An approximate line attractor in the hypothalamus encodes an aggressive state.

The hypothalamus regulates innate social behaviors, including mating and aggression. These behaviors can be evoked by optogenetic stimulation of specific neuronal subpopulations within MPOA and VMHvl, respectively. Here, we perform dynamical systems modeling of population neuronal activity in these nuclei during social behaviors. In VMHvl, unsupervised analysis identified a dominant dimension of neural activity with a large time constant (>50 s), generating an approximate line attractor in neural state space. Progression of the neural trajectory along this attractor was correlated with an escalation of agonistic behavior, suggesting that it may encode a scalable state of aggressiveness. Consistent with this, individual differences in the magnitude of the integration dimension time constant were strongly correlated with differences in aggressiveness. In contrast, approximate line attractors were not observed in MPOA during mating; instead, neurons with fast dynamics were tuned to specific actions. Thus, different hypothalamic nuclei employ distinct neural population codes to represent similar social behaviors.

A genetically tractable jellyfish model for systems and evolutionary neuroscience.

Jellyfish are radially symmetric organisms without a brain that arose more than 500 million years ago. They achieve organismal behaviors through coordinated interactions between autonomously functioning body parts. Jellyfish neurons have been studied electrophysiologically, but not at the systems level. We introduce Clytia hemisphaerica as a transparent, genetically tractable jellyfish model for systems and evolutionary neuroscience. We generate stable F1 transgenic lines for cell-type-specific conditional ablation and whole-organism GCaMP imaging. Using these tools and computational analyses, we find that an apparently diffuse network of RFamide-expressing umbrellar neurons is functionally subdivided into a series of spatially localized subassemblies whose synchronous activation controls directional food transfer from the tentacles to the mouth. These data reveal an unanticipated degree of structured neural organization in this species. Clytia affords a platform for systems-level studies of neural function, behavior, and evolution within a clade of marine organisms with growing ecological and economic importance.

Sensory representation and detection mechanisms of gut osmolality change.

Ingested food and water stimulate sensory systems in the oropharyngeal and gastrointestinal areas before absorption1,2. These sensory signals modulate brain appetite circuits in a feed-forward manner3-5. Emerging evidence suggests that osmolality sensing in the gut rapidly inhibits thirst neurons upon water intake. Nevertheless, it remains unclear how peripheral sensory neurons detect visceral osmolality changes, and how they modulate thirst. Here we use optical and electrical recording combined with genetic approaches to visualize osmolality responses from sensory ganglion neurons. Gut hypotonic stimuli activate a dedicated vagal population distinct from mechanical-, hypertonic- or nutrient-sensitive neurons. We demonstrate that hypotonic responses are mediated by vagal afferents innervating the hepatic portal area (HPA), through which most water and nutrients are absorbed. Eliminating sensory inputs from this area selectively abolished hypotonic but not mechanical responses in vagal neurons. Recording from forebrain thirst neurons and behavioural analyses show that HPA-derived osmolality signals are required for feed-forward thirst satiation and drinking termination. Notably, HPA-innervating vagal afferents do not sense osmolality itself. Instead, these responses are mediated partly by vasoactive intestinal peptide secreted after water ingestion. Together, our results reveal visceral hypoosmolality as an important vagal sensory modality, and that intestinal osmolality change is translated into hormonal signals to regulate thirst circuit activity through the HPA pathway.

Distinct hypothalamic control of same- and opposite-sex mounting behaviour in mice.

Animal behaviours that are superficially similar can express different intents in different contexts, but how this flexibility is achieved at the level of neural circuits is not understood. For example, males of many species can exhibit mounting behaviour towards same- or opposite-sex conspecifics1, but it is unclear whether the intent and neural encoding of these behaviours are similar or different. Here we show that female- and male-directed mounting in male laboratory mice are distinguishable by the presence or absence of ultrasonic vocalizations (USVs)2-4, respectively. These and additional behavioural data suggest that most male-directed mounting is aggressive, although in rare cases it can be sexual. We investigated whether USV+ and USV- mounting use the same or distinct hypothalamic neural substrates. Micro-endoscopic imaging of neurons positive for oestrogen receptor 1 (ESR1) in either the medial preoptic area (MPOA) or the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) revealed distinct patterns of neuronal activity during USV+ and USV- mounting, and the type of mounting could be decoded from population activity in either region. Intersectional optogenetic stimulation of MPOA neurons that express ESR1 and vesicular GABA transporter (VGAT) (MPOAESR1∩VGAT neurons) robustly promoted USV+ mounting, and converted male-directed attack to mounting with USVs. By contrast, stimulation of VMHvl neurons that express ESR1 (VMHvlESR1 neurons) promoted USV- mounting, and inhibited the USVs evoked by female urine. Terminal stimulation experiments suggest that these complementary inhibitory effects are mediated by reciprocal projections between the MPOA and VMHvl. Together, these data identify a hypothalamic subpopulation that is genetically enriched for neurons that causally induce a male reproductive behavioural state, and indicate that reproductive and aggressive states are represented by distinct population codes distributed between MPOAESR1 and VMHvlESR1 neurons, respectively. Thus, similar behaviours that express different internal states are encoded by distinct hypothalamic neuronal populations.

Neural heterogeneity controls computations in spiking neural networks.

The brain is composed of complex networks of interacting neurons that express considerable heterogeneity in their physiology and spiking characteristics. How does this neural heterogeneity influence macroscopic neural dynamics, and how might it contribute to neural computation? In this work, we use a mean-field model to investigate computation in heterogeneous neural networks, by studying how the heterogeneity of cell spiking thresholds affects three key computational functions of a neural population: the gating, encoding, and decoding of neural signals. Our results suggest that heterogeneity serves different computational functions in different cell types. In inhibitory interneurons, varying the degree of spike threshold heterogeneity allows them to gate the propagation of neural signals in a reciprocally coupled excitatory population. Whereas homogeneous interneurons impose synchronized dynamics that narrow the dynamic repertoire of the excitatory neurons, heterogeneous interneurons act as an inhibitory offset while preserving excitatory neuron function. Spike threshold heterogeneity also controls the entrainment properties of neural networks to periodic input, thus affecting the temporal gating of synaptic inputs. Among excitatory neurons, heterogeneity increases the dimensionality of neural dynamics, improving the network's capacity to perform decoding tasks. Conversely, homogeneous networks suffer in their capacity for function generation, but excel at encoding signals via multistable dynamic regimes. Drawing from these findings, we propose intra-cell-type heterogeneity as a mechanism for sculpting the computational properties of local circuits of excitatory and inhibitory spiking neurons, permitting the same canonical microcircuit to be tuned for diverse computational tasks.

Stimulus-specific hypothalamic encoding of a persistent defensive state.

Persistent neural activity in cortical, hippocampal, and motor networks has been described as mediating working memory for transiently encountered stimuli1,2. Internal emotional states, such as fear, also persist following exposure to an inciting stimulus3, but it is unclear whether slow neural dynamics are involved in this process. Neurons in the dorsomedial and central subdivisions of the ventromedial hypothalamus (VMHdm/c) that express the nuclear receptor protein NR5A1 (also known as SF1) are necessary for defensive responses to predators in mice4-7. Optogenetic activation of these neurons, referred to here as VMHdmSF1 neurons, elicits defensive behaviours that outlast stimulation5,8, which suggests the induction of a persistent internal state of fear or anxiety. Here we show that in response to naturalistic threatening stimuli, VMHdmSF1 neurons in mice exhibit activity that lasts for many tens of seconds. This persistent activity was correlated with, and required for, persistent defensive behaviour in an open-field assay, and depended on neurotransmitter release from VMHdmSF1 neurons. Stimulation and calcium imaging in acute slices showed that there is local excitatory connectivity between VMHdmSF1 neurons. Microendoscopic calcium imaging of VMHdmSF1 neurons revealed that persistent activity at the population level reflects heterogeneous dynamics among individual cells. Unexpectedly, distinct but overlapping VMHdmSF1 subpopulations were persistently activated by different modalities of threatening stimulus. Computational modelling suggests that neither recurrent excitation nor slow-acting neuromodulators alone can account for persistent activity that maintains stimulus identity. Our results show that stimulus-specific slow neural dynamics in the hypothalamus, on a time scale orders of magnitude longer than that of working memory in the cortex9,10, contribute to a persistent emotional state.

PyRates-A code-generation tool for modeling dynamical systems in biology and beyond.

The mathematical study of real-world dynamical systems relies on models composed of differential equations. Numerical methods for solving and analyzing differential equation systems are essential when complex biological problems have to be studied, such as the spreading of a virus, the evolution of competing species in an ecosystem, or the dynamics of neurons in the brain. Here we present PyRates, a Python-based software for modeling and analyzing differential equation systems via numerical methods. PyRates is specifically designed to account for the inherent complexity of biological systems. It provides a new language for defining models that mirrors the modular organization of real-world dynamical systems and thus simplifies the implementation of complex networks of interacting dynamic entities. Furthermore, PyRates provides extensive support for the various forms of interaction delays that can be observed in biological systems. The core of PyRates is a versatile code-generation system that translates user-defined models into "backend" implementations in various languages, including Python, Fortran, Matlab, and Julia. This allows users to apply a wide range of analysis methods for dynamical systems, eliminating the need for manual translation between code bases. PyRates may also be used as a model definition interface for the creation of custom dynamical systems tools. To demonstrate this, we developed two extensions of PyRates for common analyses of dynamic models of biological systems: PyCoBi for bifurcation analysis and RectiPy for parameter fitting. We demonstrate in a series of example models how PyRates can be used in combination with PyCoBi and RectiPy for model analysis and fitting. Together, these tools offer a versatile framework for applying computational modeling and numerical analysis methods to dynamical systems in biology and beyond.

"I realized I was not alone": A mixed-methods investigation of the implementation of Ubuntu groups to reduce burnout and social isolation in an allopathic medical School in the Southeastern United States.

PURPOSE/BACKGROUND: Healthcare providers experience higher rates of workplace burnout, a reality highlighted by the COVID-19 pandemic. In response, small groups, inspired by South African philosophy, Ubuntu, were introduced to decrease burnout and social isolation and build community and belonging. This study examines how participation in these groups can impact these measures. METHODS: In this mixed-methods study, trained facilitators led small groups that utilized story-sharing to foster connections within the group and broader community. Quantitative and qualitative data were analyzed separately and merged to identify convergence. RESULTS: Three main qualitative themes emerged: 1) seeking and building connections and community, 2) curiosity, learning, and growing, and 3) open-hearted and thriving. These themes were linked to quantitative outcomes, showing a statistically significant decrease in social isolation among staff/faculty and students. Furthermore, faculty/staff exhibited reduced burnout compared to students, while students reported increased feelings of belonging. CONCLUSION: Participation in Ubuntu groups positively influenced students' sense of belonging, reduced faculty/staff burnout, and alleviated social isolation for all participants. Future research should explore the potential of this intervention to further promote wellness on medical campuses. Programs emphasizing the well-being of individuals, including faculty, staff, and students, are crucial for supporting the overall health of medical communities and the wider society.

Social behaviour shapes hypothalamic neural ensemble representations of conspecific sex.

All animals possess a repertoire of innate (or instinctive) behaviours, which can be performed without training. Whether such behaviours are mediated by anatomically distinct and/or genetically specified neural pathways remains unknown. Here we report that neural representations within the mouse hypothalamus, that underlie innate social behaviours, are shaped by social experience. Oestrogen receptor 1-expressing (Esr1+) neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) control mating and fighting in rodents. We used microendoscopy to image Esr1+ neuronal activity in the VMHvl of male mice engaged in these social behaviours. In sexually and socially experienced adult males, divergent and characteristic neural ensembles represented male versus female conspecifics. However, in inexperienced adult males, male and female intruders activated overlapping neuronal populations. Sex-specific neuronal ensembles gradually separated as the mice acquired social and sexual experience. In mice permitted to investigate but not to mount or attack conspecifics, ensemble divergence did not occur. However, 30 minutes of sexual experience with a female was sufficient to promote the separation of male and female ensembles and to induce an attack response 24 h later. These observations uncover an unexpected social experience-dependent component to the formation of hypothalamic neural assemblies controlling innate social behaviours. More generally, they reveal plasticity and dynamic coding in an evolutionarily ancient deep subcortical structure that is traditionally viewed as a 'hard-wired' system.

Determining massage dose-response to improve cancer-related symptom cluster of pain, fatigue, and sleep disturbance: A 7-arm randomized trial in palliative cancer care.

BACKGROUND: The efficacy of various massage doses in palliative cancer care settings is still debated, and no specific protocol is available. AIM: Evaluating response to various massage doses for symptom cluster of pain-fatigue-sleep. DESIGN: A 7-arm randomized-controlled trial with weekly massage for 4 weeks depending on the prescribed dose (15-, 30-, or 60-min; 2× or 3×/week) and a 4-week follow-up. The intensities of pain, fatigue, and sleep disturbance were measured using a 0-10 scale at nine-timepoint; baseline, weekly during the intervention, and the follow-up period. Then, the mean scores of the three symptoms were calculated as the symptom cluster intensity at each timepoint. IRCT.ir IRCT20150302021307N5. SETTING/PARTICIPANTS: Adults with cancer (n = 273) who reported all three symptoms at three oncology centers in Iran. RESULTS: The odds of clinical improvement (at least 30% reduction in symptom cluster intensity from baseline) increased with dose-escalation significantly [(OR = 17.37; 95% CI = 3.87-77.90 for 60-min doses); (OR = 11.71; 95% CI = 2.60-52.69, for 30-min doses); (OR = 4.36; 95% CI = 0.94-20.32, for 15-min doses)]. The effect durability was significantly shorter at 15-min doses compared to 30- and 60-min doses. The odds of improvement for doses 3×/week was not significant compared to doses 2×/week (OR = 12.27 vs OR = 8.34); however, the effect durability for doses 3×/week was significantly higher. CONCLUSIONS: The findings indicated that dose-escalation increases the efficacy of massage for the pain-fatigue-sleep symptom cluster. Although the 60-min doses were found to be more effective, the 30-min doses can be considered more practical because they are less costly and time-consuming. Our findings can be helpful to develop massage guidelines in palliative care settings. TRIAL REGISTRATION: Iranian Registry of Clinical Trials, IRCT20150302021307N5.

Brain biopsy in neurological disease of unknown etiology: A single-center 12-year retrospective analysis.

There are no international guidelines for brain biopsy in neurological disease of unknown etiology, yet most practicing neurologists will encounter difficult cases in which biopsy is considered. This patient cohort is heterogenous, and it is unclear in which circumstances biopsy is most useful. We performed an audit of brain biopsies reviewed in our neuropathology department from 2010 to 2021. Of 9,488 biopsies, 331 biopsies undertaken for an undiagnosed neurological disease were identified. Where documented, the commonest symptoms were hemorrhage, encephalopathy, and dementia. 29% of biopsies were non-diagnostic. The most common clinically relevant findings on biopsy were infection, cerebral amyloid angiopathy with or without angiitis, and demyelination. Rarer conditions included CNS vasculitis, non-infectious encephalitis, and Creutzfeldt Jakob Disease. We highlight the value of brain biopsy in the workup of cryptogenic neurological disease despite recent advances in less invasive diagnostics.

Development and validation of a patient-reported outcome measure for systemic sclerosis: the EULAR Systemic Sclerosis Impact of Disease (ScleroID) questionnaire.

OBJECTIVES: Patient-reported outcome measures (PROMs) are important for clinical practice and research. Given the high unmet need, our aim was to develop a comprehensive PROM for systemic sclerosis (SSc), jointly with patient experts. METHODS: This European Alliance of Associations for Rheumatology (EULAR)-endorsed project involved 11 European SSc centres. Relevant health dimensions were chosen and prioritised by patients. The resulting Systemic Sclerosis Impact of Disease (ScleroID) questionnaire was subsequently weighted and validated by Outcome Measures in Rheumatology criteria in an observational cohort study, cross-sectionally and longitudinally. As comparators, SSc-Health Assessment Questionnaire (HAQ), EuroQol Five Dimensional (EQ-5D), Short Form-36 (SF-36) were included. RESULTS: Initially, 17 health dimensions were selected and prioritised. The top 10 health dimensions were selected for the ScleroID questionnaire. Importantly, Raynaud's phenomenon, impaired hand function, pain and fatigue had the highest patient-reported disease impact. The validation cohort study included 472 patients with a baseline visit, from which 109 had a test-retest reliability visit and 113 had a follow-up visit (85% female, 38% diffuse SSc, mean age 58 years, mean disease duration 9 years). The total ScleroID score showed strong Pearson correlation coefficients with comparators (SSc-HAQ, 0.73; Patient's global assessment, Visual Analogue Scale 0.77; HAQ-Disability Index, 0.62; SF-36 physical score, -0.62; each p<0.001). The internal consistency was strong: Cronbach's alpha was 0.87, similar to SSc-HAQ (0.88) and higher than EQ-5D (0.77). The ScleroID had excellent reliability and good sensitivity to change, superior to all comparators (intraclass correlation coefficient 0.84; standardised response mean 0.57). CONCLUSIONS: We have developed and validated the EULAR ScleroID, which is a novel, brief, disease-specific, patient-derived, disease impact PROM, suitable for research and clinical use in SSc.

Neglecting physician desires to teach at an academic medical facility: A mixed method investigation of the consequences.

PURPOSE: Recent findings have suggested that physicians who spend more time participating in their most meaningful job activities (e.g. teaching) are less likely to experience burnout. The current study aimed to expound upon this finding, focusing specifically on the role of teaching in promoting meaning and preventing burnout. METHOD: A total of 428 physicians at a large academic healthcare institution completed an online survey that included measures of burnout and other relevant variables. In the second part of this study, 20 physicians participated in interviews with the aim of expounding upon and contextualizing the findings from Part 1. RESULTS: Results from Part 1 suggested that although meaningfulness derived from teaching was associated with reduced burnout, this association was only true for those who indicated that clinical teaching was among the most meaningful parts of being a physician. In addition, physicians were less likely to spend time working on their most meaningful job activity when it was teaching. Part 2 illustrated why teaching in the clinical environment can be so meaningful and protective against burnout. CONCLUSIONS: Many physicians are unable to teach due to the increasing demands of medical institutions, which may contribute to the increasing levels of burnout in healthcare providers.

Definitive chemoradiotherapy for cervical cancer: A 11-year population-based study.

PURPOSE: To assess the recurrence pattern and survival in women treated with definitive chemoradiotherapy for cervical cancer. METHODS: A retrospective cohort study of women FIGO (2012) stage IB2 to IVA from the Grampian region of Scotland between February 2000 and March 2011. These women were followed up until April 2018. RESULTS: A total of 121 eligible women allocated with mean age at treatment 50.59 years (SD = 13.98, range 22-82). Tumours staged: IB2: n = 24 (19.8%), II: n = 45 (37.2%), III: n = 43 (35.5%) and IVA: n = 7 (5.8%). Two (1.7%) women had no available data. Fifty-five (45.5%) women had recurrence after treatment, and 51 (42.15%) women died from the disease. The sites of recurrence were as follows: central pelvic only (n = 4, 7.27%), pelvic and distant (n = 39, 70.91%) and distant only (n = 12, 21.82%) with median time from end of treatment to first recurrence 44 months (range 2-98), 26 months (range 1-146) and 22 months (range 3-66) respectively. 5-and 8-year overall survival was 76.0% (95% CI: 68.8%-84.0%) and 64.4% (95% CI: 56.4%-73.5%) respectively. CONCLUSIONS: Though overall survival is better than with radiotherapy alone, recurrence occurs up to 10 years after treatment. This raises the issues of how to reduce late recurrence and the appropriateness of current follow-up protocols.

Automated measurement of mouse social behaviors using depth sensing, video tracking, and machine learning.

A lack of automated, quantitative, and accurate assessment of social behaviors in mammalian animal models has limited progress toward understanding mechanisms underlying social interactions and their disorders such as autism. Here we present a new integrated hardware and software system that combines video tracking, depth sensing, and machine learning for automatic detection and quantification of social behaviors involving close and dynamic interactions between two mice of different coat colors in their home cage. We designed a hardware setup that integrates traditional video cameras with a depth camera, developed computer vision tools to extract the body "pose" of individual animals in a social context, and used a supervised learning algorithm to classify several well-described social behaviors. We validated the robustness of the automated classifiers in various experimental settings and used them to examine how genetic background, such as that of Black and Tan Brachyury (BTBR) mice (a previously reported autism model), influences social behavior. Our integrated approach allows for rapid, automated measurement of social behaviors across diverse experimental designs and also affords the ability to develop new, objective behavioral metrics.

Tools Clinicians Can Use to Help Get Patients Active.

An epidemic of physical inactivity has given rise to a population struggling with early mortality and an increase in chronic non-communicable diseases such as cardiovascular disease, diabetes, and cancer. Primary care providers as well as other clinicians are in a position to help overcome this epidemic of physical inactivity. The goal of this commentary is to provide clinicians with resources and recommendations from the recent literature to help overcome barriers to physical activity counseling and help patients become physically active. Theory-based interventions from communication and exercise prescriptions to wearables and mobile health technology are discussed. Limitations and future directions are explored.

Comparative analysis of colorimetric staining in skin using open-source software.

Colorimetric staining techniques such as immunohistochemistry (IHC), immunofluorescence (IF) and histochemistry (HC) provide useful information regarding the localization and relative amount of a molecule/substance in skin. We have developed a novel, straightforward method to assess colorimetric staining by combining features from two open-source software programs. As a proof of principle, we demonstrate the utility of this approach by analysing changes in skin melanin deposition during the radiation-induced tanning response of Yucatan mini-pigs. This method includes a visualization step to validate the accuracy of colour selection before quantitation to ensure accuracy. The data show that this method is robust and will provide a means to obtain accurate comparative analyses of staining in IHC/IF/HC samples.

Content of non-pharmacological care for systemic sclerosis and educational needs of European health professionals: a EUSHNet survey.

OBJECTIVES: To describe the non-pharmacological care in systemic sclerosis (SSc) provided by European health professionals (HPs) including referrals, treatment targets, interventions, and educational needs. METHODS: In this observational study, European HPs working in SSc care were invited to complete an online survey through announcements by EUSTAR (European League Against Rheumatism (EULAR) Scleroderma Trials and Research) and FESCA (Federation of European Scleroderma Associations), the EULAR HPs' newsletter, websites of national patient and HP associations, and by personal invitation. RESULTS: In total, 56 HPs, from 14 different European countries and 7 different disciplines, responded to the survey. A total of 133 specific indications for referral were reported, 72% of which could be linked to the International Classification of Functioning, Disability and Health domain "body functions and structures". Of the 681 reported treatment targets 45% was related to "body functions and structures". In total, 105 different interventions were reported as being used to address these treatment targets. Almost all (98%) respondents reported having educational needs, with the topics of management of stiffness (67%), pain (60%), and impaired hand function (56%) being mentioned most frequently. CONCLUSIONS: Non-pharmacological care in SSc varies in Europe with respect to the content of interventions, reasons for referral, and treatment targets. Reasons for referral to HPs are not well-aligned to HPs subsequent treatment targets in SSc care suggesting suboptimal communication between physicians and HPs. The wide variations reported indicate a need to consolidate geographically disparate expertise within countries and to develop and improve standards of non-pharmacological care in SSc.