Controlling complexity: the clinical relevance of mouse complex genetics.

Experimental animal models are essential to obtain basic knowledge of the underlying biological mechanisms in human diseases. Here, we review major contributions to biomedical research and discoveries that were obtained in the mouse model by using forward genetics approaches and that provided key insights into the biology of human diseases and paved the way for the development of novel therapeutic approaches

Neurotransplantation therapy and cerebellar reserve

Background & Objective: Neurotransplantation has been recently the focus of interest as a promising therapy to substitute lost cerebellar neurons and improve cerebellar ataxias. However, since cell differentiation and synaptic formation are required to obtain a functional circuitry, highly integrated reproduction of cerebellar anatomy is not a simple process. Rather than a genuine replacement, recent studies have shown that grafted cells rescue surviving cells from neurodegeneration by exerting trophic effects, supporting mitochondrial function, modulating neuroinflammation, stimulating endogenous regenerative processes, and facilitating cerebellar compensatory properties thanks to neural plasticity. On the other hand, accumulating clinical evidence suggests that the self-recovery capacity is still preserved even if the cerebellum is affected by a diffuse and progressive pathology. We put forward the period with intact recovery capacity as “restorable stage” and the notion of reversal capacity as “cerebellar reserve”. Conclusion: The concept of cerebellar reserve is particularly relevant, both theoretically and practically, to target recovery of cerebellar deficits by neurotransplantation. Reinforcing the cerebellar reserve and prolonging the restorable stage can be envisioned as future endpoints of neurotransplantation.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Impaired spatial performance in cerebellar-deficient Lurcher mice is not associated with their abnormal stress response

International audienceBoth humans and laboratory animals suffering from cerebellar lesions exhibit cognitive as well as many emotional and behavioral abnormalities. These latter have been already observed in the cerebellar mutant mice currently used to highlight some aspect of autism spectrum disorders. The aim of this study was to investigate the influence of cerebellar-related stress response abnormalities on spatial learning and memory. Cerebellar-deficient Lurcher mutant mice were exposed to water environment without active escape possibility and then tested for spatial learning in the Morris water maze. As a marker of stress intensity we measured corticosterone in urine. Finally, the volumes of individual components of the adrenal gland were estimated. Though having spatial navigation deficit in the water maze, Lurcher mice preserved a substantial residuum of learning capacity. Lurcher mutants had a higher increase of cor-ticosterone level after exposure to the water environment than wild type mice. We did not observe any decrease of this physiological stress marker between the start and the end of the spatial navigation task, despite significant improvement of behavioral performances. Furthermore, zona fasciculata and zona reticularis of the adrenal cortex as well as the adrenal medulla were larger in Lurcher mice, reflecting high stress reactivity. We conclude that for both genotypes water exposure was a strong stressor and that there was no habituation to the experiment independently to the increasing controllability of the stressor (e.g. ability to find the escape platform). Based on these findings, we suggest that the enhanced stress response to water exposure is not the main factor explaining the spatial deficits in these cerebellar mutant mice

Cooperation of the vestibular and cerebellar networks in anxiety disorders and depression

International audienceThe discipline of affective neuroscience is concerned with the neural bases of emotion and mood. The past decades have witnessed an explosion of research in affective neuroscience, increasing our knowledge of the brain areas involved in fear and anxiety. Besides the brain areas that are classically associated with emotional reactivity , accumulating evidence indicates that both the vestibular and cerebellar systems are involved not only in motor coordination but also influence both cognition and emotional regulation in humans and animal models. The cerebellar and the vestibular systems show the reciprocal connection with a myriad of anxiety and fear brain areas. Perception anticipation and action are also major centers of interest in cognitive neurosciences. The cerebellum is crucial for the development of an internal model of action and the vestibular system is relevant for perception, gravity-related balance, navigation and motor decision-making. Furthermore, there are close relationships between these two systems. With regard to the cooperation between the vestibular and cerebellar systems for the elaboration and the coordination of emotional cognitive and visceral responses, we propose that altering the function of one of the systems could provoke internal model disturbances and, as a result, anxiety disorders followed potentially with depressive states

Sonic Hedgehog and Triiodothyronine Pathway Interact in Mouse Embryonic Neural Stem Cells

Neural stem cells are fundamental to development of the central nervous system (CNS)—as well as its plasticity and regeneration—and represent a potential tool for neuro transplantation therapy and research. This study is focused on examination of the proliferation dynamic and fate of embryonic neural stem cells (eNSCs) under differentiating conditions. In this work, we analyzed eNSCs differentiating alone and in the presence of sonic hedgehog (SHH) or triiodothyronine (T3) which play an important role in the development of the CNS. We found that inhibition of the SHH pathway and activation of the T3 pathway increased cellular health and survival of differentiating eNSCs. In addition, T3 was able to increase the expression of the gene for the receptor smoothened (Smo), which is part of the SHH signaling cascade, while SHH increased the expression of the T3 receptor beta gene (Thrb). This might be the reason why the combination of SHH and T3 increased the expression of the thyroxine 5-deiodinase type III gene (Dio3), which inhibits T3 activity, which in turn affects cellular health and proliferation activity of eNSCs

Task Force Paper On Cerebellar Transplantation: Are We Ready to Treat Cerebellar Disorders with Cell Therapy?

Restoration of damaged central nervous system structures, functional recovery, and prevention of neuronal loss during neurodegenerative diseases are major objectives in cerebellar research. The highly organized anatomical structure of the cerebellum with numerous inputs/outputs, the complexity of cerebellar functions, and the large spectrum of cerebellar ataxias render therapies of cerebellar disorders highly challenging. There are currently several therapeutic approaches including motor rehabilitation, neuroprotective drugs, non-invasive cerebellar stimulation, molecularly based therapy targeting pathogenesis of the disease, and neurotransplantation. We discuss the goals and possible beneficial mechanisms of transplantation therapy for cerebellar damage and its limitations and factors determining outcome

Near-complete adaptation of the PRiMA knockout to the lack of central acetylcholinesterase

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