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Abstract Background Cancer researchers use cell lines, patient-derived xenografts, engineered mice, and tumoroids as models to investigate tumor biology and to identify therapies. The generalizability and power of a model derive from the fidelity with which it represents the tumor type under investigation; however, the extent to which this is true is often unclear. The preponderance of models and the ability to readily generate new ones has created a demand for tools that can measure the extent and ways in which cancer models resemble or diverge from native tumors. Methods We developed a machine learning-based computational tool, CancerCellNet, that measures the similarity of cancer models to 22 naturally occurring tumor types and 36 subtypes, in a platform and species agnostic manner. We applied this tool to 657 cancer cell lines, 415 patient-derived xenografts, 26 distinct genetically engineered mouse models, and 131 tumoroids. We validated CancerCellNet by application to independent data, and we tested several predictions with immunofluorescence. Results We have documented the cancer models with the greatest transcriptional fidelity to natural tumors, we have identified cancers underserved by adequate models, and we have found models with annotations that do not match their classification. By comparing models across modalities, we report that, on average, genetically engineered mice and tumoroids have higher transcriptional fidelity than patient-derived xenografts and cell lines in four out of five tumor types. However, several patient-derived xenografts and tumoroids have classification scores that are on par with native tumors, highlighting both their potential as faithful model classes and their heterogeneity. Conclusions CancerCellNet enables the rapid assessment of transcriptional fidelity of tumor models. We have made CancerCellNet available as a freely downloadable R package ( https://github.com/pcahan1/cancerCellNet ) and as a web application ( http://www.cahanlab.org/resources/cancerCellNet_web ) that can be applied to new cancer models that allows for direct comparison to the cancer models evaluated here.

Abstract The Insula functions as a multisensory relay involved in socio-emotional processing with projections to sensory, cognitive, emotional, and motivational regions. Notably, the interhemispheric projection from the Insula to the contralateral Insula is a robust yet underexplored connection. Using viral-based tracing neuroanatomy, ex vivo and in vivo electrophysiology, in vivo fiber photometry along with targeted circuit manipulation, we elucidated the nature and role of InsulaIns communication in social and anxiety processing in mice. In this study, we 1) characterized the anatomical and molecular profile of the InsulaIns neurons, 2) demonstrated that stimulation of this neuronal subpopulation induces excitation in the Insula interhemispheric circuit, 3) revealed that InsulaIns neurons are essential for social discrimination after 24 h of isolation in male mice. In conclusion, our findings highlight InsulaIns neurons as a distinct class of neurons within the insula and offer new insights into the neuronal mechanisms underlying social behavior.

Abstract Background In the case of preterm birth, the idealized postnatal period is replaced by an anxious and even traumatic experience for parents. Higher prevalence of parental anxiety, postnatal depression, and posttraumatic stress disorder has been observed in mothers of preterm infants up to 18 months after childbirth. There is increasing evidence that proprioceptive stimulation has a beneficial effect on preterms’ short-term outcomes. Could this care also have an impact on parental anxiety and depressive symptoms? We reviewed recent publications on the impact on parents’ anxiety and depressive symptoms of delivering tactile and/or kinesthetic stimulation to their premature newborn. Methods We conducted a systematic review by searching the PubMed, PsycInfo, Scopus, ScienceDirect and Google Scholar databases for English-language publications from the past 10 years. We focused on the mothers or fathers of infants born preterm (before 37 weeks of gestation) who provided tactile and/or kinesthetic stimulation to their premature newborn in the neonatal intensive care unit. Relevant outcomes were the parents’ anxiety, stress, depressive symptoms, and symptoms of posttraumatic stress disorder, assessed with reliable standardized inventories. Results Eleven articles were included in the systematic review. Results suggested a beneficial effect of parents’ early tactile and kinesthetic stimulation of their preterm infants. Conclusions These interventions may act as protective factors against the occurrence of anxiety and depressive symptoms in parents and deserve to be studied further in this population.

Abstract Traumatic brain injury (TBI) has the highest incidence amongst the pediatric population and its mild severity represents the most frequent cases. Moderate and severe injuries as well as repetitive mild TBI result in lasting morbidity. However, whether a single mild TBI sustained during childhood can produce long-lasting modifications within the brain is still debated. We aimed to assess the consequences of a single juvenile mild TBI (jmTBI) at 12 months post-injury in a mouse model. Non-invasive diffusion tensor imaging (DTI) revealed significant microstructural alterations in the hippocampus and the in the substantia innominata/nucleus basalis (SI/NB), structures known to be involved in spatial learning and memory. DTI changes paralled neuronal loss, increased astrocytic AQP4 and microglial activation in the hippocampus. In contrast, decreased astrocytic AQP4 expression and microglia activation were observed in SI/NB. Spatial learning and memory were impaired and correlated with alterations in DTI-derived derived fractional ansiotropy (FA) and axial diffusivity (AD). This study found that a single juvenile mild TBI leads to significant region-specific DTI microstructural alterations, distant from the site of impact, that correlated with cognitive discriminative novel object testing and spatial memory impairments at 12 months after a single concussive injury. Our findings suggest that exposure to jmTBI leads to a chronic abnormality, which confirms the need for continued monitoring of symptoms and the development of long-term treatment strategies to intervene in children with concussions.

IntroductionPremature birth is associated with long-term somatic and neurological disorders, including cognitive, social and behavioral impairments. Moreover, the mothers of infants born preterm exhibit a higher prevalence of anxiety and depressive symptoms after birth. Early rehabilitation, developmental care, and parenting support have already been shown to have a positive impact on neurological outcome. However, no randomized controlled study has so far assessed the effects on parenting and long-term neurological outcomes of proprioceptive stimulation to trigger positive brain plasticity in very preterm babies. The CALIN project will therefore investigate the impact of sensory-tonic stimulation (STS) of extremely preterm infants by their parents on child parent interactions, infants' morphological and functional brain development and subsequent cognition (including social cognition), and parents' anxiety and depressive symptoms in the postpartum period.Methods and analysisInfants born between 25 and 32 weeks of gestation will be randomly assigned to the “STS + Kangaroo care” or “Kangaroo care” group. The primary endpoint, child and parent interactions, will be rated at 12 months corrected age using the Coding Interactive Behavior system. Secondary endpoints include: 1/functional and anatomical brain maturation sequentially assessed during neonatal hospitalization using electroencephalogram (EEG), amplitude-integrated EEG (aEEG), cranial ultrasound and MRI performed at term-corrected age, 2/social and cognitive outcomes assessed at 15 months, 2, 4 and 6 years, and 3/parents' anxiety and depressive symptoms assessed at 7 ± 1 weeks after birth, using dedicated questionnaires.Ethics and disseminationThis study was approved by the French Ethics Committee for the Protection of Persons on 18 October 2021. It is registered with the French National Agency for the Safety of Medicines and Health Products (ANSM; no. 2020-A00382–37). The registry number on ClinicalTrials.gov is NCT04380051.

Summary: A key feature of the brain is the ability to handle novelty. Anything that is new will stimulate curiosity and trigger exploration. Novelty preference has been proposed to predict increased sensitivity to cocaine. Different brain circuits are activated by novelty, but three specific brain regions are critical for exploring a novel environment: the noradrenergic neurons originating from the locus coeruleus (LC), the dopaminergic neurons from the ventral tegmental area (VTA), and the hippocampus. However, how exploring a novel environment can interfere with the reward system and control cocaine impact on VTA dopamine neuron plasticity is unclear. Here, we first investigated the effects of exposure to a novel environment on the tonic electrophysiological properties of VTA dopamine neurons. Then, we explored how exposure to a novel environment controls cocaine-evoked plasticity in dopamine neurons. Our findings indicate that LC controls VTA dopamine neurons under physiological conditions but also after cocaine.

Understanding others’ intentions requires both the identification of social cues (e.g., emotional facial expressions, gaze direction) and the attribution of a mental state to another. The neural substrates of these processes have often been studied separately, and results are heterogeneous, in part attributable to the variety of paradigms used. The aim of the present study was to explore the neural regions underlying these sociocognitive processes, using a novel naturalistic task in which participants engage with human protagonists featured in videos.A total of 51 right-handed volunteers underwent functional magnetic resonance imaging while performing the Dynamic Inference Task (DIT), manipulating the degree of inference (high vs. low), the presence of emotion (emotional vs. nonemotional), and gaze direction (direct vs. averted).High nonemotional inference elicited neural activation in temporal regions encompassing the right posterior superior temporal sulcus. The presence (vs. absence) of emotion in the high-inference condition elicited a bilateral pattern of activation in internal temporal areas around the amygdala and orbitofrontal structures, as well as activation in the right dorsomedial part of the superior frontal gyrus and the left precuneus.On account of its dynamic, naturalistic approach, the DIT seems a suitable task for exploring social interactions and the way we interact with others, both in nonclinical and clinical populations.

Background: Recent research has identified neuropsychological disorders, specifically executive function disorders, in premature children. Executive functions support goal-oriented mental activity and play a role in the development of social cognition. This underlies the social and emotional behavior of individuals. Parental anxiety is also an important environmental factor that can influence the psycho-emotional development of children.Objectives: The present protocol aims to compare the development of social cognition in school-age children born prematurely to that of school-age children born full-term, and to determine the impact of executive (dys)function and parental anxiety on such development.Methods/Design: In this cross-sectional protocol, 28 prematurely born children aged 7-10 years (“preterm”) and 28 full-term born children aged 7-10 years (“control”) will be included. The “preterm” and “control” groups will be matched for sex and age. The neuropsychological evaluation will include that of non-verbal intellectual efficiency (Raven's colored progressive matrices), verbal level (WISC-IV subtests), and executive functions (NEPSY II subtests and the opposite worlds of TEA-CH). The evaluation of social cognition will be conducted via tests of the theory of cognitive and affective mind. Several dimensions of the level of parental anxiety will be collected through the Spielberg Trait Anxiety Inventory Form Y, Beck Depression Inventory, Social Support Questionnaire-6, Parental Stress Index and, specifically for mothers, the Modified Perinatal Post-Traumatic Stress Disorder Questionnaire.Discussion: The results of this protocol will aid our understanding of the development of social cognition in premature children and to determine the factors that influence such development. This clinical research project, although following a fundamental approach, will have clinical implications because a more precise description of the development of social cognition in this school-age population will make it possible to better determine the cognitive targets of therapeutic actions and to search for predictive indices of the efficacy of practices.Trial Registration:https://clinicaltrials.gov/ct2/show/NCT03007095, identifier: NCT03007095.

Psychotic disorder refers to a spectrum of disorders that have multiple etiologies, due to the complex interaction of biological and genetic vulnerability with familial and cultural factors. A clinical high risk (CHR) for schizophrenia is defined as the presence of brief, attenuated, or intermittent psychotic symptoms in non-schizophrenic individuals. The transition to schizophrenia appears significantly more frequent in this at-risk population than in the general population. Moreover, the ability to attribute mental states to others, known as mentalizing or theory of mind, and its neural correlates found in individuals with CHR are similar to those described in patients with schizophrenia. We have therefore explored neurofunctional correlates of mentalizing in individuals with CHR vs. healthy controls, in order to identify the differences in brain activation. A neural coordinate-based activation likelihood estimation meta-analysis of existing neuroimaging data revealed that three regions displayed decreased activation in individuals with CHR, compared with healthy controls: the right temporoparietal junction, the right middle temporal gyrus, and the left precuneus. These results, combined with those in the literature, further support the hypothesis that abnormal activation of posterior brain regions involved in mentalizing correlates with psychotic symptoms in help-seeking individuals.

In recent years, sustainable community development has gained traction for addressing local environmental, social, and economic issues. Cities worldwide are committed to implementing sustainable community plans (SCPs) in their efforts to achieve sustainable development, and more recently, to localize the United Nations’ Sustainable Development Goals (SDGs). Although there are over 1000 plans in Canada, a gap exists between creating these plans and implementing them. Integrating market-based instruments (MBIs) with traditional policy tools would help to diversify revenue generation and thus mitigate these constraints. This paper presents a new and comprehensive categorization of MBIs that aligns the locally applicable ones with the environmental aims of both SCPs and SDGs. The categorization framework has been tested through focus groups with key municipal staff from two Canadian communities. The new categorization framework aligned over 50 locally applicable MBIs with 8 different environmental topics and 12 SDGs. The paper presents a useful tool for implementing SCPs and SDGs and contributes to the understanding of MBIs for enabling local progress in sustainable development.

The bed nucleus of the stria terminalis (BNST) is known to modulate anxiety-related behaviours. Here the authors show that excitatory inputs from infralimbic cortex and ventral subiculum/CA1 converge onto the same BNST neurons; stimulation of vSUB/CA1 triggers LTP in BNST and reduces anxiety in rats.

The ventral subiculum (vSUB) plays a key role in addiction, and identifying the neuronal circuits and synaptic mechanisms by which vSUB alters the excitability of dopamine neurons is a necessary step to understand the motor changes induced by cocaine. Here, we report that high-frequency stimulation of the vSUB (HFSvSUB) over-activates ventral tegmental area (VTA) dopamine neurons in vivo and triggers long-lasting modifications of synaptic transmission measured ex vivo. This potentiation is caused by NMDA-dependent plastic changes occurring in the bed nucleus of the stria terminalis (BNST). Finally, we report that the modification of the BNST-VTA neural circuits induced by HFSvSUB potentiates locomotor activity induced by a sub-threshold dose of cocaine. Our findings unravel a neuronal circuit encoding behavioral effects of cocaine in rats and highlight the importance of adaptive modifications in the BNST, a structure that influences motivated behavior as well as maladaptive behaviors associated with addiction.

ObjectivesLanguage modifications are a core feature of mania, but little is known about the semantic mechanisms behind these disturbances. The aim of the present study was thus to identify deficits in semantic inhibition and their respective neural activation patterns in a sample of individuals assessed for hypomanic personality traits.MethodsThirty-six young adults with no neurological or psychiatric diagnoses were assessed for hypomanic personality traits with the Hypomanic Personality Scale (HPS) and underwent an fMRI task of semantic ambiguity resolution.ResultsRegression analyses revealed a positive association between the HPS score and activity in the left superior frontal gyrus, left inferior parietal lobule, and anterior cingulate gyrus during semantic ambiguity resolution.ConclusionWe found a link between HPS scores and brain areas that are part of the cognitive control loop and semantic memory network during language processing in a nonclinical sample of individuals. The hyperactivation of these regions may reflect a compensatory neural response in a population with greater vulnerability to BD.

Irony is a kind of figurative language used by a speaker to say something that contrasts with the context and, to some extent, lends humor to a situation. However, little is known about the brain regions that specifically support the processing of these two common features of irony. The present study had two main aims: (i) investigate the neural basis of irony processing, by delivering short ironic spoken sentences (and their literal counterparts) to participants undergoing fMRI; and (ii) assess the neural effect of two irony parameters, obtained from normative studies: degree of contrast and humor appreciation. Results revealed activation of the bilateral inferior frontal gyrus (IFG), posterior part of the left superior temporal gyrus, medial frontal cortex, and left caudate during irony processing, suggesting the involvement of both semantic and theory-of-mind networks. Parametric models showed that contrast was specifically associated with the activation of bilateral frontal and subcortical areas, and that these regions were also sensitive to humor, as shown by a conjunction analysis. Activation of the bilateral IFG is consistent with the literature on humor processing, and reflects incongruity detection/resolution processes. Moreover, the activation of subcortical structures can be related to the reward processing of social events.

Opiate withdrawal is followed by a protracted abstinence syndrome consisting of craving and physiological changes. However, few studies have been dedicated to both the characterization and understanding of these long-term alterations in post-dependent subjects. The aim of the present study was to develop an opiate dependence model, which induces long-lasting behavioral changes in abstinent rats. Here, we first compared the effects of several protocols for the induction of opiate dependence (morphine pellets, repeated morphine or heroin injections) on the subsequent response to heroin challenges (0.25 mg/kg) at different time points during abstinence (3, 6, 9 and 18 weeks). In a second set of experiments, rats were exposed to increasing doses of heroin and subsequently monitored for general circadian activity up to 20 weeks of abstinence. Results show that heroin injections rather than the other methods of opiate administration have long-term consequences on rats’ sensitivity to heroin with its psychostimulant effects persisting up to 18 weeks of abstinence. Moreover, intermittent episodes of heroin dependence rather than a single exposure produce enduring alteration of the basal circadian activity both upon heroin cessation and protracted abstinence. Altogether, these findings suggest that the induction of heroin dependence through intermittent increasing heroin injections is the optimal method to model long-term behavioral alterations during protracted abstinence in rats. This animal model would be useful in further characterizing long-lasting changes in post-dependent subjects to help understand the prolonged vulnerability to relapse.