Role of Prefrontal Cortex in the development of Major Depressive Disorder and new possible therapeutic approaches

Major Depressive Disorder (MDD), or clinical depression, is a mood disorder which usually originates together with anxiety and other mental disorders. The link between harmful life events and the consequential MDD onset allows to categorize MDD as a stress-related illness. Particularly, the brain region controlling the top-down regulation of cognition, motion and behaviour is the prefrontal cortex (PFC), which has been found altered in MDD and anxiety-like disorders. Aim of this thesis is to analyse some molecular mechanisms in the PFC that lead to maladaptive responses to chronic stress. Research findings show that PFC neuronal al-terations are due to a lowered corticosterone-induced transcriptional regulator, Yin Yang 1 (YY1). In fact, the inactivation of YY1 makes both male and female mice more sensitive to stress. Another research found that stimulation of type 2 dopamine recep-tor (D2R) positive neurons increases the effortful responses, whereas D2R deletion in-creases despair behaviours. This result is in line with the fact that D2R agonists are widely used as adjunctive antidepressants. Moreover, depression-related behaviour is related to elimination of postsynaptic dendritic spines on PFC projection neurons. A recent report showed that an antidepressant-dose of ketamine selectively rescues elim-inated spines and restores coordinated activity in PFC circuits. Such newly formed spines have been found to be fundamental to maintain long lasting ketamine-induced effects. These studies represent an important step forward as they provide substantial evidence about the neural mechanisms of MDD.