Chronic or cumulative stress sustained over a long period of time increases the risk of affective illness. Mounting clinical and preclinical evidences support the involvement of non-coding RNA such as microRNAs (miRs) in the long-term adaptive (and maladaptive) response of the brain to psychological stressors. Among miRs, the miR-34 family plays a role in stress-related psychiatric conditions and in the neurobiological mechanisms that underlie the regulation of stress response.
Our recent data demonstrated an important role of miR-34a in mouse Dorsal Raphe Nuclei (DRN) in regulating the stress response. We found that the miR-34a is expressed with high level
and specificity in the DRN and we demonstrated that is implied in the behavioral and neurochemical response to stress.
In this research proposal we hypothesize that miR-34 involvement in stress-coping response may be acting through GABAergic signaling in DRN. After selective DRN miR-34 deletion, we will investigate the role of miR-34 in the behavioral and functional modifications induced in the mouse brain by acute stress exposure. After that, to mimic the chronic adversities exposure that occurs in clinical psychiatric onset, a chronic mild unpredictable stress paradigm will be used to evaluate behavioral and neurochemical phenotype underlying stress vulnerability and resilience.
Mood disorders like Major Depressive Disorder are a leading cause of world wide disability, however the neurobiological mechanism underlying their etiology remains largely unclear. Genetic background, sexual differences, stochastic neurodevelopmental processes and environmental factors all contribute to the onset of this disease (Nestler, 2002; McEwen, 2012; Duman, 2019).
The pharmacological treatment also present several issues. First choice therapy are Selective Serotonin Reuptake Inhibitor (SSRI). However, symptomatic complete remission occurs only in 50% of the patients, with an high risk of relapse, and SSRIs' therapeutic efficacy occurs after weeks of treatment (Hamon, 2013).
In the last few years there was a mounting interest in dysregulated excitatory/inhibitory transmission and etiology of mood disorders (for a comprehensive review see Duman, 2019). Moreover, pharmacological interventions that target Glutamate and GABA transmission seem to have fast acting, although not side effect free, antidepressant efficacy. Despite that, several clinical trials are starting to match SSRIs and GABA agonists to effectively treat mood disorders (Duman, 2019).
The aim of this research proposal is to better understand how epigenetic mechanisms interact with environmental adversities and contribute to develop a pathological outcome or to increase resilience to stress-induced depression-like phenotype in an animal model. Uncover the modulatory role on GABAergic transmission could give it's contribute to characterize a complex phenomenon such as mood disorders and to discover new therapeutic targets to treat them. Further studies will be required to investigate the molecular target modulated in our model during stress exposure.