Investigating dynamiCa++l mechanisms underlying cortical development and disease
Investigating activity-dependent processes during cortical neuronal assembly in development and disease
Mechanisms of human cortical development and neuropsychiatric disease
Investigating activity-dependent processes in cerebral cortex development and disease
The cerebral cortex contains an extraordinary diversity of excitatory projection neuron (PN) and inhibitory interneurons (IN), wired together to form complex circuits. Spatiotemporally coordinated execution of intrinsic molecular programs by PNs and INs and activity-dependent processes, contribute to cortical development and cortical microcircuits formation. Alterations of these delicate processes have often been associated to neurological/neurodevelopmental disorders. However, despite the groundbreaking discovery that spontaneous activity in the embryonic brain can shape regional identities of distinct cortical territories, it is still unclear whether this early activity contributes to define subtype-specific neuronal fate as well as circuit assembly. In this study, we combined in utero genetic perturbations via CRISPR/Cas9 system and pharmacological inhibition of selected ion channels with RNA-sequencing and live imaging technologies to identify the activity-regulated processes controlling the development of different cortical PN classes, their wiring and the acquisition of subtype specific features. Moreover, we generated human induced pluripotent stem cells (iPSCs) form patients affected by a severe, rare and untreatable form of developmental epileptic encephalopathy. By differentiating cortical organoids form patient-derived iPSCs we create human models of early electrical alterations for studying molecular, structural and functional consequences of the genetic mutations during cortical development. Our ultimate goal is to define the activity-conditioned processes that physiologically occur during the development of cortical circuits, to identify novel therapeutical paths to address the pathological consequences of neonatal epilepsies.
Common developmental mechanisms underlie multiple brain disorders linked to corpus callosum dysgenesis. (Simultaneous translation to Spanish)
The corpus callosum is the largest fibre tract in the brain of placental mammals and connects the two cerebral hemispheres. Corpus callosum dysgenesis is a developmental brain disorder that is commonly genetic and occurs in approximately 1:4000 live births. It is easily diagnosed by MRI or prenatal ultrasound and is found in isolation or together with other brain anomalies, or with other organ system defects in a large number of different congenital syndromes. Callosal dysgenesis is a structural brain wiring disorder that can impact brain function and cognition in heterogeneous ways. We aim to understand how early developmental mechanisms lead to circuit alterations that ultimately impact behaviour and cognition. Translated to Spanish by MD and Medical interpreter Trinidad Ott. El cuerpo calloso es el tracto de fibras más grande del cerebro de los mamíferos placentarios y conecta los dos hemisferios cerebrales. La disgenesia del cuerpo calloso es un trastorno del desarrollo del cerebro que comunmente es genético y ocurre en aproximadamente 1: 4000 nacidos vivos. Se diagnostica fácilmente mediante resonancia magnética o ecografía prenatal y se encuentra aislado o junto con otras anomalías cerebrales, o con otros defectos del sistema de órganos en un gran número de síndromes congénitos diferentes. La disgenesia callosa es un trastorno estructural del cableado cerebral que puede afectar la función cerebral y la cognición de formas heterogéneas. Nuestro objetivo es comprender cómo los primeros mecanismos del desarrollo conducen a alteraciones en los circuitos que, en última instancia, afectan el comportamiento y la cognición. Traducción al español por la Doctora e Intérprete Médica Trinidad Ott.
The thalamus that speaks to the cortex: spontaneous activity in the developing brain
Our research team runs several related projects studying the cellular and molecular mechanisms involved in the development of axonal connections in the brain. In particular, our aim is to uncover the principles underlying thalamocortical axonal wiring, maintenance and ultimately the rewiring of connections, through an integrated and innovative experimental programme. The development of the thalamocortical wiring requires a precise topographical sorting of its connections. Each thalamic nucleus receives specific sensory information from the environment and projects topographically to its corresponding cortical. A second level of organization is achieved within each area, where thalamocortical connections display an intra-areal topographical organization, allowing the generation of accurate spatial representations within each cortical area. Therefore, the level of organization and specificity of the thalamocortical projections is much more complex than other projection systems in the CNS. The central hypothesis of our laboratory is that thalamocortical input influences and maintains the functional architecture of the sensory cortices. We also believe that rewiring and plasticity events can be triggered by activity-dependent mechanisms in the thalamus. Three major questions are been focused in the laboratory: i) the role of spontaneous patterns of activity in thalamocortical wiring and cortical development, ii) the role of the thalamus and its connectivity in the neuroplastic cortical changes following sensory deprivation, and iii) reprogramming thalamic cells for sensory circuit restoration. Within these projects we are using several experimental programmes, these include: optical imaging, manipulation of gene expression in vivo, cell and molecular biology, biochemistry, cell culture, sensory deprivation paradigms and electrophysiology. The results derived from our investigations will contribute to our understating of how reprogramming of cortical wiring takes place following brain damage and how cortical structure is maintained.
Species-specific mechanisms of the timing of human cortical development
The human brain, in particular the cerebral cortex, has undergone rapid expansion and increased complexity during recent evolution. One striking feature of human corticogenesis is that it is highly protracted in time, from prenatal stages of neurogenesis (taking months instead of days in the mouse), to postnatal stages of neuronal maturation and circuit formation (taking years instead of weeks in the mouse). This prolonged development is thought to contribute in an important fashion to increased cortical size, but also enhanced circuit complexity and plasticity. Here we will discuss how the species-specific temporal patterning of corticogenesis is largely intrinsic to cortical progenitors and neurons, and involves human-specific genes and cell properties that underlie human brain evolution, as well as our selective sensitivity to certain brain diseases.