Year: 2021
Type: article
Abstract: This Special Issue of the European Journal of Neuroscience (EJN) is dedicated to original papers and reviews that arose from presentations given during the 13th Meeting of the International Basal Ganglia Society (IBAGS) held in Biarritz, France in the spring of 2019. The meeting was organized by Thomas Boraud and his team, with over 200 people attending. It consisted of nine oral and three poster sessions spread over 5 days. The meeting started with a clinical session during which Peter Brown (Oxford, UK) and David Devos (Lille, France) discussed advances in deep brain stimulation and other therapeutic strategies in Parkinson's disease (PD). This session was followed by an EJN Publishing workshop led by Paul Bolam (past co-editor-in-chief of EJN) and the Opening Lecture given by Hagai Bergman (Jerusalem, Israel). This triennial meeting promotes interactions between clinical and basic scientists in the field of basal ganglia and related disorders with the ultimate goal of sharing new ideas and challenging current, old and new hypotheses about basal ganglia functions and dysfunctions. The Special Issue consists of 24 articles, 7 of which are reviews and 17 are original research reports. All have gone through full peer review and revision before being accepted for publication in the Special Issue. The articles reflect the diversity of basic and clinical research in the field and the breadth of presentations given at the meeting. The presentation of articles starts with manuscripts dealing with anatomy and function of basal ganglia microcircuits followed by studies using electrophysiology and computational approaches to understand the physiology and pathophysiology of basal ganglia circuits in normal and diseased states. The Special Issue concludes with a series of articles dealing with brain network changes associated with PD and related movement disorders. In the first two studies, immuno-electron microscopy was used to examine neuroplastic changes in synaptic networks relevant to the pathophysiology of the basal ganglia-thalamocortical circuitry in PD. Albaugh and colleagues demonstrate that GABAergic interneurons in the primate ventral motor thalamus receive strong glutamatergic inputs from the deep cerebellar nuclei and the cerebral cortex. They also show that the overall pattern and density of glutamatergic innervation of this primate-specific subtype of thalamic cells is not altered in MPTP-treated parkinsonian monkeys (Albaugh et al., 2020), concluding that GABAergic interneurons are key elements of the functional circuitry of basal ganglia-thalamocortical networks in primates. In the second paper, Moore and colleagues suggest that nigrostriatal dopamine loss has a differential effect on the release of glutamate from vesicular glutamate receptor 2 (vGluT2)-containing terminals in contact with GABAergic versus dopaminergic neurons in the substantia nigra of MPTP-treated parkinsonian mice (Moore et al., 2020). These manuscripts are followed by series of articles focused on the regulation and functions of cholinergic and GABAergic striatal interneurons. Ashkenazi et al. examined whether striatal cholinergic interneurons contribute to the competition between motivated and stereotypic behaviours in rats. The authors demonstrate that selective lesion of cholinergic interneurons in the dorsolateral striatum increases stereotypic behaviour, while such a lesion in the nucleus accumbens increases sensitivity to motivation, thereby suggesting a central role of cholinergic interneurons in regulating the motivational impact of striatal-mediated behaviours (Ashkenazi et al., 2020). In their review, Martel and Apicella (2020) discuss the functional interplay between the nigrostriatal dopaminergic system and striatal cholinergic interneurons that regulates temporal processing in the striatum. This is followed by the review of Tubert and Murer that describes the alterations in cholinergic interneuron physiology that may contribute to the hyper-cholinergic state in PD (Tubert & Murer, 2020). Two additional studies examined the role of cholinergic interneurons in the regulation of striatal GABAergic projection neurons and interneurons using computational modelling. Lindroos and Kotaleski (2020) used biophysically detailed models of striatal microcircuits to predict that concurrent high intrastriatal acetylcholine and dopamine levels lead to the development of complex spiking patterns in striatal projection neurons. In another study from the same research team, the authors used computational modelling to examine the reciprocal interactions between striatal cholinergic interneurons and low-threshold spiking (LTS) interneurons. They show that their modelled connections capture the experimental evidence for physiological interactions between the two neuronal populations, and mimic findings on the muscarinic (M4) and nitric oxide modulation of LTS and cholinergic interneurons respectively (Frost Nylen et al., 2020). The next two articles focus on the function of the parvalbumin-containing, fast-spiking, striatal GABAergic interneurons. Using calcium imaging in ex vivo brain slices, Duhne and colleagues demonstrate that activation of these interneurons regulates sequences of activity in neuronal ensembles in the mouse striatum (Duhne et al., 2020). Perk et al., (2019), in their study, demonstrate that altered reward-related responses of striatal GABAergic projection neurons and fast-spiking parvalbumin-containing interneurons contribute to changes in reward-driven behaviour in the genetically hypertensive (GH) strain of hyperactive rats. The next series of articles used single unit and local field potential (LFP) in vivo recording approaches to examine the physiology and pathophysiology of basal ganglia circuits in healthy monkeys and PD patients. Wongmassang and colleagues using multi-unit recording approaches demonstrated that most movement-related pallidal neurons do not exhibit correlated activity during task performance in healthy behaving monkeys, suggesting that correlated pallidal activity may play only a minor role in regulating motor behaviour in healthy individuals (Wongmassang et al., 2020). In the following article, Deffains et al provide preliminary evidence suggesting that Designer Receptors Exclusively Activated by Designer Drugs (DREADDS) technology can be effectively used in nonhuman primates through recordings of clozapine-N-Oxide (CNO)-induced electrophysiological responses in hM4Di DREADD-transduced neurons in the external globus pallidus of rhesus monkeys (Deffains et al., 2020). Although increased beta band oscillations is considered a cardinal pathophysiological feature of PD, knowledge about the underlying substrate of these pathological oscillations in specific states remains poorly understood. To further address this issue, Belova et al. demonstrated that the pattern of LFP signals in the subthalamic nucleus of parkinsonian patients is different between rest and during movement of specific body parts. They also showed that the aperiodic 1/f broadband component of LFP spectra provides meaningful information about the activity of excitatory/inhibitory projections ratio in the LFP recording sites, suggesting that the 1/f slope may be a useful state-dependent measure of brain oscillations in diseased states (Belova et al., 2020). In another article, the same group emphasizes the importance of 1/f broadband activity as mainstream estimation of LFP spectral features together with periodic features in the globus pallidus of patients with cervical dystonia (Semenova et al., 2020). In the last paper of this series on brain oscillations and basal ganglia disorders, Al-Ozzi and colleagues demonstrate that single unit and beta oscillatory activities are modulated during visual choice preference in PD patients that undergo DBS surgery. Their findings suggest a role of the subthalamic nucleus beta activity in cognitive processing (Al-Ozzi et al., 2020). The use of computational models to understand changes that affect basal ganglia-thalamocortical circuits in normal and diseased states is critical to advance our understanding of the pathophysiology of basal ganglia disorders and predict the potential efficacy of related therapeutics. In their comprehensive review, Rubin et al raise the important point that the dopaminergic corticostriatal plasticity algorithms that have been generated through computational studies cannot be applied to a full model of the cortico-basal ganglia-thalamic (CBGT) network because the network does not know which synapses must be reinforced to favour previously rewarding actions. To overcome this problem, the authors used a biologically realistic spiking model of the full CBGT circuit to demonstrate how a network can learn to select optimal targets and to relearn action-outcome contingencies when the environment changes (Rubin et al., 2020). In the subsequent article, Girard et al present findings collected from a biologically constrained spiking neural network model of the primate basal ganglia that predicts the role of different overlapping pathways involved in action selection, highlighting their potential relevance in decision-making (Girard et al., 2020). This series of computational modelling papers ends with two studies from the group of Fred H. Hamker. In the first manuscript, Maith et al., (2020) discuss results of a computational model-based analysis of basal ganglia network changes in PD inferred from resting-state fMRI. They provide evidence that their model is highly reliable to predict firing rate changes of basal ganglia nuclei consistent with those reported in previous experimental studies, highlighting its potential relevance to understand PD-related changes of basal ganglia activity and related therapies. In the last article of this series, Goenner et al. proposes a spiking model (so-called “pause-then-cancel” model) of basal ganglia dynamics in stopping behaviour by arkypallidal neurons in the external globus pallidus. Based on experimental evidence, the premise of this model is that activation of the subthalamic nucleus induces a stimulus-unspecific pause signal followed by a stop-cue-specific cancel signal in striatal neurons innervated by arkypallidal cells. Based on this model, the authors propose that arkypallidal neurons mainly participate in stopping motor behaviours through a preferential inhibition of indirect pathway striatal projection neurons (Goenner et al., 2020). The following three articles are focused on the effects of deep brain stimulation or lesion of the subthalamic nucleus on motor and non-motor features of PD. In their review, Stefani and colleagues critically examine the strengths and shortcomings of the 6-OHDA-treated rodent model of PD to advance the refinement, and understand the underlying mechanisms of DBS technology to treat complex human brain disorders (Stefani et al., 2020). This is followed by an article by Klarendic and Kaski in which they discuss the application of DBS in different diseases and explore how distinct stimulation locations interfere with eye movement circuits and oculomotor motility (Klarendic & Kaski, 2020). Although STN DBS has significant therapeutic benefits on parkinsonian motor signs, it may sometimes result in unwanted psychiatric and cognitive side effects that dampen its efficacy in PD patients. In an attempt at furthering knowledge about the underlying substrates of these unwanted side effects, Breysse et al. suggest that lesion of the STN or zona incerta has opposite effects on risk-taking in rats. Based on their findings, the authors suggest that DBS of the STN and neighbouring regions may interfere with risky decision-making circuits and induce side effects related to impulsivity and poor decision-making in PD patients that undergo STN DBS surgery (Breysse et al., 2020). The last three articles of this Special Issue relate to brain network changes associated with PD and related movement disorders. Halperin et al. review the literature related to changes in self-motion perception and multisensory integration in PD. They propose that dysfunction of brain circuits implicated in visual, vestibular and somatosensory integration has an impact on self-motion perception in PD, suggesting that a better understanding of self-motion perception and multisensory integration in PD is essential for the development of efficient therapies to treat debilitating gait and balance problems (Halperin et al., 2020). This review is followed by the work of Sedov et al that tested the hypothesis that focal dystonia, which affects specific body parts, may have a widespread neural substrate. Through recordings of pallidal neurons in patients with cervical dystonia that underwent lesions of the internal globus pallidus, the authors conclude that the activity of pallidal neurons that drive both the neck and hand movements is affected in cervical dystonia. They also demonstrate that the feedback dependence of the neck movement-sensitive neurons is also significantly impaired in these patients suggesting that feedback-dependent neuronal properties contribute to the pathophysiology of focal dystonias (Sedov et al., 2020). The Special Issue ends with the review of Castella and Hernandez (2020) on the striatal pathophysiology of L-DOPA-induced dyskinesia. Articles presented in this Special Issue highlight some of the key areas of interest in basal ganglia research and related disease therapies that are currently being explored. We hope you find it interesting and informative and look forward to seeing you at the next IBAGS meeting in New Zealand. The peer review history for this article is available at https://publons.com/publon/10.1111/ejn.15204.
Source: European Journal of Neuroscience
DOI: 10.1111/ejn.15204
Authors: Yoland Smith, John Paul Bolam, Thomas Boraud
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W3137096092