ABSTRACT
Exposure to early life adversity is associated with both increased risk of developing schizophrenia and poorer performance on measures of social cognitive functioning. In this study, we examined whether interleukin-6 (IL-6) and Corpus Callosum (CC) microstructure mediated the association between childhood physical neglect and social cognition. Fifty-eight patients with a diagnosis of schizophrenia were included. The CANTAB emotion recognition task (unbiased hit rate) was used to assess social cognition. We found that the microstructural organization of the CC significantly mediated the association between physical neglect and emotion recognition. Furthermore, in a sequential mediation analysis that also considered the role of inflammatory response, the association between physical neglect, and lower emotion recognition performance was sequentially mediated by higher IL-6 and lower fractional anisotropy of the CC. This mediating effect of IL-6 was only present when simultaneously considering the effects of CC microstructural organization and remained significant while controlling for the effects of sex, BMI and medication dosage (but not age). Overall, the findings suggest that the association between physical neglect and poorer emotion recognition in schizophrenia occurs, at least in part, via its association with white matter microstructure.
Subject(s)
Schizophrenia , White Matter , Humans , Child , Corpus Callosum/diagnostic imaging , Schizophrenia/diagnostic imaging , Social Cognition , Interleukin-6 , Cognition/physiology , AnisotropyABSTRACT
BACKGROUND AND PURPOSE: Development of core concepts in disciplines such as biochemistry, microbiology and physiology have transformed teaching. They provide the foundation for the development of teaching resources for global educators, as well as valid and reliable approaches to assessment. An international research consensus recently identified 25 core concepts of pharmacology. The current study aimed to define and unpack these concepts. EXPERIMENTAL APPROACH: A two-phase, iterative approach, involving 60 international pharmacology education experts, was used. The first phase involved drafting definitions for core concepts and identifying key sub-concepts via a series of online meetings and asynchronous work. These were refined in the second phase, through a 2-day hybrid workshop followed by a further series of online meetings and asynchronous work. KEY RESULTS: The project produced consensus definitions for a final list of 24 core concepts and 103 sub-concepts of pharmacology. The iterative, discursive methodology resulted in modification of concepts from the original study, including change of 'drug-receptor interaction' to 'drug-target interaction' and the change of the core concept 'agonists and antagonists' to sub-concepts of drug-target interaction. CONCLUSIONS AND IMPLICATIONS: Definitions and sub-concepts of 24 core concepts provide an evidence-based foundation for pharmacology curricula development and evaluation. The next steps for this project include the development of a concept inventory to assess acquisition of concepts, as well as the development of case studies and educational resources to support teaching by the global pharmacology community, and student learning of the most critical and fundamental concepts of the discipline.
Subject(s)
Curriculum , Pharmacology , HumansABSTRACT
Recent studies have reported a negative association between exposure to childhood trauma, including physical neglect, and cognitive functioning in patients with schizophrenia. Childhood trauma has been found to influence immune functioning, which may contribute to the risk of schizophrenia and cognitive symptoms of the disorder. In this study, we aimed to test the hypothesis that physical neglect is associated with cognitive ability, and that this association is mediated by a combined latent measure of inflammatory response, and moderated by higher genetic risk for schizophrenia. The study included 279 Irish participants, comprising 102 patients and 177 healthy participants. Structural equation modelling was used to perform mediation and moderation analyses. Inflammatory response was measured via basal plasma levels of IL-6, TNF-α, and CRP, and cognitive performance was assessed across three domains: full-scale IQ, logical memory, and the emotion recognition task. Genetic variation for schizophrenia was estimated using a genome-wide polygenic score based on genome-wide association study summary statistics. The results showed that inflammatory response mediated the association between physical neglect and all measures of cognitive functioning, and explained considerably more variance than any of the inflammatory markers alone. Furthermore, genetic risk for schizophrenia was observed to moderate the direct pathway between physical neglect and measures of non-social cognitive functioning in both patient and healthy participants. However, genetic risk did not moderate the mediated pathway associated with inflammatory response. Therefore, we conclude that the mediating role of inflammatory response and the moderating role of higher genetic risk may independently influence the association between adverse early life experiences and cognitive function in patients and healthy participants.
Subject(s)
Adverse Childhood Experiences , Schizophrenia , Humans , Genome-Wide Association Study , Healthy Volunteers , Cognition/physiologyABSTRACT
Over recent years, studies have shown that science and health profession graduates demonstrate gaps in their fundamental pharmacology knowledge and ability to apply pharmacology concepts in practice. This article reviews the current challenges faced by pharmacology educators, including the exponential growth in discipline knowledge and competition for curricular time. We then argue that pharmacology education should focus on essential concepts that enable students to develop beyond 'know' towards 'know how to'. A concept-based approach will help educators prioritize and benchmark their pharmacology curriculum, facilitate integration of pharmacology with other disciplines in the curriculum, create alignment between universities and improve application of pharmacology knowledge to professional contexts such as safe prescribing practices. To achieve this, core concepts first need to be identified and unpacked, and methods for teaching and assessment using concept inventories developed. The International Society for Basic and Clinical Pharmacology Education Section (IUPHAR-Ed) Core Concepts of Pharmacology (CCP) initiative involves over 300 educators from the global pharmacology community. CCP has identified and defined the core concepts of pharmacology, together with key underpinning sub-concepts. To realize these benefits, pharmacology educators must develop methods to teach and assess core concepts. Work to develop concept inventories is ongoing, including identifying student misconceptions of the core concepts and creating a bank of multiple-choice questions to assess student understanding. Future work aims to develop and validate materials and methods to help educators embed core concepts within curricula. Potential strategies that educators can use to overcome factors that inhibit adoption of core concepts are presented.
ABSTRACT
Early life stress (ELS) can impact brain development and is a risk factor for neurodevelopmental disorders such as schizophrenia. Post-weaning social isolation (SI) is used to model ELS in animals, using isolation stress to disrupt a normal developmental trajectory. We aimed to investigate how SI affects the expression of genes in mouse hippocampus and to investigate how these changes related to the genetic basis of neurodevelopmental phenotypes. BL/6J mice were exposed to post-weaning SI (PD21-25) or treated as group-housed controls (n = 7-8 per group). RNA sequencing was performed on tissue samples from the hippocampus of adult male and female mice. Four hundred and 1,215 differentially-expressed genes (DEGs) at a false discovery rate of < 0.05 were detected between SI and control samples for males and females respectively. DEGS for both males and females were significantly overrepresented in gene ontologies related to synaptic structure and function, especially the post-synapse. DEGs were enriched for common variant (SNP) heritability in humans that contributes to risk of neuropsychiatric disorders (schizophrenia, bipolar disorder) and to cognitive function. DEGs were also enriched for genes harbouring rare de novo variants that contribute to autism spectrum disorder and other developmental disorders. Finally, cell type analysis revealed populations of hippocampal astrocytes that were enriched for DEGs, indicating effects in these cell types as well as neurons. Overall, these data suggest a convergence between genes dysregulated by the SI stressor in the mouse and genes associated with neurodevelopmental disorders and cognitive phenotypes in humans.
Subject(s)
Autism Spectrum Disorder , Adult , Humans , Male , Animals , Mice , Female , Gene Expression Profiling , Hippocampus/metabolism , Social Isolation , Synapses , Phenotype , Risk Factors , Human GeneticsABSTRACT
OBJECTIVE: The Corona Radiata (CR) is a large white matter tract in the brain comprising of the anterior CR (aCR), superior CR (sCR), and posterior CR (pCR), which have associations with cognition, self-regulation, and, in schizophrenia, positive symptom severity. This study tested the hypothesis that the microstructural organisation of the aCR, as measured by Fractional Anisotropy (FA) using Diffusion Tensor Imaging (DTI), would relate to poorer social cognitive outcomes and higher positive symptom severity for people with schizophrenia, when compared to healthy participants. We further hypothesised that increased positive symptoms would relate to poorer social cognitive outcomes. METHODS: Data were derived from n = 178 healthy participants (41 % females; 36.11 ± 12.36 years) and 58 people with schizophrenia (30 % females; 42.4 ± 11.1 years). The Positive and Negative Symptom Severity Scale measured clinical symptom severity. Social Cognition was measured using the Reading the Mind in the Eyes Test (RMET) Total Score, as well as the Positive, Neutral, and Negative stimuli valence. The ENIGMA-DTI protocol tract-based spatial statistics (TBSS) was used. RESULTS: There was a significant difference in FA for the CR, in individuals with schizophrenia compared to healthy participants. On stratification, both the aCR and pCR were significantly different between groups, with patients showing reduced white matter tract microstructural organisation. Significant negative correlations were observed between positive symptomatology and reduced microstructural organisation of the aCR. Performance for RMET negative valence items was significantly correlated bilaterally with the aCR, but not the sCR or pCR, and no relationship to positive symptoms was observed. CONCLUSIONS: These data highlight specific and significant microstructural white-matter differences for people with schizophrenia, which relates to positive clinical symptomology and poorer performance on social cognition stimuli. While reduced FA is associated with higher positive symptomatology in schizophrenia, this study shows the specific associated with anterior frontal white matter tracts and reduced social cognitive performance. The aCR may have a specific role to play in frontal-disconnection syndromes, psychosis, and social cognitive profile within schizophrenia, though further research requires more sensitive, specific, and detailed consideration of social cognition outcomes.
Subject(s)
Schizophrenia , White Matter , Female , Humans , Male , White Matter/diagnostic imaging , Diffusion Tensor Imaging/methods , Schizophrenia/complications , Schizophrenia/diagnostic imaging , Social Cognition , Brain , AnisotropyABSTRACT
Childhood trauma (CT) is associated with lower cognitive and social cognitive function in schizophrenia. Recent evidence suggests that the relationship between CT and cognition is mediated by both low-grade systemic inflammation and reduced connectivity of the default mode network (DMN) during resting state. This study sought to test whether the same pattern of associations was observed for DMN connectivity during task based activity. Fifty-three individuals with schizophrenia (SZ) or schizoaffective disorder (SZA) and one hundred and seventy six healthy participants were recruited from the Immune Response and Social Cognition (iRELATE) project. A panel of pro-inflammatory markers that included IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNFa), and C-reactive protein (CRP), were measured in plasma using ELISA. DMN connectivity was measured during an fMRI social cognitive face processing task. Patients showed evidence of low grade systemic inflammation and significantly increased connectivity between the left lateral parietal (LLP) cortex-cerebellum and LLP-left angular gyrus compared to healthy participants. Across the entire sample, IL-6 predicted increased connectivity between LLP-cerebellum, LLP-precuneus, and mPFC-bilateral-precentral-gyri and left postcentral gyrus. In turn, and again in the entire sample, IL-6 (but no other inflammatory marker) mediated the relationship between childhood physical neglect and LLP-cerebellum. Physical neglect scores also significantly predicted the positive association between IL-6 and LLP-precuneus connectivity. This is to our knowledge the first study that provides evidence that higher plasma IL-6 mediates the association between higher childhood neglect and increased DMN connectivity during task based activity. Consistent with our hypothesis, exposure to trauma is associated with weaker suppression of the DMN during a face processing task, and this association was mediated via increased inflammatory response. The findings may represent part of the biological mechanism by which CT and cognitive performance are related.
Subject(s)
Adverse Childhood Experiences , Facial Recognition , Inflammation , Schizophrenia , Schizophrenic Psychology , Adverse Childhood Experiences/psychology , Inflammation/complications , Inflammation/physiopathology , Schizophrenia/complications , Schizophrenia/physiopathology , Facial Recognition/physiology , Emotional Abuse , Child Abuse, Sexual , Humans , Male , Female , Adult , Case-Control Studies , BrainABSTRACT
Introduction: Chronic pain is often associated with comorbid anxiety and cognitive dysfunction, negatively affecting therapeutic outcomes. The influence of genetic background on such interactions is poorly understood. The stress-hyperresponsive Wistar-Kyoto (WKY) rat strain, which models aspects of anxiety and depression, displays enhanced sensitivity to noxious stimuli and impaired cognitive function, compared with Sprague-Dawley (SD) counterparts. However, pain- and anxiety-related behaviors and cognitive impairment following induction of a persistent inflammatory state have not been investigated simultaneously in the WKY rats. Here we compared the effects of complete Freund's adjuvant (CFA)-induced persistent inflammation on pain-, negative affect- and cognition-related behaviors in WKY vs. SD rats. Methods: Male WKY and SD rats received intra-plantar injection of CFA or needle insertion (control) and, over the subsequent 4 weeks, underwent behavioral tests to assess mechanical and heat hypersensitivity, the aversive component of pain, and anxiety- and cognition-related behaviors. Results: The CFA-injected WKY rats exhibited greater mechanical but similar heat hypersensitivity compared to SD counterparts. Neither strain displayed CFA-induced pain avoidance or anxiety-related behavior. No CFA-induced impairment was observed in social interaction or spatial memory in WKY or SD rats in the three-chamber sociability and T-maze tests, respectively, although strain differences were apparent. Reduced novel object exploration time was observed in CFA-injected SD, but not WKY, rats. However, CFA injection did not affect object recognition memory in either strain. Conclusions: These data indicate exacerbated baseline and CFA-induced mechanical hypersensitivity, and impairments in novel object exploration, and social and spatial memory in WKY vs. SD rats.
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PURPOSE: Function and anatomy of the visual system were evaluated in children with abusive head trauma (AHT). The relationships between retinal hemorrhages at presentation were examined with outcome measures. METHODS: Retrospective review of data in children with AHT for 1) visual acuity at last follow-up, 2) visual evoked potentials (VEP) after recovery, 3) diffusion metrics of white matter tracts and grey matter within the occipital lobe on diffusion tensor imaging (DTI), and 4) patterns of retinal hemorrhages at presentation. Visual acuity was converted into logarithm of minimum angle of resolution (logMAR) after correction for age. VEPs were also scored by objective signal-to-noise ratio (SNR). RESULTS: Of 202 AHT victims reviewed, 45 met inclusion criteria. Median logMAR was reduced to 0.8 (approximately 20/125 Snellen equivalent), with 27% having no measurable vision. Thirty-two percent of subjects had no detectable VEP signal. VEPs were significantly reduced in subjects initially presenting with traumatic retinoschisis or hemorrhages involving the macula (p < 0.01). DTI tract volumes were decreased in AHT subjects compared to controls (p < 0.001). DTI metrics were most affected in AHT victims showing macular abnormalities on follow-up ocular examination. However, DTI metrics were not correlated with visual acuity or VEPS. There was large inter-subject variability within each grouping. DISCUSSION: Mechanisms causing traumatic retinoschisis, or traumatic abnormalities of the macula, are associated with significant long-term visual pathway dysfunction. AHT associated abnormalities of the macula, and visual cortical pathways were more fully captured by VEPs than visual acuity or DTI metrics.
Subject(s)
Craniocerebral Trauma , Retinoschisis , Child , Humans , Infant , Diffusion Tensor Imaging/adverse effects , Retinal Hemorrhage/diagnosis , Retinal Hemorrhage/etiology , Evoked Potentials, Visual , Retinoschisis/diagnosis , Electroretinography , Craniocerebral Trauma/complications , Craniocerebral Trauma/diagnosis , Vision Disorders , Retrospective StudiesABSTRACT
BACKGROUND AND PURPOSE: In recent decades, a focus on the most critical and fundamental concepts has proven highly advantageous to students and educators in many science disciplines. Pharmacology, unlike microbiology, biochemistry, or physiology, lacks a consensus list of such core concepts. EXPERIMENTAL APPROACH: We sought to develop a research-based, globally relevant list of core concepts that all students completing a foundational pharmacology course should master. This two-part project consisted of exploratory and refinement phases. The exploratory phase involved empirical data mining of the introductory sections of five key textbooks, in parallel with an online survey of over 200 pharmacology educators from 17 countries across six continents. The refinement phase involved three Delphi rounds involving 24 experts from 15 countries across six continents. KEY RESULTS: The exploratory phase resulted in a consolidated list of 74 candidate core concepts. In the refinement phase, the expert group produced a consensus list of 25 core concepts of pharmacology. CONCLUSION AND IMPLICATIONS: This list will allow pharmacology educators everywhere to focus their efforts on the conceptual knowledge perceived to matter most by experts within the discipline. Next steps for this project include defining and unpacking each core concept and developing resources to help pharmacology educators globally teach and assess these concepts within their educational contexts.
ABSTRACT
Background: Both low-grade systemic inflammation and functional connectivity of the default mode network (DMN) during rest have recently been observed to mediate the association between childhood trauma (CT) and behavioural performance on an emotion recognition task. Whether inflammation also mediates the association between CT and functional connectivity of the DMN during social cognitive task performance is unknown. Methods: 51 patients with schizophrenia (SZ) or schizoaffective disorder (SZA) and 176 healthy participants completed a theory of mind (ToM) task during fMRI. IL-6 was measured in plasma using ELISA. DMN connectivity was measured during performance of the fMRI ToM task. To examine DMN connectivity, we selected 4 a priori seeds of the DMN, i.e., the medial prefrontal cortex (PFC), right lateral parietal (LP), left LP, and posterior cingulate cortex (PCC) according to the Harvard-Oxford Cortical and Subcortical Atlas (http://www.cma.mgh.harvard.edu/fsl_atlas.html) as implemented in CONN. Results: Patients showed significantly increased DMN connectivity compared to healthy participants between each of the four seeds of the DMN and with other clusters in the brain. Across the entire sample, higher levels of IL-6 predicted increased connectivity between the mPFC and regions encompassing the cerebellum (<0.001 FWE). IL-6 mediated the association between physical neglect and weaker suppression of the posterior cingulate cortex (PCC) DMN seed -left precentral and postcentral gyrus (ßINDIRECT = .0170, CI: 0.0008 to.0506) connectivity during ToM performance. Discussion: This is the first study to our knowledge that provides evidence that higher plasma IL-6 mediates the association between higher childhood neglect and increased DMN connectivity during ToM task performance. Consistent with our previous study that IL-6 mediated the association between early life stress exposure and reduced connectivity of the DMN during rest, here IL-6 mediated the association between early life stress and increased connectivity of the DMN during ToM based cognitive processing. These findings suggest a biological mechanism for how chronic stress impacts social cognitive processing.
ABSTRACT
Objective: Schizophrenia is a complex functionally debilitating neurodevelopmental disorder, with associated social cognitive impairment. Corpus Callosum (CC) white matter tracts deficits are reported for people with schizophrenia; however, few studies focus on interhemispheric processing relative to social cognition tasks. This study aimed to determine if a relationship between the CC and social cognition exists. Method: In this cross-section study, a sample of n = 178 typical controls and n = 58 people with schizophrenia completed measures of mentalising (Reading the Mind in the Eyes), emotion recognition outcome and reaction time (Emotion Recognition Test), and clinical symptoms (Positive and Negative Symptom Scale), alongside diffusion-based tract imaging. The CC and its subregions, i.e., the genu, body, and splenium were the regions of interest (ROI). Results: Reduced white matter tract integrity was observed in the CC for patients when compared to controls. Patients performed slower, and less accurately on emotion recognition tasks, which significantly and negatively correlated to the structural integrity of the CC genu. Tract integrity further significantly and negatively related to clinical symptomatology. Conclusions: People with schizophrenia have altered white matter integrity in the genu of the CC, compared to controls, which relates to cognitive deficits associated with recognising emotional stimuli accurately and quickly, and severity of clinical symptoms.
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PURPOSE: Compare follow-up optical coherence tomography (OCT) with visual function in children with abusive head trauma (shaken baby syndrome). METHODS: Retrospective follow-up studies of 3 children who were victims of abusive head trauma (AHT) within the first year of life. RESULTS: OCTs showed disrupted retinal layering, thick detached internal limiting membrane, focal posterior vitreous separation, and multilayered tractional retinoschisis. Significant vision loss occurred in 3 out of 4 eyes with a history of traumatic retinoschisis. Normal visual acuity and low-normal visual evoked potentials were measured in a child with foveal distortion, reduced global nerve fiber layer thickness, detached internal limiting membrane, and history of vitreous hemorrhage. DISCUSSION: Significant abnormalities of retinal anatomy can be detected on OCT years after AHT. OCTs and assessment of visual pathways help to elucidate causes of visual dysfunction in children with AHT.
ABSTRACT
SARS-CoV-2 variants shaped the second year of the COVID-19 pandemic and the discourse around effective control measures. Evaluating the threat posed by a new variant is essential for adapting response efforts when community transmission is detected. In this study, we compare the dynamics of two variants, Alpha and Iota, by integrating genomic surveillance data to estimate the effective reproduction number (Rt) of the variants. We use Connecticut, United States, in which Alpha and Iota co-circulated in 2021. We find that the Rt of these variants were up to 50% larger than that of other variants. We then use phylogeography to show that while both variants were introduced into Connecticut at comparable frequencies, clades that resulted from introductions of Alpha were larger than those resulting from Iota introductions. By monitoring the dynamics of individual variants throughout our study period, we demonstrate the importance of routine surveillance in the response to COVID-19.
Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/epidemiology , Genomics , Humans , Pandemics , SARS-CoV-2/genetics , United States/epidemiologyABSTRACT
The emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in late 2020 and early 2021 raised alarm worldwide because of their potential for increased transmissibility and immune evasion. Elucidating the evolutionary and epidemiologic dynamics among novel SARS-CoV-2 variants is essential for understanding the trajectory of the coronavirus disease pandemic. We describe the interplay between B.1.1.7 (Alpha) and B.1.526 (Iota) variants in New York State, USA, during December 2020-April 2021 through phylogeographic analyses, space-time scan statistics, and cartographic visualization. Our results indicate that B.1.526 probably evolved in New York City, where it was displaced as the dominant lineage by B.1.1.7 months after its initial appearance. In contrast, B.1.1.7 became dominant earlier in regions with fewer B.1.526 infections. These results suggest that B.1.526 might have delayed the initial spread of B.1.1.7 in New York City. Our combined spatiotemporal methodologies can help disentangle the complexities of shifting SARS-CoV-2 variant landscapes.
Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/epidemiology , COVID-19/virology , Humans , New York/epidemiology , New York City/epidemiology , Spatio-Temporal AnalysisSubject(s)
Evidence-Based Medicine , Health Policy , Legislation, Drug , Public Health , Humans , United KingdomABSTRACT
Movement by animals to obtain resources and avoid predation often depends on natural cycles, and human alteration of the landscape may disrupt or enhance the utility of different habitats or resources to animals through the phases of these cycles. We studied habitat selection by GPS/accelerometer-tagged great egrets (Ardea alba) foraging in areas with shellfish aquaculture infrastructure and adjacent natural wetlands, while accounting for tide-based changes in water depth. We used integrated step selection analysis to test the prediction that egrets would express stronger selection for natural wetlands (eelgrass, tidal marsh, and other tidal wetlands) than for shellfish aquaculture areas. We also evaluated differences in foraging behavior among shellfish aquaculture areas and natural wetlands by comparing speed travelled (estimated from distance between GPS locations) and energy expended (Overall Dynamic Body Acceleration) while foraging. We found evidence for stronger overall habitat selection for eelgrass than for shellfish aquaculture areas, with results conditional on water depth: egrets used shellfish aquaculture areas, but only within a much narrower range of water depths than they used eelgrass and other natural wetlands. We found only slight differences in our metrics of foraging behavior among shellfish aquaculture areas and natural wetlands. Our results suggest that although great egrets appear to perceive or experience shellfish aquaculture areas as suitable foraging habitat during some conditions, those areas provide less foraging opportunity throughout tidal cycles than natural wetlands. Thus, expanding the footprint of shellfish aquaculture into additional intertidal areas may reduce foraging opportunities for great egrets across the range of tidal cycles. Over longer time scales, the ways in which natural wetlands and shellfish aquaculture areas adapt to rising sea levels (either through passive processes or active management) may change the ratios of these wetland types and consequently change the overall value of Tomales Bay to foraging great egrets.
Subject(s)
Aquaculture/methods , Birds/physiology , Ecosystem , Feeding Behavior , Wetlands , Acceleration , Accelerometry , Animals , Conservation of Natural Resources , Estuaries , Geography , Predatory Behavior , Regression Analysis , Sea Level Rise , ShellfishABSTRACT
Maternal immune activation (MIA) is a known risk factor for schizophrenia (SCZ) and autism spectrum disorder (ASD) and is often modelled in animal studies in order to study the effect of prenatal infection on brain function including behaviour and gene expression. Although the effect of MIA on gene expression are highly heterogeneous, combining data from multiple gene expression studies in a robust method may shed light on the true underlying biological effects caused by MIA and this could inform studies of SCZ and ASD. This study combined four RNA-seq and microarray datasets in an overlap analysis and ranked meta-analysis in order to investigate genes, pathways and cell types dysregulated in the MIA mouse models. Genes linked to SCZ and ASD and crucial in neurodevelopmental processes including neural tube folding, regulation of cellular stress and neuronal/glial cell differentiation were among the most consistently dysregulated in these ranked analyses. Gene ontologies including K+ ion channel function, neuron and glial cell differentiation, synaptic structure, axonal outgrowth, cilia function and lipid metabolism were also strongly implicated. Single-cell analysis identified excitatory and inhibitory cell types in the cortex, hippocampus and striatum that may be affected by MIA and are also enriched for genes associated with SCZ, ASD and cognitive phenotypes. This points to the cellular location of molecular mechanisms that may be consistent between the MIA model and neurodevelopmental disease, improving our understanding of its utility to study prenatal infection as an environmental stressor.
Subject(s)
Brain/physiology , Gene Expression , Neurodevelopmental Disorders/etiology , Prenatal Exposure Delayed Effects/immunology , Prenatal Exposure Delayed Effects/pathology , Animals , Brain/drug effects , Disease Models, Animal , Female , Gene Expression/drug effects , Gene Ontology , Humans , Mice , Neurodevelopmental Disorders/pathology , Poly I-C/pharmacology , Pregnancy , Prenatal Exposure Delayed Effects/geneticsABSTRACT
Emerging SARS-CoV-2 variants have shaped the second year of the COVID-19 pandemic and the public health discourse around effective control measures. Evaluating the public health threat posed by a new variant is essential for appropriately adapting response efforts when community transmission is detected. However, this assessment requires that a true comparison can be made between the new variant and its predecessors because factors other than the virus genotype may influence spread and transmission. In this study, we develop a framework that integrates genomic surveillance data to estimate the relative effective reproduction number (R t ) of co-circulating lineages. We use Connecticut, a state in the northeastern United States in which the SARS-CoV-2 variants B.1.1.7 and B.1.526 co-circulated in early 2021, as a case study for implementing this framework. We find that the R t of B.1.1.7 was 6-10% larger than that of B.1.526 in Connecticut in the midst of a COVID-19 vaccination campaign. To assess the generalizability of this framework, we apply it to genomic surveillance data from New York City and observe the same trend. Finally, we use discrete phylogeography to demonstrate that while both variants were introduced into Connecticut at comparable frequencies, clades that resulted from introductions of B.1.1.7 were larger than those resulting from B.1.526 introductions. Our framework, which uses open-source methods requiring minimal computational resources, may be used to monitor near real-time variant dynamics in a myriad of settings.
ABSTRACT
Mu-opioid receptors (MOPs) mediate and modulate social reward and social interaction. However, few studies have examined the functionality of this system in rodent models of social impairment. Deficits in social motivation and cognition are observed in rodents following pre-natal exposure to the anti-epileptic valproic acid (VPA), however it is not known whether MOP functionality is altered in these animals. The present study examined the effects of acute administration of the prototypical MOP agonist morphine (1 mg/kg) on social behavioural responding in the 3-chamber test and immediate early gene expression in adolescent rats (postnatal day 28-43) prenatally exposed to VPA vs saline-exposed controls. Pharmacokinetic analysis of morphine concentration, MOP binding and expression were also examined. The data revealed that sociability and social novelty preference in the 3-chamber test were reduced in rats prenatally exposed to VPA compared to saline-exposed control counterparts. Morphine reduced both sociability and social novelty preference behaviour in saline-, but not VPA-, exposed rats. Analysis of immediate early gene expression revealed that morphine reduced the expression of cfos in the prefrontal cortex of both saline- and VPA-exposed rats and reduced expression of cfos and junb in the hippocampus of VPA-exposed rats only. Pharmacokinetic analysis revealed similar concentrations of morphine in the plasma and brain of both saline- and VPA-exposed rats and similar thalamic MOP occupancy levels. Gene and protein expression of MOP in prefrontal cortex and hippocampus did not differ between saline and VPA-exposed rats. These data indicate differential effects of morphine on social responding and immediate early gene expression in the hippocampus of VPA-exposed rats compared with saline-exposed controls. This study provides support for altered MOP functionality in rats prenatally exposed to VPA, which may underlie the social deficits observed in the model.