RESUMEN
All eutherian mammals show chromosomal sex determination with contrasting sex chromosome dosages (SCDs) between males (XY) and females (XX). Studies in transgenic mice and humans with sex chromosome trisomy (SCT) have revealed direct SCD effects on regional mammalian brain anatomy, but we lack a formal test for cross-species conservation of these effects. Here, we develop a harmonized framework for comparative structural neuroimaging and apply this to systematically profile SCD effects on regional brain anatomy in both humans and mice by contrasting groups with SCT (XXY and XYY) versus XY controls. Total brain size was substantially altered by SCT in humans (significantly decreased by XXY and increased by XYY), but not in mice. Robust and spatially convergent effects of XXY and XYY on regional brain volume were observed in humans, but not mice, when controlling for global volume differences. However, mice do show subtle effects of XXY and XYY on regional volume, although there is not a general spatial convergence in these effects within mice or between species. Notwithstanding this general lack of conservation in SCT effects, we detect several brain regions that show overlapping effects of XXY and XYY both within and between species (cerebellar, parietal, and orbitofrontal cortex), thereby nominating high priority targets for future translational dissection of SCD effects on the mammalian brain. Our study introduces a generalizable framework for comparative neuroimaging in humans and mice and applies this to achieve a cross-species comparison of SCD effects on the mammalian brain through the lens of SCT.SIGNIFICANCE STATEMENT Sex chromosome dosage (SCD) affects neuroanatomy and risk for psychopathology in humans. Performing mechanistic studies in the human brain is challenging but possible in mouse models. Here, we develop a framework for cross-species neuroimaging analysis and use this to show that an added X- or Y-chromosome significantly alters human brain anatomy but has muted effects in the mouse brain. However, we do find evidence for conserved cross-species impact of an added chromosome in the fronto-parietal cortices and cerebellum, which point to regions for future mechanistic dissection of sex chromosome dosage effects on brain development.
Asunto(s)
Encéfalo , Cromosomas Sexuales , Masculino , Femenino , Humanos , Ratones , Animales , Encéfalo/anatomía & histología , Neuroimagen , Cerebelo , Ratones Transgénicos , MamíferosRESUMEN
The PHF6 mutation c.1024C > T; p.R342X, is a recurrent cause of Börjeson-Forssman-Lehmann Syndrome (BFLS), a neurodevelopmental disorder characterized by moderate-severe intellectual disability, truncal obesity, gynecomastia, hypogonadism, long tapering fingers and large ears (MIM#301900). Here, we generated transgenic mice with the identical substitution (R342X mice) using CRISPR technology. We show that the p.R342X mutation causes a reduction in PHF6 protein levels, in both human and mice, from nonsense-mediated decay and nonsense-associated alternative splicing, respectively. Magnetic resonance imaging studies indicated that R342X mice had a reduced brain volume on a mixed genetic background but developed hydrocephaly and a high incidence of postnatal death on a C57BL/6 background. Cortical development proceeded normally, while hippocampus and hypothalamus relative brain volumes were altered. A hypoplastic anterior pituitary was also observed that likely contributes to the small size of the R342X mice. Behavior testing demonstrated deficits in associative learning, spatial memory and an anxiolytic phenotype. Taken together, the R342X mice represent a good preclinical model of BFLS that will allow further dissection of PHF6 function and disease pathogenesis.
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Modelos Animales de Enfermedad , Epilepsia/genética , Cara/anomalías , Dedos/anomalías , Predisposición Genética a la Enfermedad/genética , Trastornos del Crecimiento/genética , Hipogonadismo/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Mutación , Obesidad/genética , Proteínas Represoras/genética , Animales , Aprendizaje por Asociación/fisiología , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/patología , Células Cultivadas , Epilepsia/metabolismo , Epilepsia/fisiopatología , Cara/fisiopatología , Femenino , Dedos/fisiopatología , Perfilación de la Expresión Génica/métodos , Trastornos del Crecimiento/metabolismo , Trastornos del Crecimiento/fisiopatología , Humanos , Hipogonadismo/metabolismo , Hipogonadismo/fisiopatología , Imagen por Resonancia Magnética/métodos , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/metabolismo , Discapacidad Intelectual Ligada al Cromosoma X/fisiopatología , Ratones Endogámicos C57BL , Ratones Transgénicos , Obesidad/metabolismo , Obesidad/fisiopatología , RNA-Seq/métodos , Proteínas Represoras/metabolismo , Memoria Espacial/fisiologíaRESUMEN
Extensive evidence supports the role of the immune system in modulating brain function and behaviour. However, past studies have revealed striking heterogeneity in behavioural phenotypes produced from immune system dysfunction. Using magnetic resonance imaging, we studied the neuroanatomical differences among 11 distinct genetically modified mouse lines (n = 371), each deficient in a different element of the immune system. We found a significant and heterogeneous effect of immune dysfunction on the brains of both male and female mice. However, by imaging the whole brain and using Bayesian hierarchical modelling, we were able to identify patterns within the heterogeneous phenotype. Certain structures-such as the corpus callosum, midbrain, and thalamus-were more likely to be affected by immune dysfunction. A notable brain-behaviour relationship was identified with neuroanatomy endophenotypes across mouse models clustering according to anxiety-like behaviour phenotypes reported in literature, such as altered volume in brains regions associated with promoting fear response (e.g., the lateral septum and cerebellum). Interestingly, genes with preferential spatial expression in the most commonly affected regions are also associated with multiple sclerosis and other immune-mediated diseases. In total, our data suggest that the immune system modulates anxiety behaviour through well-established brain networks.
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Encéfalo , Neuroanatomía , Animales , Ansiedad , Teorema de Bayes , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Femenino , Imagen por Resonancia Magnética , Masculino , Ratones , FenotipoRESUMEN
E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for autism spectrum disorder (ASD) and developmental delay (DD). To investigate how Cul3 mutations impact brain development, we generated a haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering. Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior. Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development. Spatiotemporal transcriptomic and proteomic profiling of embryonic, early postnatal and adult brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Specifically, dendritic growth, filamentous actin puncta, and spontaneous network activity were reduced in Cul3 mutant mice. Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes. Our study identified defects in neuronal cytoskeleton and Rho signaling as the primary targets of Cul3 mutation during brain development.
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Trastorno del Espectro Autista , Trastorno Autístico , Animales , Trastorno del Espectro Autista/genética , Proteínas Cullin/genética , Citoesqueleto , Células Germinativas , Haploinsuficiencia/genética , Ratones , Neurogénesis/genética , ProteómicaRESUMEN
The 16p11.2 BP4-BP5 deletion and duplication syndromes are associated with a complex spectrum of neurodevelopmental phenotypes that includes developmental delay and autism spectrum disorder, with a reciprocal effect on head circumference, brain structure and body mass index. Mouse models of the 16p11.2 copy number variant have recapitulated some of the patient phenotypes, while studies in flies and zebrafish have uncovered several candidate contributory genes within the region, as well as complex genetic interactions. We evaluated one of these loci, KCTD13, by modeling haploinsufficiency and complete knockout in mice. In contrast to the zebrafish model, and in agreement with recent data, we found normal brain structure in heterozygous and homozygous mutants. However, recapitulating previously observed genetic interactions, we discovered sex-specific brain volumetric alterations in double heterozygous Kctd13xMvp and Kctd13xLat mice. Behavioral testing revealed a significant deficit in novel object recognition, novel location recognition and social transmission of food preference in Kctd13 mutants. These phenotypes were concomitant with a reduction in density of mature spines in the hippocampus, but potentially independent of RhoA abundance, which was unperturbed postnatally in our mutants. Furthermore, transcriptome analyses from cortex and hippocampus highlighted the dysregulation of pathways important in neurodevelopment, the most significant of which was synaptic formation. Together, these data suggest that KCTD13 contributes to the neurocognitive aspects of patients with the BP4-BP5 deletion, likely through genetic interactions with other loci.
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Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Trastornos de la Memoria/genética , Trastornos de la Memoria/psicología , Memoria a Corto Plazo , Complejos de Ubiquitina-Proteína Ligasa/deficiencia , Animales , Conducta Animal , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/patología , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Marcación de Gen , Sitios Genéticos , Genotipo , Masculino , Ratones , Ratones Noqueados , Fenotipo , Eliminación de Secuencia , Factores SexualesRESUMEN
Chaperone networks are dysregulated with aging, but whether compromised Hsp70/Hsp90 chaperone function disturbs neuronal resilience is unknown. Stress-inducible phosphoprotein 1 (STI1; STIP1; HOP) is a co-chaperone that simultaneously interacts with Hsp70 and Hsp90, but whose function in vivo remains poorly understood. We combined in-depth analysis of chaperone genes in human datasets, analysis of a neuronal cell line lacking STI1 and of a mouse line with a hypomorphic Stip1 allele to investigate the requirement for STI1 in aging. Our experiments revealed that dysfunctional STI1 activity compromised Hsp70/Hsp90 chaperone network and neuronal resilience. The levels of a set of Hsp90 co-chaperones and client proteins were selectively affected by reduced levels of STI1, suggesting that their stability depends on functional Hsp70/Hsp90 machinery. Analysis of human databases revealed a subset of co-chaperones, including STI1, whose loss of function is incompatible with life in mammals, albeit they are not essential in yeast. Importantly, mice expressing a hypomorphic STI1 allele presented spontaneous age-dependent hippocampal neurodegeneration and reduced hippocampal volume, with consequent spatial memory deficit. We suggest that impaired STI1 function compromises Hsp70/Hsp90 chaperone activity in mammals and can by itself cause age-dependent hippocampal neurodegeneration in mice. Cover Image for this issue: doi: 10.1111/jnc.14749.
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Envejecimiento/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Proteínas de Choque Térmico/deficiencia , Hipocampo/metabolismo , Chaperonas Moleculares/metabolismo , Adaptación Fisiológica/fisiología , Envejecimiento/genética , Animales , Células Madre Embrionarias/metabolismo , Técnicas de Inactivación de Genes/métodos , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP90 de Choque Térmico/genética , Proteínas de Choque Térmico/genética , Hipocampo/citología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Chaperonas Moleculares/genética , Neuronas/metabolismoRESUMEN
Nutrition is one of the most influential environmental factors affecting the development of different tissues and organs. It is suggested that under nutrient restriction the growth of the brain is spared as a result of the differential allocation of resources from other organs. However, it is not clear whether this sparing occurs brain-wide. Here, we analyzed morphological changes and cell composition in different regions of the offspring mouse brain after maternal exposure to nutrient restriction during pregnancy and lactation. Using high-resolution magnetic resonance imaging, we found that brain regions were differentially sensitive to maternal protein restriction and exhibited particular patterns of volume reduction. The cerebellum was reduced in absolute and relative volume, while cortex volume was relatively preserved. Alterations in cell composition (examined by the isotropic fractionator method) and organization of white matter (measured by diffusor tensor images) were also region specific. These changes were not related to the metabolic rate of the regions and were only partially explained by their specific growth trajectories. This study is a first step towards understanding the mechanisms of regional brain sparing at microstructural and macrostructural levels resulting from undernutrition.
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Encéfalo/fisiología , Proteínas en la Dieta/metabolismo , Nutrientes/deficiencia , Animales , Femenino , Imagen por Resonancia Magnética , Masculino , Exposición Materna , Ratones , Tamaño de los ÓrganosRESUMEN
Biological sex influences brain anatomy across many species. Sex differences in brain anatomy have classically been attributed to differences in sex chromosome complement (XX versus XY) and/or in levels of gonadal sex steroids released from ovaries and testes. Using the four core genotype (4CG) mouse model in which gonadal sex and sex chromosome complement are decoupled, we previously found that sex hormones and chromosomes influence the volume of distinct brain regions. However, recent studies suggest there may be more complex interactions between hormones and chromosomes, and that circulating steroids can compensate for and/or mask underlying chromosomal effects. Moreover, the impact of pre vs post-pubertal sex hormone exposure on this sex hormone/sex chromosome interplay is not well understood. Thus, we used whole brain high-resolution ex-vivo MRI of intact and pre-pubertally gonadectomized 4CG mice to investigate two questions: 1) Do circulating steroids mask sex differences in brain anatomy driven by sex chromosome complement? And 2) What is the contribution of pre- versus post-pubertal hormones to sex-hormone-dependent differences in brain anatomy? We found evidence of both cooperative and compensatory interactions between sex chromosomes and sex hormones in several brain regions, but the interaction effects were of low magnitude. Additionally, most brain regions affected by sex hormones were sensitive to both pre- and post-pubertal hormones. This data provides further insight into the biological origins of sex differences in brain anatomy.
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Encéfalo/anatomía & histología , Hormonas Esteroides Gonadales , Caracteres Sexuales , Cromosoma X , Cromosoma Y , Animales , Femenino , Genotipo , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones MutantesRESUMEN
Manganese-enhanced magnetic resonance imaging (MEMRI) is a widely used technique in rodent neuroimaging studies. Traditionally, Mn2+ is delivered to animals via a systemic injection; however, this can lead to toxic effects at high doses. Recent studies have shown that subcutaneously implanted mini-osmotic pumps can be used to continuously deliver manganese chloride (MnCl2), and that they produce satisfactory contrast while circumventing many of the toxic side effects. However, neither the time-course of signal enhancement nor the effect of continuous Mn2+ delivery on behaviour, particularly learning and memory, have been well-characterized. Here, we investigated the effect of MnCl2 dose and route of administration on a) spatial learning in the Morris Water Maze and b) tissue signal enhancement in the mouse brain. Even as early as 3 days after pump implantation, infusion of 25-50â¯mg/kg/day MnCl2 via osmotic pump produced signal enhancement as good as or better than that achieved 24â¯h after a single 50â¯mg/kg intraperitoneal injection. Neither route of delivery nor MnCl2 dose adversely affected spatial learning and memory on the water maze. However, especially at higher doses, mice receiving MnCl2 via osmotic pumps developed skin ulceration which limited the imaging window. With these findings, we provide recommendations for route and dose of MnCl2 to use for different study designs.
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Encéfalo/efectos de los fármacos , Cloruros/administración & dosificación , Imagen por Resonancia Magnética/métodos , Compuestos de Manganeso/administración & dosificación , Aprendizaje por Laberinto/efectos de los fármacos , Úlcera Cutánea/inducido químicamente , Animales , Cloruros/toxicidad , Aumento de la Imagen/métodos , Bombas de Infusión Implantables , Masculino , RatonesRESUMEN
Recent human and rodent brain imaging studies have shown that the shape of the brain can be changed by experience. These mesoscopic alterations in neuroanatomy are hypothesized to be driven by changes at the level of neuronal processes. To examine whether the shape of the brain changes rapidly, we used MRI to examine changes in the volume of the hippocampus across the 4-6 day estrous cycle in the female mouse. It is well known that changing steroid levels across the cycle influence dendritic spine maturation and alter synapse density in the hippocampus; our results show that the estrous cycle is associated with approximately 2-3% changes in hippocampal volume as seen by high-resolution ex-vivo MRI. Changes in hippocampal volume are, moreover, associated with a switch between hippocampal and striatal based navigation strategies in solving the dual choice T-maze in the same mice. A second experiment, using in-vivo MRI, suggests that these changes in hippocampal volume can occur over a 24 hour period. In summary, we show that the brain is highly plastic at a mesoscopic level of resolution detectable by MRI, that volumetric increases and decreases in hippocampal volume follow previously established patterns of changes in neuropil, and that these changes in volume predict changes in cognition.
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Ciclo Estral/fisiología , Hipocampo/anatomía & histología , Hipocampo/fisiología , Aprendizaje por Laberinto/fisiología , Plasticidad Neuronal/fisiología , Animales , Cognición , Femenino , Imagen por Resonancia Magnética , Ratones , Ratones Endogámicos C57BL , Factores de TiempoRESUMEN
Maternal environmental exposures, such as high-fat diets, diabetes and obesity, can induce long-term effects in offspring. These effects include increased risk of neurodevelopmental disorders (NDDs) including autism spectrum disorder (ASD), depression and anxiety. The mechanisms underlying these late-life neurologic effects are unknown. In this article, we measured changes in the offspring brain and determined which brain regions are sensitive to maternal metabolic milieu and therefore may mediate NDD risk. We showed that mice exposed to a maternal high-fat diet display extensive brain changes in adulthood despite being switched to a low-fat diet at weaning. Brain regions impacted by early-life diet include the extended amygdalar system, which plays an important role in reward-seeking behaviour. Genes preferentially expressed in these regions have functions related to feeding behaviour, while also being implicated in human NDDs, such as autism. Our data demonstrated that exposure to maternal high-fat diet in early-life leads to brain alterations that persist into adulthood, even after dietary modifications.
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Trastorno del Espectro Autista , Efectos Tardíos de la Exposición Prenatal , Adulto , Hijos Adultos , Animales , Trastorno del Espectro Autista/etiología , Encéfalo , Dieta Alta en Grasa/efectos adversos , Femenino , Humanos , Ratones , EmbarazoRESUMEN
BACKGROUND: Mutations in the X-linked gene DDX3X account for approximately 2% of intellectual disability in females, often comorbid with behavioral problems, motor deficits, and brain malformations. DDX3X encodes an RNA helicase with emerging functions in corticogenesis and synaptogenesis. METHODS: We generated a Ddx3x haploinsufficient mouse (Ddx3x+/- females) with construct validity for DDX3X loss-of-function mutations. We used standardized batteries to assess developmental milestones and adult behaviors, as well as magnetic resonance imaging and immunostaining of cortical projection neurons to capture early postnatal changes in brain development. RESULTS: Ddx3x+/- females showed physical, sensory, and motor delays that evolved into behavioral anomalies in adulthood, including hyperactivity, anxiety-like behaviors, cognitive impairments in specific tasks (e.g., contextual fear memory but not novel object recognition memory), and motor deficits. Motor function declined with age but not if mice were previously exposed to behavioral training. Developmental and behavioral changes were associated with a reduction in brain volume, with some regions (e.g., cortex and amygdala) disproportionally affected. Cortical thinning was accompanied by defective cortical lamination, indicating that Ddx3x regulates the balance of glutamatergic neurons in the developing cortex. CONCLUSIONS: These data shed new light on the developmental mechanisms driving DDX3X syndrome and support construct and face validity of this novel preclinical mouse model.
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Discapacidad Intelectual , Animales , ARN Helicasas DEAD-box/genética , Modelos Animales de Enfermedad , Femenino , Ratones , Neurogénesis , Fenotipo , SíndromeRESUMEN
CHD8 (chromodomain helicase DNA-binding protein 8) is a chromatin remodeler associated with autism spectrum disorders. Homozygous Chd8 deletion in mice leads to embryonic lethality, making it difficult to assess whether CHD8 regulates brain development and whether CHD8 haploinsufficiency-related macrocephaly reflects normal CHD8 functions. Here, we report that homozygous conditional knockout of Chd8 restricted to neocortical glutamatergic neurons causes apoptosis-dependent near-complete elimination of neocortical structures. These mice, however, display normal survival and hyperactivity, anxiolytic-like behavior, and increased social interaction. They also show largely normal auditory function and moderately impaired visual and motor functions but enhanced whisker-related somatosensory function. These changes accompany thalamic hyperactivity, revealed by 15.2-Tesla fMRI, and increased intrinsic excitability and decreased inhibitory synaptic transmission in thalamic ventral posterior medial (VPM) neurons involved in somatosensation. These results suggest that excitatory neuronal CHD8 critically regulates neocortical development through anti-apoptotic mechanisms, neocortical elimination distinctly affects cognitive behaviors and sensory-motor functions in mice, and Chd8 haploinsufficiency-related macrocephaly might represent compensatory responses.
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Conducta Animal , Cognición , Proteínas de Unión al ADN/metabolismo , Actividad Motora , Neocórtex/enzimología , Neuronas/metabolismo , Núcleos Talámicos Ventrales/metabolismo , Vibrisas/inervación , Animales , Apoptosis , Mapeo Encefálico , Proteínas de Unión al ADN/genética , Femenino , Genotipo , Ácido Glutámico/metabolismo , Imagen por Resonancia Magnética , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Neocórtex/patología , Neocórtex/fisiopatología , Neuronas/patología , Fenotipo , Corteza Sensoriomotora/metabolismo , Corteza Sensoriomotora/fisiopatología , Conducta Social , Transmisión Sináptica , Núcleos Talámicos Ventrales/diagnóstico por imagen , Núcleos Talámicos Ventrales/fisiopatologíaRESUMEN
ATRX gene mutations have been identified in syndromic and non-syndromic intellectual disabilities in humans. ATRX is known to maintain genomic stability in neuroprogenitor cells, but its function in differentiated neurons and memory processes remains largely unresolved. Here, we show that the deletion of neuronal Atrx in mice leads to distinct hippocampal structural defects, fewer presynaptic vesicles, and an enlarged postsynaptic area at CA1 apical dendrite-axon junctions. We identify male-specific impairments in long-term contextual memory and in synaptic gene expression, linked to altered miR-137 levels. We show that ATRX directly binds to the miR-137 locus and that the enrichment of the suppressive histone mark H3K27me3 is significantly reduced upon the loss of ATRX. We conclude that the ablation of ATRX in excitatory forebrain neurons leads to sexually dimorphic effects on miR-137 expression and on spatial memory, identifying a potential therapeutic target for neurological defects caused by ATRX dysfunction.
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Eliminación de Gen , Regulación de la Expresión Génica , Trastornos de la Memoria/genética , Trastornos de la Memoria/fisiopatología , MicroARNs/genética , Caracteres Sexuales , Aprendizaje Espacial , Proteína Nuclear Ligada al Cromosoma X/deficiencia , Animales , Secuencia de Bases , Región CA1 Hipocampal/patología , Región CA1 Hipocampal/ultraestructura , Condicionamiento Operante , Dendritas/metabolismo , Dendritas/ultraestructura , Femenino , Genotipo , Histonas/metabolismo , Lisina/metabolismo , Imagen por Resonancia Magnética , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/metabolismo , Neuronas , Especificidad de Órganos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Sinapsis/metabolismo , Sinapsis/ultraestructura , Proteína Nuclear Ligada al Cromosoma X/metabolismoRESUMEN
Background: Autism spectrum disorders (ASD) exhibit two clusters of core symptoms, i.e., social and communication impairment, and repetitive behaviors and sensory abnormalities. Our previous study demonstrated that TBR1, a causative gene of ASD, controls axonal projection and neuronal activation of amygdala and regulates social interaction and vocal communication in a mouse model. Behavioral defects caused by Tbr1 haploinsufficiency can be ameliorated by increasing neural activity via D-cycloserine treatment, an N-methyl-D-aspartate receptor (NMDAR) coagonist. In this report, we investigate the role of TBR1 in regulating olfaction and test whether D-cycloserine can also improve olfactory defects in Tbr1 mutant mice. Methods: We used Tbr1+/- mice as a model to investigate the function of TBR1 in olfactory sensation and discrimination of non-social odors. We employed a behavioral assay to characterize the olfactory defects of Tbr1+/- mice. Magnetic resonance imaging (MRI) and histological analysis were applied to characterize anatomical features. Immunostaining was performed to further analyze differences in expression of TBR1 subfamily members (namely TBR1, TBR2, and TBX21), interneuron populations, and dendritic abnormalities in olfactory bulbs. Finally, C-FOS staining was used to monitor neuronal activation of the olfactory system upon odor stimulation. Results: Tbr1+/- mice exhibited smaller olfactory bulbs and anterior commissures, reduced interneuron populations, and an abnormal dendritic morphology of mitral cells in the olfactory bulbs. Tbr1 haploinsufficiency specifically impaired olfactory discrimination but not olfactory sensation. Neuronal activation upon odorant stimulation was reduced in the glomerular layer of Tbr1+/- olfactory bulbs. Furthermore, although the sizes of piriform and perirhinal cortices were not affected by Tbr1 deficiency, neuronal activation was reduced in these two cortical regions in response to odorant stimulation. These results suggest an impairment of neuronal activation in olfactory bulbs and defective connectivity from olfactory bulbs to the upper olfactory system in Tbr1+/- mice. Systemic administration of D-cycloserine, an NMDAR co-agonist, ameliorated olfactory discrimination in Tbr1+/- mice, suggesting that increased neuronal activity has a beneficial effect on Tbr1 deficiency. Conclusions: Tbr1 regulates neural circuits and activity in the olfactory system to control olfaction. Tbr1+/- mice can serve as a suitable model for revealing how an autism causative gene controls neuronal circuits, neural activity, and autism-related behaviors.
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Trastorno del Espectro Autista/genética , Proteínas de Unión al ADN/genética , Discriminación en Psicología , Haploinsuficiencia , Percepción Olfatoria , Animales , Cicloserina/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Neuronas/patología , Bulbo Olfatorio/efectos de los fármacos , Bulbo Olfatorio/patología , Bulbo Olfatorio/fisiología , Receptores de N-Metil-D-Aspartato/agonistas , Olfato , Proteínas de Dominio T BoxRESUMEN
Autism spectrum disorder (ASD) has been hypothesized to be a result of altered connectivity in the brain. Recent imaging studies suggest accelerated maturation of the white matter in young children with ASD, with underlying mechanisms unknown. Myelin is an integral part of the white matter and critical for connectivity; however, its role in ASD remains largely unclear. Here, we investigated myelin development in a model of idiopathic ASD, the BTBR mice. Magnetic resonance imaging revealed that fiber tracts in the frontal brain of the BTBR mice had increased volume at postnatal day 6, but the difference reduced over time, reminiscent of the findings in young patients. We further identified that myelination in the frontal brain of both male and female neonatal BTBR mice was increased, associated with elevated levels of myelin basic protein. However, myelin pattern was unaltered in adult BTBR mice, revealing accelerated developmental trajectory of myelination. Consistently, we found that signaling of platelet-derived growth factor receptor alpha (PDGFRα) was reduced in the frontal brain of neonatal BTBR mice. However, levels of microRNA species known to regulate PDGFRα signaling and myelination were unaltered. Together, these results suggest that precocious myelination could potentially contribute to increased volume and connectivity of the white matter observed in young children with ASD.
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Trastorno del Espectro Autista/patología , Encéfalo/patología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Sustancia Blanca/patología , Animales , Encéfalo/anomalías , Modelos Animales de Enfermedad , Femenino , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes Neurológicos , Proteína Básica de Mielina/metabolismo , Fibras Nerviosas Mielínicas/patologíaRESUMEN
Sex differences exist in behaviors, disease and neuropsychiatric disorders. Sexual dimorphisms however, have yet to be studied across the whole brain and across a comprehensive time course of postnatal development. Here, we use manganese-enhanced MRI (MEMRI) to longitudinally image male and female C57BL/6J mice across 9 time points, beginning at postnatal day 3. We recapitulate findings on canonically dimorphic areas, demonstrating MEMRI's ability to study neuroanatomical sex differences. We discover, upon whole-brain volume correction, that neuroanatomical regions larger in males develop earlier than those larger in females. Groups of areas with shared sexually dimorphic developmental trajectories reflect behavioral and functional networks, and expression of genes involved with sex processes. Also, post-pubertal neuroanatomy is highly individualized, and individualization occurs earlier in males. Our results demonstrate the ability of MEMRI to reveal comprehensive developmental differences between male and female brains, which will improve our understanding of sex-specific predispositions to various neuropsychiatric disorders.
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Encéfalo/anatomía & histología , Encéfalo/crecimiento & desarrollo , Imagen por Resonancia Magnética/métodos , Neuroanatomía/métodos , Animales , Animales Recién Nacidos , Femenino , Masculino , Manganeso/química , Ratones Endogámicos C57BL , Factores Sexuales , Factores de TiempoRESUMEN
Males and females exhibit several differences in brain structure and function. To examine the basis for these sex differences, we investigated the influences of sex hormones and sex chromosomes on brain structure and function in mice. We used the Four Core Genotype (4CG) mice, which can generate both male and female mice with XX or XY sex chromosome complement, allowing the decoupling of sex chromosomes from hormonal milieu. To examine whole brain structure, high-resolution ex vivo MRI was performed, and to assess differences in cognitive function, mice were trained on a radial arm maze. Voxel-wise and volumetric analyses of MRI data uncovered a striking independence of hormonal versus chromosomal influences in 30 sexually dimorphic brain regions. For example, the bed nucleus of the stria terminalis and the parieto-temporal lobe of the cerebral cortex displayed steroid-dependence while the cerebellar cortex, corpus callosum, and olfactory bulbs were influenced by sex chromosomes. Spatial learning and memory demonstrated strict hormone-dependency with no apparent influence of sex chromosomes. Understanding the influences of chromosomes and hormones on brain structure and function is important for understanding sex differences in brain structure and function, an endeavor that has eventual implications for understanding sex biases observed in the prevalence of psychiatric disorders.