Dissociable hindbrain GLP1R circuits for satiety and aversion.

The most successful obesity therapeutics, glucagon-like peptide-1 receptor (GLP1R) agonists, cause aversive responses such as nausea and vomiting1,2, effects that may contribute to their efficacy. Here, we investigated the brain circuits that link satiety to aversion, and unexpectedly discovered that the neural circuits mediating these effects are functionally separable. Systematic investigation across drug-accessible GLP1R populations revealed that only hindbrain neurons are required for the efficacy of GLP1-based obesity drugs. In vivo two-photon imaging of hindbrain GLP1R neurons demonstrated that most neurons are tuned to either nutritive or aversive stimuli, but not both. Furthermore, simultaneous imaging of hindbrain subregions indicated that area postrema (AP) GLP1R neurons are broadly responsive, whereas nucleus of the solitary tract (NTS) GLP1R neurons are biased towards nutritive stimuli. Strikingly, separate manipulation of these populations demonstrated that activation of NTSGLP1R neurons triggers satiety in the absence of aversion, whereas activation of APGLP1R neurons triggers strong aversion with food intake reduction. Anatomical and behavioural analyses revealed that NTSGLP1R and APGLP1R neurons send projections to different downstream brain regions to drive satiety and aversion, respectively. Importantly, GLP1R agonists reduce food intake even when the aversion pathway is inhibited. Overall, these findings highlight NTSGLP1R neurons as a population that could be selectively targeted to promote weight loss while avoiding the adverse side effects that limit treatment adherence.

Degradation in Binaural and Spatial Hearing and Auditory Temporal Processing Abilities as a Function of Aging.

Objectives: Sensorineural hearing loss is common with advancing age, but even when hearing is normal or near normal in older persons, performance deficits are often seen for suprathreshold listening tasks such as understanding speech in background noise or localizing the direction sounds are coming from. This suggests there is also a more central source of the problem. Objectives of this study were to examine as a function of age (young adult to septuagenarian) performance on: 1) a spatial acuity task examining lateralization ability, and a spatial speech-in-noise (SSIN) recognition task, both measured in a hemi-anechoic sound field using a circular horizontal-plane loudspeaker array, and 2) a suprathreshold auditory temporal processing task and a spectro-temporal processing task, both measured under headphones. Further, we examined any correlations between the measures. Design: Subjects were 48 adults, aged 21 to 78, with either normal hearing or only a mild sensorineural hearing loss through 4000 Hz. The lateralization task measured minimum audible angle (MAA) for 500 and 4000 Hz narrowband noise (NBN) bursts in diffuse background noise for both an on-axis (subject facing 0°) and off-axis (facing 45°) listening condition at signal-to-noise ratios (SNRs) of -3, -6, -9, and -12 dB. For 42 of the subjects, SSIN testing was also completed for key word recognition in sentences in multi-talker babble noise; specifically, the separation between speech and noise loudspeakers was adaptively varied to determine the difference needed for 40% and 80% correct performance levels. Finally, auditory temporal processing ability was examined using the Temporal Fine Structure test (44 subjects), and the Spectro-Temporal Modulation test (46 subjects). Results: Mean lateralization performances were poorer (larger MAAs) in older compared to younger subjects, particularly in the more adverse listening conditions (i.e., for 4000 Hz, off-axis, and at poorer SNRs). Performance variability was notably higher for older subjects than for young adults. The 4000 Hz NBN bursts produced larger MAAs than did 500 Hz NBN bursts. The SSIN data also showed declining mean performance with age at both criterion levels, with greater variability again found for older subjects. Spearman rho analyses revealed some low to moderate, but significant correlation coefficients for age versus MAA and for age versus SSIN results. Results from both the TFS and STM showed decreased mean performance with aging, and revealed moderate, significant correlations, with the strongest relationship shown with the TFS test. Finally, of note, extended-high-frequency (EHF) hearing loss (measured between 9000 and 16,000 Hz) was found to increase with aging, but was not seen in the young adult subjects. Conclusions: Particularly for more adverse listening conditions, age-related deficits were found on both of the spatial hearing tasks and in temporal and spectro-temporal processing abilities. It may be that deficits in temporal processing ability contribute to poorer spatial hearing performance in older subjects due to inaccurate coding of binaural/interaural timing information sent from the periphery to the brainstem. In addition, EHF hearing loss may be a coexisting factor that impacts performance in older subjects.

Outcomes Following Surgical Fixation of Distal Radius Fractures in Patients With Chronic Kidney Disease.

Purpose: Moderate-to-severe chronic kidney disease (CKD, stages III-IV) and end-stage renal disease (ESRD or CKD stage V) are known to be independent risk factors for fragility fracture. Altered bone and mineral metabolism contributes to greater complications and mortality rates in the setting of fractures, although most existing literature is limited to hip fractures. We hypothesized that patients with moderate-to-severe CKD or ESRD would have greater complication rates after surgical treatment of distal radius fractures compared with those without CKD. Methods: We retrospectively identified all patients at a level 1 trauma center between 2008 and 2018 who had a diagnosis of stage III-IV CKD or ESRD at the time of operative fixation of a distal radius fracture. We recorded demographic data, comorbidities, and surgical complications. Data for readmissions within 90 days and 1-year mortality were collected. A 2:1 sex-matched control group without CKD who underwent distal radius fixation was selected for comparison, with age-adjusted analysis. Results: A total of 32 patients with CKD (78.1% CKD stage III/IV, 21.9% ESRD) and 62 without CKD were identified. The mean age was 67 ± 12 years in the CKD group and 55 ± 15 years in the control group. The CKD group had a higher Charlson Comorbidity Index (5.7 vs 2.0). Surgical complication rate in the CKD group was 12.5% (12.0% CKD III/IV; 14.3% ESRD). Neither early nor late surgical complication rates were statistically different from those in patients without CKD. Reoperation rate as well as 30- and 90-day readmission rates were similar between groups. Overall, 1-year mortality was greater in the CKD group (9.4% vs 0%). Conclusions: Surgical complications and readmission rates are similar in patients with and without CKD after distal radius fracture fixation. However, 1-year mortality rate is significantly higher after distal radius fixation in patients with moderate-to-severe CKD or ESRD. Type of study/level of evidence: Prognostic IIIa.

Outcomes Following Surgical Fixation of Upper Extremity Fractures in Patients with Chronic Kidney Disease.

Purpose: Moderate to severe (stage III-IV) chronic kidney disease (CKD) and end stage renal disease (ESRD) have been shown to be independent risk factors for sustaining a fragility fracture. High rates of complications and mortality are associated with fracture fixation in patients with CKD, but existing literature is limited. It is unknown how CKD stage III-IV or ESRD affects outcomes in upper-extremity fractures. We hypothesize that patients with CKD stage III-IV or ESRD will have high complication rates after surgical fixation of upper extremity fractures. Methods: We identified all patients between 2008 and 2018 who underwent operative fixation of an upper extremity fracture proximal to the distal radius with a diagnosis of CKD stage III-IV or ESRD at the time of injury. Those with an acute kidney injury at the time of injury or a history of a kidney transplant were excluded. Demographics, medical complications, and surgical complications were collected retrospectively. Data on readmissions within 90 days and mortality within 1 year were also collected. Results: Thirty-five patients were identified. Three patients had ESRD. Fractures included two clavicle, twelve proximal humerus, one humeral shaft, ten distal humerus, five olecranon, two ulnar shaft, one radial shaft, and two both-bone forearm fractures. In total, 91.4% of fractures were closed injuries. Surgical complications occurred in 40% of patients. The reoperation rate was 11.4%, and all cases of reoperation involved hardware removal. The all-cause 90-day readmission rate was 34.3%. The 1-year mortality rate was 8.6%. Conclusions: Surgical complications occurred in 40% of patients with CKD stage III-IV or ESRD who underwent fixation for an upper extremity fracture. It is important to counsel these patients regarding their high risk for complications. Further research is needed to investigate and identify how to mitigate risk. Type of study/level of evidence: Prognostic IV.

Computed tomographic features of canine intracranial and jugular foraminal masses involving the combined glossopharyngeal, vagus, and accessory nerve roots.

A chronic cough, gag, or retch is a common presenting clinical complaint in dogs. Those refractory to conservative management frequently undergo further diagnostic tests to investigate the cause, including CT examination of their head, neck, and thorax for detailed morphological assessment of their respiratory and upper gastrointestinal tract. This case series describes five patients with CT characteristics consistent with an intracranial and jugular foraminal mass of the combined glossopharyngeal (IX), vagus (X), and accessory (XI) cranial nerves and secondary features consistent with their paresis. The consistent primary CT characteristics included an intracranial, extra-axial, cerebellomedullary angle, and jugular foraminal soft tissue attenuating, strongly enhancing mass (5/5). Secondary characteristics included smooth widening of the bony jugular foramen (5/5), mild hyperostosis of the petrous temporal bone (3/5), isolated severe atrophy of the ipsilateral sternocephalic, cleidocephalic, and trapezius muscles (5/5), atrophy of the ipsilateral thyroarytenoideus and cricoarytenoideus muscles of the vocal fold (5/5), and an ipsilateral "dropped" shoulder (4/5). Positional variation of the patient in CT under general anesthesia made the "dropped" shoulder of equivocal significance. The reported clinical signs and secondary CT features reflect a unilateral paresis of the combined cranial nerves (IX, X, and XI) and are consistent with jugular foramen syndrome/Vernet's syndrome reported in humans. The authors believe this condition is likely chronically underdiagnosed without CT examination, and this case series should enable earlier CT diagnosis in future cases.

Utilization of biochar for remediation of heavy metals in aqueous environments: A review and bibliometric analysis.

Biochar usage for removing heavy metals from aqueous environments has emerged as a promising research area with significant environmental and economic benefits. Using the PICO approach, the research question aimed to explore using biochar to remove heavy metals from aqueous media. We merged the data from Scopus and the Web of Science Core Collection databases to acquire a comprehensive perspective of the subject. The PRISMA guidelines were applied to establish the search parameters, identify the appropriate articles, and collect the bibliographic information from the publications between 2010 and 2022. The bibliometric analysis showed that biochar-based heavy metal remediation is a research field with increasing scholarly attention. The removal of Cr(VI), Pb(II), Cd(II), and Cu(II) was the most studied among the heavy metals. We identified five main clusters centered on adsorption, water treatment, adsorption models, analytical techniques, and hydrothermal carbonization by performing keyword co-occurrence analysis. Trending topics include biochar reusability, modification, acid mine drainage (AMD), wastewater treatment, and hydrochar. The reutilization of heavy metal-loaded spent biochar includes transforming it into electrodes for supercapacitors or stable catalyst materials. This study provides a comprehensive overview of biochar-based heavy metal remediation in aquatic environments and highlights knowledge gaps and future research directions.

Cross-sectional associations of actigraphy-assessed sleep with dietary outcomes in emerging adults.

BACKGROUND/OBJECTIVES: Emerging adults (~18-28 years of age) have a high prevalence of poor sleeping habits and poor diet quality; however, little is known on whether these poor sleeping habits are associated with dietary outcomes in this age group. This study assessed associations between actigraphy-based sleep with energy intake (EI), overall diet quality, and measures of meal timing in emerging adults. SUBJECTS/METHODS: Data on 135 emerging adults (age = 19.4 ± 1.3 years; body mass index (BMI) = 26.5 ± 6.9 kg/m2; 58% female; 65% White) from the RIGHT Track Health project were used. Measures included actigraphy-assessed sleep duration, sleep efficiency, sleep timing midpoint, day-to-day sleep duration and sleep timing midpoint variability and combined sleep duration and sleep timing behaviors (early-bed/late-rise, early-bed/early-rise, late-bed/late-rise, late-bed/early-rise); EI (three 24-h dietary recalls), diet quality (Healthy Eating Index 2015 total score) and meal timing outcomes (timing of first and last meal intake, total duration, and midpoint of the eating window). RESULTS: Shorter sleep duration, later sleep timing midpoint and greater sleep efficiency, as well as combined late-bed/late-rise and late-bed/early-rise groups, were associated with lower diet quality. Greater sleep timing midpoint variability was associated with higher EI, and the late-bed/early-rise group had significantly delayed first meal timing. CONCLUSION: In emerging adults, shorter sleep duration and later sleep timing are associated with lower overall diet quality, and greater sleep timing variability is associated with higher EI. Future research is needed to examine the role of sleep on diet quality and eating habits to identify potential targets for nutritional interventions in this age group.

Hearing ability of prairie voles (Microtus ochrogaster).

The hearing abilities of mammals are impacted by factors such as social cues, habitat, and physical characteristics. Despite being used commonly to study social behaviors, hearing of the monogamous prairie vole (Microtus ochrogaster) has never been characterized. In this study, anatomical features are measured and auditory brainstem responses (ABRs) are used to measure auditory capabilities of prairie voles, characterizing monaural and binaural hearing and hearing range. Sexually naive male and female voles were measured to characterize differences due to sex. It was found that prairie voles show a hearing range with greatest sensitivity between 8 and 32 kHz, binaural hearing across interaural time difference ranges appropriate for their head sizes. No differences are shown between the sexes in binaural hearing or hearing range (except at 1 kHz), however, female voles have increased amplitude of peripheral ABR waves I and II and longer latency of waves III and IV compared to males. The results confirm that prairie voles have a broad hearing range, binaural hearing consistent with rodents of similar size, and differences in amplitudes and thresholds of monaural physiological measures between the sexes. These data further highlight the necessity to understand sex-specific differences in neural processing that may underly variability in responses between sexes.

Telemedicine in Arthroplasty Patients: Which Factors Are Associated With High Satisfaction?

Background: During the initial coronavirus pandemic lockdown period, remote hip and knee arthroplasty care was heavily employed out of necessity. However, data on patient satisfaction with telemedicine specific to hip and knee arthroplasty patients remains unknown. Methods: All patients who had a telemedicine visit in the hip and knee arthroplasty department and completed a telemedicine satisfaction survey at a specialty hospital from April 1, 2020, to December 31, 2020, were identified. Patient satisfaction with telemedicine, gauged through a series of questions, were analyzed and evaluated over time. Independent factors associated with high satisfaction, defined as the "Top Box" response to the survey question "Likelihood of your recommending our video visit service to others," were identified. Results: Overall, 29,003 patients who had an in-person or telemedicine visit in the hip and knee arthroplasty department during the study period were identified. During the initial coronavirus pandemic lockdown period, defined as April 1, 2020-May 31, 2020, rate of overall telemedicine utilization was approximately 84%. After the initial lockdown period, the rate of overall telemedicine utilization was approximately 8% of all visits per month. Average satisfaction scores for a series of 14 questions were consistently above 4.5 out of 5. Multivariable regression revealed younger age, particularly 18-64 years old, to be the only independent factor associated with high satisfaction with telemedicine. The rate of high satisfaction remained statistically similar throughout the study period (P > .05). Conclusions: Patient satisfaction with telemedicine was consistently high in various domains and remained high throughout the study period, regardless of loosened pandemic restrictions. This technology will most likely continue to be utilized, but perhaps it should be targeted at patients younger than 65 years of age.

Associations of actigraphy-assessed sleep variables with adiposity and serum cardiometabolic outcomes in emerging adults.

This study assessed associations of actigraphy-assessed sleep with adiposity and serum cardiometabolic outcomes in emerging adults, and whether sex and race modified these associations. Data on 147 emerging adults (age = 19.4 ± 1.3 years; body mass index = 26.4 ± 7.0 kg m-2 ; 59% female; 65% White) from RIGHT Track Health were used. Actigraphy-based sleep measures included sleep duration, sleep efficiency, sleep timing midpoint, day-to-day sleep duration and sleep timing midpoint variability. Combined sleep duration and sleep timing behaviours were also derived (early-bed/late-rise, early-bed/early-rise, late-bed/late-rise, late-bed/early-rise). Outcomes included body mass index and BodPod-assessed fat mass index, fasting serum leptin, C-reactive protein, and homeostatic model assessment-insulin resistance. Sleep duration was 5.4 h per night. We noted an inverse association between sleep duration and homeostatic model assessment-insulin resistance. The early-bed/early-rise group had greater body mass index, C-reactive protein and homeostatic model assessment-insulin resistance compared with the early-bed/late-rise group (referent). Sex modified associations of sleep efficiency with C-reactive protein; stratified results revealed positive association between sleep efficiency and C-reactive protein in males, but not females. Race modified associations of sleep duration with body mass index and leptin, and of sleep duration variability with C-reactive protein. Stratified analyses revealed inverse associations between sleep duration with body mass index and leptin in Black, multiracial/other race individuals only. Positive association between sleep duration variability and C-reactive protein was noted in White individuals only. Shorter sleep duration, particularly when combined with earlier sleep timing, is associated with greater adiposity and serum cardiometabolic outcomes. Additional studies are needed to assess individual- and contextual-level factors that may contribute to sex and race differences in sleep health and cardiometabolic risk in emerging adults.

Forecasting daily COVID-19 cases with gradient boosted regression trees and other methods: evidence from U.S. cities.

Introduction: There is a vast literature on the performance of different short-term forecasting models for country specific COVID-19 cases, but much less research with respect to city level cases. This paper employs daily case counts for 25 Metropolitan Statistical Areas (MSAs) in the U.S. to evaluate the efficacy of a variety of statistical forecasting models with respect to 7 and 28-day ahead predictions. Methods: This study employed Gradient Boosted Regression Trees (GBRT), Linear Mixed Effects (LME), Susceptible, Infectious, or Recovered (SIR), and Seasonal Autoregressive Integrated Moving Average (SARIMA) models to generate daily forecasts of COVID-19 cases from November 2020 to March 2021. Results: Consistent with other research that have employed Machine Learning (ML) based methods, we find that Median Absolute Percentage Error (MAPE) values for both 7-day ahead and 28-day ahead predictions from GBRTs are lower than corresponding values from SIR, Linear Mixed Effects (LME), and Seasonal Autoregressive Integrated Moving Average (SARIMA) specifications for the majority of MSAs during November-December 2020 and January 2021. GBRT and SARIMA models do not offer high-quality predictions for February 2021. However, SARIMA generated MAPE values for 28-day ahead predictions are slightly lower than corresponding GBRT estimates for March 2021. Discussion: The results of this research demonstrate that basic ML models can lead to relatively accurate forecasts at the local level, which is important for resource allocation decisions and epidemiological surveillance by policymakers.

Correcting Hip Dysplasia in Young Adults: Intraoperative Navigation and Outcomes.

Developmental dysplasia of the hip (DDH) often leads to characteristic acetabular dysplasia and typical femoral anomalies. There are numerous treatments for skeletally mature patients with DDH including hip arthroscopy, pelvic and femoral osteotomies, as well as total hip arthroplasty. Before proceeding to an arthroplasty procedure, it can be helpful to obtain an opinion of a hip preservation specialist to ascertain if alternative surgical treatments could contribute to the patient's care. In general, the use of robotic navigation has been associated with a higher proportion of cups placed in the Lewinnek safe zone, larger improvements in Harris Hip Scores, and no difference in overall complication rates in comparison to manual total hip arthroplasty. The use of robotic navigation allows for both 2-dimensional and 3-dimensional preoperative templating, enabling the surgeon to plan the position of the construct such that it achieves maximum bony purchase and hip stability. In complex DDH cases, surgeons can work with a biomechanics department to complete a fit check assessment, which utilizes 3-dimensional templating software to ascertain the appropriateness of the implant's geometry with the patient's anatomy. Furthermore, a 3-dimensional printed plastic model of the pelvis and/or femur can be constructed in order to complete a rehearsal procedure, which may be particularly helpful for those cases involving osteotomies. The literature on the use of robotic-assisted total hip arthroplasty in patients with DDH demonstrates improved component positioning in comparison to navigated as well as manual methods; however, studies with long-term follow-up in this patient population are lacking.

TNRC18 engages H3K9me3 to mediate silencing of endogenous retrotransposons.

Trimethylation of histone H3 lysine 9 (H3K9me3) is crucial for the regulation of gene repression and heterochromatin formation, cell-fate determination and organismal development1. H3K9me3 also provides an essential mechanism for silencing transposable elements1-4. However, previous studies have shown that canonical H3K9me3 readers (for example, HP1 (refs. 5-9) and MPP8 (refs. 10-12)) have limited roles in silencing endogenous retroviruses (ERVs), one of the main transposable element classes in the mammalian genome13. Here we report that trinucleotide-repeat-containing 18 (TNRC18), a poorly understood chromatin regulator, recognizes H3K9me3 to mediate the silencing of ERV class I (ERV1) elements such as LTR12 (ref. 14). Biochemical, biophysical and structural studies identified the carboxy-terminal bromo-adjacent homology (BAH) domain of TNRC18 (TNRC18(BAH)) as an H3K9me3-specific reader. Moreover, the amino-terminal segment of TNRC18 is a platform for the direct recruitment of co-repressors such as HDAC-Sin3-NCoR complexes, thus enforcing optimal repression of the H3K9me3-demarcated ERVs. Point mutagenesis that disrupts the TNRC18(BAH)-mediated H3K9me3 engagement caused neonatal death in mice and, in multiple mammalian cell models, led to derepressed expression of ERVs, which affected the landscape of cis-regulatory elements and, therefore, gene-expression programmes. Collectively, we describe a new H3K9me3-sensing and regulatory pathway that operates to epigenetically silence evolutionarily young ERVs and exert substantial effects on host genome integrity, transcriptomic regulation, immunity and development.

AgRP neuron activity promotes associations between sensory and nutritive signals to guide flavor preference.

OBJECTIVE: The learned associations between sensory cues (e.g., taste, smell) and nutritive value (e.g., calories, post-ingestive signaling) of foods powerfully influences our eating behavior [1], but the neural circuits that mediate these associations are not well understood. Here, we examined the role of agouti-related protein (AgRP)-expressing neurons - neurons which are critical drivers of feeding behavior [2; 3] - in mediating flavor-nutrient learning (FNL). METHODS: Because mice prefer flavors associated with AgRP neuron activity suppression [4], we examined how optogenetic stimulation of AgRP neurons during intake influences FNL, and used fiber photometry to determine how endogenous AgRP neuron activity tracks associations between flavors and nutrients. RESULTS: We unexpectedly found that tonic activity in AgRP neurons during FNL potentiated, rather than prevented, the development of flavor preferences. There were notable sex differences in the mechanisms for this potentiation. Specifically, in male mice, AgRP neuron activity increased flavor consumption during FNL training, thereby strengthening the association between flavors and nutrients. In female mice, AgRP neuron activity enhanced flavor-nutrient preferences independently of consumption during training, suggesting that AgRP neuron activity enhances the reward value of the nutrient-paired flavor. Finally, in vivo neural activity analyses demonstrated that acute AgRP neuron dynamics track the association between flavors and nutrients in both sexes. CONCLUSIONS: Overall, these data (1) demonstrate that AgRP neuron activity enhances associations between flavors and nutrients in a sex-dependent manner and (2) reveal that AgRP neurons track and rapidly update these associations. Taken together, our findings provide new insight into the role of AgRP neurons in assimilating sensory and nutritive signals for food reinforcement.

Photobiomodulation Can Enhance Stem Cell Viability in Cochlea with Auditory Neuropathy but Does Not Restore Hearing.

Sensorineural hearing loss is very difficult to treat. Currently, one of the techniques used for hearing rehabilitation is a cochlear implant that can transform sound into electrical signals instead of inner ear hair cells. However, the prognosis remains very poor if sufficient auditory nerve cells are not secured. In this study, the effect of mouse embryonic stem cells (mESC) and photobiomodulation (PBM) combined treatment on auditory function and auditory nerve cells in a secondary neuropathy animal model was investigated. To confirm the engraftment of stem cells in vitro, cochlear explants were treated with kanamycin (KM) to mimic nerve damage and then cocultured with GFP-mESC. GFP-mESCs were observed to have attached and integrated into the explanted samples. An animal model for secondary neurodegeneration was achieved by KM treatment and was treated by a combination therapy of GFP-mESC and NIR-PBM at 8 weeks of KM treatment. Hearing recovery by functional testing using auditory brain stem response (ABR) and eABR was measured as well as morphological changes and epifluorescence analysis were conducted after 2 weeks of combination therapy. KM treatment elevated the hearing threshold at 70-80 dB and even after the combination treatment with GFP-mESC and PBM was applied, the auditory function was not restored. In addition, the stem cells transplanted into cochlea has exponentially increased due to PBM treatment although did not produce any malignancy. This study confirmed that the combined treatment with mESC and PBM could not improve hearing or increase the response of the auditory nerve. Nevertheless, it is noteworthy in this study that the cells are distributed in most cochlear tissues and the proliferation of stem cells was very active in animals irradiated with PBM compared to other groups wherein the stem cells had disappeared immediately after transplantation or existed for only a short period of time.

AgRP neuron activity promotes associations between sensory and nutritive signals to guide flavor preference.

Objective: The learned associations between sensory cues (e.g., taste, smell) and nutritive value (e.g., calories, post-ingestive signaling) of foods powerfully influences our eating behavior [1], but the neural circuits that mediate these associations are not well understood. Here, we examined the role of agouti-related protein (AgRP)-expressing neurons - neurons which are critical drivers of feeding behavior [2; 3] - in mediating flavor-nutrient learning (FNL). Methods: Because mice prefer flavors associated with AgRP neuron activity suppression [4], we examined how optogenetic stimulation of AgRP neurons during intake influences FNL, and used fiber photometry to determine how endogenous AgRP neuron activity tracks associations between flavors and nutrients. Results: We unexpectedly found that tonic activity in AgRP neurons during FNL potentiated, rather than prevented, the development of flavor preferences. There were notable sex differences in the mechanisms for this potentiation. Specifically, in male mice, AgRP neuron activity increased flavor consumption during FNL training, thereby strengthening the association between flavors and nutrients. In female mice, AgRP neuron activity enhanced flavor-nutrient preferences independently of consumption during training, suggesting that AgRP neuron activity enhances the reward value of the nutrient-paired flavor. Finally, in vivo neural activity analyses demonstrated that acute AgRP neuron dynamics track the association between flavors and nutrients in both sexes. Conclusions: Overall, these data (1) demonstrate that AgRP neuron activity enhances associations between flavors and nutrients in a sex-dependent manner and (2) reveal that AgRP neurons track and update these associations on fast timescales. Taken together, our findings provide new insight into the role of AgRP neurons in assimilating sensory and nutritive signals for food reinforcement.

Dual effects of the small-conductance Ca2+-activated K+ current on human atrial electrophysiology and Ca2+-driven arrhythmogenesis: an in silico study.

By sensing changes in intracellular Ca2+, small-conductance Ca2+-activated K+ (SK) channels dynamically regulate the dynamics of the cardiac action potential (AP) on a beat-to-beat basis. Given their predominance in atria versus ventricles, SK channels are considered a promising atrial-selective pharmacological target against atrial fibrillation (AF), the most common cardiac arrhythmia. However, the precise contribution of SK current (ISK) to atrial arrhythmogenesis is poorly understood, and may potentially involve different mechanisms that depend on species, heart rates, and degree of AF-induced atrial remodeling. Both reduced and enhanced ISK have been linked to AF. Similarly, both SK channel up- and downregulation have been reported in chronic AF (cAF) versus normal sinus rhythm (nSR) patient samples. Here, we use our multiscale modeling framework to obtain mechanistic insights into the contribution of ISK in human atrial cardiomyocyte electrophysiology. We simulate several protocols to quantify how ISK modulation affects the regulation of AP duration (APD), Ca2+ transient, refractoriness, and occurrence of alternans and delayed afterdepolarizations (DADs). Our simulations show that ISK activation shortens the APD and atrial effective refractory period, limits Ca2+ cycling, and slightly increases the propensity for alternans in both nSR and cAF conditions. We also show that increasing ISK counteracts DAD development by enhancing the repolarization force that opposes the Ca2+-dependent depolarization. Taken together, our results suggest that increasing ISK in human atrial cardiomyocytes could promote reentry while protecting against triggered activity. Depending on the leading arrhythmogenic mechanism, ISK inhibition may thus be a beneficial or detrimental anti-AF strategy.NEW & NOTEWORTHY Using our established framework for human atrial myocyte simulations, we investigated the role of the small-conductance Ca2+-activated K+ current (ISK) in the regulation of cell function and the development of Ca2+-driven arrhythmias. We found that ISK inhibition, a promising atrial-selective pharmacological strategy against atrial fibrillation, counteracts the reentry-promoting abbreviation of atrial refractoriness, but renders human atrial myocytes more vulnerable to delayed afterdepolarizations, thus potentially increasing the propensity for ectopic (triggered) activity.

A Dynamical Systems Approach to Characterizing Brain-Body Interactions during Movement: Challenges, Interpretations, and Recommendations.

Brain-body interactions (BBIs) have been the focus of intense scrutiny since the inception of the scientific method, playing a foundational role in the earliest debates over the philosophy of science. Contemporary investigations of BBIs to elucidate the neural principles of motor control have benefited from advances in neuroimaging, device engineering, and signal processing. However, these studies generally suffer from two major limitations. First, they rely on interpretations of 'brain' activity that are behavioral in nature, rather than neuroanatomical or biophysical. Second, they employ methodological approaches that are inconsistent with a dynamical systems approach to neuromotor control. These limitations represent a fundamental challenge to the use of BBIs for answering basic and applied research questions in neuroimaging and neurorehabilitation. Thus, this review is written as a tutorial to address both limitations for those interested in studying BBIs through a dynamical systems lens. First, we outline current best practices for acquiring, interpreting, and cleaning scalp-measured electroencephalography (EEG) acquired during whole-body movement. Second, we discuss historical and current theories for modeling EEG and kinematic data as dynamical systems. Third, we provide worked examples from both canonical model systems and from empirical EEG and kinematic data collected from two subjects during an overground walking task.

Interaural frequency mismatch jointly modulates neural brainstem binaural interaction and behavioral interaural time difference sensitivity in humans.

The binaural interaction component (BIC) of the auditory brainstem response (ABR) is the difference obtained after subtracting the sum of right and left ear ABRs from binaurally evoked ABRs. The BIC has attracted interest as a biomarker of binaural processing abilities. Best binaural processing is presumed to require spectrally-matched inputs at the two ears, but peripheral pathology and/or impacts of hearing devices can lead to mismatched inputs. Such mismatching can degrade behavioral sensitivity to interaural time difference (ITD) cues, but might be detected using the BIC. Here, we examine the effect of interaural frequency mismatch (IFM) on BIC and behavioral ITD sensitivity in audiometrically normal adult human subjects (both sexes). Binaural and monaural ABRs were recorded and BICs computed from subjects in response to narrowband tones. Left ear stimuli were fixed at 4000 Hz while right ear stimuli varied over a ∼2-octave range (re: 4000 Hz). Separately, subjects performed psychophysical lateralization tasks using the same stimuli to determine ITD discrimination thresholds jointly as a function of IFM and sound level. Results demonstrated significant effects of IFM on BIC amplitudes, with lower amplitudes in mismatched conditions than frequency-matched. Behavioral ITD discrimination thresholds were elevated at mismatched frequencies and lower sound levels, but also more sharply modulated by IFM at lower sound levels. Combinations of ITD, IFM and overall sound level that resulted in fused and lateralized percepts were bound by the empirically-measured BIC, and also by model predictions simulated using an established computational model of the brainstem circuit thought to generate the BIC.