Paola Arlotta, PhD
Stanley Center for Psychiatric Research, Broad Institute
Programming, Reprogramming and Modeling of the Mammalian Cerebral Cortex
The execution of critical behaviors like movement, emotion, and intelligence relies on the orchestrated integration into functional circuits of an outstanding diversity of neuronal subtypes. Focusing on excitatory pyramidal neurons of the mammalian cerebral cortex, our work aims to understand the mechanistic principles that govern the establishment and maintenance of neuronal diversity in the central nervous system, how neuronal diversity affects the behavior of other neurons and glia during cortical development, and the boundaries of neurons’ capacity to reprogram their class-specific identity in the adult brain. At a fundamental level, we are interested in understanding how cortical neurons and circuits are generated and how they subsequently remain unchanged for life. At an applied level, we aim to explore whether neuronal reprogramming can become a valuable therapeutic tool to probe brain plasticity and to replace lost neurons.
While our work is mostly rooted in development of the murine cerebral cortex, a recent interest of our lab has been building in vitro models that resemble the cellular complexity, tissue architecture and local connectivity of the developing human cerebral cortex, which can become a platform for understanding higher-order circuit function and dysfunction that is affected in neurodevelopmental and neuropsychiatric cortical disease. To this end, we are generating next-generation, long-term cultures of 3D cerebral organoids, starting from human induced pluripotent stem cells (iPSCs) derived from control individuals, from patients with neuropsychiatric or neurodevelopmental pathology, or engineered to carry specific genetic mutations associated with these diseases.
In the long term, our work aims at developing approaches to aid neuronal regeneration in neurodegenerative diseases of the cortical output circuitry, and at understanding and modulating neuronal function in neuropsychiatric diseases affecting the cerebral cortex.