RESUMEN
The biological basis of the increased risk for psychiatric disorders seen in 15q11.2 copy number deletion is unknown. Previous work has shown disturbances in white matter tracts in human carriers of the deletion. Here, in a novel rat model, we recapitulated low dosage of the candidate risk gene CYFIP1 present within the 15q11.2 interval. Using diffusion tensor imaging, we first showed extensive white matter changes in Cyfip1 mutant rats, which were most pronounced in the corpus callosum and external capsule. Transmission electron microscopy showed that these changes were associated with thinning of the myelin sheath in the corpus callosum. Myelin thinning was independent of changes in axon number or diameter but was associated with effects on mature oligodendrocytes, including aberrant intracellular distribution of myelin basic protein. Finally, we demonstrated effects on cognitive phenotypes sensitive to both disruptions in myelin and callosal circuitry.
Asunto(s)
Haploinsuficiencia/fisiología , Vaina de Mielina/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Oligodendroglía/metabolismo , Sustancia Blanca/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Axones/metabolismo , Axones/patología , Conducta Animal , Cuerpo Calloso/metabolismo , Cuerpo Calloso/patología , Imagen de Difusión Tensora , Modelos Animales de Enfermedad , Técnicas de Inactivación de Genes , Humanos , Masculino , Proteína Básica de Mielina/metabolismo , Vaina de Mielina/patología , RatasRESUMEN
People, like animals, tend to choose the variable option when given the choice between a fixed and variable delay to reward where, in the variable delay condition, some rewards are available immediately (Laura-Jean et al. 2019 Phil. Trans. R. Soc. B 374, 20180141. ( doi:10.1098/rstb.2018.0141 )). This bias has been suggested to reflect evolutionary pressures resulting from food scarcity in the past placing a premium on obtaining food quickly that can win out against the risks of sometimes sustaining longer delays to food. The psychologies mediating this effect may become maladaptive in the developed world where food is readily available contributing, potentially, to overeating and obesity. Here, we report our development of a novel touchscreen task in mice allowing comparisons of the impact of food delay and food magnitude across species. We show that mice exhibit the typical preference, as shown by humans, for variable over fixed delays to rewards but no preference when it comes to fixed versus variable reward amounts and further show that this bias is sensitive to manipulations of the 5-HT2C receptor, a key mediator of feeding and impulse control. We discuss the data in terms of the utility of the task to model the psychologies and underlying brain mechanisms impacting on feeding behaviours. This article is part of the theme issue 'Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications'.