Descripción del proyecto
Mecanismos moleculares del desarrollo de las interneuronas corticales
La diferenciación neuronal anormal puede dar lugar a diversos trastornos neuropsiquiátricos, como la epilepsia, el autismo, el trastorno bipolar y la esquizofrenia. Las interneuronas corticales son una clase variada de neuronas inhibidoras importantes para la estabilidad de los circuitos neuronales que subyacen a las funciones encefálicas cognitivas y de orden superior. El equipo del proyecto GIDE, financiado con fondos europeos, investigará si las trayectorias del neurodesarrollo están predeterminadas por progenitores concretos durante las etapas mitóticas o surgen más tarde en el proceso de desarrollo a través de las interacciones con el entorno. En el estudio se emplearán técnicas de mapeo del destino genético, de secuenciación de ARN de célula única de alto rendimiento y de etiquetado molecular para obtener una comprensión exhaustiva de la neurogénesis a nivel celular. Además, los investigadores del proyecto se centrarán en los mecanismos genéticos que determinan la regulación del destino celular mediante procesos ambientales durante el desarrollo posnatal.
Objetivo
Cortical interneurons are a diverse class of inhibitory neurons that play a particularly important role in the stability of the neural circuits underlying cognitive and higher order brain functions. A growing body of evidence suggests that perturbation of interneuron development can result in a variety of complex neuropsychiatric disorders, including autism, bipolar disorder, and schizophrenia. Thus, elucidating how interneurons develop and integrate into canonical brain circuits is crucial for understanding the brain in both health and disease.
During perinatal development, intrinsic and environmental processes cooperate to establish the adult form of brain connectivity and behaviour control. To elucidate the molecular mechanisms underlying these interactive processes, I propose to combine genetic fate-mapping techniques with high-throughput single-cell RNA sequencing technologies to gain a detailed understanding of neurogenesis at the cellular level and elucidate how an immense diversity of interneuron subtypes is generated (Aim 1). Furthermore, I will utilize a novel retroviral barcoding strategy to reveal how much of an interneuron’s fate is genetically predetermined by lineage within progenitor zones of the ventral forebrain (Aim 2). Finally, I will study the genetic mechanisms that enable cell intrinsic programs to be shaped by environmental activity-dependent processes during the critical window of development (Aim 3). Candidate genes resulting from these aims will be functionally characterized through gain of function and loss of function methods.
This proposal takes full advantage of my extensive training in viral and mouse genetic techniques, single-cell transcriptomic data processing, and in vivo manipulation of neuronal activity. I am confident that I will be able to successfully complete the proposed aims while exploring fascinating and long-standing questions of developmental neurobiology.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
80539 Munchen
Alemania