Theta and gamma rhythmic coding through two spike output modes in the hippocampus during spatial navigation

Hippocampal CA1 neurons generate single spikes and stereotyped bursts of spikes. However, it is unclear how individual neurons dynamically switch between these output modes and whether these two spiking outputs relay distinct information. We performed extracellular recordings in spatially navigating rats and cellular voltage imaging and optogenetics in awake mice. We found that spike bursts are preferentially linked to cellular and network theta rhythms (3–12 Hz) and encode an animal's position via theta phase precession, particularly as animals are entering a place field. In contrast, single spikes exhibit additional coupling to gamma rhythms (30–100 Hz), particularly as animals leave a place field. Biophysical modeling suggests that intracellular properties alone are sufficient to explain the observed input frequency-dependent spike coding. Thus, hippocampal neurons regulate the generation of bursts and single spikes according to frequency-specific network and intracellular dynamics, suggesting that these spiking modes perform distinct computations to support spatial behavior.Fil: Lowet, Eric. Boston University; Estados UnidosFil: Sheehan, Daniel J.. Boston University; Estados UnidosFil: Chialva, Ulises. Universidad Nacional del Sur. Departamento de Matemática; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca; ArgentinaFil: De Oliveira Pena, Rodrigo. New Jersey Institute of Technology; Estados UnidosFil: Mount, Rebecca A.. Boston University; Estados UnidosFil: Xiao, Sheng. Boston University; Estados UnidosFil: Zhou, Samuel L.. Boston University; Estados UnidosFil: Tseng, Hua-an. Boston University; Estados UnidosFil: Gritton, Howard. University of Illinois. Urbana - Champaign; Estados UnidosFil: Shroff, Sanaya. Boston University; Estados UnidosFil: Kondabolu, Krishnakanth. Boston University; Estados UnidosFil: Cheung, Cyrus. Boston University; Estados UnidosFil: Wang, Yangyang. Boston University; Estados UnidosFil: Piatkevich, Kiryl D.. Westlake University; ChinaFil: Boyden, Edward S.. McGovern Institute for Brain Research; Estados Unidos. Massachusetts Institute of Technology; Estados UnidosFil: Mertz, Jerome. Boston University; Estados UnidosFil: Hasselmo, Michael E.. Boston University; Estados UnidosFil: Rotstein, Horacio. New Jersey Institute of Technology; Estados UnidosFil: Han, Xue. Boston University; Estados Unido

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

Mycobacterium avium subsp. paratuberculosis PtpA Is an Endogenous Tyrosine Phosphatase Secreted during Infection

Adaptive gene expression in prokaryotes is mediated by protein kinases and phosphatases. These regulatory proteins mediate phosphorylation of histidine or aspartate in two-component systems and serine/threonine or tyrosine in eukaryotic and eukaryote-like protein kinase systems. The genome sequence of Mycobacterium avium subsp. paratuberculosis, the causative agent of Johne's disease, does not possess a defined tyrosine kinase. Nevertheless, it encodes for protein tyrosine phosphatases. Here, we report that Map1985, is a functional low-molecular tyrosine phosphatase that is secreted intracellularly upon macrophage infection. This finding suggests that Map1985 might contribute to the pathogenesis of Mycobacterium avium subsp. paratuberculosis by dephosphorylating essential macrophage signaling and/or adaptor molecules

Mechanisms of generation of membrane potential resonance in a neuron with multiple resonant ionic currents.

Neuronal membrane potential resonance (MPR) is associated with subthreshold and network oscillations. A number of voltage-gated ionic currents can contribute to the generation or amplification of MPR, but how the interaction of these currents with linear currents contributes to MPR is not well understood. We explored this in the pacemaker PD neurons of the crab pyloric network. The PD neuron MPR is sensitive to blockers of H- (IH) and calcium-currents (ICa). We used the impedance profile of the biological PD neuron, measured in voltage clamp, to constrain parameter values of a conductance-based model using a genetic algorithm and obtained many optimal parameter combinations. Unlike most cases of MPR, in these optimal models, the values of resonant- (fres) and phasonant- (fϕ = 0) frequencies were almost identical. Taking advantage of this fact, we linked the peak phase of ionic currents to their amplitude, in order to provide a mechanistic explanation the dependence of MPR on the ICa gating variable time constants. Additionally, we found that distinct pairwise correlations between ICa parameters contributed to the maintenance of fres and resonance power (QZ). Measurements of the PD neuron MPR at more hyperpolarized voltages resulted in a reduction of fres but no change in QZ. Constraining the optimal models using these data unmasked a positive correlation between the maximal conductances of IH and ICa. Thus, although IH is not necessary for MPR in this neuron type, it contributes indirectly by constraining the parameters of ICa

Characterization of impedance amplitude <i>Z</i>(<i>f</i>) and phase <i>φ</i>(<i>f</i>) into target objective functions was performed to constrain the model parameters.

<p>The individual objective functions which collectively measure goodness-of-fit were taken as the distance away from characteristic points along the <i>Z</i>(<i>f</i>) and <i>φ</i>(<i>f</i>) profiles (green circles). <b>a</b>. The attributes used along <i>Z</i>(<i>f</i>) were <i>Z</i>₀ = <i>Z</i>(<i>f</i>₀) at <i>f</i>₀ = 0.1 Hz, <i>Z</i>(<i>f</i>₁) at <i>f</i>₁ = 4 Hz, maximum impedance <i>Z</i>_max = <i>Z</i>(<i>f</i>_res) and the two points of the profile at <i>Z</i>₀+<i>Q</i>_Z/2. <i>Q</i>_Z = <i>Z</i>_max-<i>Z</i>₀. Λ_½ is the width of the profile at <i>Z</i>₀+<i>Q</i>_Z/2. <b>b</b>. The attributes used along <i>φ</i>(<i>f</i>) were <i>φ</i>(<i>f</i>_<i>0</i>), maximum advance <i>φ</i>_max, zero-phase frequency <i>f</i>_{<i>φ</i> = 0}, <i>φ</i>_{f = 2} at 2 Hz and maximum delay <i>φ</i>_min.</p

Assessing the dependence of <i>f</i>_<i>res</i> and <i>Q</i>_<i>Z</i> of the intermediate models on the linear correlation.

<p>a. Parameter values for each model were in the intermediate group (see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005565#pcbi.1005565.g007" target="_blank">Fig 7</a>) were changed along a line parallel (‖, blue) to the correlation line (black) or along a perpendicular line (┴, grey). For each model and each line, ‖ or ┴, we fit a line to the relative change in either <i>f</i>_res or <i>Q</i>_Z as a function of the relative change in . b. The sensitivity values of <i>f</i>_<i>res</i> or <i>Q</i>_<i>Z</i> to ‖ or ┴ are shown for the three groups. c. Impedance profiles showing how <i>Q</i>_Z changes when the parameters vary along a line parallel (blue) or perpendicular (grey) to the correlation line in one optimal model. Arrows show the direction of the movement of <i>Z</i>_max and <i>f</i>_<i>res</i> for the change in parameters along ‖ or ┴.</p

Membrane potential resonance MPR of the PD neuron was measured in voltage clamp.

<p><b>a</b>. During ongoing activity, the PD neuron shows a slow-wave voltage waveform ranging approximately between -60 and -30 mV. <b>b</b>. The membrane potential (V_zap) and the injected current (I_PD) were recorded when the PD neuron was voltage-clamped using a ZAP function between -60 and -30mV and sweeping frequencies between 0.1 and 4 Hz. The arrowhead indicates resonance, where the current amplitude is minimal and <i>Z</i> is maximal. <b>c</b>. The impedance amplitude <i>Z</i>(<i>f</i>) (<b>c1</b>) and phase <i>φ</i>(<i>f</i>) (<b>c2</b>) profiles of the PD neuron recorded in 18 preparations. The cross bars show the mean and SEM of <i>f</i>_<i>res</i> and <i>Z</i>_<i>max</i> (<b>c1</b>) and <i>f</i>_{<i>φ</i> = 0} (<b>c2</b>). The shaded region indicates the 95% confidence interval. <b>d</b>. The range of three <i>Z</i>(<i>f</i>) attributes <i>f</i>_res, <i>Q</i>_Z, and <i>Λ</i>_1/2 and one <i>φ</i>(<i>f</i>) attribute <i>f</i>_{<i>φ</i> = 0}. Each attribute was normalized to the median of its distribution for cross comparison. CoV is the coefficient of variation.</p

The time constants of I_Ca activation and inactivation control <i>f</i>_res and <i>Z</i>_max.

<p>The <i>Z</i>(<i>f</i>) profiles are plotted for a randomly selected optimal model (green) at different values of (<b>a</b>) and (<b>b</b>). Note that <i>f</i>_res of the control (100%) values are at 1 Hz (dashed vertical line). The currents <i>I</i>_Ca, <i>I</i>_L and <i>I</i>_total plotted as a function of cycle phase at 50% (<b>c1</b>, <b>d1</b>), 100% (<b>c2</b>, <b>d2</b>), and 150% (<b>c3</b>, <b>d3</b>) of the control values of (<b>c</b>) and (<b>d</b>). In each panel of c and d, the currents are shown at 1 Hz (along the dashed lines in <b>a</b>, <b>b</b>) and at <i>f</i>_res (filled circles in <b>a</b>, <b>b</b>).</p