4-Year PhD student position.
Neuronal activity and formation of new connections are crucial for brain functions. Although we know that these two processes are somehow linked together, we do not actually know how this functional interplay is controlled. In this project, we will elucidate how neuronal activity contributes to the formation of new connections. Specifically, we will elucidate the regulatory mechanisms governing activity-dependent dendritic spine initiation. This knowledge is fundamental in order to tailor specific drugs to treat neuropathic pain or prevent its formation. Without exact understanding of the molecular mechanisms underlying brain functions, we are shooting in the dark with drug trials. We hypothesize that expression of spine initiation factors contributes to chronicity of neuropathic pain via reorganization of dendritic spines in the spinal cord. This hypothesis will be tested with an in vivo mouse model for neuropathic pain. A long-term goal is to pharmacologically and genetically target these mechanisms to reverse or prevent neuropathic pain.
This project will focus on two working hypotheses on the mechanisms linking neuronal activity to the formation of new connections between neurons. Our first hypothesis is that neuronal activity regulates the phosphoinositide composition on the plasma membrane, and specific phosphoinositides recruit spine initiation factors on the membrane when there is a need for a new spine. The other hypothesis is that neuronal activity regulates the expression of specific microRNAs, which will then regulate the local expression of spine initiation factors. For these studies, we will use primary hippocampal neurons and organotypic hippocampal brain slices combined with various protocols to change neuronal activity. The project represents a pioneering effort to solve at the molecular level the mechanisms underlying neuropathic pain, and the knowledge achieved will be used to design specific small molecules to treat such pain.