Title : Loss of dopaminergic nigrostriatal neurons accounts for the motivational and affective deficits in Parkinson ’ s disease

Parkinson's Disease (PD) involves the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) that is thought to cause the classical motor symptoms of this disease. However, motivational and affective impairments are also often observed in PD patients. These are usually attributed to a psychological reaction to the general motor impairment and to a loss of some of the neurons within the ventral tegmental area (VTA). We induced selective lesions of the VTA and SNc DA neurons that did not provoke motor deficits, and showed that bilateral dopamine loss within the SNc, but not within the VTA, induces motivational deficits and affective impairments that mimicked the symptoms of PD patients. Thus, motivational and affective deficits are a core impairment of PD, as they stem from the loss of the major group of neurons that degenerates in this disease (DA SNc neurons) and are independent of motor deficits. 3 Main text: Parkinson's disease (PD) is mainly characterized by a progressive degeneration of midbrain dopaminergic (DA) neurons along a caudorostral and lateromedial gradient, with a marked loss of neurons in the substantia nigra pars compacta (SNc) 1 , projecting to the dorsal striatum along the nigrostriatal pathway 2 , and a more modest loss in the ventral tegmental area (VTA) 1 , projecting to limbic and cortical areas along the mesolimbic and mesocortical pathways 2 , respectively. In addition to the classical motor symptoms, several neuropsychiatric symptoms, such as depression, anxiety and motivational deficits (apathy), are frequently observed in PD patients 3, 4. The underlying pathological mechanisms have not yet been elucidated, but these motivational and affective impairments are generally attributed to the patient's psychological reaction to the profound motor deficit and to the associated loss of dopaminergic neurons in the VTA 4, 5. This pathophysiological concept stems from a dichotomous vision of the functional role of mesencephalic DA neurons, in which motor function is attributed to the nigrostriatal system, originating from the SNc, and motivational and affective functions are attributed to the mesocorticolimbic system, originating from the VTA 2, 6, 7. Most of the data that have been used to ground this dichotomous vision of VTA-SNc neurons implication in PD symptoms have been generated using lesions of these neurons, involving various degrees of destruction of bordering zone of the VTA and SNc. Therefore, large SNc lesions inducing profound motor deficits also involve the lateral part of the VTA. …