presented more disturbed sleep (PSQI; p < .001), more severe insomnia (ISI; p < .001), shorter sleep duration (p < .001), longer sleep latency (p < .001), and less regular sleep-wake schedules (p = .005). They also reported more anxiety (HAD-A; p = .009), more depressive symptoms (HAD-D: p = .006) and more psychotraumatic symptoms (PCL-5: p = .018). Moreover, the sAU group, compared to AnoU, showed better quality of sleep (PSQI; p = .002) and less severe anxiety symptoms (HAD-A; p = .014). Maintaining a stable use was also related to a better quality of life associated with bigger homes with more frequent outdoors living spaces and higher monthly incomes. Individuals who increased their alcohol consumption during the Covid-19 lockdown exhibited more sleep and circadian rhythm disturbances, as well as more (severe) psychiatric symptoms.