Development of neuronal circuits in human brain organoids

Stem cells have the remarkable potential to differentiate into mature cell types, like neurons. In vitro culture methods enable stem cells to self-organize into three-dimensional cell assemblies referred to as organoids. Because brain organoids generated from stem cells of human origin recapitulate the embryonic development of the central nervous system, they offer an unprecedented opportunity to examine the unique features of the human brain and psychiatric disorders. This research project aims to understand the generation and properties of the neuronal circuits in human brain organoids at three functional levels. First, we will identify which types of neurons coexist at various stages of brain organoid development. Second, we will systematically investigate synaptic connections between different cell types to understand excitatory and inhibitory microcircuits. Third, we will study whether neuronal activity evoked by an external stimulation affects the structure and dynamics of developing networks. Functional methods of neuroscience have contributed to our understanding of the brain in animal models. When applied to in vitro brain organoids, intracellular techniques and silicon microelectrodes operate without complex or invasive surgical procedures. Thus, electrophysiological techniques will bring insight into the molecules, the cell types, and the functional circuits involved in neuronal communication. Also, neuronal stimulation via modern optogenetic methods will allow us to evaluate how early embryonic activity affects the development of neuronal networks. Because brain organoids will be bioengineered based on of human stem cells, the knowledge acquired will offer a direct translation of how the human brain functions and its associated diseases. The novelty of this project resides in studying developing human neuronal networks by bridging the most advanced efforts in the fields of circuit neuroscience and stem cell biology. Detailed and functional characterization of developing neuronal circuits in human brain organoids will increase our understanding of the unique features of our brains. Importantly, the pathogenesis of neurodevelopmental disorders can be understood if we gain information about the cell types, synaptic connections and circuit properties of human networks. Thus, deriving brain organoids from the stem cells of patients will open a door for the molecular identification of the mechanisms of neuropsychiatric diseases, and assist to design strategies for early therapeutic interventions.

No additional funding sources recorded.