Understanding the relationship between cortical hyperexcitability and the progression of FTD/ALS pathology and behavioral deficits in mice

Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder that causes severe personality and behavior changes. A hexanucleotide repeat expansion in the C9orf72 gene is FTD's most common genetic cause. I aim to elucidate the mechanisms of circuit dysfunction in C9orf72-FTD, focusing on understanding the relationship between cortical hyperactivity, the

progression of C9orf72 hexanucleotide repeat pathology, and behavior. Understanding these aspects is crucial for developing effective and timely treatments for FTD. The first aim of this research is to monitor the progression of neuronal activity during critical age in a robust animal model of FTD and evaluate its relationship to neuronal loss. In the second

aim, I will determine whether neuronal hyperactivity can causally drive the progression of FTD pathology and behavioral deficits. I will then test the effect of restoring neuronal activity by modulating the balance between excitation and inhibition on pathology and behavioral deficits in a C9orf72-FTD model. I will capitalize on my expertise in state-of-the-art technology, such as

multiphoton microscopy, optogenetics, and chemogenetics while acquiring knowledge and skills in FTD research, FTD animal models, and electrophysiology. A team of renowned experts in the field will provide mentorship to guide me through specialized training and ensure the establishment of an independent research career in the FTD field. The

career development plan includes attending laboratory meetings and departmental discussions, national conferences, crafting research grant proposals, and preparing manuscripts. The training will take place at Massachusetts General Hospital (MGH), a prominent teaching hospital affiliated with Harvard Medical School (HMS). MGH is renowned for its supportive research

environment, advanced resources, and collaborative atmosphere conducive to learning and research in neurodegenerative diseases. Furthermore, MGH and HMS will facilitate my professional development by granting me access to various courses and workshops to enhance my presentation, leadership, and management skills.

In summary, this award will prepare me to lead a research lab, ensuring successful electrophysiology and FTD/ALS training and an efficient transition to an independent career.