CPT1C is required for synaptic plasticity and oscillatory activity that supports motor, associative and non-associative learning.

Carnitine palmitoyltransferase 1c (CPT1C) is a neuron-specific protein widely distributed throughout the CNS and highly expressed in discrete brain areas including the hypothalamus, hippocampus, amygdala and different motor regions. Its deficiency has recently been shown to disrupt dendritic spine maturation and AMPA receptor synthesis and trafficking in the hippocampus, but its contribution to synaptic plasticity and cognitive learning and memory processes remains mostly unknown. Here, we aimed to explore the molecular, synaptic, neural network and behavioural role of CPT1C in cognition-related functions by using CPT1C knockout (KO) mice. CPT1C-deficient mice showed extensive learning and memory deficits. The CPT1C KO animals exhibited impaired motor and instrumental learning that seemed to be related, in part, to locomotor deficits and muscle weakness but not to mood alterations. In addition, CPT1C KO mice showed detrimental hippocampus-dependent spatial and habituation memory, most probably attributable to inefficient dendritic spine maturation, impairments in long-term plasticity at the CA3-CA1 synapse and aberrant cortical oscillatory activity. In conclusion, our results reveal that CPT1C is not only crucial for motor function, coordination and energy homeostasis, but also has a crucial role in the maintenance of learning and memory cognitive functions. KEY POINTS: CPT1C, a neuron-specific interactor protein involved in AMPA receptor synthesis and trafficking, was found to be highly expressed in the hippocampus, amygdala and various motor regions. CPT1C-deficient animals exhibited energy deficits and impaired locomotion, but no mood changes were found. CPT1C deficiency disrupts hippocampal dendritic spine maturation and long-term synaptic plasticity and reduces cortical γ oscillations. CPT1C was found to be crucial for motor, associative and non-associative learning and memory.

G-Protein-Gated Inwardly Rectifying Potassium (Kir3/GIRK) Channels Govern Synaptic Plasticity That Supports Hippocampal-Dependent Cognitive Functions in Male Mice.

The G-protein-gated inwardly rectifying potassium (Kir3/GIRK) channel is the effector of many G-protein-coupled receptors (GPCRs). Its dysfunction has been linked to the pathophysiology of Down syndrome, Alzheimer's and Parkinson's diseases, psychiatric disorders, epilepsy, drug addiction, or alcoholism. In the hippocampus, GIRK channels decrease excitability of the cells and contribute to resting membrane potential and inhibitory neurotransmission. Here, to elucidate the role of GIRK channels activity in the maintenance of hippocampal-dependent cognitive functions, their involvement in controlling neuronal excitability at different levels of complexity was examined in C57BL/6 male mice. For that purpose, GIRK activity in the dorsal hippocampus CA3-CA1 synapse was pharmacologically modulated by two drugs: ML297, a GIRK channel opener, and Tertiapin-Q (TQ), a GIRK channel blocker. Ex vivo, using dorsal hippocampal slices, we studied the effect of pharmacological GIRK modulation on synaptic plasticity processes induced in CA1 by Schaffer collateral stimulation. In vivo, we performed acute intracerebroventricular (i.c.v.) injections of the two GIRK modulators to study their contribution to electrophysiological properties and synaptic plasticity of dorsal hippocampal CA3-CA1 synapse, and to learning and memory capabilities during hippocampal-dependent tasks. We found that pharmacological disruption of GIRK channel activity by i.c.v. injections, causing either function gain or function loss, induced learning and memory deficits by a mechanism involving neural excitability impairments and alterations in the induction and maintenance of long-term synaptic plasticity processes. These results support the contention that an accurate control of GIRK activity must take place in the hippocampus to sustain cognitive functions.SIGNIFICANCE STATEMENT Cognitive processes of learning and memory that rely on hippocampal synaptic plasticity processes are critically ruled by a finely tuned neural excitability. G-protein-gated inwardly rectifying K+ (GIRK) channels play a key role in maintaining resting membrane potential, cell excitability and inhibitory neurotransmission. Here, we demonstrate that modulation of GIRK channels activity, causing either function gain or function loss, transforms high-frequency stimulation (HFS)-induced long-term potentiation (LTP) into long-term depression (LTD), inducing deficits in hippocampal-dependent learning and memory. Together, our data show a crucial GIRK-activity-mediated mechanism that governs synaptic plasticity direction and modulates subsequent hippocampal-dependent cognitive functions.

Spatial Memory Training Counteracts Hippocampal GIRK Channel Decrease in the Transgenic APPSw,Ind J9 Alzheimer's Disease Mouse Model.

G-protein-gated inwardly rectifying potassium (GIRK) channels are critical determinants of neuronal excitability. They have been proposed as potential targets to restore excitatory/inhibitory balance in acute amyloidosis models, where hyperexcitability is a hallmark. However, the role of GIRK signaling in transgenic mice models of Alzheimer's disease (AD) is largely unknown. Here, we study whether progressive amyloid-ß (Aß) accumulation in the hippocampus during aging alters GIRK channel expression in mutant ß-amyloid precursor protein (APPSw,Ind J9) transgenic AD mice. Additionally, we examine the impact of spatial memory training in a hippocampal-dependent task, on protein expression of GIRK subunits and Regulator of G-protein signaling 7 (RGS7) in the hippocampus of APPSw,Ind J9 mice. Firstly, we found a reduction in GIRK2 expression (the main neuronal GIRK channels subunit) in the hippocampus of 6-month-old APPSw,Ind J9 mice. Moreover, we found an aging effect on GIRK2 and GIRK3 subunits in both wild type (WT) and APPSw,Ind J9 mice. Finally, when 6-month-old animals were challenged to a spatial memory training, GIRK2 expression in the APPSw,Ind J9 mice were normalized to WT levels. Together, our results support the evidence that GIRK2 could account for the excitatory/inhibitory neurotransmission imbalance found in AD models, and training in a cognitive hippocampal dependent task may have therapeutic benefits of reversing this effect and lessen early AD deficits.

Recognition Memory Induces Natural LTP-like Hippocampal Synaptic Excitation and Inhibition.

Synaptic plasticity is a cellular process involved in learning and memory by which specific patterns of neural activity adapt the synaptic strength and efficacy of the synaptic transmission. Its induction is governed by fine tuning between excitatory/inhibitory synaptic transmission. In experimental conditions, synaptic plasticity can be artificially evoked at hippocampal CA1 pyramidal neurons by repeated stimulation of Schaffer collaterals. However, long-lasting synaptic modifications studies during memory formation in physiological conditions in freely moving animals are very scarce. Here, to study synaptic plasticity phenomena during recognition memory in the dorsal hippocampus, field postsynaptic potentials (fPSPs) evoked at the CA3-CA1 synapse were recorded in freely moving mice during object-recognition task performance. Paired pulse stimuli were applied to Schaffer collaterals at the moment that the animal explored a new or a familiar object along different phases of the test. Stimulation evoked a complex synaptic response composed of an ionotropic excitatory glutamatergic fEPSP, followed by two inhibitory responses, an ionotropic, GABAA-mediated fIPSP and a metabotropic, G-protein-gated inwardly rectifying potassium (GirK) channel-mediated fIPSP. Our data showed the induction of LTP-like enhancements for both the glutamatergic and GirK-dependent components of the dorsal hippocampal CA3-CA1 synapse during the exploration of novel but not familiar objects. These results support the contention that synaptic plasticity processes that underlie hippocampal-dependent memory are sustained by fine tuning mechanisms that control excitatory and inhibitory neurotransmission balance.

Hippocampal long-term synaptic depression and memory deficits induced in early amyloidopathy are prevented by enhancing G-protein-gated inwardly rectifying potassium channel activity.

Hippocampal synaptic plasticity disruption by amyloid-ß (Aß) peptides + thought to be responsible for learning and memory impairments in Alzheimer's disease (AD) early stage. Failures in neuronal excitability maintenance seems to be an underlying mechanism. G-protein-gated inwardly rectifying potassium (GirK) channels control neural excitability by hyperpolarization in response to many G-protein-coupled receptors activation. Here, in early in vitro and in vivo amyloidosis mouse models, we study whether GirK channels take part of the hippocampal synaptic plasticity impairments generated by Aß1-42 . In vitro electrophysiological recordings from slices showed that Aß1-42 alters synaptic plasticity by switching high-frequency stimulation (HFS) induced long-term potentiation (LTP) to long-term depression (LTD), which led to in vivo hippocampal-dependent memory deficits. Remarkably, selective pharmacological activation of GirK channels with ML297 rescued both HFS-induced LTP and habituation memory from Aß1-42 action. Moreover, when GirK channels were specifically blocked by Tertiapin-Q, their activation with ML297 failed to rescue LTP from the HFS-dependent LTD induced by Aß1-42 . On the other hand, the molecular analysis of the recorded slices by western blot showed that the expression of GIRK1/2 subunits, which form the prototypical GirK channel in the hippocampus, was not significantly regulated by Aß1-42 . However, immunohistochemical examination of our in vivo amyloidosis model showed Aß1-42 to down-regulate hippocampal GIRK1 subunit expression. Together, our results describe an Aß-mediated deleterious synaptic mechanism that modifies the induction threshold for hippocampal LTP/LTD and underlies memory alterations observed in amyloidosis models. In this scenario, GirK activation assures memory formation by preventing the transformation of HFS-induced LTP into LTD.

Role of GirK Channels in Long-Term Potentiation of Synaptic Inhibition in an In Vivo Mouse Model of Early Amyloid-ß Pathology.

Imbalances of excitatory/inhibitory synaptic transmission occur early in the pathogenesis of Alzheimer's disease (AD), leading to hippocampal hyperexcitability and causing synaptic, network, and cognitive dysfunctions. G-protein-gated potassium (GirK) channels play a key role in the control of neuronal excitability, contributing to inhibitory signaling. Here, we evaluate the relationship between GirK channel activity and inhibitory hippocampal functionality in vivo. In a non-transgenic mouse model of AD, field postsynaptic potentials (fPSPs) from the CA3⁻CA1 synapse in the dorsal hippocampus were recorded in freely moving mice. Intracerebroventricular (ICV) injections of amyloid-ß (Aß) or GirK channel modulators impaired ionotropic (GABAA-mediated fPSPs) and metabotropic (GirK-mediated fPSPs) inhibitory signaling and disrupted the potentiation of synaptic inhibition. However, the activation of GirK channels prevented Aß-induced changes in GABAA components. Our data shows, for the first time, the presence of long-term potentiation (LTP) for both the GABAA and GirK-mediated inhibitory postsynaptic responses in vivo. In addition, our results support the importance of an accurate level of GirK-dependent signaling for dorsal hippocampal performance in early amyloid pathology models by controlling the excess of excitation that disrupts synaptic plasticity processes.

Systematic review and meta analysis of cross immunity and the smokers paradox in COVID19.

COVID-19 pandemic, caused by the novel SARS-CoV-2 virus, has raised significant interest in understanding potential cross-immunity mechanisms. Recent evidence suggests that T-cells associated with common cold coronaviruses (229E, NL63, OC43, HKU1) may provide some level of cross-immunity against SARS-CoV-2. It is also known that the prevalence of smokers among patients admitted to hospital for COVID-19 is lower than expected according to the corresponding country's smoking prevalence, which is known as smoker's paradox in COVID-19. No clear consensus to explain it has yet been reached. This phenomenon suggests a complex interaction between smoking and immune response. Nonetheless, very few works have studied the prevalence of smokers in those infected by common cold coronaviruses, and its relation to COVID-19 has not been investigated. We performed a systematic review and meta-analysis to study the prevalence of smokers among patients infected by common cold coronaviruses, and to compare them to the corresponding country's smoking prevalence. L'Abbé plots were used to visually assess the consistency of the observed effects across the different studies included in the meta-analysis. Additionally, significant differences were found in smoking prevalence among the various types of ccCoV, indicating the need for further research into the biological mechanisms driving these disparities. The results show that smoking prevalence is higher among those patients infected by these coronaviruses than in the general population (OR = 1.37, 95% CI: 0.81-2.33). A study was separately done for the four coronavirus types, and the prevalence of smokers was higher in three of the four than that corresponding to country, gender and study year: OC43 (OR = 1.93, 95% CI: 0.64-5.82); HKU1 (OR = 3.62, 95% CI: 1.21-10.85); NL63 (OR = 1.93, 95% CI: 0.64-5.82); 229E (OR = 0.97, 95% CI: 0.50-1.90). The heterogeneity of the studies was assessed using the Cochrane Chi-squared test, I-squared (I2), and Tau-squared (τ2). This detailed statistical analysis enhances the robustness of our findings and highlights the variations in smoking prevalence among different ccCoVs. Our data suggest that COVID-19 might be less prevalent among smokers due to greater cross-immunity from a larger number or more recent infections by common cold coronaviruses than the non-smoking population, which would explain smoker's paradox in COVID-19. IMPLICATIONS. The low prevalence of current smokers among SARS-CoV-2 patients is a finding recurrently repeated, even leading to postulate the "smoker's paradox" in COVID-19. This fact compelled us to study the prevalence of smokers among patients infected by common cold coronaviruses, and to compare them to the corresponding country's smoking prevalence. Our data could explain smoker's paradox in COVID-19 by a greater cross immunity due to a larger number, or more recent infections by common cold coronaviruses than the non-smoking population. This manuscript allow understand potential unrevealed mechanism for low prevalence of current smokers among SARS-CoV-2 patients.

Factors associated with the effectiveness of high-flow therapy in patients with acute hypoxemic respiratory failure: An observational study.

BACKWARD: The COVID-19 pandemic has severely tested global health systems. Non-invasive respiratory support, especially combining high-flow nasal cannula (HFNC) and continuous positive airway pressure, has effectively treated COVID-19 induced Acute Hypoxemic Respiratory Failure and reduced mortality. However, HFNC alone is more comfortable, better tolerated, and less costly than non-invasive ventilation. Understanding which patients benefit from HFNC monotherapy versus combined therapies is essential. METHODS: This observational study included patients admitted to the intermediate respiratory care unit of a COVID-19 hospital between December 2020 and September 2021. All patients treated with HFNC were included (n = 1301). HFNC failure was defined as the need for escalated therapy (non-invasive ventilation, intubation) or death. Epidemiological, clinical, non-invasive respiratory support parameters, and laboratory data were collected, and a multivariable analysis identified key determinants. RESULTS: HFNC was successful in 39.9 % of patients. (n = 511) Risk factors for HFNC failure included increased age, male gender, obesity, obstructive sleep apnea, higher respiratory rate, initial SpO2/FiO2 ≤ 148, and initial PaO2/FiO2 ≤ 100. An increase in the ROX Index at 24 h and slower disease progression were associated with successful treatment. These findings led to the developmet of an index to identify patients who benefit most from HFNC monotherapy. CONCLUSIONS: HFNC monotherapy can be effective for a specific profile of patients with Acute Hypoxemic Respiratory Failure due to COVID-19. This tool may help manage these patients more appropriately. Further studies are needed to determine if these findings can be applied to Acute Hypoxemic Respiratory Failure caused by other pathologies. IMPLICATIONS FOR CLINICAL PRACTICE: This study underscores the importance of early identification and management of patients at risk of HFNC failure in intermediate respiratory care units. By recognizing factors such as age, comorbidities, and respiratory indices, healthcare providers can implement targeted strategies to enhance HFNC success. These strategies may include more stringent monitoring, tailored respiratory support, and timely escalation to more intensive therapies if needed. Our findings highlight the need for a comprehensive approach to managing severe respiratory failure in critical care settings, ultimately improving patient outcomes and reducing the burden on healthcare systems.

BETA-HYDROXYBUTYRATE COUNTERACTS THE DELETERIOUS EFFECTS OF A SATURATED HIGH-FAT DIET ON SYNAPTIC AMPA RECEPTORS AND COGNITIVE PERFORMANCE.

The ketogenic diet, characterized by high fat and low carbohydrates, has gained popularity not only as a strategy for managing body weight but also for its efficacy in delaying cognitive decline associated with neurodegenerative diseases and the aging process. Since this dietary approach stimulates the liver's production of ketone bodies, primarily ß-hydroxybutyrate (BHB), which serves as an alternative energy source for neurons, we investigated whether BHB could mitigate impaired AMPA receptor trafficking, synaptic dysfunction, and cognitive decline induced by metabolic challenges such as saturated fatty acids. Here, we observe that, in cultured primary cortical neurons, exposure to palmitic acid (200µM) decreased surface levels of glutamate GluA1-containing AMPA receptors, whereas unsaturated fatty acids, such as oleic acid and ω-3 docosahexaenoic acid (200µM), and BHB (5mM) increased them. Furthermore, BHB countered the adverse effects of palmitic acid on synaptic GluA1 levels in hippocampal neurons, as well as excitability and plasticity in hippocampal slices. Additionally, daily intragastric administration of BHB (100 mg/kg/day) for two months reversed cognitive impairment induced by a saturated high-fat diet (49% of calories from fat) in a mouse experimental model of obesity. In summary, our findings underscore the significant impact of fatty acids and ketone bodies on AMPA receptors abundance, synaptic function and neuroplasticity, shedding light on the potential use of BHB to delay cognitive impairments associated with metabolic diseases.

Targeting epigenetics: A novel promise for Alzheimer's disease treatment.

So far, the search for a cure for Alzheimer Disease (AD) has been unsuccessful. The only approved drugs attenuate some symptoms, but do not halt the progress of this disease, which affects 50 million people worldwide and will increase its incidence in the coming decades. Such scenario demands new therapeutic approaches to fight against this devastating dementia. In recent years, multi-omics research and the analysis of differential epigenetic marks in AD subjects have contributed to our understanding of AD; however, the impact of epigenetic research is yet to be seen. This review integrates the most recent data on pathological processes and epigenetic changes relevant for aging and AD, as well as current therapies targeting epigenetic machinery in clinical trials. Evidence shows that epigenetic modifications play a key role in gene expression, which could provide multi-target preventative and therapeutic approaches in AD. Both novel and repurposed drugs are employed in AD clinical trials due to their epigenetic effects, as well as increasing number of natural compounds. Given the reversible nature of epigenetic modifications and the complexity of gene-environment interactions, the combination of epigenetic-based therapies with environmental strategies and drugs with multiple targets might be needed to properly help AD patients.

Efficacy and safety of anti-amyloid-ß monoclonal antibodies in current Alzheimer's disease phase III clinical trials: A systematic review and interactive web app-based meta-analysis.

The risk-benefit profile of anti-Aß monoclonal antibodies (mAbs) in Alzheimer's disease (AD) remains unclear, especially concerning their safety and overall effects on AD progression and cognitive function. Here, we investigated cognitive, biomarker and side effects of anti-Aß mAbs in large phase III randomized placebo-controlled clinical trials (RCTs) in sporadic AD. The search was performed on Google Scholar, PubMed and ClinicalTrials.gov by applying Jadad score to evaluate the methodological quality of the reports. Studies were excluded if they scored < 3 on Jadad scale or if they analyzed less than 200 sporadic AD patients. We followed PRISMA guidelines and DerSimonian-Laird random-effects model in R. Primary outcomes were cognitive: AD Assessment Scale-Cognitive Subscale (ADAS-Cog), Mini Mental State Examination (MMSE) and Clinical Dementia Rating Scale-sum of Boxes (CDR-SB). Secondary and tertiary outcomes included biomarkers of Aß and tau pathology, adverse events, and performance on Alzheimer's Disease Cooperative Study - Activities of Daily Living Scale. The meta-analysis included 14,980 patients in 14 studies and four mAbs: Bapineuzumab, Aducanumab, Solanezumab and Lecanemab. The results of this study suggest that anti-Aß mAbs statistically improved cognitive and biomarker outcomes, particularly Aducanumab and Lecanemab. However, while cognitive effects were of small effect sizes, these drugs considerably increased risk of side effects such as Amyloid Related Imaging Abnormalities (ARIA), especially in APOE-ε4 carriers. Meta-regression revealed that higher (better) baseline MMSE score was associated with improved ADAS Cog and CDR-SB. In order to improve reproducibility and update the analysis in the future, we developed AlzMeta.app, web-based application freely available at https://alzmetaapp.shinyapps.io/alzmeta/.

Impairments in hippocampal oscillations accompany the loss of LTP induced by GIRK activity blockade.

Learning and memory occurrence requires of hippocampal long-term synaptic plasticity and precise neural activity orchestrated by brain network oscillations, both processes reciprocally influencing each other. As G-protein-gated inwardly rectifying potassium (GIRK) channels rule synaptic plasticity that supports hippocampal-dependent memory, here we assessed their unknown role in hippocampal oscillatory activity in relation to synaptic plasticity induction. In alert male mice, pharmacological GIRK modulation did not alter neural oscillations before long-term potentiation (LTP) induction. However, after an LTP generating protocol, both gain- and loss-of basal GIRK activity transformed LTP into long-term depression, but only specific suppression of constitutive GIRK activity caused a disruption of network synchronization (δ, α, γ bands), even leading to long-lasting ripples and fast ripples pathological oscillations. Together, our data showed that constitutive GIRK activity plays a key role in the tuning mechanism of hippocampal oscillatory activity during long-term synaptic plasticity processes that underlies hippocampal-dependent cognitive functions.

Systematic characterization of a non-transgenic Aß1-42 amyloidosis model: synaptic plasticity and memory deficits in female and male mice.

BACKGROUND: The amyloid-ß (Aß) cascade is one of the most studied theories linked to AD. In multiple models, Aß accumulation and dyshomeostasis have shown a key role in AD onset, leading to excitatory/inhibitory imbalance, the impairments of synaptic plasticity and oscillatory activity, and memory deficits. Despite the higher prevalence of Alzheimer's disease (AD) in women compared to men, the possible sex difference is scarcely explored and the information from amyloidosis transgenic mice models is contradictory. Thus, given the lack of data regarding the early stages of amyloidosis in female mice, the aim of this study was to systematically characterize the effect of an intracerebroventricular (icv.) injection of Aß1-42 on hippocampal-dependent memory, and on associated activity-dependent synaptic plasticity in the hippocampal CA1-CA3 synapse, in both male and female mice. METHODS: To do so, we evaluated long term potentiation (LTP) with ex vivo electrophysiological recordings as well as encoding and retrieval of spatial (working, short- and long-term) and exploratory habituation memories using Barnes maze and object location, or open field habituation tasks, respectively. RESULTS: Aß1-42 administration impaired all forms of memory evaluated in this work, regardless of sex. This effect was displayed in a long-lasting manner (up to 17 days post-injection). LTP was inhibited at a postsynaptic level, both in males and females, and a long-term depression (LTD) was induced for the same prolonged period, which could underlie memory deficits. CONCLUSIONS: In conclusion, our results provide further evidence on the shifting of LTP/LTD threshold due to a single icv. Aß1-42 injection, which underly cognitive deficits in the early stages of AD. These long-lasting cognitive and functional alterations in males and females validate this model for the study of early amyloidosis in both sexes, thus offering a solid alternative to the inconsistence of amyloidosis transgenic mice models.

This study focuses on investigating how amyloid-ß (Aß), a key toxic protein in Alzheimer's disease (AD), impacts memory and functioning of the synapses in both male and female mice.Our primary objective was to comprehensively understand the impact of Aß_1­42, a specific form of Aß, when introduced into the brain's ventricles, focusing on memory processes associated with the hippocampus, a brain region vital for learning and memory.Prior research established Aß's significance in AD and memory decline. However, despite the higher prevalence of AD in females, the connection between Aß, memory, and sex differences required further exploration. Furthermore, findings from experiments utilizing Aß transgenic mice have offered conflicting outcomes. Here, by administering Aß_1­42 to male and female mice, we systematically assessed memory using cognitive tasks. Results were consistent: memory deficits were evident in both sexes, persisting for up to 17 days post-injection.Delving deeper, we explored alterations in synaptic plasticity, a cornerstone of learning and memory. Our investigations unveiled disruptions in long-term potentiation (LTP) and long-term depression (LTD)­essential synaptic processes­in both male and female mice subjected to Aß_1­42 injection.These intriguing findings underscore Aß_1­42's lasting influence on memory and synaptic function, emphasizing its role in early AD-related cognitive decline. Additionally, our study highlights the potential of this experimental model to investigate early AD across sex differences, offering a promising alternative to the existing array Aß transgenic mouse models and addressing the need for a more consistent investigative framework.

Effect of the Early Combination of Continuous Positive Airway Pressure and High-Flow Nasal Cannula on Mortality and Intubation Rates in Patients With COVID-19 and Acute Respiratory Distress Syndrome. The DUOCOVID Study.

INTRODUCTION: Non invasive respiratory support (NIRS) is useful for treating acute respiratory distress syndrome (ARDS) secondary to COVID-19, mainly in mild-moderate stages. Although continuous positive airway pressure (CPAP) seems superior to other NIRS, prolonged periods of use and poor adaptation may contribute to its failure. The combination of CPAP sessions and high-flow nasal cannula (HFNC) breaks could improve comfort and keep respiratory mechanics stable without reducing the benefits of positive airway pressure (PAP). Our study aimed to determine if HFNC+CPAP initiates early lower mortality and endotracheal intubation (ETI) rates. METHODS: Subjects were admitted to the intermediate respiratory care unit (IRCU) of a COVID-19 monographic hospital between January and September 2021. They were divided according to Early HFNC+CPAP (first 24h, EHC group) and Delayed HFNC+CPAP (after 24h, DHC group). Laboratory data, NIRS parameters, and the ETI and 30-day mortality rates were collected. A multivariate analysis was performed to identify the risk factors associated with these variables. RESULTS: The median age of the 760 included patients was 57 (IQR 47-66), who were mostly male (66.1%). The median Charlson Comorbidity Index was 2 (IQR 1-3) and 46.8% were obese. The median PaO2/FiO2 upon IRCU admission was 95 (IQR 76-126). The ETI rate in the EHC group was 34.5%, with 41.8% for the DHC group (p=0.045), while 30-day mortality was 8.2% and 15.5%, respectively (p=0.002). CONCLUSIONS: Particularly in the first 24h after IRCU admission, the HFNC+CPAP combination was associated with a reduction in the 30-day mortality and ETI rates in patients with ARDS secondary to COVID-19.

Acquisition-dependent modulation of hippocampal neural cell adhesion molecules by associative motor learning.

It is widely accepted that some types of learning involve structural and functional changes of hippocampal synapses. Cell adhesion molecules neural cell adhesion molecule (NCAM), its polysialylated form polysialic acid to NCAM (PSA-NCAM), and L1 are prominent modulators of those changes. On the other hand, trace eyeblink conditioning, an associative motor learning task, requires the active participation of hippocampal circuits. However, the involvement of NCAM, PSA-NCAM, and L1 in this type of learning is not fully known. Here, we aimed to investigate the possible time sequence modifications of such neural cell adhesion molecules in the hippocampus during the acquisition of a trace eyeblink conditioning. To do so, the hippocampal expression of NCAM, PSA-NCAM, and L1 was assessed at three different time points during conditioning: after one (initial acquisition), three (partial acquisition), and six (complete acquisition) sessions of the conditioning paradigm. The conditioned stimulus (CS) was a weak electrical pulse separated by a 250-ms time interval from the unconditioned stimuli (US, a strong electrical pulse). An acquisition-dependent regulation of these adhesion molecules was found in the hippocampus. During the initial acquisition of the conditioning eyeblink paradigm (12 h after 1 and 3 days of training), synaptic expression of L1 and PSA-NCAM was transiently increased in the contralateral hippocampus to the paired CS-US presentations, whereas, when the associative learning was completed, such increase disappeared, but a marked and bilateral upregulation of NCAM was found. In conclusion, our findings show a specific temporal pattern of hippocampal CAMs expression during the acquisition process, highlighting the relevance of NCAM, PSA-NCAM, and L1 as learning-modulated molecules critically involved in remodeling processes underlying associative motor-memories formation.

Clinical characteristics and respiratory care in hospitalized vaccinated SARS-CoV-2 patients.

Background: The main objective of the present study was to analyze both clinical characteristics and evolution during hospitalization of a cohort of patients admitted for COVID-19 pneumonia who were not vaccinated, or with a complete or incomplete vaccination schedule. Methods: This COVID-19 specialized single-center cohort study of 1888 COVID-19 patients hospitalized at the "Enfermera Isabel Zendal" Emergencies Hospital (HEEIZ), Madrid (Spain) was performed between July 1 and September 30, 2021. It compared the results of 1327 hospitalized unvaccinated patients to 209 hospitalized fully vaccinated and 352 hospitalized partially vaccinated patients. The four different COVID-19 vaccines authorized in Spain during the time-period studied were: BNT162b2 (Pfizer); ChAdOx1 nCoV-19 (AstraZeneca), mRNA-1273 (Moderna); Ad26.COV2.S (Janssen). Findings: Hospitalized patients' median age was 41 years (IQR 33-50) for the unvaccinated and 61 years (IQR 53-67) for the fully vaccinated ones. The main comorbidities were obesity, hypertension and diabetes mellitus. 20% of unvaccinated patients (266) required noninvasive respiratory care, as did 14% (51) of partially and 14% (30) of fully vaccinated; 6% (78) of the unvaccinated patients also needed invasive respiratory care, as did 5% (16) of partially and 11 (5%) fully vaccinated. Interpretation: Fully vaccinated patients were 84% (95% CI: 82-86%) less likely to be admitted to hospital, and protection rose for those aged <50 years. Once hospitalized, vaccinated patients displayed more protection against requiring respiratory care than unvaccinated ones, despite being older and having more comorbidities. No differences appeared for the four studied COVID-19 vaccines and complying with vaccination recommendations proved relevant. Funding: The research was funded by the "Plan Propio de Investigación" Program of the Castilla-La Mancha University /European Regional Development Fund (2021-GRIN-31,039).

TRP channels and neural persistent activity.

One of the integrative properties of the nervous system is its capability to, by transient motor commands or brief sensory stimuli, evoke persistent neuronal changes, mainly as a sustained, tonic action potential firing. This neural activity, named persistent activity, is found in a good number of brain regions and is thought to be a neural substrate for short-term storage and accumulation of sensory or motor information [1]. Examples of this persistent neural activity have been reported in prefrontal [2] and entorhinal [3] cortices, as part of the neural mechanisms involved in short-term working memory [4]. Interestingly, the general organization of the motor systems assumes the presence of bursts of short-lasting motor commands encoding movement characteristics such as velocity, duration, and amplitude, followed by a maintained tonic firing encoding the position at which the moving appendage should be maintained [5, 6]. Generation of qualitatively similar sustained discharges have also been found in spinal and supraspinal regions in relation to pain processing [7, 8]. Thus, persistent neural activity seems to be necessary for both behavioral (positions of fixation) and cognitive (working memory) processes. Persistent firing mechanisms have been proposed to involve the participation of a non-specific cationic current (CAN current) mainly mediated by activation of TRPC channels. Because the function and generation of persistent activity is still poorly understood, here we aimed to review and discuss the putative role of TRP-like channels on its generation and/or maintenance.

Past, present and future of therapeutic strategies against amyloid-ß peptides in Alzheimer's disease: a systematic review.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in ageing, affecting around 46 million people worldwide but few treatments are currently available. The etiology of AD is still puzzling, and new drugs development and clinical trials have high failure rates. Urgent outline of an integral (multi-target) and effective treatment of AD is needed. Accumulation of amyloid-ß (Aß) peptides is considered one of the fundamental neuropathological pillars of the disease, and its dyshomeostasis has shown a crucial role in AD onset. Therefore, many amyloid-targeted therapies have been investigated. Here, we will systematically review recent (from 2014) investigational, follow-up and review studies focused on anti-amyloid strategies to summarize and analyze their current clinical potential. Combination of anti-Aß therapies with new developing early detection biomarkers and other therapeutic agents acting on early functional AD changes will be highlighted in this review. Near-term approval seems likely for several drugs acting against Aß, with recent FDA approval of a monoclonal anti-Aß oligomers antibody -aducanumab- raising hopes and controversies. We conclude that, development of oligomer-epitope specific Aß treatment and implementation of multiple improved biomarkers and risk prediction methods allowing early detection, together with therapies acting on other factors such as hyperexcitability in early AD, could be the key to slowing this global pandemic.

Therapeutic potential of targeting G protein-gated inwardly rectifying potassium (GIRK) channels in the central nervous system.

G protein-gated inwardly rectifying potassium channels (Kir3/GirK) are important for maintaining resting membrane potential, cell excitability and inhibitory neurotransmission. Coupled to numerous G protein-coupled receptors (GPCRs), they mediate the effects of many neurotransmitters, neuromodulators and hormones contributing to the general homeostasis and particular synaptic plasticity processes, learning, memory and pain signaling. A growing number of behavioral and genetic studies suggest a critical role for the appropriate functioning of the central nervous system, as well as their involvement in many neurologic and psychiatric conditions, such as neurodegenerative diseases, mood disorders, attention deficit hyperactivity disorder, schizophrenia, epilepsy, alcoholism and drug addiction. Hence, GirK channels emerge as a very promising tool to be targeted in the current scenario where these conditions already are or will become a global public health problem. This review examines recent findings on the physiology, function, dysfunction, and pharmacology of GirK channels in the central nervous system and highlights the relevance of GirK channels as a worthful potential target to improve therapies for related diseases.

A rapamycin-sensitive signaling pathway is essential for the full expression of persistent pain states.

Translational control through the mammalian target of rapamycin (mTOR) is critical for synaptic plasticity, cell growth, and axon guidance. Recently, it was also shown that mTOR signaling was essential for the maintenance of the sensitivity of subsets of adult sensory neurons. Here, we show that persistent pain states, but not acute pain behavior, are substantially alleviated by centrally administered rapamycin, an inhibitor of the mTOR pathway. We demonstrate that rapamycin modulates nociception by acting on subsets of primary afferents and superficial dorsal horn neurons to reduce both primary afferent sensitivity and central plasticity. We found that the active form of mTOR is present in a subpopulation of myelinated dorsal root axons, but rarely in unmyelinated C-fibers, and heavily expressed in the dorsal horn by lamina I/III projection neurons that are known to mediate the induction and maintenance of pain states. Intrathecal injections of rapamycin inhibited the activation of downstream targets of mTOR in dorsal horn and dorsal roots and reduced the thermal sensitivity of A-fibers. Moreover, in vitro studies showed that rapamycin increased the electrical activation threshold of Adelta-fibers in dorsal roots. Together, our results imply that central rapamycin reduces neuropathic pain by acting both on an mTOR-positive subset of A-nociceptors and lamina I projection neurons and suggest a new pharmacological route for therapeutic intervention in persistent pain states.