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?The ROAMER European project (27 national associations/organizations of psychiatrists and health professionals) identified disease mechanisms and therapeutic innovation as top research priorities against stress-induced mental illnesses. As currently understood, underlying mechanisms are complex, cannot be ascribed to a single genetic or environmental factor, but they usually result in neuroinflammation, metabolic dysfunctions and “synaptopathies” in limbic and cortical micro- and macro-circuits. So, neuropsychiatric disorders induced by stress most likely arise from a complex interplay of genetics and environment. Two HYPOTHETICAL frameworks show great promise: i) reduced responsiveness to the anti-inflammatory stress hormone glucocorticoid and ii) lack of brain-derived neurotrophic factor (BDNF) support. We propose a novel mechanism unifying both frameworks to explain how glucocorticoids activities can change from beneficial to detrimental. It relies on the context at exposure, if BDNF signaling is ON or OFF to produce a unique glucocorticoid response distinct from the sum of individual responses. One STRATEGY to demonstrate coincidence detection between the glucocorticoid and BDNF signaling routes is to disrupt one signaling hub that integrates both pathways. We identified one such signaling hub using mass spectrometry (Lambert M. et al. 2013 MCB Biology 33, 3700-3714). SPICED is a multimodal study combining neuroimaging, genetics and behavior to characterize the role of BDNF-induced GR phosphorylation on the remodeling of neuronal connectivity in the context of stress, learning and memory.?OBJECTIVES: 1-In vivo characterization of GR phosphorylation and animal model of stress 2-In vivo molecular replacement of endogenous GR by a BDNF-insensitive GR mutant 3-Mechanism of dendritic spine loss by the GR phosphorylation-sensitive gene, nr4a1 4-Multimodal in vivo imaging of spine turnover in NR4A1 knockout and GR-3A knockin mice. 5- Recovery from chronic stress episodes: Molecular versus pharmacological approaches?WORK PERFORMED SINCE THE BEGINNING OF THE PROJECTWe used in vitro and in vivo models to characterize a novel molecular mechanism of coincidence detection that could be involved in the encoding of the synaptic trace of memory. To prove the existence of this mechanism we devised experiments to assess the interaction between genes (BDNF, TrkB, GR) and the environment (stress, glucocorticoid therapy, antidepressant treatment, learning and memory). To this end all experiments are performed in vivo because the complexity of cortical micro and macro-circuits plasticity in response to a psychological stress or motor skill learning can not be reproduced in a culture in vitro system. The objectives 1 and 2 are complete and resulted in the publication (Arango-Lievano M. et al. Neurotrophic-priming of glucocorticoid receptor signaling is essential for neuronal plasticity to stress and antidepressant treatment. PNAS 2015; 112(51):15737-42) advertised nationally by the institute national des science biologiques (CNRS headquarter) and by a companion preview article by the world specialist Bruce McEwen (Commentary in PNAS 112(51):15544-5).The objective 3 is advanced with a publication already submitted (Arango-Lievano M et al Orphan receptor NR4A1 acts in stress-mediated synaptic loss via a mitochondrial signaling pathway) but rejected. The objective 4 is started. The conditional flex knockin mouse is constructed and already backcrossed in the ROSA26-CRE background. Mice are viable and display stress coping defects (ongoing). The objective 5 is partly started. NR4A1 antagonists did not work as expected in neurons. Instead, we use drugs that target mitochondrial functions (ongoing). MAIN RESULTS:-GR phosphorylation responds to stress, glucocorticoid therapy, antidepressants (objective 1) -Disruption of GR phosphorylation at BDNF-sensitive site recapitulates the effects of chronic stress on neuronal connectivity in a cortico-cortical circuit (objective 2) -Ectopic expression of NR4A1 diminished the connectivity of cortical neurons in vivo and impaired mitochondrial functions in vitro (objective 3).-Knockdown of NR4A1 protected cortical neurons against dendritic spine loss in response to chronic stress and chronic glucocorticoid therapy (objective 3).-We generate the conditional knockin mouse backcrossed with ROSA26-CRE to delete GR phosphorylation sites in all the cells of the organism (objective 4)-We characterized a cortical engram of long-term memory of motor skill learning that is encoded by structural changes in existing circuits (objective 4).? RESULTS, IMPACT:Elucidating if BDNF signaling provides context to glucocorticoid functions on behavior and neural network plasticity and how they interact during the progression of a chronic stress disorder is relevant, addressing a significant knowledge gap in disease pathophysiology and diagnosis. ................
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