Role of hevin in the neuroplasticity of stress-rel.. (matrixresilience)
Role of hevin in the neuroplasticity of stress-related disorders and addiction
Date du début: 1 sept. 2013,
Date de fin: 31 août 2017
Matricellular proteins mediate interaction between cells and the extracellular matrix and are essential regulators of synaptic function and architecture. Recently, the two prototypical matricellular proteins SPARC and hevin have been implicated in depression-like behaviors, antidepressant response and resilience to stress. I found that hevin is induced by chronic social stress in the nucleus accumbens (NAc), a key brain reward region, only in resilient individuals. Importantly, its overexpression in susceptible mice could reverse social avoidance. This key observation, along with other evidence supporting a role for hevin in synaptogenesis and its presence at excitatory synapses, suggests that hevin is involved in the neuroplasticity underlying positive affect and motivation.My main objective is to define the role of hevin in the adatation to stress and drugs of abuse. I plan to combine my expertise in rodent behavior, neuroanatomy, pharmacology, molecular biology and viral-mediated gene transfer to first determine in which cell type hevin is induced in the NAc plays a role in resilience. I will manipulate hevin in selective cells using Cre transgenic mice and flox-STOP viruses in order to test whether it is required for resilience and antidepressant treatment in these cells. In the second aim, I will extend this anatomical and functional approach to study other emotionally-related behaviors, in particular in response to cocaine. I will also study the effect of hevin manipulation on dendritic spine morphology. Third, I will determine the mechanism controlling and regulating hevin in primary neuronal cultures. Last, I will identify hevin binding partners through co-immunoprecipitation and proteomics.This focus of research is particularly novel and promising, and is expected to bring benefit for psychiatric disorders such as depression and addiction, in addition to fundamentally advancing the field of neuronal plasticity, hence the neural basis of learning and memor
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