Replication Stress Shapes a Protective Chromatin Environment across Fragile Genomic Regions.

Recent integrative epigenome analyses highlight the importance of functionally distinct chromatin states for accurate cell function. How these states are established and maintained is a matter of intense investigation. Here, we present evidence for DNA damage as an unexpected means to shape a protective chromatin environment at regions of recurrent replication stress (RS). Upon aberrant fork stalling, DNA damage signaling and concomitant H2AX phosphorylation coordinate the FACT-dependent deposition of macroH2A1.2, a histone variant that promotes DNA repair by homologous recombination (HR). MacroH2A1.2, in turn, facilitates the accumulation of the tumor suppressor and HR effector BRCA1 at replication forks to protect from RS-induced DNA damage. Consequently, replicating primary cells steadily accrue macroH2A1.2 at fragile regions, whereas macroH2A1.2 loss in these cells triggers DNA damage signaling-dependent senescence, a hallmark of RS. Altogether, our findings demonstrate that recurrent DNA damage contributes to the chromatin landscape to ensure the epigenomic integrity of dividing cells.

Cortical Networks Relating to Arousal Are Differentially Coupled to Neural Activity and Hemodynamics.

Even in the absence of specific sensory input or a behavioral task, the brain produces structured patterns of activity. This organized activity is modulated by changes in arousal. Here, we use wide-field voltage imaging to establish how arousal relates to cortical network voltage and hemodynamic activity in spontaneously behaving head-fixed male and female mice expressing the voltage-sensitive fluorescent FRET sensor Butterfly 1.2. We find that global voltage and hemodynamic signals are both positively correlated with changes in arousal with a maximum correlation of 0.5 and 0.25, respectively, at a time lag of 0 s. We next show that arousal influences distinct cortical regions for both voltage and hemodynamic signals. These include a broad positive correlation across most sensory-motor cortices extending posteriorly to the primary visual cortex observed in both signals. In contrast, activity in the prefrontal cortex is positively correlated to changes in arousal for the voltage signal while it is a slight net negative correlation observed in the hemodynamic signal. Additionally, we show that coherence between voltage and hemodynamic signals relative to arousal is strongest for slow frequencies below 0.15 Hz and is near zero for frequencies >1 Hz. We finally show that coupling patterns are dependent on the behavioral state of the animal with correlations being driven by periods of increased orofacial movement. Our results indicate that while hemodynamic signals show strong relations to behavior and arousal, these relations are distinct from those observed by voltage activity.

FOXS1 is increased in liver fibrosis and regulates TGFß responsiveness and proliferation pathways in human hepatic stellate cells.

Liver fibrosis commences with liver injury stimulating transforming growth factor beta (TGFß) activation of hepatic stellate cells (HSCs), causing scarring and irreversible damage. TGFß induces expression of the transcription factor Forkhead box S1 (FOXS1) in hepatocytes and may have a role in the pathogenesis of hepatocellular carcinoma (HCC). To date, no studies have determined how it affects HSCs. We analyzed human livers with cirrhosis, HCC, and a murine fibrosis model and found that FOXS1 expression is significantly higher in fibrotic livers but not in HCC. Next, we treated human LX2 HSC cells with TGFß to activate fibrotic pathways, and FOXS1 mRNA was significantly increased. To study TGFß-FOXS1 signaling, we developed human LX2 FOXS1 CRISPR KO and scrambled control HSCs. To determine differentially expressed gene transcripts controlled by TGFß-FOXS1, we performed RNA-seq in the FOXS1 KO and control cells and over 400 gene responses were attenuated in the FOXS1 KO HSCs with TGFß-activation. To validate the RNA-seq findings, we used our state-of-the-art PamGene PamStation kinase activity technology that measures hundreds of signaling pathways nonselectively in real time. Using our RNA-seq data, kinase activity data, and descriptive measurements, we found that FOXS1 controls pathways mediating TGFß responsiveness, protein translation, and proliferation. Our study is the first to identify that FOXS1 may serve as a biomarker for liver fibrosis and HSC activation, which may help with early detection of hepatic fibrosis or treatment options for end-stage liver disease.

Estrogens rapidly shape synaptic and intrinsic properties to regulate the temporal precision of songbird auditory neurons.

Sensory neurons parse millisecond-variant sound streams like birdsong and speech with exquisite precision. The auditory pallial cortex of vocal learners like humans and songbirds contains an unconventional neuromodulatory system: neuronal expression of the estrogen synthesis enzyme aromatase. Local forebrain neuroestrogens fluctuate when songbirds hear a song, and subsequently modulate bursting, gain, and temporal coding properties of auditory neurons. However, the way neuroestrogens shape intrinsic and synaptic properties of sensory neurons remains unknown. Here, using a combination of whole-cell patch clamp electrophysiology and calcium imaging, we investigate estrogenic neuromodulation of auditory neurons in a region resembling mammalian auditory association cortex. We found that estradiol rapidly enhances the temporal precision of neuronal firing via a membrane-bound G-protein coupled receptor and that estradiol rapidly suppresses inhibitory synaptic currents while sparing excitation. Notably, the rapid suppression of intrinsic excitability by estradiol was predicted by membrane input resistance and was observed in both males and females. These findings were corroborated by analysis of in vivo electrophysiology recordings, in which local estrogen synthesis blockade caused acute disruption of the temporal correlation of song-evoked firing patterns. Therefore, on a modulatory timescale, neuroestrogens alter intrinsic cellular properties and inhibitory neurotransmitter release to regulate the temporal precision of higher-order sensory neurons.

Delayed elective total shoulder arthroplasty: causes and eventual outcomes.

PURPOSE: The purpose of this study is to identify risk factors for delays in planned total shoulder arthroplasty (TSA) and determine the perioperative outcomes of TSAs that experienced a delay. METHODS: The American College of Surgeons National Quality Improvement Program (NSQIP) database was queried from 2006 to 2019 for primary TSA. Delayed TSA was defined as surgery that occurred greater than one day after hospital admission. Patient demographics, comorbidities, and post-operative complications were collected and compared; the incidence of delayed TSA was analyzed. RESULTS: The delayed patients were older, had a higher BMI, a higher rate of recent prior major surgery, and more comorbidities. Delayed patients had higher rates of postoperative complications, return to the OR, and 30-day readmission. Between 2006 and 2019, the rate of delayed TSA decreased. CONCLUSION: Surgeons should take care to ensure that patients with comorbidities undergo thorough preoperative clearance to prevent same-day cancellations and postoperative complications.

Discovery of Strong 3-Nitro-2-Phenyl-2H-Chromene Analogues as Antitrypanosomal Agents and Inhibitors of Trypanosoma cruzi Glucokinase.

Chagas disease is one of the world's neglected tropical diseases, caused by the human pathogenic protozoan parasite Trypanosoma cruzi. There is currently a lack of effective and tolerable clinically available therapeutics to treat this life-threatening illness and the discovery of modern alternative options is an urgent matter. T. cruzi glucokinase (TcGlcK) is a potential drug target because its product, d-glucose-6-phosphate, serves as a key metabolite in the pentose phosphate pathway, glycolysis, and gluconeogenesis. In 2019, we identified a novel cluster of TcGlcK inhibitors that also exhibited anti-T. cruzi efficacy called the 3-nitro-2-phenyl-2H-chromene analogues. This was achieved by performing a target-based high-throughput screening (HTS) campaign of 13,040 compounds. The selection criteria were based on first determining which compounds strongly inhibited TcGlcK in a primary screen, followed by establishing on-target confirmed hits from a confirmatory assay. Compounds that exhibited notable in vitro trypanocidal activity over the T. cruzi infective form (trypomastigotes and intracellular amastigotes) co-cultured in NIH-3T3 mammalian host cells, as well as having revealed low NIH-3T3 cytotoxicity, were further considered. Compounds GLK2-003 and GLK2-004 were determined to inhibit TcGlcK quite well with IC50 values of 6.1 µM and 4.8 µM, respectively. Illuminated by these findings, we herein screened a small compound library consisting of thirteen commercially available 3-nitro-2-phenyl-2H-chromene analogues, two of which were GLK2-003 and GLK2-004 (compounds 1 and 9, respectively). Twelve of these compounds had a one-point change from the chemical structure of GLK2-003. The analogues were run through a similar primary screening and confirmatory assay protocol to our previous HTS campaign. Subsequently, three in vitro biological assays were performed where compounds were screened against (a) T. cruzi (Tulahuen strain) infective form co-cultured within NIH-3T3 cells, (b) T. brucei brucei (427 strain) bloodstream form, and (c) NIH-3T3 host cells alone. We report on the TcGlcK inhibitor constant determinations, mode of enzyme inhibition, in vitro antitrypanosomal IC50 determinations, and an assessment of structure-activity relationships. Our results reveal that the 3-nitro-2-phenyl-2H-chromene scaffold holds promise and can be further optimized for both Chagas disease and human African trypanosomiasis early-stage drug discovery research.

Ipsilateral Stimulus Encoding in Primary and Secondary Somatosensory Cortex of Awake Mice.

Lateralization is a hallmark of somatosensory processing in the mammalian brain. However, in addition to their contralateral representation, unilateral tactile stimuli also modulate neuronal activity in somatosensory cortices of the ipsilateral hemisphere. The cellular organization and functional role of these ipsilateral stimulus responses in awake somatosensory cortices, especially regarding stimulus coding, are unknown. Here, we targeted silicon probe recordings to the vibrissa region of primary (S1) and secondary (S2) somatosensory cortex of awake head-fixed mice of either sex while delivering ipsilateral and contralateral whisker stimuli. Ipsilateral stimuli drove larger and more reliable responses in S2 than in S1, and activated a larger fraction of stimulus-responsive neurons. Ipsilateral stimulus-responsive neurons were rare in layer 4 of S1, but were located in equal proportion across all layers in S2. Linear classifier analyses further revealed that decoding of the ipsilateral stimulus was more accurate in S2 than S1, whereas S1 decoded contralateral stimuli most accurately. These results reveal substantial encoding of ipsilateral stimuli in S1 and especially S2, consistent with the hypothesis that higher cortical areas may integrate tactile inputs across larger portions of space, spanning both sides of the body.SIGNIFICANCE STATEMENT Tactile information obtained by one side of the body is represented in the activity of neurons of the opposite brain hemisphere. However, unilateral tactile stimulation also modulates neuronal activity in the other, or ipsilateral, brain hemisphere. This ipsilateral activity may play an important role in the representation and processing of tactile information, in particular when the sense of touch involves both sides of the body. Our work in the whisker system of awake mice reveals that neocortical ipsilateral activity, in particular that of deep layer excitatory neurons of secondary somatosensory cortex (S2), contains information about the presence and the velocity of unilateral tactile stimuli, which supports a key role for S2 in integrating tactile information across both body sides.

Rapid Cortical Adaptation and the Role of Thalamic Synchrony during Wakefulness.

Rapid sensory adaptation is observed across all sensory systems, and strongly shapes sensory percepts in complex sensory environments. Yet despite its ubiquity and likely necessity for survival, the mechanistic basis is poorly understood. A wide range of primarily in vitro and anesthetized studies have demonstrated the emergence of adaptation at the level of primary sensory cortex, with only modest signatures in earlier stages of processing. The nature of rapid adaptation and how it shapes sensory representations during wakefulness, and thus the potential role in perceptual adaptation, is underexplored, as are the mechanisms that underlie this phenomenon. To address these knowledge gaps, we recorded spiking activity in primary somatosensory cortex (S1) and the upstream ventral posteromedial (VPm) thalamic nucleus in the vibrissa pathway of awake male and female mice, and quantified responses to whisker stimuli delivered in isolation and embedded in an adapting sensory background. We found that cortical sensory responses were indeed adapted by persistent sensory stimulation; putative excitatory neurons were profoundly adapted, and inhibitory neurons only modestly so. Further optogenetic manipulation experiments and network modeling suggest this largely reflects adaptive changes in synchronous thalamic firing combined with robust engagement of feedforward inhibition, with little contribution from synaptic depression. Taken together, these results suggest that cortical adaptation in the regime explored here results from changes in the timing of thalamic input, and the way in which this differentially impacts cortical excitation and feedforward inhibition, pointing to a prominent role of thalamic gating in rapid adaptation of primary sensory cortex.SIGNIFICANCE STATEMENT Rapid adaptation of sensory activity strongly shapes representations of sensory inputs across all sensory pathways over the timescale of seconds, and has profound effects on sensory perception. Despite its ubiquity and theoretical role in the efficient encoding of complex sensory environments, the mechanistic basis is poorly understood, particularly during wakefulness. In this study in the vibrissa pathway of awake mice, we show that cortical representations of sensory inputs are strongly shaped by rapid adaptation, and that this is mediated primarily by adaptive gating of the thalamic inputs to primary sensory cortex and the differential way in which these inputs engage cortical subpopulations of neurons.

Understanding repeat hospitalizations in intermediate-to-high risk aortic stenosis patients following transcatheter aortic valve replacement.

OBJECTIVES: We describe the causes, timing and predictors of readmissions and analyze its impact on clinical outcomes in intermediate-to-high-risk patients with severe symptomatic aortic stenosis (AS) who underwent transcatheter aortic valve replacement (TAVR). BACKGROUND: Intermediate-high risk TAVR patients with severe AS have an increased risk for hospital readmissions due to the high burden of comorbidities. METHODS: Patients who underwent TAVR from 2012 to 2018 at a single tertiary cardiac center were included and followed for 1 year. Readmissions were categorized as noncardiovascular (non-CV) and CV. RESULTS: A total of 611 patients (410 with no readmissions, 201 with ≥1 readmissions) were included. There was a total of 317 readmissions (mean: 1.58 ± 1.09 per readmitted patient) with 65 patients having ≥2 readmissions. 64.0% were non-CV and 36.0% were CV. The top three CV causes were pacemaker/implantable cardioverter-defibrillator placement, bleeding, and stroke. About 23% occurred at 1 m, the majority were CV; 45% occurred between 7 and 12 m, the majority were non-CV. Those with ≥1 readmissions had a higher burden of comorbidities including peripheral arterial disease, diabetes, immunosuppression, prior percutaneous coronary interventions, and dialysis. Readmissions were associated with higher 1-year mortality (adjusted hazard ratio: 2.53, 95% confidence interval: 1.40-4.59; p = 0.002). High-risk patients had higher non-CV readmissions (0.37 ± 0.79 vs. 0.25 ± 0.62; p = 0.044) compared to intermediate-risk patients but similar CV readmissions (p = 0.645). CONCLUSIONS: Understanding readmissions post-TAVR will promote the early identification of at-risk groups and the implementation of preventative measures to improve outcomes and reduce the burden and costs of readmissions.

Clinical and radiographic outcomes following reverse total shoulder arthroplasty in patients 60 years of age and younger.

BACKGROUND: Although initially indicated for use in older patients, reverse total shoulder arthroplasty (rTSA) is being increasingly used in younger patients. The purpose of this study is to compare the clinical and radiographic outcomes of patients aged <60 years to those aged 60-79 years following primary rTSA. METHODS: 154 patients aged <60 years and 1763 patients aged 60-79 years were identified from an international multi-institutional Western Institutional Review Board-approved registry with a minimum 2 years' follow-up. All patients were evaluated and scored preoperatively and at latest follow-up using 5 outcome scoring metrics and 4 active range of motion (ROM) measurements. RESULTS: Patients aged <60 years were more often male (P = .023), had a higher body mass index (P = .001), higher rates of previous surgery (57% vs. 27%, P < .001), higher rates of post-traumatic arthritis (11% vs. 5%, P < .001) and inflammatory arthropathy (13% vs. 4%, P < .001), and lower rates of rotator cuff tear arthropathy (25% vs. 38%, P = .006). There were no differences in ROM between the groups but patients aged <60 years had significantly lower function and outcome metric scores and higher pain scores at latest follow-up. Adverse event rates were similar between the 2 groups, but patients aged <60 years were more likely to require revision (5.2% vs. 1.8%, P = .004). Patients aged <60 years also had lower satisfaction scores (much better/better 86% vs. 92%, P = .006). CONCLUSION: At a mean follow-up of 47 months, primary rTSA patients aged <60 years had worse clinical outcomes compared with those aged 60-79 years, with lower outcome scores, increased pain, lower function scores, and less patient satisfaction. Patients aged <60 years had higher rates of previous surgery, inflammatory arthropathy, and post-traumatic arthritis, whereas those aged 60-79 years had higher rates of rotator cuff tear arthropathy. Although complications were similar, younger patients had 3 times the risk of revision rTSA.

Clinical and radiographic outcomes after reverse total shoulder arthroplasty in patients 80 years of age and older.

BACKGROUND: Previous studies have found less favorable outcomes for patients aged 80 years and older after primary reverse total shoulder arthroplasty (rTSA). However, they are based on small sample sizes with no control group for comparison. The purpose of this study is to compare the clinical, functional, and radiographic outcomes after primary rTSA in patients aged 80 years and older with a younger cohort of patients aged 60-79 years. METHODS: Patients undergoing primary rTSA between 2004 and 2018 were identified within a multi-institutional database with a minimum of 2 years of follow-up. All patients received the same platform prosthesis. Patients were divided into 2 groups based on age: 80 years and older (n = 369) and 60-79 years (n = 1764). Statistical analyses were performed to compare the 2 age cohorts based on pre- and postoperative function and range of motion (ROM) scores, adverse event rates, pain scores, and patient satisfaction. RESULTS: Patients aged 80 years and older had lower preoperative functional and ROM scores relative to patients aged 60-79 years. The differences observed in active abduction, active forward elevation, and Constant scores exceed the minimal clinically important difference (MCID). The evaluation of function and ROM at latest follow-up showed that patients in both age cohorts had significant improvements that exceeded both the MCID and substantial clinical benefit, but older patients still scored lower relative to younger patients, with the differences in active abduction and Constant scores exceeding the MCID. Despite the lower scores observed in older patients, both groups report similar satisfaction (93% in older patients vs. 92% in younger patients, P = .379). There were no differences between the 2 age cohorts with regard to humeral radiolucent lines (9.2% vs. 8.7%, P = .765), scapular notching (11.0% vs. 10.3%, P = .727), adverse events (3.5% vs. 3.3%, P = .863), and revisions (0.8% vs. 1.8%, P = .188). CONCLUSIONS: Patients aged 80 years and older can expect significant improvements in function and ROM after primary rTSA, with satisfaction similar to that of patients aged 60-79 years. Patients in both age cohorts have similar rates of adverse events and revisions, and the rates observed in patients 80 years and older are much lower than what has previously been reported in the literature. rTSA in patients age 80 years and older is a beneficial surgery with outcomes similar to those found in younger patients, and age should not be a limiting factor when considering rTSA.

Thalamic state influences timing precision in the thalamocortical circuit.

Sensory signals from the outside world are transduced at the periphery, passing through thalamus before reaching cortex, ultimately giving rise to the sensory representations that enable us to perceive the world. The thalamocortical circuit is particularly sensitive to the temporal precision of thalamic spiking due to highly convergent synaptic connectivity. Thalamic neurons can exhibit burst and tonic modes of firing that strongly influence timing within the thalamus. The impact of these changes in thalamic state on sensory encoding in the cortex, however, remains unclear. Here, we investigated the role of thalamic state on timing in the thalamocortical circuit of the vibrissa pathway in the anesthetized rat. We optogenetically hyperpolarized thalamus while recording single unit activity in both thalamus and cortex. Tonic spike-triggered analysis revealed temporally precise thalamic spiking that was locked to weak white-noise sensory stimuli, whereas thalamic burst spiking was associated with a loss in stimulus-locked temporal precision. These thalamic state-dependent changes propagated to cortex such that the cortical timing precision was diminished during the hyperpolarized (burst biased) thalamic state. Although still sensory driven, the cortical neurons became significantly less precisely locked to the weak white-noise stimulus. The results here suggests a state-dependent differential regulation of spike timing precision in the thalamus that could gate what signals are ultimately propagated to cortex.NEW & NOTEWORTHY The majority of sensory signals are transmitted through the thalamus. There is growing evidence of complex thalamic gating through coordinated firing modes that have a strong impact on cortical sensory representations. Optogenetic hyperpolarization of thalamus pushed it into burst firing that disrupted precise time-locked sensory signaling, with a direct impact on the downstream cortical encoding, setting the stage for a timing-based thalamic gate of sensory signaling.

Inferring thalamocortical monosynaptic connectivity in vivo.

As the tools to simultaneously record electrophysiological signals from large numbers of neurons within and across brain regions become increasingly available, this opens up for the first time the possibility of establishing the details of causal relationships between monosynaptically connected neurons and the patterns of neural activation that underlie perception and behavior. Although recorded activity across synaptically connected neurons has served as the cornerstone for much of what we know about synaptic transmission and plasticity, this has largely been relegated to ex vivo preparations that enable precise targeting under relatively well-controlled conditions. Analogous studies in vivo, where image-guided targeting is often not yet possible, rely on indirect, data-driven measures, and as a result such studies have been sparse and the dependence upon important experimental parameters has not been well studied. Here, using in vivo extracellular single-unit recordings in the topographically aligned rodent thalamocortical pathway, we sought to establish a general experimental and computational framework for inferring synaptic connectivity. Specifically, attacking this problem within a statistical signal detection framework utilizing experimentally recorded data in the ventral-posterior medial (VPm) region of the thalamus and the homologous region in layer 4 of primary somatosensory cortex (S1) revealed a trade-off between network activity levels needed for the data-driven inference and synchronization of nearby neurons within the population that results in masking of synaptic relationships. Here, we provide a framework for establishing connectivity in multisite, multielectrode recordings based on statistical inference, setting the stage for large-scale assessment of synaptic connectivity within and across brain structures.NEW & NOTEWORTHY Despite the fact that all brain function relies on the long-range transfer of information across different regions, the tools enabling us to measure connectivity across brain structures are lacking. Here, we provide a statistical framework for identifying and assessing potential monosynaptic connectivity across neuronal circuits from population spiking activity that generalizes to large-scale recording technologies that will help us to better understand the signaling within networks that underlies perception and behavior.

Evaluation of Noninvasive Hemoglobin Measurements in Trauma Patients: A Repeat Study.

INTRODUCTION: Reliable, accurate, and non-invasive hemoglobin measurements would be useful in the trauma setting. The aim of this study was to re-examine the ability of the Masimo Radical 7 in this setting after recent hardware and software improvements. METHODS: Level 1 Trauma patients were prospectively enrolled in the study over a 9-mo period with the goal of obtaining 3 paired data points from 150 patients admitted to the ICU or IMU. Hospital laboratory hemoglobin values were compared with cyanomethemoglobin (HiCN) and Masimo device hemoglobin (SpHb) values using comparison plots and Bland-Altman analysis. RESULTS: A total of 380 patients were enrolled in the study with 150 of those being admitted to the ICU or IMU. Comparison of hospital lab hemoglobin and HiCN (n = 494) found a correlation of R2 = 0.92. Comparison of hospital lab hemoglobin and Masimo device hemoglobin (n = 218) found a correlation of R2 = 0.27. Bland-Altman analysis of the 218 of the comparable hospital hemoglobin and Masimo device hemoglobin values had a bias of 0.505 g/dL with 95% of values within the limits of agreement of 4.06 g/dL to -3.60 g/dL. CONCLUSIONS: The Masimo Radical 7 device has the potential to provide timely, useful clinical information, but it is not currently able to serve as an initial noninvasive diagnostic tool for trauma patients. There was poor correlation between clinical Hgb and SpHb, and because of that, SpHb should not be used to evaluate hemoglobin levels in trauma patients.

Stimulus Context and Reward Contingency Induce Behavioral Adaptation in a Rodent Tactile Detection Task.

Behavioral adaptation is a prerequisite for survival in a constantly changing sensory environment, but the underlying strategies and relevant variables driving adaptive behavior are not well understood. Many learning models and neural theories consider probabilistic computations as an efficient way to solve a variety of tasks, especially if uncertainty is involved. Although this suggests a possible role for probabilistic inference and expectation in adaptive behaviors, there is little if any evidence of this relationship experimentally. Here, we investigated adaptive behavior in the rat model by using a well controlled behavioral paradigm within a psychophysical framework to predict and quantify changes in performance of animals trained on a simple whisker-based detection task. The sensory environment of the task was changed by transforming the probabilistic distribution of whisker deflection amplitudes systematically while measuring the animal's detection performance and corresponding rate of accumulated reward. We show that the psychometric function deviates significantly and reversibly depending on the probabilistic distribution of stimuli. This change in performance relates to accumulating a constant reward count across trials, yet it is exempt from changes in reward volume. Our simple model of reward accumulation captures the observed change in psychometric sensitivity and predicts a strategy seeking to maintain reward expectation across trials in the face of the changing stimulus distribution. We conclude that rats are able maintain a constant payoff under changing sensory conditions by flexibly adjusting their behavioral strategy. Our findings suggest the existence of an internal probabilistic model that facilitates behavioral adaptation when sensory demands change.SIGNIFICANCE STATEMENT The strategy animals use to deal with a complex and ever-changing world is a key to understanding natural behavior. This study provides evidence that rodent behavioral performance is highly flexible in the face of a changing stimulus distribution, consistent with a strategy to maintain a desired accumulation of reward.

State-aware detection of sensory stimuli in the cortex of the awake mouse.

Cortical responses to sensory inputs vary across repeated presentations of identical stimuli, but how this trial-to-trial variability impacts detection of sensory inputs is not fully understood. Using multi-channel local field potential (LFP) recordings in primary somatosensory cortex (S1) of the awake mouse, we optimized a data-driven cortical state classifier to predict single-trial sensory-evoked responses, based on features of the spontaneous, ongoing LFP recorded across cortical layers. Our findings show that, by utilizing an ongoing prediction of the sensory response generated by this state classifier, an ideal observer improves overall detection accuracy and generates robust detection of sensory inputs across various states of ongoing cortical activity in the awake brain, which could have implications for variability in the performance of detection tasks across brain states.

Soft and MRI Compatible Neural Electrodes from Carbon Nanotube Fibers.

Soft and magnetic resonance imaging (MRI) compatible neural electrodes enable stable chronic electrophysiological measurements and anatomical or functional MRI studies of the entire brain without electrode interference with MRI images. These properties are important for many studies, ranging from a fundamental neurophysiological study of functional MRI signals to a chronic neuromodulatory effect investigation of therapeutic deep brain stimulation. Here we develop soft and MRI compatible neural electrodes using carbon nanotube (CNT) fibers with a diameter from 20 µm down to 5 µm. The CNT fiber electrodes demonstrate excellent interfacial electrochemical properties and greatly reduced MRI artifacts than PtIr electrodes under a 7.0 T MRI scanner. With a shuttle-assisted implantation strategy, we show that the soft CNT fiber electrodes can precisely target specific brain regions and record high-quality single-unit neural signals. Significantly, they are capable of continuously detecting and isolating single neuronal units from rats for up to 4-5 months without electrode repositioning, with greatly reduced brain inflammatory responses as compared to their stiff metal counterparts. In addition, we show that due to their high tensile strength, the CNT fiber electrodes can be retracted controllably postinsertion, which provides an effective and convenient way to do multidepth recording or potentially selecting cells with particular response properties. The chronic recording stability and MRI compatibility, together with their small size, provide the CNT fiber electrodes unique research capabilities for both basic and applied neuroscience studies.

Primary Tactile Thalamus Spiking Reflects Cognitive Signals.

Little is known about whether information transfer at primary sensory thalamic nuclei is modified by behavioral context. Here we studied the influence of previous decisions/rewards on current choices and preceding spike responses of ventroposterior medial thalamus (VPm; the primary sensory thalamus in the rat whisker-related tactile system). We trained head-fixed rats to detect a ramp-like deflection of one whisker interspersed within ongoing white noise stimulation. Using generative modeling of behavior, we identify two task-related variables that are predictive of actual decisions. The first reflects task engagement on a local scale ("trial history": defined as the decisions and outcomes of a small number of past trials), whereas the other captures behavioral dynamics on a global scale ("satiation": slow dynamics of the response pattern along an entire session). Although satiation brought about a slow drift from Go to NoGo decisions during the session, trial history was related to local (trial-by-trial) patterning of Go and NoGo decisions. A second model that related the same predictors first to VPm spike responses, and from there to decisions, indicated that spiking, in contrast to behavior, is sensitive to trial history but relatively insensitive to satiation. Trial history influences VPm spike rates and regularity such that a history of Go decisions would predict fewer noise-driven spikes (but more regular ones), and more ramp-driven spikes. Neuronal activity in VPm, thus, is sensitive to local behavioral history, and may play an important role in higher-order cognitive signaling.SIGNIFICANCE STATEMENT It is an important question for perceptual and brain functions to find out whether cognitive signals modulate the sensory signal stream and if so, where in the brain this happens. This study provides evidence that decision and reward history can already be reflected in the ascending sensory pathway, on the level of first-order sensory thalamus. Cognitive signals are relayed very selectively such that only local trial history (spanning a few trials) but not global history (spanning an entire session) are reflected.

Impact of prehospital airway management on combat mortality.

INTRODUCTION: Analysis of modern military conflicts suggests that airway compromise remains the second leading cause of preventable death of combat fatalities. This study compares outcomes of combat casualties that received prehospital airway interventions, specifically bag valve mask (BVM) ventilation, cricothyrotomy, and supraglottic airway (SGA) placement. The goal is to compare the effectiveness of airway management strategies used in the military pre-hospital setting. METHODS: This retrospective chart review of 1267 US Army medical evacuation patient care records, compared outcomes of casualties that received prehospital advanced airway interventions. The patients consisted of US military injured in Operation Enduring Freedom January 2011-March 2014. Compared outcomes consisted of vent-, ICU-, and hospital-free days. RESULTS: Those with SGA placement experienced fewer vent-free days, ICU-free days, and hospital-free days compared to BVM and cricothyrotomy patients. The groups did not significantly differ in rates of 30-day survival. The odds for survival were not significantly higher for BVM versus SGA patients (OR 1.5, 95% CI 0.2-9.8), cricothyrotomy versus SGA patients (OR 3.9, 95% CI 0.6-24.9), or cricothyrotomy versus BVM patients (OR 2.7, 95% CI 0.5-13.8) in a logistic regression model adjusting for GCS. CONCLUSION: This study supports prehospital BVM ventilation as a possible alternative to cricothyrotomy as there was no difference in measured outcomes between the groups. It further cautions against SGA use in the prehospital combat setting due to higher morbidity demonstrated by fewer ventilator, hospital, and ICU free days than those receiving cricothyrotomy or BVM ventilation. There was no difference in 30-day survival between the groups.

Thalamic state control of cortical paired-pulse dynamics.

Sensory stimulation drives complex interactions across neural circuits as information is encoded and then transmitted from one brain region to the next. In the highly interconnected thalamocortical circuit, these complex interactions elicit repeatable neural dynamics in response to temporal patterns of stimuli that provide insight into the circuit properties that generated them. Here, using a combination of in vivo voltage-sensitive dye (VSD) imaging of cortex, single-unit recording in thalamus, and optogenetics to manipulate thalamic state in the rodent vibrissa pathway, we probed the thalamocortical circuit with simple temporal patterns of stimuli delivered either to the whiskers on the face (sensory stimulation) or to the thalamus directly via electrical or optogenetic inputs (artificial stimulation). VSD imaging of cortex in response to whisker stimulation revealed classical suppressive dynamics, while artificial stimulation of thalamus produced an additional facilitation dynamic in cortex not observed with sensory stimulation. Thalamic neurons showed enhanced bursting activity in response to artificial stimulation, suggesting that bursting dynamics may underlie the facilitation mechanism we observed in cortex. To test this experimentally, we directly depolarized the thalamus, using optogenetic modulation of the firing activity to shift from a burst to a tonic mode. In the optogenetically depolarized thalamic state, the cortical facilitation dynamic was completely abolished. Together, the results obtained here from simple probes suggest that thalamic state, and ultimately thalamic bursting, may play a key role in shaping more complex stimulus-evoked dynamics in the thalamocortical pathway. NEW & NOTEWORTHY: For the first time, we have been able to utilize optogenetic modulation of thalamic firing modes combined with optical imaging of cortex in the rat vibrissa system to directly test the role of thalamic state in shaping cortical response properties.