Inhibitory circuits of the cortex : control of rhythmic and stimulus evoked activity

We are surrounded by a world, which makes sense, only because we make sense of it. At every instant in our waking life we estimate the state of the world based on sensory data, then we reshape the world to meet our goals. How are these sensations encoded, goals represented and action computed? To answer these questions we dissect the biological circuitry in our brains that seamlessly performs these computations. To study the dynamics of neural circuits, we specifically focus on the role inhibition in shaping signal processing. This work examines how inhibitory circuits process increasingly complex forms of afferent input. First, we characterize and model local circuit responses to brief impulses of afferent activity. We find that local circuits generate feedforward inhibition in the first few milliseconds after an afferent impulse. This inhibition adjusts the excitability of the local population normalizing it to the afferent excitation level. Then, in the next few milliseconds, as individual local pyramidal cells spike they immediately recruit a distinct recurrent inhibitory circuit. This feedback circuit is extremely sensitive responding with negative feedback when even a single local pyramidal cell is active. By modeling the circuit dynamics during these stages in cortical processing we quantitatively demonstrate that the feedforward and feedback inhibitory circuits are tuned to be both sensitive to sparse activity and yet maintain fidelity with which a cortical circuit represents inputs at high activity levels. Next, the role inhibition during spontaneous rhythmic activity is dissected. Our results demonstrate that by rapidly balancing excitation with inhibition, cortical networks can swiftly modulate rhythms over a wide band of frequencies. Finally, we investigate the role of a distinct type of inhibitory interneuron during the first stage of cortical visual processing. Using optogenetics to either enhance or suppress parvalbumin positive interneurons spiking, we demonstrate that these neurons play a key role in modulating the selectivity of responses in primary visual cortex. Together, these results demonstrate the multifaceted role inhibitory circuits play in signal processing and shaping cortical computation; adding to our communal effort to develop a complete picture of how neural circuitry performs computations and encodes sensatio

Anticoagulation in COVID-19

As hospitals worldwide continue to admit an influx of coronavirus disease 2019 (COVID-19) patients, the puzzling pathogenesis behind the witnessed mortality rates is progressively being pieced together. Aside from the established respiratory involvement, the cardiac system has recently been implicated, albeit with controversial mechanisms. New data from cohort studies and autopsies suggest a potential role for coagulopathy in COVID-19. Although the exact mechanism may likewise remain controversial, several clinical implications are now imperative for discussion

Input normalization by global feedforward inhibition expands cortical dynamic range

The cortex is sensitive to weak stimuli, but responds to stronger inputs without saturating. The mechanisms that enable this wide range of operation are not fully understood. We found that the amplitude of excitatory synaptic currents necessary to fire rodent pyramidal cells, the threshold excitatory current, increased with stimulus strength. Consequently, the relative contribution of individual afferents in firing a neuron was inversely proportional to the total number of active afferents. Feedforward inhibition, acting homogeneously across pyramidal cells, ensured that threshold excitatory currents increased with stimulus strength. In contrast, heterogeneities in the distribution of excitatory currents in the neuronal population determined the specific set of pyramidal cells recruited. Together, these mechanisms expand the range of afferent input strengths that neuronal populations can represent.Fil: Pouille, Frédéric. University Of California. Department Of Neurobiology; Estados UnidosFil: Marin Burgin, Antonia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. University Of California. Department Of Neurobiology; Estados UnidosFil: Adesnik, Hillel. University Of California. Department Of Neurobiology; Estados UnidosFil: Atallah, Bassam V.. University Of California. Department Of Neurobiology; Estados UnidosFil: Scanziani, Massimo. University Of California. Department Of Neurobiology; Estados Unido

The Safety and Effectiveness of Apixaban in Patients with End-Stage Kidney Disease on Dialysis: A Retrospective Observational Study

Background: Apixaban has been increasingly utilized for various FDA-approved indications, including stroke prevention and venous thromboembolism (VTE) treatment in patients with end stage kidney disease (ESKD) on hemodialysis. However, the safety and efficacy of its use in this population is not well established. Hence, the purpose of this study is to evaluate the safety and effectiveness of apixaban by examining outcomes in this population. Methods: This was a retrospective observational study that involved adults with ESKD who were on hemodialysis and prescribed apixaban from our hospital’s outpatient pharmacy between 1 May 2015, and 31 March 2022. Demographics, apixaban indications, dose appropriateness, concomitant antiplatelet use, and comorbidities data were collected. Bleeding and thromboembolic events were also collected. Results: Sixty-six patients fulfilled the inclusion criteria, 50% of them males. Median age was 71 (63.5–82) years, and the median BMI 28.2 (59.5–86.25) kg/m2. The median follow-up time was 5 (1.9–12.3) months. Concomitant antiplatelet use (39.4%) and high medication adherence (84.8%) were observed. During follow-up, major bleeding events occurred in 15.2% of cases, with minor bleeding being more common (36.4%), and VTE and stroke events occurred in 4.5% of cases; appropriate dosing was prevalent (62.1%), and there was an overall all-cause mortality rate of 34.8%. Most patients received a 2.5 mg BID apixaban dose (56.1%), including both NVAF and VTE groups. Notably, the multivariate logistic regression analysis indicated that weight, and daily dose were insignificant predictors of bleeding events (p = 0.104, 0.591), however, the BMI was the main independent risk factor for bleeding in this population [OR = 0.9, 95% CI: 0.8–0.99; p = 0.023]. Conclusions: Our analysis of apixaban-treated ESKD patients highlights that the risk of bleeding is significant, and BMI was the main independent risk factor. A larger prospective study is needed to confirm our findings

QT Prolongation in Critically Ill Patients With SARS-CoV-2 Infection.

BACKGROUND: Several reports linked the use of repurposed drugs such as hydroxychloroquine (HCQ), azithromycin, lopinavir/ritonavir, and favipiravir with QT interval prolongation in patients with SARS-CoV2 infection. Little is known about the risk factors for QT interval prolongation in this population. We sought to describe the prevalence and identify the main risk factors associated with clinically significant corrected QT (QTc) prolongation in this population. METHODS: We conducted a retrospective analysis of critically ill patients who were admitted to our intensive care unit (ICU), had at least one electrocardiogram performed during their ICU stay, and tested positive for SARs-CoV-2. Clinically significant QTc interval prolongation was defined as QTc >500 milliseconds (ms). RESULTS: Out of the 111 critically ill patients with SARS-CoV-2 infection, QTc was significantly prolonged in 47 cases (42.3%). Patients with a clinically significant QTc prolongation had significantly higher proportions of history of cardiac diseases/surgery (22 [46.8%] vs. 10 [15.6%], P < .001), hypokalemia (10 [21.3] vs. 5 [7.8%], P = .04), and male gender (95% vs. 82.8%, P = .036) than patients with QTc ≤500 ms, respectively. A total of 46 patients (41.4%) received HCQ, 28 (25.2%) received lopinavir/ritonavir, and 5 (4.5%) received azithromycin. Multivariate logistic regression analysis showed that a history of cardiac disease was the only independent factor associated with clinically significant QTc prolongation (P = .004 for the likelihood-ratio test). CONCLUSION: The prevalence of clinically significant QTc prolongation in critically ill patients with SARS-CoV-2 infection was high and independent of drugs used. Larger prospective observational studies are warranted to elucidate independent risk factors associated with clinically significant QTc prolongation in this study population

Thrombotic events following tocilizumab therapy in critically ill COVID-19 patients: a Façade for prognostic markers

Background: Hospitals in the Middle East Gulf region have experienced an influx of COVID-19 patients to their medical wards and intensive care units. The hypercoagulability of these patients has been widely reported on a global scale. However, many of the experimental treatments used to manage the various complications of COVID-19 have not been widely studied in this context. The effect of the current treatment protocols on patients' diagnostic and prognostic biomarkers may thus impact the validity of the algorithms adopted.Case presentation: In this case series, we report four cases of venous thromboembolism and 1 case of arterial thrombotic event, in patients treated with standard or intensified prophylactic doses of unfractionated heparin or low molecular weight heparin at our institution. Tocilizumab has been utilized as an add-on therapy to the standard of care to treat patients with SARS-CoV-2 associated acute respiratory distress syndrome, in order to dampen the hyperinflammatory response. It is imperative to be aware that this drug may be masking the inflammatory markers (e.g. IL6, CRP, fibrinogen, and ferritin), without reducing the risk of thrombotic events in this population, creating instead a façade of an improved prognostic outcome. However, the D-dimer levels remained prognostically reliable in these cases, as they were not affected by the drug and continued to be at the highest level until event occurrence.Conclusions: In the setting of tocilizumab therapy, traditional prognostic markers of worsening infection and inflammation, and thus potential risk of acute thrombosis, should be weighed carefully as they may not be reliable for prognosis and may create a façade of an improved prognostic outcome insteasd. Additionally, the fact that thrombotic events continued to be observed despite decrease in inflammatory markers and the proactive anticoagulative approach adopted, raises more questions about the coagulative mechanisms at play in COVID-19, and the appropriate management strategy.</p

Rapid target-specific remodeling of fast-spiking inhibitory circuits after loss of dopamine.

In Parkinson's disease (PD), dopamine depletion alters neuronal activity in the direct and indirect pathways and leads to increased synchrony in the basal ganglia network. However, the origins of these changes remain elusive. Because GABAergic interneurons regulate activity of projection neurons and promote neuronal synchrony, we recorded from pairs of striatal fast-spiking (FS) interneurons and direct- or indirect-pathway MSNs after dopamine depletion with 6-OHDA. Synaptic properties of FS-MSN connections remained similar, yet within 3 days of dopamine depletion, individual FS cells doubled their connectivity to indirect-pathway MSNs, whereas connections to direct-pathway MSNs remained unchanged. A model of the striatal microcircuit revealed that such increases in FS innervation were effective at enhancing synchrony within targeted cell populations. These data suggest that after dopamine depletion, rapid target-specific microcircuit organization in the striatum may lead to increased synchrony of indirect-pathway MSNs that contributes to pathological network oscillations and motor symptoms of PD.</p

Fluid Shear Stress Promotes Placental Growth Factor Upregulation in Human Syncytiotrophoblast Through the cAMP–PKA Signaling Pathway

International audienceThe effects of fluid shear stress (FSS) on the human syncytiotrophoblast and its biological functions have never been studied. During pregnancy, the syncytiotrophoblast is the main source of placental growth factor (PlGF), a proangiogenic factor involved in the placental angiogenesis and the vascular adaptation to pregnancy. The role of FSS in regulating PlGF expression in syncytiotrophoblasts is unknown. We investigated the impact of FSS on the production and secretion of the PlGF by the human syncytiotrophoblasts in primary cell culture. Laminar and continuous FSS (1 dyn cm-2) was applied to human syncytiotrophoblasts cultured in a parallel-plate flow chambers. Secreted levels of PlGF, sFlt-1 (soluble fms-like tyrosin kinase-1), and prostaglandin E2 were tested by immunologic assay. PlGF levels of mRNA and intracellular protein were examined by RT-PCR and Western blot, respectively. Intracellular cAMP levels were examined by time-resolved fluorescence resonance energy transfer cAMP accumulation assay. Production of cAMP and PlGF secretion was significantly increased in FSS conditions compared with static conditions. Western blot analysis of cell extracts exposed to FSS showed an increased phosphorylation of protein kinase A substrates and cAMP response element-binding protein on serine 133. FSS-induced phosphorylation of cAMP response element-binding protein and upregulation of PlGF were prevented by inhibition of protein kinase A with H89 (3 μmol/L). FSS also triggers intracellular calcium flux, which increases the synthesis and release of prostaglandin E2. The enhanced intracellular cAMP in FSS conditions was blocked by COX1/COX2 (cyclooxygenase) inhibitors, suggesting that the increase in prostaglandin E2 production could activate the cAMP/protein kinase A pathway in an autocrine/paracrine fashion. FSS activates the cAMP/protein kinase A pathway leading to upregulation of PlGF in human syncytiotrophoblast