Neurocentre Magendie

Abstract Healthy energy balance relies on an equilibrated trade-off between the respective drives for food and exercise. However, the motivation circuitry underlying the choice between these two rewards remains unknown. Here, we developed a neuroeconomic model wherein mice living in operant chambers needed to choose between standard food and wheel running under increasing effort demands. Reward seeking resistance to increasing costs was then quantified using feeding and exercise essential values (EVs). Through conditional genetics and viral approaches, we show that cannabinoid type-1 receptors (CB 1 Rs) located on GABAergic neurons gate in necessary and sufficient manners exercise EV, exercise preference over feeding and exercise duration per rewarded sequence. Further, we report that these GABAergic neurons are located in the ventromedial striatum in males, but not females. CB 1 R deletion from medium spiny neurons did not impact exercise motivation, revealing an unforeseen role for ventromedial striatal GABAergic interneurons in effort-based decision-making between food and exercise.

Craniopharyngiomas are low-grade suprasellar intracranial tumours associated with hypothalamic-pituitary axis dysfunction and obesity. This scoping review aimed to explore the potential impact of hyperphagic eating behaviour and appetitive factors on the development of craniopharyngioma-associated obesity and to identify areas for future intervention. PRISMA-ScR and JBI methodology was followed. Five databases and two trial registries were searched. All published studies of patients with childhood or adult-onset craniopharyngioma that addressed eating behaviours in conjunction with pharmaceutical/surgical interventions, neuroimaging, endocrine responses, energy expenditure, sleep and/or neuropsychology were included in this review. Evidence surrounding eating behaviours in craniopharyngioma patients was sparce with only 10 of the 50 included papers using validated eating behaviour assessments. Eating behaviour was included as a primary outcome (n=7), secondary outcome (n=12) or commented on without formal measurement (n=31). Few studies included patients with adult-onset craniopharyngioma (n=8) or compared patients with craniopharyngioma with and without obesity (n=2), and no papers were identified that attempted to modify eating behaviours as an intervention for craniopharyngioma-related obesity. Further understanding of eating behaviour in craniopharyngioma patients through longer-term research with validated measures will improve our understanding of mechanisms underlying craniopharyngioma-associated obesity and inform clinical practice by allowing treatments tailored for patient-centred care.

Severe calorie restriction in mouse models has highlighted the crucial role of the ghrelin system in maintaining glycemia and promoting survival. We hypothesized that if ghrelin acts as a survival signal, enhancing the responsivity of the GH secretagogue receptor (GHSR) should favor GHSR protective responses. To test this, we used rats with genetically enhanced GHSR sensitivity (GhsrQ343X) and wild‐type littermate controls and examined their acute responses to pharmacological challenges. Consistent with our hypothesis, GhsrQ343X rats, despite normal glucose and insulin tolerance, exhibited a significant increase in blood glucose in response to GHSR agonism, accompanied by elevated counter‐regulatory hormones including corticosterone. Concurrently, these rats displayed a notable decrease in locomotor activity and delayed feeding response. Also, GHSR agonism partially altered the cocaine‐induced hyperlocomotion of GhsrQ343X rats while they showed unaltered locomotor sensitization to cocaine. At the cellular level, functional studies indicated that the GhsrQ343X mutation prolongs ghrelin‐induced GHSR‐G protein canonical signaling. Altogether, in a model of increased GHSR sensitivity, GHSR agonist stimulation was sufficient to promote a robust blood glucose increase, while the acute feeding response was delayed in a context of unexpected hypolocomotor response. This mechanism may have implications for severe states of undernutrition such as restrictive anorexia nervosa.

Cerebrospinal fluid (CSF) is a key biological matrix that reflects the physiological and pathological states of the central nervous system (CNS). It supports brain function by regulating ionic balance, facilitating molecular transport, and clearing metabolic waste. In this article, we present a standardized protocol for CSF collection along with an integrative multiplatform metabolomic workflow that combines proton nuclear magnetic resonance spectroscopy (1H-NMRS) and high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS). Integrating these complementary analytical modalities enhances metabolite coverage and improves analytical robustness, enabling a more comprehensive and reliable characterization of the CSF metabolome. This workflow supports the discovery of potential biomarkers and advances our understanding of neurochemical alterations within the CNS.

HIV-1 transmission depends on the structure and immune cell composition of mucosal epithelia. Transmission mechanisms involve direct infection of CD4+ T-cells or macrophages, and indirect viral transfer to CD4+ T-cells from Langerhans cells (LCs) or dendritic cells (DCs). LCs-mediated HIV-1 transfer is inhibited by the neuropeptide calcitonin gene-related peptide (CGRP), due to upstream activation in LCs of the transient receptor potential vanilloid 1 (TRPV1) ion channel. Herein, we investigated the potential anti-HIV-1 roles of cannabidiol (CBD), the non-psychoactive compound in Cannabis sativa, which has well-described immunosuppressive functions and principally activates TRPV1 over its cognate CB1 and CB2 receptors. We found that via TRPV1 activation, CBD inhibits in-vitro infection of mucosal HIV-1 cellular targets. Specifically, CBD inhibits macrophages HIV-1 direct infection, and CD4+ T-cells HIV-1 direct infection or upon viral transfer from LCs and DCs. Moreover, inhibition of macrophages infection and LCs-mediated HIV-1 transfer involves secreted CGRP. Importantly, CBD also blocks early events of HIV-1 transmission ex-vivo in human inner foreskin tissues, namely formation of epidermal LC-T-cell conjugates and resulting CD4+ T-cells infection. Altogether, CBD inhibits infection of all HIV-1 cellular targets, and commercial CBD products might be repositioned as novel HIV-1 pre-exposure prophylaxis, namely CBD PrEP.

Altered sensory perception is a hallmark of autism and determines how autistic individuals engage with their environment. Among sensory modalities, tactile perception is particularly critical for daily functioning and social interactions. While these sensory alterations are thought to contribute to the cognitive differences observed in autism, the impact of cognitive processes —such as categorization, prior experience, and attention — on sensory perception remains poorly understood. In this study, we investigated the influence of top-down cognitive processes on tactile perception in the Fmr1-/y genetic mouse model of autism. We developed a translational, forepaw-based decision-making task designed to dissociate stimulus-driven tactile responses from those modulated by cognitive factors. This approach enabled us to assess multiple aspects of perceptual processing, including perceptual learning, stimulus categorization and discrimination, as well as the influence of prior experience and attention. Mice were initially trained to distinguish between high- and low-salience stimuli and were subsequently tested with a continuum of intermediate stimulus intensities. Our results revealed salience-dependent cognitive alterations that significantly influenced sensory performance. During the training phase, Fmr1-/y mice exhibited an increased choice consistency bias in low-salience trials, resulting in impaired perceptual learning. In the testing phase, Fmr1-/y mice demonstrated enhanced tactile discrimination under low-salience conditions, driven by a reduced influence of categorization during decision-making. However, increased tactile discrimination was dissociable from attention, with Fmr1-/y mice displaying attentional deficits under conditions of high cognitive load despite their enhanced tactile sensitivity. Together, our findings reveal that cognitive context critically shapes sensory phenotypes in autism. They advocate for a shift beyond traditional sensory–cognitive dichotomies to better capture the dynamic interplay between perceptual and cognitive alterations in autism.

Abstract A hallmark of Alzheimer’s disease (AD) is the accumulation of amyloid plaques, primarily composed of misfolded amyloid β (Aβ) peptides. We employed complementary high-resolution imaging techniques to investigate the plaque penetrability and the extracellular space (ECS) rheology in a mouse model of AD. Two-photon shadow imaging in vivo confirmed that a dense ring of cells surrounds cortical amyloid plaques but highlighted the diffusional penetrability of the amyloid core. Quantum dot tracking unveiled that ECS diffusional parameters are heterogeneous in and around plaques, with an elevated diffusivity within and around plaques compared to WT-tissue. The amyloid core showed low nanoparticle density, varying by plaque phenotype. Carbon nanotube tracking confirmed these altered local rheological properties at the level of the whole cortex of AD mice. Finally, we found the extracellular matrix to be dysregulated within the amyloid plaque, which may account for the observed alterations in diffusivity. Our study provides fresh insights for understanding Aβ plaque penetration, a prerequisite for therapeutic development.

The mechanism of action of serotonergic psychedelics is increasingly explored worldwide due to their clinical benefits in various psychiatric conditions. Beyond the stimulation of serotonin 2A (5-HT2A) receptors, psychedelics may desynchronize activity between brain regions, however the involvement of the corresponding neurotransmission systems has been largely overlooked. Given that monoaminergic systems target virtually all brain regions and play a role in exploratory behavior, we hypothesized that psychedelics disrupt the coherence of monoamine systems across brain regions during forced exploratory behavior in mice. Using post-mortem tissue quantification of serotonin (5-HT), dopamine (DA), noradrenaline (NA), and their metabolites in 28 distinct brain regions, we observed a dense and highly organized pattern of correlations within and between monoamines in vehicle-treated mice. This organization was disrupted by both the psychedelic 5-HT2A receptor agonist TCB-2 (0.3, 3 and 10mg/kg) and the antagonist MDL-100,907 (0.2mg/kg), both of which decreased correlations between regional neurochemical concentrations. Interestingly, the combination of MDL-100,907 and TCB-2 partially restored correlations. Quantitatively, TCB-2 dose-dependently decreased 5-HT turnover (metabolite/5-HT) across all brain regions, and DA turnover (3-methoxytyramine/DA) in the striatum. TCB-2 also enhanced markers of the DA and NA systems in certain brain regions, notably including the anterior cingulate cortex. MDL-100,907, which had minimal impact on monoamine levels when administered alone, reduced TCB-2 (3mg/kg)-induced head twitches and increased monoamine concentrations in the anterior cingulate cortex, but did not affect the TCB-2-induced decrease 5-HT turnover across the brain. These data suggest that the functional connectivity of monoaminergic systems during exploration is highly sensitive to modulation through either activation or blockade of 5-HT2A receptors.

Innovative treatment strategies for pituitary tumors are necessary to limit the disease burden and to improve survival in cases of carcinomas. The paucity and inaccuracy of available preclinical models substantially hamper pituitary research and drug discovery. Hence, we describe a novel method to generate orthotopic pituitary tumors via stereotaxic injection of somatotroph GC cells into the pituitaries of immunocompetent Wistar Furth rats. Tumor growth was monitored by repeated 7 Tesla magnetic resonance imaging. The procedure consistently led to rapidly expanding intra- and suprasellar growth hormone-secreting tumors within their native anatomical environment. The generated tumors faithfully reproduced the microarchitecture of human somatotroph pituitary adenomas, including the immune infiltrates and other typical components of their microenvironment, which is a prerequisite for testing immunomodulating agents. This orthotopic model of proliferative pituitary tumors developed in immunocompetent hosts therefore unlocks new opportunities for preclinical studies.