Effects of dopamine depletion on LFP oscillations in striatum are task- and learning-dependent and selectively reversed by l -DOPA

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...

A biophysical model of the cortex-basal ganglia-thalamus network in the 6-OHDA lesioned rat model of Parkinson’s disease

“…8(A),(B),(C)), in agreement with experimental observations following unilateral 6-OHDA lesion (Cruz et al, 2012). The model STN and GPi neurons also exhibited low-frequency oscillatory activity in the alpha band (~ 9 Hz) in the PD condition (Fig.…”

Hypocretin (orexin) is critical in sustaining theta/gamma-rich waking behaviors that drive sleep need

“…This may be relevant to narcolepsy symptomatology, as β and slow-γ synchrony is seen in dopamine-depleted mice performing specific tasks and can correlate with motor dysfunction (22). We thus demonstrate that baseline dark and precataplexy define two spontaneous waking paradigms that rely on Hcrt to (i) stably express TDW, (ii) maintain normal TDW θ oscillatory frequency, and (iii) limit a concomitant slow-γ component.…”

“…Abnormally high β and slow-γ synchrony is associated with motor disorders, including Parkinson's disease (PD). Depletion of striatal dopamine also causes amplified β (11-to 15-Hz) and slow-γ (40-to 53-Hz) activity in mice (22). The "antimovement" β band of PD patients correlates with impaired movement, and decreases with therapy and functional improvement.…”

Linking oscillations in cerebellar circuits

“…In Parkinsonian models, dopamine depletion leads to an increase in the oscillatory phenomena (Bergman et al, 1998; Hammond et al, 2007; Lemaire et al, 2012). Not all of the oscillations described in the above sections are primarily present in neuropathophysiological models; on the other hand, certain neuropathophysiological models appear to have enhanced types of oscillations.…”