No abstract

A major physiologic sign in Parkinson disease is the occurrence of abnormal oscillations in cortico-basal ganglia circuits, which can be normalized by L-DOPA therapy. Under normal circumstances, oscillatory activity in these circuits is modulated as behaviors are learned and performed, but how dopamine depletion affects such modulation is not yet known. We here induced unilateral dopamine depletion in the sensorimotor striatum of rats and then recorded local field potential (LFP) activity in the dopamine-depleted region and its contralateral correspondent as we trained the rats on a conditional T-maze task. Unexpectedly, the dopamine depletion had little effect on oscillations recorded in the pretask baseline period. Instead, the depletion amplified oscillations across delta (∼3 Hz), theta (∼8 Hz), beta (∼13 Hz), and low-gamma (∼48 Hz) ranges selectively during task performance times when each frequency band was most strongly modulated, and only after extensive training had occurred. High-gamma activity (65-100 Hz), in contrast, was weakened independent of task time or learning stage. The depletion also increased spike-field coupling of fast-spiking interneurons to low-gamma oscillations. L-DOPA therapy normalized all of these effects except those at low gamma. Our findings suggest that the task-related and learning-related dynamics of LFP oscillations are the primary targets of dopamine depletion, resulting in overexpression of behaviorally relevant oscillations. L-DOPA normalizes these dynamics except at low-gamma, linked by spike-field coupling to fast-spiking interneurons, now known to undergo structural changes after dopamine depletion and to lack normalization of spike activity following L-DOPA therapy. L oss of the dopamine-containing innervation of the basal ganglia is a primary pathology in Parkinson disease, resulting, in addition to its behavioral effects, in abnormal local field potential (LFP) oscillations within cortico-basal ganglia circuits (1-4). Clinical evidence suggests that successful therapies for Parkinson disease reduce these abnormal LFP oscillations (3-6), establishing them as a central feature of Parkinson disease. In particular, abnormally strong beta-range oscillations (12-30 Hz) and weakened high-frequency gamma oscillations (>70 Hz) have been found in basal ganglia structures. The "antimovement" beta-band oscillations are reduced by both L-DOPA therapy and by deep brain stimulation (DBS) (3-6). How these observations relate to the proposed network functions of oscillatory neural activity is not yet clear. LFP oscillations have been linked not only to motor control but also to sensory perception, attention, learning, memory formation, and interregional communication (7-11). In Parkinson disease models, abnormal patterns of synchrony have been found in rest and locomotion (12)(13)(14), but the effect of dopamine loss on LFP oscillations during complex tasks requiring learning and decision making has not been explored.Here we report that dopamine depletion in the sensorimotor striatum...

Long-term levodopa (l-dopa) treatment in patients with Parkinson´s disease (PD) is associated with the development of motor complications (ie, motor fluctuations and dyskinesias). The principal etiopathogenic factors are the degree of nigro-striatal dopaminergic loss and the duration and dose of l-dopa treatment. In this review article we concentrate on analysis of the mechanisms underlying l-dopa-induced dyskinesias, a phenomenon that causes disability in a proportion of patients and that has not benefited from major therapeutic advances. Thus, we discuss the main neurotransmitters, receptors, and pathways that have been thought to play a role in l-dopa-induced dyskinesias from the perspective of basic neuroscience studies. Some important advances in deciphering the molecular pathways involved in these abnormal movements have occurred in recent years to reveal potential targets that could be used for therapeutic purposes. However, it has not been an easy road because there have been a plethora of components involved in the generation of these undesired movements, even bypassing the traditional and well-accepted dopamine receptor activation, as recently revealed by optogenetics. Here, we attempt to unify the available data with the hope of guiding and fostering future research in the field of striatal activation and abnormal movement generation. © 2017 International Parkinson and Movement Disorder Society.