Pars Reticulata Research Articles

Oral Transport, Penetration, and Aspiration in PD: Insights from a RCT on STN + SNr Stimulation.

Dysphagia is frequent and detrimental in advanced Parkinson's disease (PD) and does not respond to standard treatments. Experimental models suggested that pathological overactivity of the substantia nigra pars reticulata (SNr) may hinder oral contributions to swallowing. Here, we hypothesized that the combined stimulation of subthalamic nucleus (STN) and SNr improves measures of dysphagia after eight weeks of active treatment. We enrolled 20 PD patients with dysphagia and deep brain stimulation (DBS). Patients were assessed in 'medication on' and 'STN' stimulation at baseline (V1) and then were randomized 1:1 to 'STN' or 'STN + SNr' stimulation. In addition, patients of both groups received swallowing therapy as a standard of care. The primary endpoint was the change in Penetration-Aspiration Scale (PAS) at eight-week follow-up (V2) with respect to the baseline (V1) under the hypothesis, that 'STN + SNr' was superior to 'STN'. We obtained further secondary endpoints on oral preparation, transport, pharyngeal phase, penetration, and aspiration. PAS change from V1 to V2 was not significantly different between groups (p = 0.221). When considering all patients for secondary analyses, we found that the entire study cohort showed better PAS scores at V2 compared to V1 irrespective from DBS treatment allocation (p = 0.0156). Both STN and STN + SNr treatments were safe. 'STN + SNr' stimulation was not superior compared to standard 'STN' stimulation both on PAS and the secondary endpoints. We found that the entire study cohort improved dysphagia after eight weeks, which presumably mirrors the effect of continued swallowing therapy and the increased patient attention on swallowing.

Kappa-opioid receptor blockade in the inferior colliculus of prey threatened by pit vipers decreases anxiety and panic-like behaviour.

The dorsal midbrain comprises dorsal columns of the periaqueductal grey matter and corpora quadrigemina. These structures are rich in beta-endorphinergic and leu-enkephalinergic neurons and receive GABAergic inputs from substantia nigra pars reticulata. Although the inferior colliculus (IC) is mainly involved in the acoustic pathways, the electrical and chemical stimulation of central and pericentral nuclei of the IC elicits a vigorous defensive behaviour. The defensive immobility and escape elicited by IC activation is commonly related to panic-like emotional states. To investigate the role of κ-opioid receptor of the IC in the antiaversive effects of endogenous opioid receptor blockade in a dangerous situation, male Wistar rats were pretreated in the IC with the κ-opioid receptor-selective antagonist nor-binaltorphimine at different concentrations and submitted to the non-enriched polygonal arena for a snake panic test in the presence of a rattlesnake and, after 24 h, prey were resubmitted to the experimental context. The snakes elicited in prey a set of antipredatory behaviours, such as the anxiety-like responses of defensive attention and risk assessment, and the panic-like reactions of defensive immobility and either escape or active avoidance during the elaboration of unconditioned and conditioned fear-related responses. Pretreatment of the IC with microinjections of nor-binaltorphimine at higher concentrations significantly decreased the frequency and duration of both anxiety- and panic-attack-like behaviours. These findings suggest that κ-opioid receptor blockade in the IC causes anxiolytic- and panicolytic-like responses in threatening conditions, and that kappa-opioid receptor-selective antagonists can be a putative coadjutant treatment for panic syndrome treatment.

Optogenetic stimulation of dorsal striatum bidirectionally controls seizures.

Engagement of the striatum (caudate/putamen) and other basal ganglia nuclei during seizures was first observed over 75 years ago. Basal ganglia output nuclei, and the substantia nigra pars reticulata, in particular, have well-established anti-seizure effects across a large array of experimental models. However, striatal control of seizures is understudied. To address this gap, we used optogenetic approaches to activate and inactivate neurons in the dorsal striatum of Sprague-Dawley rats submitted to the gamma-butyrolactone (GBL) model of absence epilepsy, amygdala kindling model of temporal lobe epilepsy, and pilocarpine-induced Status Epilepticus (SE). All tests were performed on a within-subject basis. Animals were tested in two different light frequencies (5 Hz and 100 Hz). Open-loop (continuous light delivery) optogenetic activation of the dorsal striatal neurons robustly suppressed seizures in all models. On the other hand, optogenetic silencing of the dorsal striatal neurons increased absence seizure expression and facilitated SE onset but had no effect on kindled limbic seizures. In the GBL model, we also verified if the closed- loop strategy (light delivery in response to seizure detection) would be enough to induce antiseizure effects. On-demand light delivery in ChR2-expressing animals reduced SWD duration, while the same approach in ArchT-expressing animals increased SWD duration. These results demonstrated previously unrecognized anti-absence effects associated with striatal continuous and on-demand neuromodulation. Together, these findings document a robust, bidirectional role of the dorsal striatum in the control of seizure generation and propagation in a variety of seizure models, including focal seizure onset and generalized seizures.

Segregated basal ganglia output pathways correspond to genetically divergent neuronal subclasses.

The basal ganglia control multiple sensorimotor behaviors though anatomically segregated and topographically organized subcircuits with outputs to specific downstream circuits. However, it is unclear how the anatomical organization of basal ganglia output circuits relates to the molecular diversity of cell types. Here, we demonstrate that the major output nucleus of the basal ganglia, the substantia nigra pars reticulata (SNr) is comprised of transcriptomically distinct subclasses that reflect its distinct progenitor lineages. We show that these subclasses are topographically organized within SNr, project to distinct targets in the midbrain and hindbrain, and receive inputs from different striatal subregions. Finally, we show that these mouse subclasses are also identifiable in human SNr neurons, suggesting that the genetic organization of SNr is evolutionarily conserved. These findings provide a unifying logic for how the developmental specification of diverse SNr neurons relates to the anatomical organization of basal ganglia circuits controlling specialized downstream brain regions.

Calbindin and Girk2/Aldh1a1 define resilient vs vulnerable dopaminergic neurons in a primate Parkinson’s disease model

The differential vulnerability of dopaminergic neurons of the substantia nigra pars compacta (SNc) is a critical and unresolved question in Parkinson´s disease. Studies in mice show diverse susceptibility of subpopulations of nigral dopaminergic neurons to various toxic agents. In the primate midbrain, the molecular phenotypes of dopaminergic neurons and their differential vulnerability are poorly characterized. We performed a detailed histological study to determine the anatomical distribution of different molecular phenotypes within identified midbrain neurons and their selective vulnerability in control and MPTP-treated monkeys. In the ventral tier of the SNc (nigrosome), neurons rich in Aldh1a1 and Girk2 are intermingled, whereas calbindin is the marker that best identifies the most resilient neurons located in the dorsal tier and ventral tegmental area, recapitulating the well-defined dorsoventral axis of susceptibility to degeneration of dopaminergic neurons. In particular, a loss of Aldh1a1+ neurons in the ventral SNc was observed in parallel to the progressive development of parkinsonism. Aldh1a1+ neurons were the main population of vulnerable dopaminergic nigrostriatal-projecting neurons, while Aldh1a1- neurons giving rise to nigropallidal projections remained relatively preserved. Moreover, bundles of entwined Aldh1a1+ dendrites with long trajectories extending towards the substantia nigra pars reticulata emerged from clusters of Aldh1a1+ neurons and colocalized with dense cannabinoid receptor 1 afferent fibers likely representing part of the striatonigral projection that is affected in human disorders, including Parkinson´s disease. In conclusion, vulnerable nigrostriatal-projecting neurons can be identified by using Aldh1a1 and Girk2. Further studies are needed to define the afferent/efferent projection patterns of these most vulnerable neurons.

Inhibitory basal ganglia nuclei differentially innervate pedunculopontine nucleus subpopulations and evoke opposite motor and valence behaviors.

The canonical basal ganglia model predicts that the substantia nigra pars reticulata (SNr) and the globus pallidus externa (GPe) will have specific effects on locomotion: the SNr inhibiting locomotion and the GPe enhancing it. In this manuscript, we use in vivo optogenetics to show that a projection-defined neural subpopulation within each structure exerts non-canonical effects on locomotion. These non-canonical subpopulations are defined by their projection to the pedunculopontine nucleus (PPN) and mediate opposing effects on reward. To understand how these structures differentially modulate the PPN, we use ex vivo whole-cell recording with optogenetics to comprehensively dissect the SNr and GPe connections to regionally- and molecularly-defined populations of PPN neurons. The SNr inhibits all PPN subtypes, but most strongly inhibits caudal glutamatergic neurons. The GPe selectively inhibits caudal glutamatergic and GABAergic neurons, avoiding both cholinergic and rostral cells. This circuit characterization reveals non-canonical basal ganglia pathways for locomotion and valence.

Volitional modulation of neuronal activity in the external globus pallidus by engagement of the cortical-basal ganglia circuit.

Volitional modulation of neural activity is not confined to the cortex but extends to various brain regions. Yet, it remains unclear whether neurons in the basal ganglia structure, the external globus pallidus (GPe), can be volitionally controlled. Here, we employed a volitional conditioning task to compare the volitional modulation of GPe and primary motor cortex (M1) neurons as well as the underlying circuits and control mechanisms. The results revealed that the volitional modulation of GPe neuronal activity engaged both M1 and substantia nigra pars reticulata (SNr) neurons, indicating the involvement of the cortex-GPe-SNr loop. In contrast, the volitional modulation of M1 neurons primarily occurred through the engagement of M1 local circuitry. Furthermore, lesioning M1 neurons did not affect the volitional learning or volitional control signal in GPe, whereas lesioning of GPe neurons impaired the learning process for the volitional modulation of M1 neuronal activity at the intermediate stage. Additionally, lesion of GPe neurons enhanced M1 neuronal activity when performing the volitional control task without reward delivery and a random reward test. Taken together, our findings demonstrated that GPe neurons could be volitionally controlled by engagement of the cortical-basal ganglia circuit and inhibit learning process for the volitional modulation of M1 neuronal activity by regulating M1 neuronal activity. Thus, GPe neurons can be effectively harnessed for independent volitional modulation for neurorehabilitation in patients with cortical damage. KEY POINTS: The cortical-basal ganglia circuit contributes to the volitional modulation of GPe neurons. Volitional modulation of M1 neuronal activity mainly engages M1 local circuitry. Bilateral GPe lesioning impedes volitional learning at the intermediate stages. Lesioning of GPe neurons inhibits volitional learning process by regulating M1 neuronal activity.

Optogenetic fMRI reveals therapeutic circuits of subthalamic nucleus deep brain stimulation

While deep brain stimulation (DBS) is widely employed for managing motor symptoms in Parkinson's disease (PD), its exact circuit mechanisms remain controversial. To identify the neural targets affected by therapeutic DBS in PD, we analyzed DBS-evoked whole brain activity in female hemi-parkinsonian rats using functional magnetic resonance imaging (fMRI). We delivered subthalamic nucleus (STN) DBS at various stimulation pulse repetition rates using optogenetics, allowing unbiased examination of cell-type specific STN feedforward neural activity. Unilateral optogenetic STN DBS elicited pulse repetition rate-dependent alterations of blood-oxygenation-level-dependent (BOLD) signals in SNr (substantia nigra pars reticulata), GP (globus pallidus), and CPu (caudate putamen). Notably, this modulation effectively ameliorated pathological circling behavior in animals expressing the kinetically faster Chronos opsin, but not in animals expressing ChR2. Furthermore, mediation analysis revealed that the pulse repetition rate-dependent behavioral rescue was significantly mediated by optogenetic DBS induced activity changes in GP and CPu, but not in SNr. This suggests that the activation of GP and CPu are critically involved in the therapeutic mechanisms of STN DBS.

The Basal Ganglia Downstream Control of Action - An Evolutionarily Conserved Strategy.

The motor areas of the cortex and the basal ganglia both contribute to determining which motor actions will be recruited at any moment in time, and their functions are intertwined. Here, we review the basal ganglia mechanisms underlying the selection of behavior of the downstream control of motor centers in the midbrain and brainstem and show that the basic organization of the forebrain motor system is evolutionarily conserved throughout vertebrate phylogeny. The output level of the basal ganglia (e.g. substantia nigra pars reticulata) has GABAergic neurons that are spontaneously active at rest and inhibit a number of specific motor centers, each of which can be relieved from inhibition if the inhibitory output neurons themselves become inhibited. The motor areas of the cortex act partially via the dorsolateral striatum (putamen), which has specific modules for the forelimb, hindlimb, trunk, etc. Each module operates in turn through the two types of striatal projection neurons that control the output modules of the basal ganglia and thereby the downstream motor centers. The mechanisms for lateral inhibition in the striatum are reviewed as well as other striatal mechanisms contributing to action selection. The motor cortex also exerts a direct excitatory action on specific motor centers. An overview is given of the basal ganglia control exerted on the different midbrain/brainstem motor centers, and the efference copy information fed back via the thalamus to the striatum and cortex, which is of importance for the planning of future movements.

Identifying discriminative features of brain network for prediction of Alzheimer's disease using graph theory and machine learning.

Alzheimer's disease (AD) is a challenging neurodegenerative condition, necessitating early diagnosis and intervention. This research leverages machine learning (ML) and graph theory metrics, derived from resting-state functional magnetic resonance imaging (rs-fMRI) data to predict AD. Using Southwest University Adult Lifespan Dataset (SALD, age 21-76 years) and the Open Access Series of Imaging Studies (OASIS, age 64-95 years) dataset, containing 112 participants, various ML models were developed for the purpose of AD prediction. The study identifies key features for a comprehensive understanding of brain network topology and functional connectivity in AD. Through a 5-fold cross-validation, all models demonstrate substantial predictive capabilities (accuracy in 82-92% range), with the support vector machine model standing out as the best having an accuracy of 92%. Present study suggests that top 13 regions, identified based on most important discriminating features, have lost significant connections with thalamus. The functional connection strengths were consistently declined for substantia nigra, pars reticulata, substantia nigra, pars compacta, and nucleus accumbens among AD subjects as compared to healthy adults and aging individuals. The present finding corroborate with the earlier studies, employing various neuroimagining techniques. This research signifies the translational potential of a comprehensive approach integrating ML, graph theory and rs-fMRI analysis in AD prediction, offering potential biomarker for more accurate diagnostics and early prediction of AD.

Convergence of inputs from the basal ganglia with layer 5 of motor cortex and cerebellum in mouse motor thalamus.

A key to motor control is the motor thalamus, where several inputs converge. One excitatory input originates from layer 5 of primary motor cortex (M1L5), while another arises from the deep cerebellar nuclei (Cb). M1L5 terminals distribute throughout the motor thalamus and overlap with GABAergic inputs from the basal ganglia output nuclei, the internal segment of the globus pallidus (GPi), and substantia nigra pars reticulata (SNr). In contrast, it is thought that Cb and basal ganglia inputs are segregated. Therefore, we hypothesized that one potential function of the GABAergic inputs from basal ganglia is to selectively inhibit, or gate, excitatory signals from M1L5 in the motor thalamus. Here, we tested this possibility and determined the circuit organization of mouse (both sexes) motor thalamus using an optogenetic strategy in acute slices. First, we demonstrated the presence of a feedforward transthalamic pathway from M1L5 through motor thalamus. Importantly, we discovered that GABAergic inputs from the GPi and SNr converge onto single motor thalamic cells with excitatory synapses from M1L5. Separately, we also demonstrate that, perhaps unexpectedly, GABAergic GPi and SNr inputs converge with those from the Cb. We interpret these results to indicate that a role of the basal ganglia is to gate the thalamic transmission of M1L5 and Cb information to cortex.

Freezing of gait: pharmacological and surgical options.

The primary aim of this review is to describe and update the pathophysiological and relevant therapeutic strategies for freezing of gait (FoG) in patients with Parkinson's disease (PD). FoG presumably involves dysfunction of multiple cortical and subcortical components, including dopaminergic and nondopaminergic circuits. In this regard, levodopa and physical therapy represent the first-choice therapeutic options for PD patients with FoG. However, the relationship between FoG and levodopa is not fully predictable. For those patients with levodopa-resistant FoG, there is promising but still controversial data on the benefits of bilateral high-frequency transcranial magnetic stimulation and deep brain stimulation on the subthalamic nuclei, substantia nigra pars reticulata, pedunculopontine nucleus, and the Fields of Forel. On the other hand, general exercise, gait training with a treadmill, focus attention on gait training, and conventional physiotherapy have demonstrated moderate to large benefits in FoG. FOG requires different treatment strategies. The inclusion of adequate detection and prediction of FoG combined with double-blind, and statistically powered protocols are needed to improve patients' quality of life, the motor and nonmotor symptoms and societal burden associated with FoG.

Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity.

The globus pallidus externus (GPe) is a central component of the basal ganglia circuit, receiving strong input from the indirect pathway and regulating a variety of functions, including locomotor output and habit formation. We recently showed that it also acts as a gatekeeper of cocaine-induced behavioral plasticity, as inhibition of parvalbumin-positive cells in the GPe (GPe PV ) prevents the development of cocaine-induced reward and sensitization. However, the molecular and circuit mechanisms underlying this function are unknown. Here we show that GPe PV cells control cocaine reward and sensitization by inhibiting GABAergic neurons in the substantia nigra pars reticulata (SNr GABA ), and ultimately, selectively modulating the activity of ventral tegmental area dopamine (VTA DA ) cells projecting to the lateral shell of the nucleus accumbens (NAcLat). A major input to GPe PV cells is the indirect pathway of the dorsomedial striatum (DMS D 2 ), which receives DAergic innervation from collaterals of VTA DA →NAcLat cells, making this a closed-loop circuit. Cocaine likely facilitates reward and sensitization not directly through actions in the GPe, but rather in the upstream DMS, where the cocaine-induced elevation of DA triggers a depression in DMS D 2 cell activity. This cocaine-induced elevation in DA levels can be blocked by inhibition of GPe PV cells, closing the loop. Interestingly, the level of GPe PV cell activity prior to cocaine administration is correlated with the extent of reward and sensitization that animals experience in response to future administration of cocaine, indicating that GPe PV cell activity is a key predictor of future behavioral responses to cocaine. Single nucleus RNA-sequencing of GPe cells indicated that genes encoding voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability are downregulated in GPe PV cells following a single cocaine exposure, contributing to the elevation in GPe PV cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of Salvia rosmarinus (rosemary) extract, reduced GPe PV cell excitability and also impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its potential as a therapeutic to counteract psychostimulant use disorder. Our findings illuminate the molecular and circuit mechanisms by which the GPe orchestrates brain-wide changes in response to cocaine that are required for reward, sensitization, and self-administration behaviors.

Iron deposition in subcortical nuclei of Parkinson's disease: A meta-analysis of quantitative iron-sensitive magnetic resonance imaging studies.

Iron deposition plays a crucial role in the pathophysiology of Parkinson's disease (PD), yet the distribution pattern of iron deposition in the subcortical nuclei has been inconsistent across previous studies. We aimed to assess the difference patterns of iron deposition detected by quantitative iron-sensitive magnetic resonance imaging (MRI) between patients with PD and patients with atypical parkinsonian syndromes (APSs), and between patients with PD and healthy controls (HCs). A systematic literature search was conducted on PubMed, Embase, and Web of Science databases to identify studies investigating the iron content in PD patients using the iron-sensitive MRI techniques (R2* and quantitative susceptibility mapping [QSM]), up until May 1, 2023. The quality assessment of case-control and cohort studies was performed using the Newcastle-Ottawa Scale, whereas diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies-2. Standardized mean differences and summary estimates of sensitivity, specificity, and area under the curve (AUC) were calculated for iron content, using a random effects model. We also conducted the subgroup-analysis based on the MRI sequence and meta-regression. Seventy-seven studies with 3192 PD, 209 multiple system atrophy (MSA), 174 progressive supranuclear palsy (PSP), and 2447 HCs were included. Elevated iron content in substantia nigra (SN) pars reticulata (P <0.001) and compacta (P <0.001), SN (P <0.001), red nucleus (RN, P <0.001), globus pallidus (P <0.001), putamen (PUT, P=0.009), and thalamus (P=0.046) were found in PD patients compared with HCs. PD patients showed lower iron content in PUT (P <0.001), RN (P=0.003), SN (P=0.017), and caudate nucleus (P=0.027) than MSA patients, and lower iron content in RN (P=0.001), PUT (P <0.001), globus pallidus (P=0.004), SN (P=0.015), and caudate nucleus (P=0.001) than PSP patients. The highest diagnostic accuracy distinguishing PD from HCs was observed in SN (AUC: 0.85), and that distinguishing PD from MSA was found in PUT (AUC: 0.90). In addition, the best diagnostic performance was achieved in the RN for distinguishing PD from PSP (AUC: 0.84). Quantitative iron-sensitive MRI could quantitatively detect the iron content of subcortical nuclei in PD and APSs, while it may be insufficient to accurately diagnose PD. Future studies are needed to explore the role of multimodal MRI in the diagnosis of PD. PROSPERO; CRD42022344413.

Energetic dysfunction and iron overload in early Parkinson's disease: Two distinct mechanisms?

IntroductionIdentifying biomarkers reflecting cellular dysfunctions in early Parkinson's disease patients (ePD) is needed to develop targeted therapeutic strategies. We aimed to determine if cellular energetic dysfunction related to increased brain sodium concentration would be co-located to microstructural alterations and iron deposition in ePD. MethodsWe prospectively included 12 ePD (mean disease duration 20.0 ± 10.2 months) and 13 healthy controls (HC), scanned with a 7 T 1H and 23Na MRI. Complementary voxel-based and region-based assessments were performed, the latter utilizing a high-resolution multimodal template we created (combining quantitative T1 maps (qT1), transverse relaxation rate (R2*), quantitative magnetic susceptibility mapping (QSM) images) from 200 subjects. This template allowed a precise multiparametric assessment of sodium concentration, QSM, R2*, qT1, mean diffusivity, and fractional anisotropy values. A two-sided p-value<0.05 was considered statistically significant after the Bonferroni correction. ResultsRelative to HC, ePD showed significantly higher sodium concentration in left Substantia nigra (SN) pars reticulata (46.13 mM ± 3.52 vs 38.60 mM ± 6.10, p = 0.038), a subpart of the SN pars compacta (SNc) and ventral tegmental area, Putamen, Globus Pallidum external, accumbens nucleus and claustrum. Significantly increased QSM and R2* values, and decreased T1 values, were limited to the Nigrosomes 1 (Nig) and right SNc (all p < 0.05). QSM values in the Nig were significantly correlated to UPDRS-III scores (r = 0.91,p < 0.001). ConclusionIn ePD, brain sodium accumulation was broad and dissociated from iron accumulation. As with iron accumulation, a sodium-related pathophysiological approach could lead to identifying potential new therapeutic agents and deserves further investigation.

Neurochemistry and circuit organization of the lateral spiriform nucleus of birds: A uniquely nonmammalian direct pathway component of the basal ganglia.

We used diverse methods to characterize the role of avian lateral spiriform nucleus (SpL) in basal ganglia motor function. Connectivity analysis showed that SpL receives input from globus pallidus (GP), and the intrapeduncular nucleus (INP) located ventromedial to GP, whose neurons express numerous striatal markers. SpL-projecting GP neurons were large and aspiny, while SpL-projecting INP neurons were medium sized and spiny. Connectivity analysis further showed that SpL receives inputs from subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr), and that the SNr also receives inputs from GP, INP, and STN. Neurochemical analysis showed that SpL neurons express ENK, GAD, and a variety of pallidal neuron markers, and receive GABAergic terminals, some of which also contain DARPP32, consistent with GP pallidal and INP striatal inputs. Connectivity and neurochemical analysis showed that the SpL input to tectum prominently ends on GABAA receptor-enriched tectobulbar neurons. Behavioral studies showed that lesions of SpL impair visuomotor behaviors involving tracking and pecking moving targets. Our results suggest that SpL modulates brainstem-projecting tectobulbar neurons in a manner comparable to the demonstrated influence of GP internus on motor thalamus and of SNr on tectobulbar neurons in mammals. Given published data in amphibians and reptiles, it seems likely the SpL circuit represents a major direct pathway-type circuit by which the basal ganglia exerts its motor influence in nonmammalian tetrapods. The present studies also show that avian striatum is divided into three spatially segregated territories with differing connectivity, a medial striato-nigral territory, a dorsolateral striato-GP territory, and the ventrolateral INP motor territory.

Striatal parvalbumin interneurons are activated in a mouse model of cerebellar dystonia.

Dystonia is thought to arise from abnormalities in the motor loop of the basal ganglia; however, there is an ongoing debate regarding cerebellar involvement. We adopted an established cerebellar dystonia mouse model by injecting ouabain to examine the contribution of the cerebellum. Initially, we examined whether the entopeduncular nucleus (EPN), substantia nigra pars reticulata (SNr), globus pallidus externus (GPe) and striatal neurons were activated in the model. Next, we examined whether administration of a dopamine D1 receptor agonist and dopamine D2 receptor antagonist or selective ablation of striatal parvalbumin (PV, encoded by Pvalb)-expressing interneurons could modulate the involuntary movements of the mice. The cerebellar dystonia mice had a higher number of cells positive for c-fos (encoded by Fos) in the EPN, SNr and GPe, as well as a higher positive ratio of c-fos in striatal PV interneurons, than those in control mice. Furthermore, systemic administration of combined D1 receptor agonist and D2 receptor antagonist and selective ablation of striatal PV interneurons relieved the involuntary movements of the mice. Abnormalities in the motor loop of the basal ganglia could be crucially involved in cerebellar dystonia, and modulating PV interneurons might provide a novel treatment strategy.

Auditory oddball responses in the human subthalamic nucleus and substantia nigra pars reticulata

The auditory oddball is a mainstay in research on attention, novelty, and sensory prediction. How this task engages subcortical structures like the subthalamic nucleus and substantia nigra pars reticulata is unclear. We administered an auditory OB task while recording single unit activity (35 units) and local field potentials (57 recordings) from the subthalamic nucleus and substantia nigra pars reticulata of 30 patients with Parkinson's disease undergoing deep brain stimulation surgery. We found tone modulated and oddball modulated units in both regions. Population activity differentiated oddball from standard trials from 200 ms to 1000 ms after the tone in both regions. In the substantia nigra, beta band activity in the local field potential was decreased following oddball tones. The oddball related activity we observe may underlie attention, sensory prediction, or surprise-induced motor suppression.

Enhancing Attentional Performance in Parkinson's Disease: The Impact of Combined Deep Brain Stimulation of the Substantia Nigra Pars Reticulata and the Subthalamic Nucleus

ObjectiveThe concomitant stimulation of the subthalamic nucleus and the substantia nigra pars reticulata is a promising approach to improve treatment of refractory axial symptoms in Parkinson's disease. While dual stimulation of the subthalamic nucleus and the substantia nigra pars reticulata has previously shown beneficial effects on gait, the role of the substantia nigra, a crucial component of the basal ganglia circuitry, in cognitive functions such as attention and executive control remains underexplored. This study aimed to investigate the impact of selective substantia nigra pars reticulata stimulation on attentional performance in patients receiving standard deep brain stimulation of the subthalamic nucleus. MethodsTwelve patients with bilateral subthalamic nucleus stimulation underwent computerized assessment of attention using a simple reaction time task. Reaction times were assessed under standard stimulation of the subthalamic nucleus versus simultaneous stimulation of the subthalamic nucleus and the substantia nigra pars reticulata. ResultsThe results revealed a significant improvement in reaction times during the simple reaction time task when patients received dual stimulation compared to standard stimulation. ConclusionsOur findings provide further evidence for the pivotal role of the substantia nigra pars reticulata in cognitive functions such as attention. Despite the limitations of the study, including a small sample size, our results suggest potential benefits of simultaneous deep brain stimulation of the subthalamic nucleus and the substantia nigra pars reticulata on attentional performance in patients with Parkinson's disease. Further research with larger cohorts is warranted to confirm these findings and better understand the underlying mechanisms.

α4 nicotinic receptors on GABAergic neurons mediate a cholinergic analgesic circuit in the substantia nigra pars reticulata.

Nicotinic acetylcholine receptors (nAChRs) regulate pain pathways with various outcomes depending on receptor subtypes, neuron types, and locations. But it remains unknown whether α4β2 nAChRs abundantly expressed in the substantia nigra pars reticulata (SNr) have potential to mitigate hyperalgesia in pain states. We observed that injection of nAChR antagonists into the SNr reduced pain thresholds in naïve mice, whereas injection of nAChR agonists into the SNr relieved hyperalgesia in mice, subjected to capsaicin injection into the lower hind leg, spinal nerve injury, chronic constriction injury, or chronic nicotine exposure. The analgesic effects of nAChR agonists were mimicked by optogenetic stimulation of cholinergic inputs from the pedunculopontine nucleus (PPN) to the SNr, but attenuated upon downregulation of α4 nAChRs on SNr GABAergic neurons and injection of dihydro-β-erythroidine into the SNr. Chronic nicotine-induced hyperalgesia depended on α4 nAChRs in SNr GABAergic neurons and was associated with the reduction of ACh release in the SNr. Either activation of α4 nAChRs in the SNr or optogenetic stimulation of the PPN-SNr cholinergic projection mitigated chronic nicotine-induced hyperalgesia. Interestingly, mechanical stimulation-induced ACh release was significantly attenuated in mice subjected to either capsaicin injection into the lower hind leg or SNI. These results suggest that α4 nAChRs on GABAergic neurons mediate a cholinergic analgesic circuit in the SNr, and these receptors may be effective therapeutic targets to relieve hyperalgesia in acute and chronic pain, and chronic nicotine exposure.