Exposure to traumatic stressors causes long lasting changes in emotionality and behavior increasing susceptibility to disease and mental disorders. Many studies had reported that stress is able to impair specific synaptic functions in neural circuit that plays a key role in development and expression of stress-related disorders. Epigenetic factors have emerged as one of the most promising areas for earlier prevention and novel therapy for stress-related disorders and it has been demonstrated that microRNAs (miRs) play a central role in epigenetic regulation of several psychiatric disorders.
Consistently, different reports suggest a crucial role for miRs in modulating neurobiological processes, including dendritic morphological changes and neurotransmitters homeostasis. MicroRNAs (miRs)-34 have recently been implicated in emotional responses to stress and pathogenesis of psychopatologies. Interestingly, miRNAs can exert their action also locally at the level of synapses and thus regulate the experience-dependent remodeling specific neural circuits, with obvious implications for neuropsychiatric disorders. In order to improve our understanding of the regulatory function of miRNAs in the brain and exploit the miRNAs for the design of new drugs, the cell-type specific expression need to be identified.
On the basis of our preliminary data the present project will evaluate, in mouse model of stress, the role of miR-34a in the selective regulation of GABAergic transmission in the dorsal raphe nuclei (DRN). Moreover the implication of this regulation on the manifestation of depressive-like phenotypes following exposure to chronic stress will be evaluated.
Stress-related disorders, including depression is a major public health concern. Despite tremendous advances, the pathogenic mechanisms associated with stress-related psychiatric disorders are still unclear. Specific preventive and therapeutic measures against stress-related psychopatologies are needed for reducing healthcare costs. A significant number of depressed subjects do not respond to the currently available medication, and side effects related to them affect compliance. These phenomena is mainly due to the fact that the drugs act on targets that regulate different physiological functions. A better understanding of the etiology and pathophysiology of stress-related mood disorders is needed to facilitate development of novel and improved therapeutical approaches.
Epigenetics is one of the most promising emerging areas that will help develop more efficacious and cost-effective therapy. MicroRNAs, small non-coding RNA molecules that negatively regulate mRNAs transcription, have been found to be important in the pathogenesis of psychiatric disorders related to stress. Several preclinical and clinical studies demonstrating the involvement of microRNAs in several aspects of neural plasticity, neurogenesis, and stress response, provide strong evidence that these molecules can not only play a critical role in psychopatologies pathogenesis, but can also open up new ways for the development of therapeutic targets.
Upon completion of the project we expect to provide experimental evidence showing that miR-34a can have a leading role on cellular adaptations of Dorsal Raphe GABAergic neurons associated with the stress response and stress-induced behavioral modifications.
Furthermore, the data from this project could also have implications for the study of the molecular mechanisms of response to pharmacological classes with GABAergic action such as anxiolytics and antiepileptics.