Rôle de l’amygdale dans les symptômes émotionnels de la Maladie de Huntington : étude d’un modèle de rat transgénique, BACHD

Huntington’s disease (HD) is a genetic neurodegenerative disorder, caused by an expanded CAG repeat in the gene encoding the huntingtin protein. At the presymptomatic phase, before motor symptoms occur, psychiatric and emotional disorders are observed with high prevalence in HD patients. Agitation, anxiety and irritability are often described but also depression and/or apathy, associated with a lack of emotional control.In search of the pathophysiology underlying the emotional (dys)functions of HD, we studied the role of the amygdala (especially the central nucleus (CeA)). This structure is known to be involved in emotional regulation and has a reduced volume and a large number of aggregates in both patients and transgenic rat models.To study the emotional symptoms of HD we used a recent model of transgenic rats, BACHD. Our results show that these animals are hyper-anxious and hyper-reactive to threatening situations at an early stage of the disease. BACHD rats also have a high number of large aggregates, increasing with age, specifically in the CeA compared to the basolateral nucleus (BLA). In addition, pharmacological modulation of the CeA induce differential behavioral effects in BACHD rats compared to WT rats, evidencing a functional deficit of the structure at an early stage of the disease. Finally, the cellular hyper-activity observed in the CeA (medial part) of BACHD rats could account for the emotional hyper-reactivity of these animals and participate of emotional disorders of HD.La Maladie de Huntington (MH) est une pathologie génétique neurodégénérative, causée par un nombre anormalement élevé de répétitions du codon CAG dans le gène codant pour la protéine huntingtine (htt). A un stade pré-symptomatique (avant les symptômes moteurs), des troubles émotionnels sont souvent observés chez les patients MH, tels une agitation, une anxiété, une irritabilité ainsi qu’une tendance à la dépression, une apathie et une perte du contrôle émotionnel. Dans le but d’étudier la physiopathologie sous-jacentes aux (dys)fonctions émotionnelles de la MH, nous analysons le rôle de l’amygdale (en particulier le noyau central (CeA)). Cette structure est connue pour être impliquée dans la régulation du processus émotionnel et avoir un volume réduit ainsi qu’un grand nombre d’agrégats chez les patients et chez des modèles animaux transgéniques.Afin d’étudier les symptômes émotionnels de la MH, nous avons utilisé un modèle de rats transgéniques récent, les BACHD. Nos résultats montrent que ces animaux sont hyper-anxieux et hyper-réactifs face aux situations menaçantes à un stade précoce de la maladie. Ces rats BACHD présentent également un nombre élevé d’agrégats de grande taille augmentant en fonction de l’âge spécifiquement dans le CeA par rapport au noyau basolateral (BLA). De plus, la modulation pharmacologique du CeA entraine un effet comportemental différentiel chez les rats BACHD par rapport aux rats normaux, attestant d’un défaut fonctionnel de cette structure à un stade précoce de la maladie. Finalement, l’hyper-activité cellulaire observée dans le CeA (partie médiane) des rats BACHD pourrait expliquer l’hyper-réactivité émotionnelle de ces animaux et participer aux troubles émotionnels de la MH

Role of amygdala in the emotional symptoms of Huntington's disease : study of a transgenic rat model, BACHD

La Maladie de Huntington (MH) est une pathologie génétique neurodégénérative, causée par un nombre anormalement élevé de répétitions du codon CAG dans le gène codant pour la protéine huntingtine (htt). A un stade pré-symptomatique (avant les symptômes moteurs), des troubles émotionnels sont souvent observés chez les patients MH, tels une agitation, une anxiété, une irritabilité ainsi qu’une tendance à la dépression, une apathie et une perte du contrôle émotionnel. Dans le but d’étudier la physiopathologie sous-jacentes aux (dys)fonctions émotionnelles de la MH, nous analysons le rôle de l’amygdale (en particulier le noyau central (CeA)). Cette structure est connue pour être impliquée dans la régulation du processus émotionnel et avoir un volume réduit ainsi qu’un grand nombre d’agrégats chez les patients et chez des modèles animaux transgéniques. Afin d’étudier les symptômes émotionnels de la MH, nous avons utilisé un modèle de rats transgéniques récent, les BACHD. Nos résultats montrent que ces animaux sont hyper-anxieux et hyper-réactifs face aux situations menaçantes à un stade précoce de la maladie. Ces rats BACHD présentent également un nombre élevé d’agrégats de grande taille augmentant en fonction de l’âge spécifiquement dans le CeA par rapport au noyau basolateral (BLA). De plus, la modulation pharmacologique du CeA entraine un effet comportemental différentiel chez les rats BACHD par rapport aux rats normaux, attestant d’un défaut fonctionnel de cette structure à un stade précoce de la maladie. Finalement, l’hyper-activité cellulaire observée dans le CeA (partie médiane) des rats BACHD pourrait expliquer l’hyper-réactivité émotionnelle de ces animaux et participer aux troubles émotionnels de la MH.Huntington’s disease (HD) is a genetic neurodegenerative disorder, caused by an expanded CAG repeat in the gene encoding the huntingtin protein. At the presymptomatic phase, before motor symptoms occur, psychiatric and emotional disorders are observed with high prevalence in HD patients. Agitation, anxiety and irritability are often described but also depression and/or apathy, associated with a lack of emotional control.In search of the pathophysiology underlying the emotional (dys)functions of HD, we studied the role of the amygdala (especially the central nucleus (CeA)). This structure is known to be involved in emotional regulation and has a reduced volume and a large number of aggregates in both patients and transgenic rat models. To study the emotional symptoms of HD we used a recent model of transgenic rats, BACHD. Our results show that these animals are hyper-anxious and hyper-reactive to threatening situations at an early stage of the disease. BACHD rats also have a high number of large aggregates, increasing with age, specifically in the CeA compared to the basolateral nucleus (BLA). In addition, pharmacological modulation of the CeA induce differential behavioral effects in BACHD rats compared to WT rats, evidencing a functional deficit of the structure at an early stage of the disease. Finally, the cellular hyper-activity observed in the CeA (medial part) of BACHD rats could account for the emotional hyper-reactivity of these animals and participate of emotional disorders of HD

The Alteration of Emotion Regulation Precedes the Deficits in Interval Timing in the BACHD Rat Model for Huntington Disease

International audienceHuntington disease (HD) is an autosomal dominantly inherited, progressive neurodegenerative disorder which is accompanied by executive dysfunctions and emotional alteration. The aim of the present study was to assess the impact of emotion/stress on on-going highly demanding cognitive tasks, i.e., temporal processing, as a function of age in BACHD rats (a "full length" model of HD). Middle-aged (4-6 months) and old (10-12 months) rats were first trained on a 2 vs. 8-s temporal discrimination task, and then exposed to a series of bisection tests under normal and stressful (10 mild unpredictable foot-shocks) conditions. The animals were then trained on a peak interval task, in which reinforced fixed-interval (FI) 30-s trials were randomly intermixed with non-reinforced probe trials. After training, the effect of stress upon time perception was again assessed. Sensitivity to foot-shocks was also assessed independently. The results show effects of both age and genotype, with largely greater effects in old BACHD animals. The older BACHD animals had impaired learning in both tasks, but reached equivalent levels of performance as WT animals at the end of training in the temporal discrimination task, while remaining impaired in the peak interval task. Whereas sensitivity to foot-shock did not differ between BACHD and WT rats, delivery of foot-shocks during the test sessions had a disruptive impact on temporal behavior in WT animals, an effect which increased with age. In contrast, BACHD rats, independent of age, did not show any significant disruption under stress. In conclusion, BACHD rats showed a disruption in temporal learning in late symptomatic animals. Age-related modification in stress-induced impairment of temporal control of behavior was also observed, an effect which was greatly reduced in BACHD animals, thus confirming previous results suggesting reduced emotional reactivity in HD animals. The results suggest a staggered onset in cognitive and emotional alterations in HD, with emotional alteration being the earliest, possibly related to different time courses of degeneration in cortico-striatal and amygdala circuits

Evaluation of the Role of the Immune System Response After Minibeam Radiation Therapy

International audiencePurpose: Minibeam radiation therapy (MBRT) is an innovative technique that uses a spatial dose modulation. The dose distribution consists of high doses (peaks) in the path of the minibeam and low doses (valleys). The underlying biological mechanism associated with MBRT efficacy remains currently unclear and thus we investigated the potential role of the immune system after treatment with MBRT.Methods and materials: Rats bearing an orthotopic glioblastoma cell line were treated with 1 fraction of high dose conventional radiation therapy (30 Gy) or 1 fraction of the same mean dose in MBRT. Both immunocompetent (F344) and immunodeficient (Nude) rats were analyzed in survival studies. Systemic and intratumoral immune cell population changes were studied with flow cytometry and immunohistochemistry (IHC) 2 and 7 days after the irradiation.Results: The absence of response of Nude rats after MBRT suggested that T cells were key in the mode of action of MBRT. An inflammatory phenotype was observed in the blood 1 week after irradiation compared with conventional irradiation. Tumor immune cell analysis by flow cytometry showed a substantial infiltration of lymphocytes, specifically of CD8 T cells and B cells in both conventional and MBRT-treated animals. IHC revealed that MBRT induced a faster recruitment of CD8 and CD4 T cells. Animals that were cured by radiation therapy did not suffer tumor growth after reimplantation of tumoral cells, proving the long-term immunity response generated after a high dose of radiation.Conclusions: Our findings show that MBRT can elicit a robust antitumor immune response in glioblastoma while avoiding the high toxicity of a high dose of conventional radiation therapy

Evaluation of the Role of the Immune System Response After Minibeam Radiation Therapy

International audiencePurpose: Minibeam radiation therapy (MBRT) is an innovative technique that uses a spatial dose modulation. The dose distribution consists of high doses (peaks) in the path of the minibeam and low doses (valleys). The underlying biological mechanism associated with MBRT efficacy remains currently unclear and thus we investigated the potential role of the immune system after treatment with MBRT.Methods and materials: Rats bearing an orthotopic glioblastoma cell line were treated with 1 fraction of high dose conventional radiation therapy (30 Gy) or 1 fraction of the same mean dose in MBRT. Both immunocompetent (F344) and immunodeficient (Nude) rats were analyzed in survival studies. Systemic and intratumoral immune cell population changes were studied with flow cytometry and immunohistochemistry (IHC) 2 and 7 days after the irradiation.Results: The absence of response of Nude rats after MBRT suggested that T cells were key in the mode of action of MBRT. An inflammatory phenotype was observed in the blood 1 week after irradiation compared with conventional irradiation. Tumor immune cell analysis by flow cytometry showed a substantial infiltration of lymphocytes, specifically of CD8 T cells and B cells in both conventional and MBRT-treated animals. IHC revealed that MBRT induced a faster recruitment of CD8 and CD4 T cells. Animals that were cured by radiation therapy did not suffer tumor growth after reimplantation of tumoral cells, proving the long-term immunity response generated after a high dose of radiation.Conclusions: Our findings show that MBRT can elicit a robust antitumor immune response in glioblastoma while avoiding the high toxicity of a high dose of conventional radiation therapy

X-rays minibeam radiation therapy at a conventional irradiator: Pilot evaluation in F98-glioma bearing rats and dose calculations in a human phantom

International audienceMinibeam radiation therapy (MBRT) is a type of spatial fractionated radiotherapy that uses submillimetric beams. This work reports on a pilot study on normal tissue response and the increase of the lifespan of glioma-bearing rats when irradiated with a tabletop x-ray system. Our results show a significant widening of the therapeutic window for brain tumours treated with MBRT: an important proportion of long-term survivals (60%) coupled with a significant reduction of toxicity when compared with conventional (broad beam) irradiations. In addition, the clinical translation of the minibeam treatment at a conventional irradiator is evaluated through a possible human head treatment pla

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Evaluation of the Role of the Immune System Response After Minibeam Radiation Therapy

International audiencePurpose: Minibeam radiation therapy (MBRT) is an innovative technique that uses a spatial dose modulation. The dose distribution consists of high doses (peaks) in the path of the minibeam and low doses (valleys). The underlying biological mechanism associated with MBRT efficacy remains currently unclear and thus we investigated the potential role of the immune system after treatment with MBRT.Methods and materials: Rats bearing an orthotopic glioblastoma cell line were treated with 1 fraction of high dose conventional radiation therapy (30 Gy) or 1 fraction of the same mean dose in MBRT. Both immunocompetent (F344) and immunodeficient (Nude) rats were analyzed in survival studies. Systemic and intratumoral immune cell population changes were studied with flow cytometry and immunohistochemistry (IHC) 2 and 7 days after the irradiation.Results: The absence of response of Nude rats after MBRT suggested that T cells were key in the mode of action of MBRT. An inflammatory phenotype was observed in the blood 1 week after irradiation compared with conventional irradiation. Tumor immune cell analysis by flow cytometry showed a substantial infiltration of lymphocytes, specifically of CD8 T cells and B cells in both conventional and MBRT-treated animals. IHC revealed that MBRT induced a faster recruitment of CD8 and CD4 T cells. Animals that were cured by radiation therapy did not suffer tumor growth after reimplantation of tumoral cells, proving the long-term immunity response generated after a high dose of radiation.Conclusions: Our findings show that MBRT can elicit a robust antitumor immune response in glioblastoma while avoiding the high toxicity of a high dose of conventional radiation therapy

Proton minibeam radiation therapy widens the therapeutic index for high-grade gliomas

Abstract Proton minibeam radiation therapy (pMBRT) is a novel strategy which has already shown a remarkable reduction in neurotoxicity as to compared with standard proton therapy. Here we report on the first evaluation of tumor control effectiveness in glioma bearing rats with highly spatially modulated proton beams. Whole brains (excluding the olfactory bulb) of Fischer 344 rats were irradiated. Four groups of animals were considered: a control group (RG2 tumor bearing rats), a second group of RG2 tumor-bearing rats and a third group of normal rats that received pMBRT (70 Gy peak dose in one fraction) with very heterogeneous dose distributions, and a control group of normal rats. The tumor-bearing and normal animals were followed-up for 6 months and one year, respectively. pMBRT leads to a significant tumor control and tumor eradication in 22% of the cases. No substantial brain damage which confirms the widening of the therapeutic window for high-grade gliomas offered by pMBRT. Additionally, the fact that large areas of the brain can be irradiated with pMBRT without significant side effects, would allow facing the infiltrative nature of gliomas

Proton FLASH Radiation Therapy and Immune Infiltration: Evaluation in an Orthotopic Glioma Rat Model

International audienceFLASH radiation therapy (FLASH-RT) is a promising radiation technique that uses ultrahigh doses of radiation to increase the therapeutic window of the treatment. FLASH-RT has been observed to provide normal tissue sparing at high dose rates and similar tumor control compared with conventional RT, yet the biological processes governing these radiobiological effects are still unknown. In this study, we sought to investigate the potential immune response generated by FLASH-RT in a high dose of proton therapy in an orthotopic glioma rat model