Brain in a Dish

Modeling cortical development 

In the last 10 years the team developed protocols to steer the differentiation of mouse and human pluripotent cells toward distinct brain identities. Using in vitro models of embryonic development, we aim to discover new molecular mechanisms of corticogenesis control and of cortical activity. We have focused our attention to the mechanisms generating different cortical (pallial) structures: cerebral cortex, hippocampus, entorhinal cortex. We have assayed in vitro differentiated cells in experiments of grafting into the mouse brain. We are actively analyzing the formation of functional neural networks with distinct patterns of neuronal firing rate and synchronization depending on the identity of neural cell progenitors. These activities rely on the availability of facilities and methods that we have acquired in the last decade. A large and comprehensive facility of cell culture of Bio@SNS is devoted to the neuralization of mouse embryonic stem cells (mEScs) and human induced pluripotent cells (hiPSCs) to generate 2D neural cultures, brain organoids and neuronal cultures for neuronal activity studies. Methods of computational analyses of mRNA and miRNA libraries have been developed to address the molecular analysis of cultured neurons. A new platform for the parallel analysis and stimulation of 4096 independent electrodes was recently acquired to study the electrical activity of 2D neuronal networks.

Research goals

Cerebral cortex evolution

Understanding the mechanisms generating the expansion of the cerebral cortex in mammals, by investigating the generation and expansion of the outer radial cells in cortical organoids of different mammal species. Indeed, the outer radial glia is just the cell type generating the supra-granular neurons that are typical of associating cortical areas in higher mammals, including primates and humans. This activity is one of the frontiers in neurodevelopment and the team of neural stem cells of Bio@SNS has the technical expertise and the cultural background required to address it. 

Entorhinal cortex

Investigating the mechanisms of degeneration of human entorhinal neurons and their relationship with altered patterns of neuronal activity, using in vitro corticalized hiPSCs. The ability to model in vitro the embryonic development, the synaptic maturation and the activity of human entorhinal neurons will allow the team to investigate the initial steps of Alzheimer disease neurodegeneration. 

Astrocyte plasticity

Finding differences between the genetic programs of embryonic neurogenesis, embryonic astrogliogenesis and adult astrogliosis. Recently, the team has developed a method to control the switch between neurogenesis and astrogliogenesis in vitro, thus permitting the investigation of the master genes controlling the switch. We will carry out longitudinal comparisons of the transcriptome of neural cultures under neurogenesis or astrogliogenesis, and the transcriptome of cerebral cortex under astrogliogenesis induced by experimental stroke. This approach will allow to sort out master genes of neurogenesis and to perform assays of astrocyte-to-neuron conversion in animal models of neurodegeneration induced by injury. 

Neuronal networks in vitro

Investigating the development and the maturation of cerebral cortex neuronal networks derived from hiPScs, focusing on the contribution of inhibitory neurons to the plasticity and the performance of the networks in assays of synaptic potentiation. This activity is crucial to understanding the contribution of the GABAergic inhibition in the formation of healthy cortical networks and its involvement in distinct neuro-diseases such as epilepsy, schizophrenia, cognitive and depressive disorders.