The cortico-basal ganglia pathway is involved in normal motor control and implicated in multiple movement disorders. Brief repetitive muscle contractions known as motor tics are a common symptom in several basal ganglia related motor disorders. We used focal micro-injections of the GABA-A antagonist bicuculline to the sensorimotor putamen of behaving primates to induce stereotyped tics similar to those observed in human disorders. This focal disruption of GABA transmission in the putamen led to motor tics confined to a single or a few muscles. The temporal and structural properties of the tics were identified using electromyogram and frame-by-frame analysis of multi-camera video recordings. During experimental sessions the tics would wax and wane, but their size and shape remained highly stereotyped within the session. Neuronal spiking activity and local field potentials were recorded simultaneously from multiple locations along the cortico-basal ganglia pathway: motor cortex, putamen and globus pallidus external and internal segments. The local field potentials displayed stereotyped tic-related voltage transients lasting several hundred milliseconds. These 'local field potential spikes', which appeared throughout the cortico-basal ganglia pathway, were consistently observed in close temporal association to the motor tics. During tic expression, neuronal activity was altered in most of the recorded neurons in a temporally focal manner, displaying phasic firing rate modulations time locked to the tics. Consistent with theoretical models of tic generation, transient inhibition of the basal ganglia output nucleus prior to and during tic expression was observed. The phasic reduction of basal ganglia output was correlated with a disinhibition of cortical activity, manifesting as short bursts of activity in motor cortex. The results demonstrate that the basal ganglia provide a finely timed disinhibition in the output nuclei of the basal ganglia. However, a large fraction of the neurons were simultaneously inhibited during tics, although tics were only manifested in a small confined muscle group. This suggests that rather than representing a specific action within the basal ganglia itself, these nuclei provide a temporally exact but spatially distributed release signal. The tics induced by striatal disinhibition bear a striking resemblance to motor tics recognized in human pathologies associated with basal ganglia dysfunction. The neuronal changes observed during tic formation may provide valuable insights into the underlying mechanism of tic disorders, as well as into basic information processing in the cortico-basal ganglia loop.
Motor tics are sudden, brief, repetitive movements that constitute the main symptom of Tourette syndrome (TS). Multiple lines of evidence suggest the involvement of the cortico-basal ganglia system, and in particular the basal ganglia input structure—the striatum in tic formation. The striatum receives somatotopically organized cortical projections and contains an internal GABAergic network of interneurons and projection neurons' collaterals. Disruption of local striatal GABAergic connectivity has been associated with TS and was found to induce abnormal movements in model animals. We have previously described the behavioral and neurophysiological characteristics of motor tics induced in monkeys by local striatal microinjections of the GABAA antagonist bicuculline. In the current study we explored the abnormal movements induced by a similar manipulation in freely moving rats. We targeted microinjections to different parts of the dorsal striatum, and examined the effects of this manipulation on the induced tic properties, such as latency, duration, and somatic localization. Tics induced by striatal disinhibition in monkeys and rats shared multiple properties: tics began within several minutes after microinjection, were expressed solely in the contralateral side, and waxed and waned around a mean inter-tic interval of 1–4 s. A clear somatotopic organization was observed only in rats, where injections to the anterior or posterior striatum led to tics in the forelimb or hindlimb areas, respectively. These results suggest that striatal disinhibition in the rat may be used to model motor tics such as observed in TS. Establishing this reliable and accessible animal model could facilitate the study of the neural mechanisms underlying motor tics, and the testing of potential therapies for tic disorders.
Extracellular recordings in primates have identified two types of neurons in the external segment of the globus pallidus (GPe): high frequency pausers (HFP) and low frequency bursters (LFB). The aim of the current study was to test whether the properties of HFP and LFB neurons recorded extracellularly in the primate GPe are linked to cellular mechanisms underlying the generation of action potential (AP) firing. Thus, we recorded from primate and rat globus pallidus neurons. Extracellular recordings in primates revealed that in addition to differences in firing patterns the APs of neurons in these two groups have different widths (APex). To quantitatively investigate this difference and to explore the heterogeneity of pallidal neurons we carried out cell-attached and whole-cell recordings from acute slices of the rat globus pallidus (GP, the rodent homolog of the primate GPe), examining both spontaneous and evoked activity. Several parameters related to the extracellular activity were extracted in order to subdivide the population of recorded GP neurons into groups. Statistical analysis showed that the GP neurons in the rodents may be differentiated along six cellular parameters into three subgroups. Combining two of these groups allowed a better separation of the population along nine parameters. Four of these parameters (Fmax, APamp, APhw, and AHPs amplitude) form a subset, suggesting that one group of neurons may generate APs at significantly higher frequencies than the other group. This may suggest that the differences between the HFP and LFB neurons in the primate are related to fundamental underlying differences in their cellular properties.
Motor tics are involuntary brief muscle contractions that interfere with ongoing behavior and appear as a symptom in several human disorders. While the pathophysiology of tics is still largely unknown, multiple lines of evidence suggest the involvement of the corticobasal ganglia loop in tic disorders. We administered local microinjections of bicuculline into the putamen of Macaca fascicularis monkeys to induce motor tics, while simultaneously recording neuronal activity from the primary motor cortex, putamen, and globus pallidus. These data were used to explore the spatial and temporal properties of tic-related neuronal activity within the cortico-basal ganglia system. In the putamen, tics were associated with brief bursts of activity of phasically active neurons (presumably the projection neurons) and complex excitation-inhibition patterns of tonically active neurons. Tic-related activity within the putamen was spatially focused and somatotopically organized. In the globus pallidus, tic-related activity was diffusely distributed throughout the motor territory. Ticrelated activity in the putamen usually preceded the tic-related activations in the cortex, but in the globus pallidus, tic-related activity was mostly later than the cortex. These findings shed new light on the role of the different basal ganglia nuclei in the generation of motor tics. Despite the early and somatotopically focused nature of tic-related activity in the input stage of the basal ganglia, tic-related activity in the output nucleus is temporally late and diffusely distributed, making it incompatible with a role in tic initiation. Instead, abnormal basal ganglia activity may serve to modulate motor patterns or activate learning mechanisms, thus augmenting further tic expression.
Globus Pallidus external segment (GPe) neurons are well-characterized in behaving primates. Based on their firing properties, these neurons are commonly divided into two distinct groups: high frequency pausers (HFP) and low frequency bursters (LFB). However, no such characterization has been made for behaving rats. The current study characterizes and categorizes extracellularly recorded GPe neurons in freely moving rats, and compares these results to those obtained by extracellular recordings in behaving primates using the same analysis methods. Analysis of our data recorded in rats revealed two distinct neuronal populations exhibiting firing-pattern characteristics that are similar to those obtained in primates. These characteristic firing patterns are conserved between species although the firing rate is significantly lower in rats than in primates. Significant differences in waveform duration and shape were insufficient to create a reliable waveform-based classification in either species. The firing pattern analogy may emphasize conserved processing properties over firing rate per-se. Given the similarity in GPe neuronal activity between human and non-human primates in different pathologies, our results encourage information transfer using complementary studies across species in the GPe to acquire a better understanding of the function of this nucleus in health and disease.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.