Job ID: 106515
PhD project – Role of surround inhibition in generalization and propagation of epileptic activity in the neonatal brain in vivo
Position: Ph.D. Student
Deadline: 2 April 2023
Employment Start Date: 2 October 2023
Contract Length: 3 years
Institution: Aix Marseille Université
Department: Institut de Neurobiologie de la Méditerranée INMED
The NeuroSchool PhD Program of Aix-Marseille University (France) has launched its annual calls for PhD scholarships for students with a master’s degree in a non-French university.
The following project is one of the 14 proposed projects. Not all proposed projects will be funded, check our website for details.
Summary: Epilepsy is a neurological disease involving recurrent seizures, which affects up to 1.5% of human neonates (Sheth et al., 1999; Solomon et al., 1984). The neonatal focal seizures may often propagate and degenerate into generalized seizures (Pisani et al., 2021). In the mature brain there are mechanisms preventing the progression of focal epileptic activity to generalized seizure. One of them is epileptic surround inhibition (ESI) that limits the interictal-to-ictal transition and spread of epileptic activity (Prince & Wilder, 1967). ESI arise from i) modulations of blood flow and oxygen delivery, ii) long-range and local inhibitory circuitry. Neonatal nervous system is characterized by the low level of the neurovascular coupling maturation (Kozberg et al., 2013; Zehendner et al., 2013) and immaturity of the interneuronal based inhibition (Daw et al., 2007; Doischer et al., 2008; Minlebaev et al., 2011) putting the question about the efficiency and existence of those mechanisms early in development.
Our hypothesis is that immature neurovascular coupling and inhibitory circuits are inefficient to generate surround inhibition resulting in easily propagating epileptic discharges and their degeneration into the epileptic activity in the developing cortex. Our PhD project is to test this hypothesis using a combination of sophisticated imaging and electrophysiological recordings from rodent models of epileptic activity in vivo.
In the Task 1.1 we will evaluate the efficiency of GABAergic inhibition during the neonatal and juvenile periods of development. We will characterize the developmental changes in chloride homeostasis and derived functional changes in GABAA mediated transmission using the combination of electrophysiological recordings and the optical intrinsic signal imaging (OIS). Our preliminary results show the efficiency of GABAergic inhibition starting early in development, we plan to validate our results using the selective pharmacological antagonists (bumetanide and VU0463271, respectively).
In the Task 1.2 we will characterize the contribution of the interneurons in suppression of the neuronal activity during the epileptic conditions using OIS and intracellular calcium imaging in transgenic mice expressing the calcium sensor GCamp6 in interneurons. The spatial and temporal crosscorrelation of the epileptic signal and interneurons activity will validate the interneuronal contribution in mechanisms of ESI.
In the Task 2 we will answer the question of the inadequate metabolic supply as an antiepileptic mechanism by characterizing the blood flow changes in the developing rat neocortex using multiwavelength OIS imaging. The result will be detailed description of the hemovascular changes and oxygenation of the neuronal tissue over extended cortical surface during epileptic activity in the immature nervous system.
All the resources required for realization of these objectives are available in INMED. These complementary sets of expertise will therefore allow us to explore the mechanisms underlying the generalization and propagation of epileptic activity in the neonatal brain in vivo.
The PhD student to be recruited should be highly motivated and versatile, with a background in experimental biology, especially in neuroimaging (using OIS), electrophysiology (extra- and intracellular recordings) in vivo and appropriate analytic skills.