RESUMEN
The brain controls nearly all bodily functions via spinal projecting neurons (SPNs) that carry command signals from the brain to the spinal cord. However, a comprehensive molecular characterization of brain-wide SPNs is still lacking. Here we transcriptionally profiled a total of 65,002 SPNs, identified 76 region-specific SPN types, and mapped these types into a companion atlas of the whole mouse brain1. This taxonomy reveals a three-component organization of SPNs: (1) molecularly homogeneous excitatory SPNs from the cortex, red nucleus and cerebellum with somatotopic spinal terminations suitable for point-to-point communication; (2) heterogeneous populations in the reticular formation with broad spinal termination patterns, suitable for relaying commands related to the activities of the entire spinal cord; and (3) modulatory neurons expressing slow-acting neurotransmitters and/or neuropeptides in the hypothalamus, midbrain and reticular formation for 'gain setting' of brain-spinal signals. In addition, this atlas revealed a LIM homeobox transcription factor code that parcellates the reticulospinal neurons into five molecularly distinct and spatially segregated populations. Finally, we found transcriptional signatures of a subset of SPNs with large soma size and correlated these with fast-firing electrophysiological properties. Together, this study establishes a comprehensive taxonomy of brain-wide SPNs and provides insight into the functional organization of SPNs in mediating brain control of bodily functions.
Asunto(s)
Encéfalo , Perfilación de la Expresión Génica , Vías Nerviosas , Neuronas , Médula Espinal , Animales , Ratones , Hipotálamo , Neuronas/metabolismo , Neuropéptidos , Médula Espinal/citología , Médula Espinal/metabolismo , Encéfalo/citología , Encéfalo/metabolismo , Neurotransmisores , Mesencéfalo/citología , Formación Reticular/citología , Electrofisiología , Cerebelo/citología , Corteza Cerebral/citologíaRESUMEN
BACKGROUND: Autistic children have been shown to have less complete definitions of friendships and higher levels of loneliness than their non-autistic peers. However, no known studies have explored sex differences in autistic children's understanding of friendships and reported loneliness across development. Autistic girls demonstrate higher levels of social motivation than autistic boys and appear to "fit in" with their peers, but they often have difficulty recognizing reciprocal friendships during middle childhood. As autistic girls develop a more complex understanding of friendship during adolescence, they may begin to redefine their friendships and experience heightened loneliness. Here, we explored how autistic and non-autistic boys and girls define the meaning of friendship and report feelings of loneliness across development. We also examined their perceptions of friendships and loneliness. METHODS: This mixed-methods study analyzed the transcribed clinical evaluations of 58 autistic children (29 girls) matched to 42 non-autistic children (21 girls) on age and IQ. Transcripts were coded for four categories that children used to define friendships-personality, companionship, dependability, and intimacy-and for reported loneliness. We then compared these codes across diagnosis, sex, and age. Content analyses were further implemented to gain a more holistic understanding of children's perceptions of friendships and loneliness. RESULTS: Girls, regardless of diagnosis, were more likely than boys to refer to personality when defining the meaning of friendship, and the likelihood of referring to dependability and intimacy increased with age. Most children reported having at least one friend, though some autistic adolescents reported not having friends or were uncertain whether they had friends. While autistic and non-autistic boys and girls were equally likely to report feeling lonely at times, several autistic girls and boys reported being frequently lonely. LIMITATIONS: This study was a secondary data analysis. The standardized set of questions on the ADOS limited the amount of information that children provided about their friendships and perceptions of loneliness. CONCLUSION: As with non-autistic children, autistic children acquire a more complex understanding of friendship throughout development. However, as children begin to prioritize dependability and intimacy in friendships, autistic adolescents may have difficulty developing friendships characterized by these constructs. Furthermore, the quantity and/or quality of autistic children's friendships may not be sufficient to alleviate loneliness.
Asunto(s)
Amigos , Soledad , Adolescente , Humanos , Niño , Masculino , Femenino , Caracteres Sexuales , Relaciones Interpersonales , Grupo ParitarioRESUMEN
BACKGROUND: Autistic children report higher levels of bullying victimization than their non-autistic peers. However, autistic children with fewer social difficulties, as measured on the Autism Diagnostic Observation Schedule (ADOS), are more likely to report being bullied. Autistic children with stronger social skills may not only be more likely to identify and report incidents of bullying, but they may also be more likely to interact with their non-autistic peers, increasing their likelihood of being victimized. Autistic girls may be especially at-risk of experiencing bullying victimization, as a growing body of research suggests that autistic girls demonstrate fewer social difficulties and are more socially motivated than autistic boys. Here, we explored reported problems with peers and bullying victimization among a carefully matched sample of autistic and non-autistic boys and girls. Qualitative methods were further implemented to gain a more holistic understanding of the social experiences of autistic boys and girls. METHODS: This mixed-methods study analyzed the transcribed clinical evaluations of 58 autistic children (29 girls) matched to 42 non-autistic children (21 girls) on age and IQ. Within each diagnostic group, boys and girls were matched on ADOS severity score. We compared reported problems with peers and bullying victimization across sex and diagnosis. Among autistic children, we further examined whether ADOS social affect (SA), restricted repetitive behaviors, and severity scores predicted problems with peers and bullying victimization. We then identified themes related to personal experiences of victimization. RESULTS: Autistic children were more likely than non-autistic children to have experienced bullying victimization, and autistic children with lower ADOS severity and SA scores were more likely to report having been bullied. While autistic boys and girls reported similar levels of bullying victimization, qualitative analyses revealed sex differences in the underlying causes of peer conflict. LIMITATIONS: This study was a secondary data analysis. The standardized set of questions on the ADOS limited the amount of information that children provided about their peer relationships, and variations in follow-up questions may have influenced children's responses. CONCLUSIONS: Although autism symptomatology places autistic children at greater risk for bullying victimization compared to their non-autistic peers, greater social challenges among autistic children are associated with lower rates of victimization. This study further highlights the importance of using mixed-methods approaches to discover nuances in the social experiences of autistic girls and boys that may become opportunities for support.
Asunto(s)
Trastorno Autístico , Acoso Escolar , Víctimas de Crimen , Humanos , Masculino , Niño , Femenino , Grupo Paritario , CogniciónRESUMEN
Ferroptosis, a non-apoptotic form of programmed cell death, is triggered by oxidative stress in cancer, heat stress in plants, and hemorrhagic stroke. A homeostatic transcriptional response to ferroptotic stimuli is unknown. We show that neurons respond to ferroptotic stimuli by induction of selenoproteins, including antioxidant glutathione peroxidase 4 (GPX4). Pharmacological selenium (Se) augments GPX4 and other genes in this transcriptional program, the selenome, via coordinated activation of the transcription factors TFAP2c and Sp1 to protect neurons. Remarkably, a single dose of Se delivered into the brain drives antioxidant GPX4 expression, protects neurons, and improves behavior in a hemorrhagic stroke model. Altogether, we show that pharmacological Se supplementation effectively inhibits GPX4-dependent ferroptotic death as well as cell death induced by excitotoxicity or ER stress, which are GPX4 independent. Systemic administration of a brain-penetrant selenopeptide activates homeostatic transcription to inhibit cell death and improves function when delivered after hemorrhagic or ischemic stroke.
Asunto(s)
Isquemia Encefálica , Péptidos de Penetración Celular/farmacología , Ferroptosis/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hemorragias Intracraneales , Neuronas , Fosfolípido Hidroperóxido Glutatión Peroxidasa/biosíntesis , Selenio/farmacología , Accidente Cerebrovascular , Transcripción Genética/efectos de los fármacos , Animales , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Hemorragias Intracraneales/tratamiento farmacológico , Hemorragias Intracraneales/metabolismo , Hemorragias Intracraneales/patología , Masculino , Ratones , Neuronas/metabolismo , Neuronas/patología , Factor de Transcripción Sp1/metabolismo , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Factor de Transcripción AP-2/metabolismoRESUMEN
Mutations in progranulin (GRN) cause heterogeneous clinical syndromes, including behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), corticobasal syndrome (CBS) and Alzheimer-type dementia (AD-type dementia). Human studies have shown that presymptomatic GRN carriers feature reduced connectivity in the salience network, a system targeted in bvFTD. Mice with homozygous deletion of GRN, in contrast, show thalamo-cortical hypersynchrony due to aberrant pruning of inhibitory synapses onto thalamo-cortical projection neurons. No studies have systematically explored the intrinsic connectivity networks (ICNs) targeted by the four GRN-associated clinical syndromes, or have forged clear links between human and mouse model findings. We compared 17 preclinical GRN carriers (14 "presymptomatic" clinically normal and three "prodromal" with mild cognitive symptoms) to healthy controls to assess for differences in cognitive testing and gray matter volume. Using task-free fMRI, we assessed connectivity in the salience network, a non-fluent variant primary progressive aphasia network (nfvPPA), the perirolandic network (CBS), and the default mode network (AD-type dementia). GRN carriers and controls showed similar performance on cognitive testing. Although carriers showed little evidence of brain atrophy, markedly enhanced connectivity emerged in all four networks, and thalamo-cortical hyperconnectivity stood out as a unifying feature. Voxelwise assessment of whole brain degree centrality, an unbiased graph theoretical connectivity metric, confirmed thalamic hyperconnectivity. These results show that human GRN disease and the prevailing GRN mouse model share a thalamo-cortical network hypersynchrony phenotype. Longitudinal studies will determine whether this network physiology represents a compensatory response as carriers approach symptom onset, or an early and sustained preclinical manifestation of lifelong progranulin haploinsufficiency.
Asunto(s)
Corteza Cerebral/fisiopatología , Disfunción Cognitiva/fisiopatología , Conectoma/métodos , Demencia Frontotemporal/fisiopatología , Red Nerviosa/fisiopatología , Síntomas Prodrómicos , Progranulinas/genética , Tálamo/fisiopatología , Adulto , Anciano , Corteza Cerebral/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Femenino , Demencia Frontotemporal/diagnóstico por imagen , Heterocigoto , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Red Nerviosa/diagnóstico por imagen , Tálamo/diagnóstico por imagenRESUMEN
The human cerebral cortex possesses distinct structural and functional features that are not found in the lower species traditionally used to model brain development and disease. Accordingly, considerable attention has been placed on the development of methods to direct pluripotent stem cells to form human brain-like structures termed organoids. However, many organoid differentiation protocols are inefficient and display marked variability in their ability to recapitulate the three-dimensional architecture and course of neurogenesis in the developing human brain. Here, we describe optimized organoid culture methods that efficiently and reliably produce cortical and basal ganglia structures similar to those in the human fetal brain in vivo. Neurons within the organoids are functional and exhibit network-like activities. We further demonstrate the utility of this organoid system for modeling the teratogenic effects of Zika virus on the developing brain and identifying more susceptibility receptors and therapeutic compounds that can mitigate its destructive actions.
Asunto(s)
Antirretrovirales/farmacología , Corteza Cerebral/citología , Evaluación Preclínica de Medicamentos/métodos , Organoides/virología , Cultivo Primario de Células/métodos , Virus Zika/efectos de los fármacos , Línea Celular , Corteza Cerebral/virología , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Células Madre Embrionarias/virología , Humanos , Neuronas/citología , Neuronas/metabolismo , Neuronas/virología , Organoides/citología , Organoides/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Factor de Transcripción STAT3/metabolismo , Tirosina Quinasa c-Mer/metabolismoRESUMEN
Humans and songbirds are two of the rare animal groups that modify their innate vocalizations. The identification of FOXP2 as the monogenetic locus of a human speech disorder exhibited by members of the family referred to as KE enables the first examination of whether molecular mechanisms for vocal learning are shared between humans and songbirds. Here, in situ hybridization analyses for FoxP1 and FoxP2 in a songbird reveal a corticostriatal expression pattern congruent with the abnormalities in brain structures of affected KE family members. The overlap in FoxP1 and FoxP2 expression observed in the songbird suggests that combinatorial regulation by these molecules during neural development and within vocal control structures may occur. In support of this idea, we find that FOXP1 and FOXP2 expression patterns in human fetal brain are strikingly similar to those in the songbird, including localization to subcortical structures that function in sensorimotor integration and the control of skilled, coordinated movement. The specific colocalization of FoxP1 and FoxP2 found in several structures in the bird and human brain predicts that mutations in FOXP1 could also be related to speech disorders.