Parkinson’s Disease (PD) is a progressive and incurable neurodegenerative disease characterized by an irreversible loss of nigrostriatal dopaminergic neurons. Its symptomatology evolves over the years from a prodromal stage, including neuropsychiatric symptoms such as loss of motivation and anxiety, to a clinical stage with significant motor impairments. Today, the causes of PD pathogenesis are still poorly understood. In this context, we recently performed a translational metabolomic study using PD patients and rat models, which revealed a decoupling between the glycolysis and the Krebs cycle. These metabolic perturbations strongly suggest that impairments of the Pyruvate Dehydrogenase (PDH), the key enzyme linking these two metabolic pathways and which has been shown to be downregulated in the nigrostriatal pathways of PD patients, could be a major actor in the mechanisms underlying the pathogenesis of PD. Based on this, our work aims to better decipher the role of this enzyme in PD pathophysiology by inducing a PDH downregulation in the nigrostriatal pathway of healthy rats by using a AAV-microRNA strategy and stereotaxic surgery. The results show that this strategy has induced a 20% nigrostriatal PDH downregulation, resulting in the development of a hypo-motivated state with anxious behaviors but without motor impairments. These symptoms are reminiscent of a prodromal-like PD symptomatology, and they are associated with the evidences of a parkinsonian-like metabolic profile in both blood and brain. This could indicate a PDH dysfunction at an early stage in the pathophysiology of PD and could highlight the PDH as a new potential therapeutic target.