Multi-Neuronal Recordings in the Basal Ganglia in Normal and Dystonic Rats

Abstract

Classical rate-based pathway models are invaluable for conceptualizing direct/indirect basal ganglia pathways, but cannot account for many aspects of normal and abnormal motor control. To better understand the contribution of patterned basal ganglia signaling to normal and pathological motor control, we simultaneously recorded multi-neuronal and EMG activity in normal and dystonic rats. We used the jaundiced Gunn rat model of kernicterus as our experimental model of dystonia. Stainless steel head fixtures were implanted on the skulls and EMG wires were inserted into antagonistic hip muscles in nine dystonic and nine control rats. Under awake, head-restrained conditions, neuronal activity was collected from up to three microelectrodes inserted in the principal motor regions of the globus pallidus (GP), subthalamic nucleus, and entopeduncular nucleus (EP). In normal animals, most neurons discharged in regular or irregular patterns, without appreciable bursting. In contrast, in dystonic animals, neurons discharged in slow bursty or irregular, less bursty patterns. In normal rats, a subset of neurons showed brief discharge bursts coinciding with individual agonist or antagonist EMG bursts. In contrast, in dystonics, movement related discharges were characterized by more prolonged bursts which persist over multiple dystonic co-contraction epics. The pattern of movement related decreases in discharge activity however did not differ in dystonics compared to controls. In severely dystonic rats, exclusively, simultaneously recorded units often showed abnormally synchronized movement related pauses in GP and bursts in EP. In conclusion, our findings support that slow, abnormally patterned neuronal signaling is a fundamental pathophysiological feature of intrinsic basal ganglia nuclei in dystonia. Moreover, from our findings, we suggest that excessive movement related silencing of neuronal signaling in GP profoundly disinhibits EP and in turn contributes to sustained, unfocused dystonic muscle contractions.

It's not just the basal ganglia: Cerebellum as a target for dystonia therapeutics

“…In a rat model of kernicterus‐induced striatal dystonia, neurons in the globus pallidus (GP), subthalamic nucleus (STN), and entopeduncular nucleus fired in a more irregular manner with many exhibiting bursts of activity uncommon under normal conditions . Dystonic muscle contractions in this model were shown to correlate with periods of bursting of specific neurons, suggesting that burst firing in the basal ganglia may be an electrophysiological signature of dystonia …”

The external globus pallidus: progress and perspectives

“…Finally, though its aetiology has yet to be discovered, there is compelling evidence from both human patients and animal models of dystonia that aberrant activity is present in the GPe (Starr et al ., ; Chiken et al ., ; Baron et al ., ; Nambu et al ., ; Nishibayashi et al ., ). Dystonia is characterized by involuntary repetitive twisting and sustained muscle contractions that result in abnormal movements and postures (Breakefield et al ., ; Schwarz & Bressman, ; Tanabe et al ., ; Albanese et al ., ; Jinnah & Factor, ).…”

“…Highly synchronous bursting in the GPe correlates with hypokinetic symptoms of Parkinson's disease (PD; Pan & Walters, ; Filion & Tremblay, ; Filion et al ., ; Hutchison et al ., ; Nini et al ., ; Rothblat & Schneider, ; Hassani et al ., ; Taha et al ., ; Bergman et al ., ; Boraud et al ., ; Wichmann et al ., ; El‐Deredy et al ., ; Magill et al ., , ; Magnin et al ., ; Raz et al ., ; Brown et al ., ; Bar‐Gad et al ., ; Starr et al ., , ; Heimer et al ., ; Wichmann & Soares, ; Kita, ; Tang et al ., ; Zold et al ., ,b; Mallet et al ., ; Sani et al ., ; Chan et al ., ). Similarly, aberrant GPe neuron activity is also observed in Huntington's disease (HD) and dystonia (Starr et al ., , ; Chiken et al ., ; Baron et al ., ; Nambu et al ., ; Nishibayashi et al ., ), arguing for the centrality of the GPe in motor function and dysfunction. Despite its critical role in regulating motor activity, the organization of GPe neurons within the basal ganglia circuitry remains poorly understood, preventing us from understanding how GPe activity is regulated in behavioural and disease contexts.…”

Are the neuromotor disabilities of bilirubin-induced neurologic dysfunction disorders related to the cerebellum and its connections?

“…Dystonia is also a prominent feature in Gunn rat pups [33,62,63] and neonatal Ugt1 -/--deficient mice [22,64] both robust models of kernicterus. The former is used as an experimental model of dystonia [33,62,63].…”

“…The former is used as an experimental model of dystonia [33,62,63]. Although these models show basal ganglia injury [4,65], the sine qua non of bilirubin-induced murine neuropathology is cerebellar damage [4,65] and resultant cerebellar hypoplasia [21,29,66].…”