Systems-level neurophysiological state characteristics for drug evaluation in an animal model of levodopa-induced dyskinesia

Abstract

Disorders affecting the central nervous system have proven particularly hard to treat, and disappointingly few novel therapies have reached the clinics in recent decades. A better understanding of the physiological processes in the brain underlying various symptoms could therefore greatly improve the rate of progress in this field. We here show how systems-level descriptions of different brain states reliably can be obtained through a newly developed method based on large-scale recordings in distributed neural networks encompassing several different brain structures. Using this technology, we characterize the neurophysiological states associated with parkinsonism and levodopa-induced dyskinesia in a rodent model of Parkinson's disease together with pharmacological interventions aimed at reducing dyskinetic symptoms. Our results show that the obtained electrophysiological data add significant information to conventional behavioral evaluations and hereby elucidate the underlying effects of treatments in greater detail. Taken together, these results potentially open up for studies of neurophysiological mechanisms underlying symptoms in a wide range of neurological and psychiatric conditions that until now have been very hard to investigate in animal models of disease.

Motor deficits and beta oscillations are dissociable in an alpha‐synuclein model of Parkinson's disease

“…Finally, tyrosine hydroxylase synthesis inhibition resulted in cortical high‐frequency oscillations (HFO) occurring at two distinct peaks (~120 and ~90 Hz) in both lesioned and control hemispheres. In the 6‐OHDA model, ~80 Hz cortical HFO have been associated with dyskinesia (Halje et al ., ; Tamtè et al ., ), a well described side effect of levodopa therapy (Winkler et al ., ). However, the HFOs described in the current work were not associated to exaggerated or involuntary movements but rather to complete immobility as observed in the open field arena.…”

Animal models of l‐dopa‐induced dyskinesia in Parkinson's disease

“…Rodent models of LID are highly predictive of pharmacological effects seen in NHP models, which are generally regarded as the gold standard for translational research on the subject because of their remarkable physical similarities to humans. With few PD patients 131 Increased microvessel density in motor striatum/putamen Rat 132 PD patients 132,133 Flow-metabolism dissociation "on" L-dopa in striatum and GP Rat 79,81 PD patients 80 Peaks of striatal DA release shortly after dosing L-dopa Rat 134 PD patients 135 Enhanced theta-band LFP oscillations in STN and/or SNr Rat 136,137 PD patients 138 Narrowband-gamma LFP oscillations in motor cortex Rat 82 PD patients 83 Data from PD patients were obtained through either postmortem biochemical/histochemical analyses or brain imaging studies in vivo. Human data on LFP oscillations were obtained with electrophysiological recordings in patients requiring DBS surgery.…”

On the neuronal circuitry mediating l-DOPA-induced dyskinesia

“…For example, Judie Walters’ lab has found that the power of cortical 80 Hz oscillations gradually increases as dyskinetic behaviors become more severe during a course of l -DOPA treatment (Dupre et al 2016 ). The link between narrowband gamma and LID is currently being explored at several levels (Delaville et al 2015 ; Belic et al 2016 ; Dupre et al 2016 , 2015 ; Tamte et al 2016 ). Because cortical activity is under strong control of thalamic input, it is possible that an aberrant thalamic input could be driving fast cortical oscillations in LID (Dupre et al 2015 ).…”