Search

International audience; Background:Brain development during embryogenesis and in early postnatal life is particularlycomplex and involves the interplay of many cellular processes and molecular mechanisms, makingit extremely vulnerable to exogenous insults, including ionizing radiation (IR). Microcephaly is oneof the most frequent neurodevelopmental abnormalities that is characterized by small brain size,and is often associated with intellectual deficiency. Decades of research span from epidemiologicaldata onin uteroexposure of the A-bomb survivors, to studies on animal and cellular models thatallowed deciphering the most prominent molecular mechanisms leading to microcephaly. TheAdverse Outcome Pathway (AOP) framework is used to organize, evaluate and portray the scien-tific knowledge of toxicological effects spanning different biological levels of organizations, fromthe initial interaction with molecular targets to the occurrence of a disease or adversity. In the pre-sent study, the framework was used in an attempt to organize the current scientific knowledge onmicrocephaly progression in the context of ionizing radiation (IR) exposure. This work was per-formed by a group of experts formed during a recent workshop organized jointly by theMultidisciplinary European Low Dose Initiative (MELODI) and the European Radioecology Alliance(ALLIANCE) associations to present the AOP approach and tools. Here we report on the develop-ment of a putative AOP for congenital microcephaly resulting from IR exposure based on discus-sions of the working group and we emphasize the use of a novel machine-learning approach toassist in the screening of the available literature to develop AOPs.Conclusion:The expert consultation led to the identification of crucial biological events for theprogression of microcephaly upon exposure to IR, and highlighted current knowledge gaps. Themachine learning approach was successfully used to screen the existing knowledge and helped torapidly screen the body of evidence and in particular the epidemiological data. This systematicreview approach also ensured that the analysis was sufficiently comprehensive to identify themost relevant data and facilitate rapid and consistent AOP development. We anticipate that asmachine learning approaches become more user-friendly through easy-to-use web interface, thiswould allow AOP development to become more efficient and less time consuming

The link between mutations associated with intellectual disability (ID) and the mechanisms underlying cognitive dysfunctions remains largely unknown. Here, we focused on PAK3, a serine/threonine kinase whose gene mutations cause X-linked ID. We generated a new mutant mouse model bearing the missense R67C mutation of the Pak3 gene (Pak3-R67C), known to cause moderate to severe ID in humans without other clinical signs and investigated hippocampal-dependent memory and adult hippocampal neurogenesis. Adult male Pak3-R67C mice exhibited selective impairments in long-term spatial memory and pattern separation function, suggestive of altered hippocampal neurogenesis. A delayed non-matching to place paradigm testing memory flexibility and proactive interference, reported here as being adult neurogenesis-dependent, revealed a hypersensitivity to high interference in Pak3-R67C mice. Analyzing adult hippocampal neurogenesis in Pak3-R67C mice reveals no alteration in the first steps of adult neurogenesis, but an accelerated death of a population of adult-born neurons during the critical period of 18–28 days after their birth. We then investigated the recruitment of hippocampal adult-born neurons after spatial memory recall. Post-recall activation of mature dentate granule cells in Pak3-R67C mice was unaffected, but a complete failure of activation of young DCX + newborn neurons was found, suggesting they were not recruited during the memory task. Decreased expression of the KCC2b chloride cotransporter and altered dendritic development indicate that young adult-born neurons are not fully functional in Pak3-R67C mice. We suggest that these defects in the dynamics and learning-associated recruitment of newborn hippocampal neurons may contribute to the selective cognitive deficits observed in this mouse model of ID.

Existing and future nuclear fusion technologies involve the production and use of large quantities of tritium, a highly volatile, but low toxicity beta-emitting isotope of hydrogen. Tritium has received international attention because of public and scientific concerns over its release to the environment and the potential health impact of its internalization. This article provides a brief summary of the current state of knowledge of both the biological and regulatory aspects of tritium exposure; it also explores the gaps in this knowledge and provides recommendations on the best ways forward for improving our understanding of the health effects of low-level exposure to it. Linking health effects specifically to tritium exposure is challenging in epidemiological studies due to high uncertainty in tritium dosimetry and often suboptimal cohort sizes. We therefore argued that limits for tritium in drinking water should be based on evidence derived from controlled in vivo animal tritium toxicity studies that use realistically low levels of tritium. This article presents one such mouse study, undertaken within an international collaboration, and discusses the implications of its main findings, such as the similarity of the biokinetics of tritiated water (HTO) and organically bound tritium (OBT) and the higher biological effectiveness of OBT. This discussion is consistent with the position expressed in this article that in vivo animal tritium toxicity studies carried out within large, multi-partner collaborations allow evaluation of a great variety of health-related endpoints and essential to the development of international consensus on the regulation of tritium levels in the environment. Environ. Mol. Mutagen. 59:586-594, 2018. © 2018 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.

This article illustrates the use of a multi-criteria decision making approach, based on desirability functions, to identify an appropriate adjuvant composition for an influenza vaccine to be used in elderly. The proposed adjuvant system contained two main elements: monophosphoryl lipid and α-tocopherol with squalene in an oil/water emulsion. The objective was to elicit a stronger immune response while maintaining an acceptable reactogenicity and safety profile. The study design, the statistical models, the choice of the desirability functions, the computation of the overall desirability index, and the assessment of the robustness of the ranking are all detailed in this manuscript.

Existing and future nuclear fusion technologies involve the production and use of large quantities of tritium, a highly volatile, but low toxicity beta-emitting isotope of hydrogen. Tritium has received international attention because of public and scientific concerns over its release to the environment and the potential health impact of its internalization. This article provides a brief summary of the current state of knowledge of both the biological and regulatory aspects of tritium exposure; it also explores the gaps in this knowledge and provides recommendations on the best ways forward for improving our understanding of the health effects of low-level exposure to it. Linking health effects specifically to tritium exposure is challenging in epidemiological studies due to high uncertainty in tritium dosimetry and often suboptimal cohort sizes. We therefore argued that limits for tritium in drinking water should be based on evidence derived from controlled in vivo animal tritium toxicity studies that use realistically low levels of tritium. This article presents one such mouse study, undertaken within an international collaboration, and discusses the implications of its main findings, such as the similarity of the biokinetics of tritiated water (HTO) and organically bound tritium (OBT) and the higher biological effectiveness of OBT. This discussion is consistent with the position expressed in this article that in vivo animal tritium toxicity studies carried out within large, multi-partner collaborations allow evaluation of a great variety of health-related endpoints and essential to the development of international consensus on the regulation of tritium levels in the environment. Environ. Mol. Mutagen. 59:586-594, 2018. © 2018 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.

Background: Patient-reported outcomes (PROs) are particularly relevant in influenza vaccine trials in the elderly where reduction in symptom severity could prevent illness-related functional impairment. Objectives: To evaluate PROs in people aged 65years receiving two different vaccines. Methods: This was a phase III, randomised, observer-blind study (NCT00753272) of the AS03-adjuvanted inactivated trivalent split-virion influenza vaccine (AS03-TIV) versus non-adjuvanted vaccine (TIV). Using the FluiiQ questionnaire, symptom (systemic, respiratory, total) and life impact (activities, emotions, relationships) scores were computed as exploratory endpoints, with minimal important difference (MID) in influenza severity between vaccines considered post-hoc as >7%. Vaccine efficacy of AS03-TIV relative to TIV in severe influenza (hospitalisation, complication, most severe one-third of episodes based on the area under the curve for systemic symptom score) was calculated post-hoc. The main analyses (descriptive) were conducted in the according-to-protocol cohort (n=280 AS03-TIV, n=315 TIV) for influenza confirmed by culture or reverse transcriptase polymerase chain reaction. Results: Mean systemic symptom, total symptom and impact on activities scores were lower with AS03-TIV versus TIV. Mean respiratory symptom, impact on emotions and impact on relationships scores were similar. Influenza tended to be less severe with AS03-TIV, but the MID was reached only for impact on activities (mean 9 center dot 0%). Relative vaccine efficacy in severe influenza was 29 center dot 38% (95% CI: 7 center dot 60-46 center dot 02). Conclusions: AS03-TIV had advantages over TIV in impact on systemic symptoms and activities as measured by the FluiiQ in elderly people. Higher efficacy of AS03-TIV relative to TIV was shown for prevention of severe illness.

Pathogenic bacterial colonisation in Cystic Fibrosis patients is associated with a poor prognosis; thus, protective measures need to be taken to prevent their transmission. We studied the extent of contamination in the environment of hospitalised children with cystic fibrosis (CF) associated with specific activities.We assessed the levels of bacterial contamination in 432 air and surface samples collected from various locations in our CF centre over a three-month period: the bedrooms, corridor, communal showers, school, leisure centre and the respiratory functional explorations (RFE) unit. Staphylococcus aureus and Pseudomonas aeruginosa strains found in bedrooms and the RFE were compared with those found in patient expectorations using pulsed field gel electrophoresis.In all sampling locations, there were high levels of airborne contamination just after the presence of patients or nursing staff. In the bedrooms, the amount of S. aureus or P. aeruginosa in the air, at wake-up and after physiotherapy, were significantly higher than that after the bedroom had been cleaned. For P. aeruginosa, 33% of isolates were multiresistant to antibiotics; 50% of the colonised patients had the same P. aeruginosa strain in their sputum as in air taken from their bedroom. P. aeruginosa was detected in 23% of samples taken from the surfaces in the showers after patient washing. Very low levels of pathogenic bacteria were found in samples from the other locations.Overall, activities with the highest risk of contamination in the CF ward are physiotherapy and washing in the communal shower room. We therefore recommend to open windows after physiotherapy and to implement a strong decontamination after showers.

International audience; Each year, millions of people worldwide are treated for primary or recurrent pelvic malignancies, involving radiotherapy in almost 50% of cases. Delayed development of visceral complications after radiotherapy is recognized in cancer survivors. Therapeutic doses of radiation may lead to the damage of healthy tissue around the tumor and abdominal pain. Because of the lack of experimental models, the underlying mechanisms of radiation-induced long-lasting visceral pain are still unknown. This makes managing radiation-induced pain difficult, and the therapeutic strategies proposed are mostly inefficient. The aim of our study was to develop an animal model of radiation-induced visceral hypersensitivity to (1) analyze some cellular and molecular mechanisms involved and (2) to test a therapeutic strategy using mesenchymal stromal cells (MSCs). Using a single 27-Grays colorectal irradiation in rats, we showed that such exposure induces a persistent visceral allodynia that is associated with an increased spinal sensitization (enhanced p-ERK neurons), colonic neuroplasticity (as increased density of substance P+ nerve fibers), and colonic mast cell hyperplasia and hypertrophy. Mast cell stabilization by ketotifen provided evidence of their functional involvement in radiation induced allodynia. Finally, intravenous injection of 1.5 million MSCs, 4 weeks after irradiation, induced a time-dependent reversion of the visceral allodynia and a reduction of the number of anatomical interactions between mast cells and PGP9.51 nerve fibers. Moreover, unlike ketotifen, MSC treatment has the key advantage to limit radiation-induced colonic ulceration. This work provides new insights into the potential use of MSCs as cellular therapy in the treatment of pelvic radiation disease.

Baseline human papillomavirus (HPV) prevalence and type distribution were evaluated in young Chinese women enrolled in a clinical trial of an HPV vaccine (ClinicalTrials.gov registration NCT00779766). Cervical specimens and blood samples were collected at baseline from women aged 18–25 years (n = 6,051) from four sites across Jiangsu province. Cervical specimens were tested for HPV DNA by SPF10 PCR-DEIA-LiPA25 version 1, and HPV-16/18 type-specific polymerase chain reaction. Anti-HPV-16 and anti-HPV-18 antibody titres were quantified by enzyme-linked immunosorbent assay. At baseline, 15.3% of women were DNA positive for any of 14 HPV high-risk (hr) types (HPV-16/18/31/33/35/39/45/51/52/56/58/59/66/68). The most commonly detected hrHPV types in cervical specimens were HPV-52 (4.0%) and HPV-16 (3.7%). High-risk HPV DNA-positivity increased with severity of cytological abnormalities: 39.3% in atypical squamous cells of undetermined significance, 85.0% in low-grade squamous intraepithelial lesions and 97.8% in high-grade squamous intraepithelial lesions (HSIL). The hrHPV types most frequently detected in HSIL were HPV-16 (63.0%), HPV-18 (17.4%), HPV-52 (17.4%), HPV-58 (15.2%) and HPV-33 (15.2%). The hrHPV types most frequently detected in cervical intraepithelial neoplasia 2+ were HPV-16 (66.1%), HPV-33 (16.1%), HPV-52 (16.1%), HPV-58 (14.5%) and HPV-51 (11.3%). Multiple hrHPV infections were reported for 24.4% of hrHPV DNA positive women. Regardless of baseline HPV DNA status, 30.5% and 16.0% of subjects were initially seropositive for anti-HPV-16 and anti-HPV-18, respectively. In conclusion, the high baseline seropositivity rate and intermediate prevalence of cervical hrHPV types in Chinese women aged 18–25 years underlines the importance of early HPV vaccination in this population. What's new? In China, cervical cancer is the second most frequent cancer among women aged 15–44 years. The authors collected baseline data on prevalence and type distribution of human papillomavirus (HPV) from more than 6,000 healthy Chinese women aged 18–25 years participating in a large vaccine efficacy trial. Regardless of cytology, 15.3% of women were positive for high-risk HPV types, with HPV-52 (4.0%), HPV-16 (3.7%), HPV-51 (1.7%) and HPV-58 (1.5%) being the most frequently detected. This high baseline prevalence of high-risk HPV types underscores the importance of early vaccination among Chinese women.

International audience; Patients who undergo pelvic radiotherapy may develop severe and chronic complications resulting from gastrointestinal alterations. The lack of curative treatment highlights the importance of novel and effective therapeutic strategies. We thus tested the therapeutic benefit of mesenchymal stem cells (MSC) treatment and proposed molecular mechanisms of action. MSC efficacy was tested in an experimental model of radiation-induced severe colonic ulceration histologically similar to that observed in patients. In this model, MSC from bone marrow were administered intravenously, immediately or three weeks (established lesions) after irradiation. MSC therapy reduces radiation-induced colonic ulceration and increases animal survival. MSC treatment induces therapeutic efficacy whatever the time of cell infusion. Infused-MSC engraft in the colon but also increase endogenous MSC mobilization in blood that have lasting benefits over time. In vitro analysis demonstrates that the MSC effect is mediated by paracrine mechanisms through the non-canonical WNT (Wingless integration site) pathway. In irradiated rat colons, MSC treatment increases the expression of the non-canonical WNT4 ligand by epithelial cells. The epithelial regenerative process is improved after MSC injection by stimulation of colonic epithelial cells positive for SOX9 (SRY-box containing gene 9) progenitor/stem cell markers. This study demonstrates that MSC treatment induces stimulation of endogenous host progenitor cells to improve the regenerative process and constitutes an initial approach to arguing in favor of the use of MSC to limit/reduce colorectal damage induced by radiation. © 2013 Sémont et al.

Background Improved influenza vaccines are needed to reduce influenza-associated complications in older adults. The aim of this study was to identify the optimal formulation of adjuvanted seasonal influenza vaccine for use in elderly people. Methods This observer-blind, randomized study assessed the optimal formulation of adjuvanted seasonal influenza vaccine based on immunogenicity and safety in participants aged ≥65 years. Participants were randomized (~200 per group) to receive one dose of non-adjuvanted vaccine or one of eight formulations of vaccine formulated with a squalene and tocopherol oil-in-water emulsion-based Adjuvant System (AS03C, AS03B or AS03A, with 2.97, 5.93 and 11.86 mg tocopherol, respectively) together with the immunostimulant monophosphoryl lipid A (MPL, doses of 0, 25 or 50 mg). Hemagglutination-inhibition (HI) antibody responses and T-cell responses were assessed on Day 0 and 21 days post-vaccination. The ratio of HI-based geometric mean titers in adjuvanted versus non-adjuvanted vaccine groups were calculated and the lower limit of the 90% confidence interval was transformed into a desirability index (a value between 0 and 1) in an experimental domain for each vaccine strain, and plotted in relation to the AS03 and MPL dose combination in the formulation. This model was used to assess the optimal formulation based on HI antibody titers. Reactogenicity and safety were also assessed. The immunogenicity and safety analyses were used to evaluate the optimal formulation of adjuvanted vaccine. Results In the HI antibody-based model, an AS03 dose–response was evident; responses against the A/H1N1 and A/H3N2 strains were higher for all adjuvanted formulations versus non-adjuvanted vaccine, and for the AS03A-MPL25, AS03B-MPL25 and AS03B-MPL50 formulations against the B strain. Modelling using more stringent criteria (post hoc) showed a clear dose-range effect for the AS03 component against all strains, whereas MPL showed a limited effect. Higher T-cell responses for adjuvanted versus non-adjuvanted vaccine were observed for all except two formulations (AS03C and AS03B-MPL25). Reactogenicity increased with increasing AS03 dosage, and with MPL. No safety concerns were raised. Conclusions Five formulations containing AS03A or AS03B were identified as potential candidates to improve immune responses to influenza vaccination; AS03B without MPL showed the best balance between improved immunogenicity and acceptable reactogenicity. Trial registration This trial is registered at ClinicalTrials.gov, NCT00540592

In developing countries, risk of human papillomavirus (HPV) infection may be increased by the high prevalence of human immunodeficiency virus (HIV) infection. We evaluated the safety and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine in HIV-infected women in South Africa. Asymptomatic HIV-positive women aged 18–25 years (N=120) were stratified by CD4+ T-cell count and randomised (1:1) to receive HPV-16/18 vaccine (Cervarix®; GlaxoSmithKline Vaccines) or placebo (Al[OH]3) at 0, 1 and 6 months (double-blind). HIV-negative women (N=30) received HPV-16/18 vaccine (open label). Anti-HPV-16/18 antibody and CD4+ T-cell responses, CD4+ T-cell count, HIV viral load, HIV clinical stage and safety were evaluated for 12 months. The safety and reactogenicity profile of the HPV-16/18 vaccine was comparable in HIV-positive and HIV-negative women. Irrespective of baseline HPV status, all HIV-positive and HIV-negative women who received the HPV-16/18 vaccine were seropositive for both HPV-16 and HPV-18 after the second vaccine dose (month 2) and remained seropositive for both antigens at month 12. Anti-HPV-16/18 antibody titres at month 12 remained substantially above levels associated with natural infection. The HPV-16/18 vaccine induced sustained anti-HPV-16/18 CD4+ T-cell responses in both HIV-positive and HIV-negative women. No impact of baseline CD4+ T-cell count or HIV viral load was observed on the magnitude of the immune response in HIV-positive women. In HIV-positive women, CD4+ T-cell count, HIV viral load and HIV clinical stage were unaffected by HPV-16/18 vaccine administration. In conclusion, the HPV-16/18 AS04-adjuvanted vaccine appears immunogenic and well-tolerated in women with HIV infection.Study ID: 107863/NCT00586339.

Melatonin is a powerful antioxidant and a synchronizer of many physiological processes. Alteration in melatonin signaling has been reported in a broad range of diseases, but little is known about the genetic variability of this pathway in humans. Here, we sequenced all the genes of the melatonin pathway -AA-NAT, ASMT, MTNR1A, MTNR1B and GPR50 - in 321 individuals from Sweden including 101 patients with attention-deficit/hyperactivity disorder (ADHD) and 220 controls from the general population. We could find several damaging mutations in patients with ADHD, but no significant enrichment compared with the general population. Among these variations, we found a splice site mutation in ASMT (IVS5+2TC) and one stop mutation in MTNR1A (Y170X) - detected exclusively in patients with ADHD - for which biochemical analyses indicated that they abolish the activity of ASMT and MTNR1A. These genetic and functional results represent the first comprehensive ascertainment of melatonin signaling deficiency in ADHD.

International audience; ContexteLes études épidémiologiques mettent en évidence un lien entre l’exposition aux rayonnements ionisants à des doses modérées (>500mGy) et le développement de pathologies cardiovasculaires.Les études expérimentales ne montrent pas de lien entre exposition chronique à très faibles doses (150mGy-300mGy) de rayonnements ionisants et le développement de l’athérosclérose.Le stress est un des premiers facteurs de risque cardiovasculaire. Il a été montré qu’un stress psychosocial est associé à une augmentation de l’oxydation des lipides mais également des cytokines pro-inflammatoires induisant une aggravation des maladies cardiovasculaires.Aucune étude n’a cependant mis en évidence la réponse d’une co-exposition associant rayonnements ionisants et co-facteur de risque tel que le stress sur les pathologies du coeur et des vaisseaux.MéthodePar une approche in vivo nous allons exposer des souris ApoE-/- aux rayonnements ionisants gamma à faibles doses (dose cumulée de 70mGy et 800mGy) chronique (6μGy/h) et exposer dans le même temps au stress. A l’issue de cette co-exposition l’objectif sera d’évaluer : Les paramètres fonctionnels et physiopathologiques du coeur et des vaisseaux Le profil moléculaire des vaisseaux, du coeur et du sang (approches métabolomiques) Les conséquences sur la vascularisation cérébrale (densité vasculaire et l’inflammation cérébrale)RésultatsCe projet est dans une phase de validation du modèle de stress que nous avons initié par l’ajout de litière de rat. A cette étape de l’étude, les résultats ne mettent pas en évidence de perte de poids mais les mesures de pression artérielle et le dosage d’hormones de stress doivent venir compléter l’étude.ConclusionSIROCCO dispose d’atouts majeurs pour progresser vers l’importance des facteurs risques tels que l’hypercholestérolémie et le stress dans la réponse des faibles doses sur des pathologies chroniques comme les pathologies cardiovasculaires. SIROCCO va également permettre par une approche moléculaire à grande échelle de comprendre les mécanismes à court terme et de faire un lien avec d’éventuelles apparitions de troubles fonctionnels à long terme aussi bien chez les animaux mâles que chez les femelles. Ces études vont permettre en complémentarité avec les études épidémiologiques de mieux comprendre les mécanismes impliqués après exposition à faibles doses dans des contextes micro-environnementaux à risque.Mots-clés (5 maximum)Co-expositions, facteurs de risques, rayonnements ionisants, stress, maladies cardiovasculaires

The effects of cerebral exposure at low-to-moderate doses of ionizing radiation (IRs) on the adult cognition exposed during childhood are not clearly established in humans and there is a lack of experimental data on this subject. However, high-dose studies teach us that hippocampus (HPC) irradiation (IR), a site of adult neurogenesis, appears to participate in the development of cognitive impairment in adulthood. In this thesis, we investigated and compared the effects of postnatal whole brain (WB) or dorsal dentate gyrus (DDG) of HPC exposure , on long-term spatial memory (MSLT). Both models were exposed with a single dose of 0.25, 0.5, 1 or 2 Gy. Our results provide evidence that learning is not affected, 3 months after IR, in all our experimental conditions. The restitution of spatial memory, tested 10 days later, is altered only by DDG exposure at the dose of 1 Gy. Thus, we demonstrated that the dose-response relationship is not linear after localized exposure of GDD. We also demonstrated that WB or DDG exposure at the dose of 1 Gy has a different impact on adult hippocampal neurogenesis, a cellular process involved in MSLT. DDG exposure induces, among other things, an increase of cell proliferation while WB exposure induces their decrease, 2 months after IR. Only DDG exposure results in reducing the percentage of new mature neurons, 3 months after IR. The different alterations on adult hippocampal neurogenesis process could explain, in part, the results obtained during the restoration of spatial memory, in our two models exposed at 1 Gy. These results demonstrate that WB exposure is less deleterious than DDG exposure under our experimental conditions. This study helps improve our knowledge of the effects of exposure at low-to-moderate doses of IRs on the brain and a substructure of the hippocampus.; Les effets d’une exposition cérébrale à des doses faibles à modérées de rayonnements ionisants (RIs) sur la cognition des adultes exposés pendant leur enfance ne sont pas clairement établis chez l’Homme et un manque de données expérimentales existe à ce sujet. Toutefois, les études menées à fortes doses nous rapportent que l’irradiation (IR) de l’hippocampe (HPC), un des lieux de neurogenèse adulte, semble jouer un rôle dans l’apparition des troubles cognitifs à l’âge adulte. Dans cette thèse, nous avons étudié et comparé les effets d’une irradiation postnatale du cerveau entier (CV) ou du gyrus denté dorsal (GDD) de l’HPC sur la mémoire spatiale à long-terme (MSLT). Les deux modèles ont été exposés avec une dose unique de 0.25, 0.5, 1 ou 2 Gy. Nos résultats démontrent que l’apprentissage n’est pas modifié, 3 mois après l’IR, dans toutes nos conditions expérimentales. La restitution de la mémoire spatiale, testée 10 jours plus tard, est altérée seulement par l’exposition du GDD à la dose de 1 Gy. Ainsi, nous avons démontré que la relation dose réponse n‘est pas linéaire après une exposition localisée du GDD.Nous avons également démontré que l’exposition du CV ou du GDD à la dose de 1 Gy impacte différemment la neurogenèse hippocampique adulte, un processus cellulaire impliqué dans la MSLT. L’exposition localisée du GDD induit, entre autres, une augmentation de la prolifération cellulaire alors qu’une exposition du CV induit leur diminution, 2 mois après l’IR. Seule l’exposition du GDD a pour conséquence de diminuer le pourcentage de nouveaux neurones matures, 3 mois après l’IR. Les altérations différentes du processus de neurogenèse hippocampique adulte pourraient expliquer, en partie, les résultats obtenus lors de la restitution de la mémoire spatiale, dans nos deux modèles exposés à la dose de 1 Gy. Ces résultats démontrent que l’exposition du CV est moins délétère que l’exposition du GDD dans nos conditions expérimentales. Cette étude permet d’améliorer nos connaissances sur les effets d’une exposition à des doses faibles à modérées de RIs sur le cerveau et une sous-structure de l’hippocampe.