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Molecular diversification of inhibitory neurons during development

Project description

Molecular mechanisms of cortical interneuron development

Abnormal neuronal differentiation can result in a variety of neuropsychiatric disorders, including epilepsy, autism, bipolar disorder and schizophrenia. Cortical interneurons are a diverse class of inhibitory neurons that are important for the stability of the neural circuits underlying cognitive and higher-order brain functions. The EU-funded GIDE project will investigate whether neurodevelopmental trajectories are predetermined by particular progenitors during mitotic stages or emerge later in the development process through interactions with the environment. The study will employ genetic fate-mapping, high-throughput single-cell RNA sequencing and molecular tagging techniques to gain a detailed understanding of neurogenesis at the cellular level. Furthermore, the researchers will focus on the genetic mechanisms that determine cell fate regulation by environmental processes during postnatal development.

Objective

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.

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Coordinator

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Net EU contribution
€ 1 493 382,00
Address
Hofgartenstrasse 8
80539 Munchen
Germany

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Region
Bayern Oberbayern München, Kreisfreie Stadt
Activity type
Research Organisations
Links
Other funding
€ 0,00

Beneficiaries (1)