FUNCTIONAL COMMUNICATION OF MONOAMINERGIC SYSTEMS IN RESILIENCE TO CHRONIC STRESS

Depression is the leading cause of disability worldwide. Although it is triggered by stress, some individuals do not develop the condition and demonstrate an ability to adapt to stress: resilience. The chronic social defeat stress (CSDS) model captures this variability by distinguishing susceptible from resilient animals, and has highlighted the central role of monoaminergic, noradrenergic (NE), serotonergic (5-HT), and dopaminergic (DA) systems in resilience. Activation of NE neurons in the locus coeruleus (LC) promotes resilience by inhibiting the activity of DA neurons from the ventral tegmental area (VTA), while inhibition of 5HT neurons in the raphe nucleus (RN) projecting to VTA reverses susceptibility.Our hypothesis is that a functional LC->RN dialogue modulates the behavioral outcome of CSDS via selective control of the VTA-DA system. To test this hypothesis, we performed an anatomical and functional characterization of LC->RN projections, focused on dorsal vs median raphe targets by measuring NE fiber density and correlating it with 5HT target neurons activation. Anatomical mapping was extended to presynaptic analysis of LC-NE->RN neurons using retrograde viral vectors in DBHcre mice, combined with post-mortem functional analysis of circuits recruitment after CSDS, via quantification of c-Fos activity marker in LC-NE->RN neurons. Finally, the dynamic activity of these circuits will be studied in vivo using calcium imaging (miniscope). This longitudinal study will identify whether activity signatures are associated with resilience.
This study aims to define the role of LC->RN circuits in stress resilience by linking their dynamics activity patterns to behavioral outcomes, thereby identifying potential therapeutic targets.