Sodium Leak Research Articles

Congenital Ataxia with Progressive Cerebellar Atrophy, Camptodactyly, and Hypertrichosis: A Novel Recognizable Phenotype for NALCN Heterozygous Variants.

Non-selective sodium leak channel (NALCN) protein encoded by the NALCN gene is of key importance for neuronal cell excitability. Previous reports showed that biallelic NALCN pathogenic variants cause infantile hypotonia with psychomotor retardation and characteristic facies 1 (IHPRF1) while monoallelic variants lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD). In our work, we aimed to expand the heterozygous NALCN-related clinical spectrum, presenting two affected individuals and a literature review. We describe two new unrelated subjects harboring monoallelic NALCN pathogenic variants identified through clinical exome sequencing and review the current literature of other heterozygous NALCN patients. The c.3542G > A (p.Arg1181Gln) and the novel c.3423C > A (p.Phe1141Leu) heterozygous missense variants were disclosed in two subjects manifesting a similar phenotype characterized by congenital ataxia with progressive cerebellar atrophy, camptodactyly, and hypertrichosis of the arms (CAPCACH). Other NALCN subjects with overlapping features have already been reported. A combination of these clinical and neuroimaging findings suggests the definition of the new CAPCACH phenotype. We expand the heterozygous NALCN-related clinical spectrum from the more severe CLIFFAHDD to the milder CAPCACH phenotype. These conditions should be considered in the differential diagnosis of syndromic congenital ataxias, and the presence of camptodactyly and/or hypertrichosis may represent peculiar diagnostic clues.

Investigation on multi-dimensional short-term behaviour through benchmark analysis of a large-volume sodium combustion experiment

ABSTRACT For sodium-cooled fast reactors, understanding sodium combustion behaviour is crucial for managing sodium leakage accidents. In this study, we perform benchmark analyses of the Sandia National Laboratories (SNL) T3 experiment using the multi-dimensional thermal hydraulic code AQUA-SF. Conducted in an enclosed space with a large vessel volume of 100 m3 and a sodium mass flow rate of 1 kg/s, the experiment highlighted the multi-dimensional effects of local temperature increase shortly after sodium injection. This study aims to extend the capabilities of AQUA-SF by focusing on the simulation of these multi-dimensional temperature variations, in particular, the formation of high-temperature regions at the bottom of the vessel. The proposed models include the temporary stopping of sodium droplet ignition and spray combustion of sodium splash on the floor. Furthermore, it has been shown that an additional heat source near the floor is essential to enhance the reproduction of the high-temperature region at the bottom. Therefore, case studies including sensitivity analyses of spray cone angle and prolonged combustion of droplets on the floor are conducted. This comprehensive approach provides valuable insights into the temperature dynamics of sodium combustion and safety measures in sodium-cooled fast reactors.

Thermally induced neuronal plasticity in the hypothalamus mediates heat tolerance

Heat acclimation is an adaptive process that improves physiological performance and supports survival in the face of increasing environmental temperatures, but the underlying mechanisms are not well understood. Here we identified a discrete group of neurons in the mouse hypothalamic preoptic area (POA) that rheostatically increase their activity over the course of heat acclimation, a property required for mice to become heat tolerant. In non-acclimated mice, peripheral thermoafferent pathways via the parabrachial nucleus activate POA neurons and mediate acute heat-defense mechanisms. However, long-term heat exposure promotes the POA neurons to gain intrinsically warm-sensitive activity, independent of thermoafferent parabrachial input. This newly gained cell-autonomous warm sensitivity is required to recruit peripheral heat tolerance mechanisms in acclimated animals. This pacemaker-like, warm-sensitive activity is driven by a combination of increased sodium leak current and enhanced utilization of the NaV1.3 ion channel. We propose that this salient neuronal plasticity mechanism adaptively drives acclimation to promote heat tolerance.

The background sodium leak channel NALCN is a major controlling factor in pituitary cell excitability.

The pituitary gland produces and secretes a variety of hormones that are essential to life, such as for the regulation of growth and development, metabolism, reproduction, and the stress response. This is achieved through an intricate signalling interplay between the brain and peripheral feedback signals that shape pituitary cell excitability by regulating the ion channel properties of these cells. In addition, endocrine anterior pituitary cells spontaneously fire action potentials to regulate the intracellular calcium ([Ca2+]i) level, an essential signalling conduit for hormonal secretion. To this end, pituitary cells must regulate their resting membrane potential (RMP) close to the firing threshold, but the molecular identity of the ionic mechanisms responsible for this remains largely unknown. Here, we revealed that the sodium leak channel NALCN, known to modulate neuronal excitability elsewhere in the brain, regulates excitability in the mouse anterior endocrine pituitary cells. Using viral transduction combined with powerful electrophysiology methods and calcium imaging, we show that NALCN forms the major Na+ leak conductance in these cells, appropriately tuning cellular RMP for sustaining spontaneous firing activity. Genetic depletion of NALCN channel activity drastically hyperpolarised these cells, suppressing their firing and [Ca2+]i oscillations. Remarkably, despite this profound function of NALCN conductance in controlling pituitary cell excitability, it represents a very small fraction of the total cell conductance. Because NALCN responds to hypothalamic hormones, our results also provide a plausible mechanism through which hormonal feedback signals from the brain and body could powerfully affect pituitary activity to influence hormonal function. KEY POINTS: Pituitary hormones are essential to life as they regulate important physiological processes, such as growth and development, metabolism, reproduction and the stress response. Pituitary hormonal secretion relies on the spontaneous electrical activity of pituitary cells and co-ordinated inputs from the brain and periphery. This appropriately regulates intracellular calcium signals in pituitary cells to trigger hormonal release. Using viral transduction in combination with electrophysiology and calcium imaging, we show that the activity of the background leak channel NALCN is a major controlling factor in eliciting spontaneous electrical activity and intracellular calcium signalling in pituitary cells. Remarkably, our results revealed that a minute change in NALCN activity could have a major influence on pituitary cell excitability. Our study provides a plausible mechanism through which the brain and body could intricately control pituitary activity to influence hormonal function.

NALCN Promoter Methylation as a Biomarker for Metastatic Risk in a Cohort of Non-Small Cell Lung Cancer Patients.

Liquid biopsy enables real-time monitoring of tumor development and response to therapy through the analysis of CTCs and ctDNA. NALCN is a sodium leak channel that is frequently involved in tumor evolution and immunity and acts as a tumor suppressor. Deletion of NALCN has been shown to increase cancer metastasis and the number of CTCs in peripheral blood. In this study, we investigated for the first time NALCN promoter methylation in (a) Aza-treated cell lines (A549, TE671, BT20, and MDA-MB-468), (b) paired NSCLC tissues (n = 22), and (c) plasma cell-free DNA (ctDNA) from patients with NSCLC (early stage n = 39, metastatic n = 39) and DNA from 10 healthy donors (HD) using a newly developed highly specific and sensitive real-time MSP method. Treatment with 5'-aza-dC induced the expression of NALCN only in the A549 cell line, suggesting that DNA methylation regulates its expression in certain cancers. The mRNA expression levels of NALCN were quantified in non-small cell lung cancer (NSCLC) and adjacent non-cancerous tissues, and it was found to be underexpressed in 54.5% of tumor tissues, with significantly higher expression in recurrence-free patients (p = 0.009) than in patients who relapsed. The NALCN methylation level was not statisticallysignificantlycorrelated with the corresponding expression (p = 0.439), while Kaplan-Meier analysis showed an association between NALCN promoter hypermethylation and worse disease-free intervals (DFIs) (p = 0.017). Evaluation of NALCN methylation in ctDNA revealed that it was detected in 5.1% of early and 10.2% of advanced cases. Our results strongly suggest that epigenetic inactivation of NALCN may be a predictor of metastasis in NSCLC. Our results should be validated in further studies based on a larger patient cohort to further investigate whether DNA methylation of the NALCN promoter could serve as a potential prognostic DNA methylation biomarker and predictor of metastasis in NSCLC.

Characterization of Sodium Thermal Insulation Reaction Product and its Effect on Fatigue Crack Growth in 316 LN Austenitic Steel

Though sodium is the most preferred coolant for fast breeder reactors due to excellent heat transfer capabilities, its high chemical reactivity poses a concern during accidental leaks. Despite defense in depth in various levels for protecting the sodium leaks in the heat transport circuits, small undetected leaks may lead to localized degradation of structural material due to deposition of reaction products in the leak zone. Experiments have been conducted by exposing SS-316 LN specimens to sodium–glass wool interaction zone at 300 °C in air to study the influence of reaction products on chemical composition and crack growth properties. Post-exposure X-ray diffraction analysis of the samples revealed presence of silicates and aluminates of sodium in the outer layers, and complex ternary and quaternary oxides of sodium, iron, chromium and nickel in the inner layers. Scanning electron microscopy analysis revealed deposition of oxides on the exposed surface. Elemental analysis of the samples carried out by energy-dispersive spectroscopy indicated leaching of major alloying elements like chromium, nickel and iron to a depth of about ~ 25 µm from the exposed surface. Room-temperature fatigue crack growth studies on the exposed specimen shown considerable reduction in crack initiation (threshold) fracture toughness range ΔKth.

Improvement and validation of discrete-sectional method based code for fast reactor aerosol dynamics

The study of the dynamics of aerosols produced during a severe accident is vital to the safety analysis of a Sodium-cooled Fast Reactor (SFR). Sodium leakage into the containment following a severe accident may result in the production of sodium aerosols along with fission product aerosols. The in-containment radioactive source term depends upon the settling behaviour of fission product aerosols, which co-agglomerate with sodium fire aerosols. Hence, an in-depth understanding of the dynamics and deposition of aerosols within the containment is essential for the safety assessment of an SFR. The current work uses an open-source code based on the Discrete-Sectional (DS) method to solve the simplified form of General Dynamics Equation (GDE) for aerosols relevant to fast reactors. Aerosols of SrO2, CeO2 and sodium are considered in the present work. The DS code has been modified and further improved by including gravitational coagulation, turbulent coagulation, Brownian deposition, gravitational deposition and thermophoretic deposition so that the code can handle the different processes leading to the deposition of aerosols following a sodium fire. The code is also enhanced to account for the effect of relative humidity through the modified Cooper's equation. The improved code is then validated with different experiments conducted in the Aerosol Test Facility (ATF), India; Mini Sodium Fire Facility (MINA), India; and AHMED (Aerosol and Heat Transfer Measurement Device), Finland. Validation from different facilities confirms the applicability of the code to various scenarios. It is found that the modified DS code could predict the decay of suspended mass concentration of aerosols in different enclosures with reasonable accuracy.

Unplugging lateral fenestrations of NALCN reveals a hidden drug binding site within the pore region

The sodium (Na+) leak channel (NALCN) is a member of the four-domain voltage-gated cation channel family that includes the prototypical voltage-gated sodium and calcium channels (NaVs and CaVs, respectively). Unlike NaVs and CaVs, which have four lateral fenestrations that serve as routes for lipophilic compounds to enter the central cavity to modulate channel function, NALCN has bulky residues (W311, L588, M1145, and Y1436) that block these openings. Structural data suggest that occluded fenestrations underlie the pharmacological resistance of NALCN, but functional evidence is lacking. To test this hypothesis, we unplugged the fenestrations of NALCN by substituting the four aforementioned residues with alanine (AAAA) and compared the effects of NaV, CaV, and NALCN blockers on both wild-type (WT) and AAAA channels. Most compounds behaved in a similar manner on both channels, but phenytoin and 2-aminoethoxydiphenyl borate (2-APB) elicited additional, distinct responses on AAAA channels. Further experiments using single alanine mutants revealed that phenytoin and 2-APB enter the inner cavity through distinct fenestrations, implying structural specificity to their modes of access. Using a combination of computational and functional approaches, we identified amino acid residues critical for 2-APB activity, supporting the existence of drug binding site(s) within the pore region. Intrigued by the activity of 2-APB and its analogues, we tested compounds containing the diphenylmethane/amine moiety on WT channels. We identified clinically used drugs that exhibited diverse activity, thus expanding the pharmacological toolbox for NALCN. While the low potencies of active compounds reiterate the pharmacological resistance of NALCN, our findings lay the foundation for rational drug design to develop NALCN modulators with refined properties.

Sodium Leak Channel in Glutamatergic Neurons of the Lateral Parabrachial Nucleus Helps to Maintain Respiratory Frequency Under Sevoflurane Anesthesia.

The lateral parabrachial nucleus (PBL) is implicated in the regulation of respiratory activity. Sodium leak channel (NALCN) mutations disrupt the respiratory rhythm and influence anesthetic sensitivity in both rodents and humans. Here, we investigated whether the NALCN in PBL glutamatergic neurons maintains respiratory function under general anesthesia. Our results showed that chemogenetic activation of PBL glutamatergic neurons increased the respiratory frequency (RF) in mice; whereas chemogenetic inhibition suppressed RF. NALCN knockdown in PBL glutamatergic neurons but not GABAergic neurons significantly reduced RF under physiological conditions and caused more respiratory suppression under sevoflurane anesthesia. NALCN knockdown in PBL glutamatergic neurons did not further exacerbate the respiratory suppression induced by propofol or morphine. Under sevoflurane anesthesia, painful stimuli rapidly increased the RF, which was not affected by NALCN knockdown in PBL glutamatergic neurons. This study suggested that the NALCN is a key ion channel in PBL glutamatergic neurons that maintains respiratory frequency under volatile anesthetic sevoflurane but not intravenous anesthetic propofol.

Influence of Clinical and Genetic Factors on Propofol Dose Requirements: A Genome-wide Association Study.

Propofol is a widely used intravenous hypnotic. Dosing is based mostly on weight, with great interindividual variation in consumption. Suggested factors affecting propofol requirements include age, sex, ethnicity, anxiety, alcohol consumption, smoking, and concomitant valproate use. Genetic factors have not been widely explored. This study considered 1,000 women undergoing breast cancer surgery under propofol and remifentanil anesthesia. Depth of anesthesia was monitored with State Entropy (GE Healthcare, Finland). Propofol requirements during surgery were recorded. DNA from blood was genotyped with a genome-wide array. A multivariable linear regression model was used to assess the relevance of clinical variables and select those to be used as covariates in a genome-wide association study. Imputed genotype data were used to explore selected loci further. In silico functional annotation was used to explore possible consequences of the discovered genetic variants. Additionally, previously reported genetic associations from candidate gene studies were tested. Body mass index, smoking status, alcohol use, remifentanil dose (ln[mg · kg-1 · min-1]), and average State Entropy during surgery remained statistically significant in the multivariable model. Two loci reached genome-wide significance (P < 5 × 10-8). The most significant associations were for single-nucleotide polymorphisms rs997989 (30 kb from ROBO3), likely affecting expression of another nearby gene, FEZ1, and rs9518419, close to NALCN (sodium leak channel); rs10512538 near KCNJ2 encoding the Kir2.1 potassium channel showed suggestive association (P = 4.7 × 10-7). None of these single-nucleotide polymorphisms are coding variants but possibly affect the regulation of nearby genes. None of the single-nucleotide polymorphisms previously reported as affecting propofol pharmacokinetics or pharmacodynamics showed association in the data. In this first genome-wide association study exploring propofol requirements, This study discovered novel genetic associations suggesting new biologically relevant pathways for propofol and general anesthesia. The roles of the gene products of ROBO3/FEZ1, NALCN, and KCNJ2 in propofol anesthesia warrant further studies.

Activity of the Sodium Leak Channel Maintains the Excitability of Paraventricular Thalamus Glutamatergic Neurons to Resist Anesthetic Effects of Sevoflurane in Mice.

Stimulation of the paraventricular thalamus has been found to enhance anesthesia recovery; however, the underlying molecular mechanism by which general anesthetics modulate paraventricular thalamus is unclear. This study aimed to test the hypothesis that the sodium leak channel (NALCN) maintains neuronal activity in the paraventricular thalamus to resist anesthetic effects of sevoflurane in mice. Chemogenetic and optogenetic manipulations, in vivo multiple-channel recordings, and electroencephalogram recordings were used to investigate the role of paraventricular thalamus neuronal activity in sevoflurane anesthesia. Virus-mediated knockdown and/or overexpression was applied to determine how NALCN influenced excitability of paraventricular thalamus glutamatergic neurons under sevoflurane. Viral tracers and local field potentials were used to explore the downstream pathway. Single neuronal spikes in the paraventricular thalamus were suppressed by sevoflurane anesthesia and recovered during emergence. Optogenetic activation of paraventricular thalamus glutamatergic neurons shortened the emergence period from sevoflurane anesthesia, while chemogenetic inhibition had the opposite effect. Knockdown of the NALCN in the paraventricular thalamus delayed the emergence from sevoflurane anesthesia (recovery time: from 24 ± 14 to 64 ± 19 s, P < 0.001; concentration for recovery of the righting reflex: from 1.13% ± 0.10% to 0.97% ± 0.13%, P < 0.01). As expected, the overexpression of the NALCN in the paraventricular thalamus produced the opposite effects. At the circuit level, knockdown of the NALCN in the paraventricular thalamus decreased the neuronal activity of the nucleus accumbens, as indicated by the local field potential and decreased single neuronal spikes in the nucleus accumbens. Additionally, the effects of NALCN knockdown in the paraventricular thalamus on sevoflurane actions were reversed by optical stimulation of the nucleus accumbens. Activity of the NALCN maintains the excitability of paraventricular thalamus glutamatergic neurons to resist the anesthetic effects of sevoflurane in mice.

Interactions Between Molten Sodium and Standard Pipe Insulation

Abstract Safety system design and implementation are critical to the operation of any nuclear plant. For sodium-cooled nuclear reactors, hazards external to the reactor core are present in the form of molten sodium that leaks through degraded piping structures. These structures are often clad in high-temperature insulation to preserve the heat needed to keep the sodium molten in the piping. While large sodium leaks are quite noticeable and often result in hazardous fire situations, small leaks of molten sodium are often masked by the shroud of insulation until a large pool of material has collected outside of the failed pipe. This study concentrated on the physical and chemical interactions between molten sodium and standard fiberglass insulation in temperatures ranging from 100 °C to 500 °C. The degradation of the insulation material begins with the volatilization of the organic binder around 250 °C, thereafter the insulation deteriorates at an advanced rate in areas that are in direct contact with the sodium. Chemical profile data were collected for a variety of sample locations that were in contact with the molten sodium, with only a slight increase in the amount of sodium present that can be attributed to the external sodium source. In this way, the molten sodium chemically reacts with the insulation, which accelerates the degradation of the insulation in locations where the sodium is in direct contact with the insulation. These reactions are enhanced by the temperature of the sodium.

Numerical Evaluation of Sodium Droplet Swarm Combustion and Its Modeling Optimization

Because of its superior thermal-hydraulic qualities, liquid sodium has been applied to a variety of industries, including energy storage, solar energy, sodium-cooled fast reactors, and aerospace. However, fires brought on by sodium leaks at high pressure can have major thermodynamic repercussions and put employees and equipment in use at risk directly or indirectly. As a result, a realistic and accurate forecast of the combustion behavior of sodium droplet swarm can offer technical backing for the use of liquid sodium in engineering as well as a way of sodium fire prevention and control. Spray dynamics (droplet settling, droplet particle size distribution, etc.), combustion kinetics (premixed combustion, gas phase combustion, etc.), sodium aerosol diffusion, and other specialized phenomena all contribute to the complex process of sodium droplet swarm combustion. The NACOM code created by Brookhaven National Laboratory for sodium droplet swarm combustion is utilized in this paper as a framework. The code is first validated using the benchmark of the sodium droplet swarm combustion tests carried out by prestigious institutions. The validation results demonstrate that the code’s drag model, droplet combustion model, and heat transfer model are to blame for the significantly overestimated thermodynamic effects of sodium droplet swarm combustion. NACOM is subsequently developed twice for the authors’ previously developed vapor-liquid two-layer-structure drag model, chemical kinetic combustion model, and suitable heat transfer coefficient. It is then thoroughly assessed for the separate-effects tests and integral-effects test. The evaluation results demonstrate that the optimized drag model accelerates the settling of sodium droplets due to the consideration of the sodium-vapor drag reduction effect, reducing the thermodynamic effects of liquid sodium combustion; the optimized premixed combustion model can accurately predict the low-temperature sodium droplet swarm combustion conditions, resolving the issue of serious misvaluation of the original version of NACOM. The associated research findings can serve as valuable resources and tools for deeper comprehension of the combustion effects and mechanisms of sodium droplet swarm under various operating settings (such as leakage rate and oxygen concentration).

Role of sodium leak channel (NALCN) in sensation and pain: an overview.

The sodium leak channel (NALCN) is widely expressed in the central nervous system and plays a pivotal role in regulating the resting membrane potential (RMP) by mediating the Na+ leak current. NALCN was first reported in 1999, and since then, increasing evidence has provided insights into the structure and functions of NALCN. As an essential component of neuronal background currents, NALCN has been shown to be involved in many important physiological functions, particularly in the respiratory rhythm, as NALCN mutant mice have a severely disrupted respiratory rhythm and die within 24h of birth. Many patients with NALCN mutations also develop serious clinical syndromes, such as severe hypotonia, speech impairment, and cognitive delay. Recently, emerging studies have clarified the human NALCN structure and revealed additional properties and functions of NALCN. For instance, accumulating evidence highlights that the NALCN is involved in normal sensation and pain. Here, we review the current literature and summarize the role of the NALCN in sensation and pain.

Proximal tubular dysfunction as a predictor of AKI in Hospitalized COVID-19 patients.

High concentration of Angiotensin converting enzyme receptors in the proximal tubules make kidneys an early target in COVID-19. Proximal tubular dysfunction (PTD) may act as an early predictor of acute kidney injury (AKI) and more severe disease. This prospective observational study was conducted in the COVID unit, Bangabandhu Sheikh Mujib Medical University. 87 COVID-19 patients without known kidney disease were screened for 6 markers of PTD on admission-hyperuricosuria, normoglycemic glycosuria, proteinuria, renal phosphate leak, sodium leak and potassium leak. Positivity of 2 of the first 4 markers was considered as PTD. 35 patients with PTD and 35 without PTD were followed up throughout their hospital stay. 52.9% had PTD on admission. The most prevalent markers were renal sodium leak (67%), followed by proteinuria (66.7%), hyperuricosuria (42.5%), potassium leak (32.2%), phosphate leak (28.7%) and normoglycemic glycosuria (20.7%). Mean age was 55.7 years. 32.9% patients developed AKI. PTD group had higher odds of developing AKI (odds ratio 17.5 for stage 1, 24.8 for stage 2 and 25.5 for stage 3; p<0.0001). The mean duration of hospital stay was 9 days higher in the PTD group (p<0.001). PTD group also had higher odds of transferring to ICU (OR = 9.4, p = 0.002), need for mechanical ventilation (OR = 10.1, p = 0.002) and death (OR = 10.3, p = 0.001). 32.6% had complete PTD recovery during follow-up. Proximal tubular dysfunction is highly prevalent in COVID-19 patients very early in the disease and may act as a predictor of AKI, ICU transfer, need for mechanical ventilation and death.

NALCN Channels Are Not Major targets of Gα o or Gα q Modulation in the C. elegans Egg-Laying Behavior Circuit.

Sodium leak channels (NALCN) are regulators of cell membrane potential. Previous studies in mammalian neurons and C. elegans have shown that Gα q and Gα o signaling antagonistically modulates NALCN activity to regulate neuron excitability and neurotransmitter release for behavior. Here, we test whether NALCNs mediate the effects of Gα q and/or Gα o signaling in the C. elegans egg-laying circuit. We find that while gain-of-function NALCN mutants exhibit hyperactive egg-laying behavior, NALCNs are not required for the effects of Gα q or Gα o signaling for egg laying. These results show that NALCNs are not major effectors of G-protein signaling for C. elegans egg-laying behavior.

Prediction of sodium leakage droplet size distribution in sodium-cooled fast reactor loop

Sodium spray fire is a significant containment-related safety concern in sodium-cooled fast reactors (SFRs). The droplet size distribution of sodium spray is an important factor affecting the combustion intensity of sodium spray fire. Due to the unstable chemical properties of sodium, water is usually used to simulate sodium to carry out spray experiments, and the droplet size relationship between them needs to be obtained. Based on the unstable wave theory, the droplet size similarity model characterized by liquid physical property parameters and atomization pressure difference is developed and verified from the two aspects of pressure and physical property parameters, and compared with existing models. Furthermore, an experimental facility of water atomization using a nozzle to simulate a break is built and the droplet size of water atomization under the differential pressure range of 1.0 bar–6.0 bar is obtained. The droplet size similarity model is used to predict the sodium atomization droplet size at 300–600 °C under different pressures based on these experimental data.

Numerical analysis of liquid sodium spreading on sloped floor surface under pool fire scenario in SFR systems

The accidental leaks of coolant from the heat transport circuit of Sodium-cooled Fast Reactor (SFR) can create fire events due to the reactivity of sodium with atmospheric oxygen, which can pose threat to safe operation of the reactor. The leaked sodium eventually reaches the cell floor, spreads gradually, and forms a burning pool. The thermal consequences of pool fire depend on its surface area, which is determined by the spreading process of sodium on the floor surface. In this context, numerical investigation has been carried out on the spreading behavior of burning sodium pool on the plane/sloped cell floor by developing a 3-D numerical model based on the viscous-gravity current equation of the shallow layer model. The governing equations of the model have been solved numerically by implementing the Finite Volume Method. The model developed has been validated using the experimental results published on liquid pool spreading under burning and non-burning conditions on plane and sloped floors for different leak rates. Using this model, numerical simulations have been carried out on sodium pool spreading under various leak scenarios envisaged in SFR cells based on the specific burning characteristics of sodium pool fire. The time-varying pool size and shape, pool height profile, and maximum pool area have been estimated for a wide range of sodium leak rates and typical floor slopes of interest to nuclear power plants. These predictions contribute towards the numerical evaluation of sodium pool fire scenarios pertaining to the safety of SFR.

Targeting parvalbumin-expressing neurons in the substantia nigra pars reticulata restores motor function in parkinsonian mice

The activity of substantia nigra pars reticulata (SNr) neurons, the main output structure of basal ganglia, is altered in Parkinson's disease (PD). However, neither the underlying mechanisms nor the type of neurons responsible for PD-related motor dysfunctions have been elucidated yet. Here, we show that parvalbumin-expressing SNr neurons (SNr-PV+) occupy dorsolateral parts and possess specific electrophysiological properties compared with other SNr cells. We also report that only SNr-PV+ neurons' intrinsic excitability is reduced by downregulation of sodium leak channels in a PD mouse model. Interestingly, in anesthetized parkinsonian mice invivo, SNr-PV+ neurons display a bursty pattern of activity dependent on glutamatergic tone. Finally, we demonstrate that chemogenetic inhibition of SNr-PV+ neurons is sufficient to alleviate motor impairments in parkinsonian mice. Overall, our findings establish cell-type-specific dysfunction in experimental parkinsonism in the SNr and provide a potential cellular therapeutic target to alleviate motor symptoms in PD.

Contributions of the Sodium Leak Channel NALCN to Pacemaking of Medial Ventral Tegmental Area and Substantia Nigra Dopaminergic Neurons.

We tested the role of the sodium leak channel, NALCN, in pacemaking of dopaminergic neuron (DAN) subpopulations from adult male and female mice. In situ hybridization revealed NALCN RNA in all DANs, with lower abundance in medial ventral tegmental area (VTA) relative to substantia nigra pars compacta (SNc). Despite lower relative abundance of NALCN, we found that acute pharmacological blockade of NALCN in medial VTA DANs slowed pacemaking by 49.08%. We also examined the electrophysiological properties of projection-defined VTA DAN subpopulations identified by retrograde labeling. Inhibition of NALCN reduced pacemaking in DANs projecting to medial nucleus accumbens (NAc) and others projecting to lateral NAc by 70.74% and 31.98%, respectively, suggesting that NALCN is a primary driver of pacemaking in VTA DANs. In SNc DANs, potentiating NALCN by lowering extracellular calcium concentration speeded pacemaking in wildtype but not NALCN conditional knockout mice, demonstrating functional presence of NALCN. In contrast to VTA DANs, however, pacemaking in SNc DANs was unaffected by inhibition of NALCN. Instead, we found that inhibition of NALCN increased the gain of frequency-current plots at firing frequencies slower than spontaneous firing. Similarly, inhibition of the hyperpolarization-activated cyclic nucleotide-gated (HCN) conductance increased gain but had little effect on pacemaking. Interestingly, simultaneous inhibition of NALCN and HCN resulted in significant reduction in pacemaker rate. Thus, we found NALCN makes substantial contributions to driving pacemaking in VTA DAN subpopulations. In SNc DANs, NALCN is not critical for pacemaking but inhibition of NALCN makes cells more sensitive to hyperpolarizing stimuli.SIGNIFICANCE STATEMENT Pacemaking in midbrain dopaminergic neurons (DAN) relies on multiple subthreshold conductances, including a sodium leak. Whether the sodium leak channel, NALCN, contributes to pacemaking in DANs located in the VTA and the SNc has not yet been determined. Using electrophysiology and pharmacology, we show that NALCN plays a prominent role in driving pacemaking in projection-defined VTA DAN subpopulations. By contrast, pacemaking in SNc neurons does not rely on NALCN. Instead, the presence of NALCN regulates the excitability of SNc DANs by reducing the gain of the neuron's response to inhibitory stimuli. Together, these findings will inform future efforts to obtain DAN subpopulation-specific treatments for use in neuropsychiatric disorders.