Job ID: 61725
PhD position in Neurophysiology
Position: Ph.D. Student
Deadline: 1 December 2021
Employment Start Date: 10 January 2022
Contract Length: 3 years
Institution: Université de Strasbourg / Inserm
Department: Centre de Recherche en Biomédecine de Strasbourg (CRBS)
PhD in Neurophysiology : assessing the molecular mechanisms behind cortical hyperexcitability and CSN hyperactivity
ALS is the most common adult-onset motor neuron disease, affecting 120 000 new individuals worldwide each year, and the third most frequent neurodegenerative disease after Alzheimer’s (AD) and Parkinson’s diseases (PD). The relatively low prevalence of ALS (4-8/100 000) is due to its extremely rapid progression, leading to death within 2-5 years after disease onset. ALS diagnosis relies on the detection of the combined degeneration of corticospinal neurons (CSN) in the cerebral cortex, and bulbar and spinal motor neurons (MN) in the brain stem and spinal cord. This dual contribution is particularly relevant since ALS is the most severe disease of the adult motor system, in comparison to diseases that target either CSN or MN. Yet, as opposed to the spinal cord and its MN, little is known about the contribution of the cerebral cortex and its CSN to disease onset and progression. Using mouse genetics, we recently demonstrated that the cerebral cortex plays a detrimental role in ALS, and that CSN are responsible for transmitting this detrimental message to their downstream targets (Burg et al., Ann Neurol, 2020), in accordance with the corticofugal hypothesis of ALS. Further work ruled out the possibility of a prion-like propagation of toxic misfolded proteins from the cerebral cortex to its spinal target along the corticospinal tract (Scekic-Zahirovic et al., Prog Neurobiol, 2021).
Earlier work reported motor cortex hyperexcitability in both sporadic and familial ALS patients. This type of cortical dysfunction precedes appearance of the first motor signs, and negatively correlates with patients’ survival. Until recently, cortical hyperexcitability was hypothesized to trigger corticospinal neuron hyperactivity leading to glutamatergic excitotoxicity on downstream motor neurons, but had not been proven. A recent study in wildtype animals demonstrated that chemogenetically-induced hyperactivity of CSN is sufficient to trigger MN degeneration and motor symptoms (Haidar et al., bioRxiv, 2021). Building on a substantial amount of unpublished data, the PhD project that we propose is intended to investigate the molecular and cellular origins of cortical hyperexcitability and CSN hyperactivity. Our preliminary data 1) indicate that mouse models of ALS recapitulate cortical hyperexcitability; 2) uncover CSN-specific cell intrinsic mechanisms that could account for their altered excitability and activity; 3) further inform on additional cell-extrinsic mechanisms involved in cortical circuit dysfunction. Using electrophysiology, mouse genetics, pharmacology and chemogenetics, we propose to further shed light on the mechanisms behind cortical hyperexcitability and CNS hyperactivity in ALS, in order to propose and test new therapeutic approaches based on the restauration of proper cortical circuits functioning.
Our Inserm Unit 1118 is located in the newly delivered Centre de Recherche en Biomédecine de Strasbourg (CRBS), on the Faculty of Medicine of the University of Strasbourg. Our lab aims at deciphering the pathological mechanisms that trigger Amyotrophic Lateral Sclerosis (ALS) and Fronto-Temporal Dementia (FTD), two closely related fatal and currently untreatable neurodegenerative diseases.