Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors.

Recent investigations have revealed that the genetic deletion of P2X7 receptors (P2rx7) results in an antidepressant phenotype in mice. However, the link between the deficiency of P2rx7 and changes in behavior has not yet been explored. In the present study, we studied the effect of genetic deletion of P2rx7 on neurochemical changes in the hippocampus that might underlie the antidepressant phenotype. P2X7 receptor deficient mice (P2rx7-/-) displayed decreased immobility in the tail suspension test (TST) and an attenuated anhedonia response in the sucrose preference test (SPT) following bacterial endotoxin (LPS) challenge. The attenuated anhedonia was reproduced through systemic treatments with P2rx7 antagonists. The activation of P2rx7 resulted in the concentration-dependent release of [3H]glutamate in P2rx7+/+ but not P2rx7-/- mice, and the NR2B subunit mRNA and protein was upregulated in the hippocampus of P2rx7-/- mice. The brain-derived neurotrophic factor (BDNF) expression was higher in saline but not LPS-treated P2rx7-/- mice; the P2rx7 antagonist Brilliant blue G elevated and the P2rx7 agonist benzoylbenzoyl ATP (BzATP) reduced BDNF level. This effect was dependent on the activation of NMDA and non-NMDA receptors but not on Group I metabotropic glutamate receptors (mGluR1,5). An increased 5-bromo-2-deoxyuridine (BrdU) incorporation was also observed in the dentate gyrus derived from P2rx7-/- mice. Basal level of 5-HT was increased, whereas the 5HIAA/5-HT ratio was lower in the hippocampus of P2rx7-/- mice, which accompanied the increased uptake of [3H]5-HT and an elevated number of [3H]citalopram binding sites. The LPS-induced elevation of 5-HT level was absent in P2rx7-/- mice. In conclusion there are several potential mechanisms for the antidepressant phenotype of P2rx7-/- mice, such as the absence of P2rx7-mediated glutamate release, elevated basal BDNF production, enhanced neurogenesis and increased 5-HT bioavailability in the hippocampus

Statut moléculaire - oncogènes et gènes suppresseurs de tumeurs - des tumeurs gliales de l'adulte en relation avec le grade anatomo-pathologique et l'évolution tumorale

POITIERS-BU Médecine pharmacie (861942103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Network-level prediction of set-shifting deterioration after lower-grade glioma resection

International audienceOBJECTIVE The aim of this study was to predict set-shifting deterioration after resection of low-grade glioma. METHODS The authors retrospectively analyzed a bicentric series of 102 patients who underwent surgery for low-grade glioma. The difference between the completion times of the Trail Making Test parts B and A (TMT B-A) was evaluated preoperatively and 3–4 months after surgery. High dimensionality of the information related to the surgical cavity topography was reduced to a small set of predictors in four different ways: 1) overlap between surgical cavity and each of the 122 cortical parcels composing Yeo’s 17-network parcellation of the brain; 2) Tractotron: disconnection by the cavity of the major white matter bundles; 3) overlap between the surgical cavity and each of Yeo’s networks; and 4) disconets: signature of structural disconnection by the cavity of each of Yeo’s networks. A random forest algorithm was implemented to predict the postoperative change in the TMT B-A z-score. RESULTS The last two network-based approaches yielded significant accuracies in left-out subjects (area under the receiver operating characteristic curve [AUC] approximately equal to 0.8, p approximately equal to 0.001) and outperformed the two alternatives. In single tree hierarchical models, the degree of damage to Yeo corticocortical network 12 (CC 12) was a critical node: patients with damage to CC 12 higher than 7.5% (cortical overlap) or 7.2% (disconets) had much higher risk to deteriorate, establishing for the first time a causal link between damage to this network and impaired set-shifting. CONCLUSIONS The authors’ results give strong support to the idea that network-level approaches are a powerful way to address the lesion-symptom mapping problem, enabling machine learning–powered individual outcome predictions

Network-behavior mapping of lasting executive impairments after low-grade glioma surgery

International audienceExecutive functions (EF) may be significantly impaired following low-grade glioma (LGG) surgery, especially in the event of white matter (WM) disruption. The aim of this study was to identify the connective tracts associated with EF impairments after LGG surgery, and to provide new insights into the WM network architecture of EF. EF measurements were collected in 270 patients at the chronic postoperative phase. This comprised cognitive flexibility, verbal inhibition and fluency abilities (phonological and categorical). The scores were z-corrected for age and educational level, and further submitted to a principal component analysis (PCA). Tracwise and disconnectome-behavior analyses were then performed using EF measures independently but also the extracted components from PCA. For the first analyses, 15 tracts of interest were selected. Two principal components were extracted from the behavioral data, interpreted as 'EF' and 'language' components. Robust, bonferroni-corrected correlations were established between the EF component and Layers II and III of the left superior longitudinal fasciculus, and between phonological fluency/inhibition and the same tracts. Less powerful but still significant correlations were also observed with the left frontal aslant and fronto-striatal tracts. These results were confirmed by disconnectome-behavior analyses. Our results indicate that surgically-related disruption of the fronto-parietal and the frontal cortico-subcortical connectivity, and of the frontal aslant tract, is related to long-lasting EF impairments. In addition to providing new insights into the WM pathways supporting EF, these findings are especially useful for both surgical planning and the predictive approach of neuropsychological disorders in the context of LGG surgery

Quantitative sensory testing profiles in children, adolescents and young adults (6–20 years) with cerebral palsy : Hints for a neuropathic genesis of pain syndromes

Introduction: Many patients with cerebral palsy (CP) suffer chronic pain as one of the most limiting factors in their quality of life. In CP patients, pain mechanisms are not well understood, and pain therapy remains a challenge. Quantitative sensory testing (QST) might provide unique information about the functional status of the somatosensory system and therefore better guide pain treatment. Objectives: To understand better the underlying pain mechanisms in pediatric CP patients, we aimed to assess clinical and pain parameters, as well as QST profiles, which were matched to the patients' cerebral imaging pathology. Patients and methods: Thirty CP patients aged 6–20 years old (mean age 12 years) without intellectual impairment underwent standardized assessments of QST. Cerebral imaging was reassessed. QST results were compared to age- and sex-matched controls (multiple linear regression; Fisher's exact test; linear correlation analysis). Results: CP patients were less sensitive to all mechanical and thermal stimuli than healthy controls but more sensitive to all mechanical pain stimuli (each p < 0.001). Fifty percent of CP patients showed a combination of mechanical hypoesthesia, thermal hypoesthesia and mechanical hyperalgesia; 67% of CP patients had periventricular leukomalacia (PVL), which was correlated with mechanic (r = 0.661; p < 0.001) and thermal (r = 0.624; p = 0.001) hypoesthesia. Conclusion: The combination of mechanical hypoesthesia, thermal hypoesthesia and mechanical hyperalgesia in our CP patients implicates lemniscal and extralemniscal neuron dysfunction in the thalamus region, likely due to PVL. We suspect that extralemniscal tracts are involved in the original of pain in our CP patients, as in adults

Expression of a gap junction protein, connexin43, in a large panel of human gliomas: new insights

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