Resilience and vulnerability to stressful stimuli can influence mood disorders' onset. According to learned helplessness paradigm, different degrees of control that individuals can exert over stressors are a crucial variable in coping response and psychopathological outcome.
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. Our recent works demonstrated an important role of miR-34a in mouse Dorsal Raphe Nuclei (DRN) in regulating stress response. We found that the miR-34a is expressed with high level and specificity in the DRN, exerting a modulatory role on genes related to plasticity as well as stress-related psychiatric illnesses.
In this research proposal we hypothesize that miR-34 specifically interfere with cortical inhibition of DRN, mainly acting on GABA interneurons.
Mir-34 Wild Type and Knockout mice will be exposed to either excapable or inescapable stressors and their depression-like behavior will be evaluated. After that, GABAergic DRN activation in response to this stressful conditions will be analyzed using c-fos expression.
Learned helplessness, a paradigm widley used in preclinical research, is capable to induce in mice a behavioral outcome that reproduces the mayority of symptoms required in mood disorders' diagnosys (Maier, 2016). The incontrollability of averse events was investigated in human subjects, finding an interaction with depression traits in healty as well as sub-clinical depressed people (Havranek et al., 2015). Non medicated depressed patients are more vulnerable to stress incontrollability, showing biased cortical processing even after control riacquisition (Diener et al., 2009). Furthermore, uncontrollability and severity assessment of averse events increase depression and anxiety symptoms, that in turn affect future risk evaluation, thus creating a positive feedback loop that could precipitate worsening symptoms over time (Fasset-Carman et al., 2018).
In the last few years there was a mounting interest in dysregulated excitatory/inhibitory transmission and etiology of mood disorders (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 investigate the role of miR-34 in top-down stress-related circuits, focusing on DRN GABAergic transmission involved control evaluation and response. Describing this fine tuning exerted on specific neuronal population could contribute to better characterize etiology of mood disorders and suggest new therapeutic targets.