Control of Basal Ganglia Output by Direct and Indirect Pathway Projection Neurons

AbstractThe classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and how they are involved in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting role of dSPNs in the dorsomedial striatum (DMSdSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum (DLSdSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1+ neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinson’s disease, the dSPN-Npas1+ projection was dramatically strengthened. As DLSdSPN-Npas1+ projection suppresses movement, the enhancement of this projection represents a circuit mechanism for the hypokinetic symptoms of Parkinson’s disease that has not been previously considered.Significance statementIn the classic basal ganglia model, the striatum is described as a divergent structure—it controls motor and adaptive functions through two segregated, opponent output streams. However, the experimental results that show the projection from direct-pathway neurons to the external pallidum have been largely ignored. Here, we showed that this striatopallidal sub-pathway targets a select subset of neurons in the external pallidum and is motor-suppressing. We found that this sub-pathway undergoes plastic changes in a Parkinson’s disease model. In particular, our results suggest that the increase in strength of this sub-pathway contributes to the slowness or reduced movements observed in Parkinson’s disease.

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Dopamine regulates distinctively the activity patterns of striatal output neurons in advanced parkinsonian primates

Journal of Neurophysiology ◽

10.1152/jn.00910.2014 ◽

2015 ◽

Vol 113 (5) ◽

pp. 1533-1544 ◽

Cited By ~ 25

Author(s):

Arun Singh ◽

Li Liang ◽

Yoshiki Kaneoke ◽

Xuebing Cao ◽

Stella M. Papa

Keyword(s):

Basal Ganglia ◽

Firing Pattern ◽

Activity Patterns ◽

Receptor Activation ◽

Firing Frequency ◽

Projection Neurons ◽

Indirect Pathway ◽

Response Compatible ◽

Motor Abnormalities ◽

The Impact

Nigrostriatal dopamine denervation plays a major role in basal ganglia circuitry disarray and motor abnormalities of Parkinson's disease (PD). Studies in rodent and primate models have revealed that striatal projection neurons, namely, medium spiny neurons (MSNs), increase the firing frequency. However, their activity pattern changes and the effects of dopaminergic stimulation in such conditions are unknown. Using single-cell recordings in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates with advanced parkinsonism, we studied MSN activity patterns in the transition to different motor states following levodopa administration. In the “off” state (baseline parkinsonian disability), a burst-firing pattern accompanied by prolonged silences (pauses) was found in 34% of MSNs, and 80% of these exhibited a levodopa response compatible with dopamine D1 receptor activation (direct pathway MSNs). This pattern was highly responsive to levodopa given that bursting/pausing almost disappeared in the “on” state (reversal of parkinsonism after levodopa injection), although this led to higher firing rates. Nonbursty MSNs fired irregularly with marked pausing that increased in the on state in the MSN subset with a levodopa response compatible with dopamine D2 receptor activation (indirect pathway MSNs), although the pause increase was not sustained in some units during the appearance of dyskinesias. Data indicate that the MSN firing pattern in the advanced parkinsonian monkey is altered by bursting and pausing changes and that dopamine differentially and inefficiently regulates these behaviorally correlated patterns in MSN subpopulations. These findings may contribute to understand the impact of striatal dysfunction in the basal ganglia network and its role in motor symptoms of PD.

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Dysregulation of the basal ganglia indirect pathway prior to cell loss in the Q175 mouse model of Huntington's disease

10.1101/2021.01.06.425589 ◽

2021 ◽

Author(s):

Joshua Callahan ◽

David L Wokosin ◽

Mark D Bevan

Keyword(s):

Basal Ganglia ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Ex Vivo ◽

Cell Loss ◽

Projection Neurons ◽

Indirect Pathway ◽

Cortical Input ◽

Psychomotor Symptoms

The psychomotor symptoms of Huntington's disease (HD) are linked to degeneration of the basal ganglia indirect pathway. To determine how this pathway is perturbed prior to cell loss, optogenetic- and reporter-guided electrophysiological interrogation approaches were applied to early symptomatic 6-month-old Q175 HD mice. Although cortical activity was unaffected, indirect pathway striatal projection neurons were hypoactive in vivo, consistent with reduced cortical input strength and dendritic excitability. Downstream parvalbumin-expressing prototypic external globus pallidus (GPe) neurons were hyperactive in vivo and exhibited elevated autonomous firing ex vivo. Optogenetic inhibition of prototypic GPe neurons ameliorated the abnormal hypoactivity of postsynaptic subthalamic nucleus (STN) and putative arkypallidal neurons in vivo. In contrast to STN neurons, autonomous arkypallidal activity was unimpaired ex vivo. Together with previous studies, these findings demonstrate that basal ganglia indirect pathway neurons are highly dysregulated in Q175 mice through changes in presynaptic activity and/or intrinsic properties 6-12 months before cell loss.

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Radial glial lineage progression and differential intermediate progenitor amplification underlie striatal compartments and circuit organization

10.1101/244327 ◽

2018 ◽

Cited By ~ 2

Author(s):

Sean M. Kelly ◽

Ricardo Raudales ◽

Miao He ◽

Jannifer Lee ◽

Yongsoo Kim ◽

...

Keyword(s):

Basal Ganglia ◽

Late Phase ◽

Projection Neurons ◽

Limited Capacity ◽

Indirect Pathway ◽

Intermediate Progenitors ◽

Lateral Ganglionic Eminence ◽

Glial Progenitors ◽

Radial Glial ◽

Glial Lineage

SUMMARYThe circuitry of the striatum is characterized by two organizational plans: the division into striosome and matrix compartments, thought to mediate evaluation and action, and the direct and indirect pathways, thought to promote or suppress behavior. The developmental origins of and relationships between these organizations are unknown, leaving a conceptual gap in understanding the cortico-basal ganglia system. Through genetic fate mapping, we demonstrate that striosome-matrix compartmentalization arises from a lineage program embedded in lateral ganglionic eminence radial glial progenitors mediating neurogenesis through two distinct types of intermediate progenitors (IPs). The early phase of this program produces striosomal spiny projection neurons (SPNs) through fate-restricted apical IPs (aIPSs) with limited capacity; the late phase produces matrix SPNs through fate-restricted basal IPs (bIPMs) with expanded capacity. Remarkably, direct and indirect pathway SPNs arise within both aIPS and bIPM pools, suggesting that striosome-matrix architecture is the fundamental organizational plan of basal ganglia circuitry organization.

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Corticostriatal Hypermetabolism in Moyamoya Disease-Induced Hemichorea: Two Case Reports and a Literature Review

Frontiers in Neurology ◽

10.3389/fneur.2021.649014 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wen-biao Xian ◽

Xiang-song Zhang ◽

Xin-chong Shi ◽

Gan-hua Luo ◽

Chang Yi ◽

...

Keyword(s):

Basal Ganglia ◽

Functional Connectivity ◽

Literature Review ◽

Moyamoya Disease ◽

Fdg Pet ◽

Emission Computed Tomography ◽

Projection Neurons ◽

Pathophysiological Mechanism ◽

Indirect Pathway ◽

Pubmed Database

Moyamoya disease (MMD) is a rare cause of chorea, and its pathophysiological mechanism remains unclear. We explore the use of cerebral positron emission tomography (PET) to study brain functional connectivity in 2 patients with MMD-induced hemichorea. Abnormal metabolism of brain was analyzed by 18F-fluorodeoxyglucose (18F-FDG) PET images. Dopamine transporters (DAT) PET evaluated the integrity of the cerebral dopamine system. A comprehensive systemic literature search of the PubMed database was also conducted. The 18F-FDG imaging of our patients showed no responsible hypometabolism in affected brain areas, while hypermetabolism in the affected caudate nucleus, putamen and fronto-parietal areas could be seen. DAT PET imaging was normal in patient 1 (a 23-year-old woman), while remarkably reduced DAT binding was seen in the left striatum of patient 2 (a 48-year-old woman). The literature review of 9 publications revealed that 11 patients who underwent single photon emission computed tomography (SPECT) showed cerebral hypoperfusion in the cortex and subcortical area; 18F-FDG PET was performed in 3 cases, which revealed hypermetabolism in the affected striatum in 2 cases. These findings suggest that the striatal and cortical hypermetabolism in the first patient result from underactivity in indirect pathway from basal ganglia-thalamocortical circuits, causing increased activity of excitatory glutamatergic thalamostriatal and thalamocortical projection neurons. The collateral vessels in the basal ganglia might lead to disruption of normal basal ganglia signaling. A dominant left hemisphere with corpus callosal connections to the right basal ganglia resulting into left hemichorea is the most probable explanation for the second patient. We have identified abnormal functional connectivity in basal ganglia-thalamocortical circuits in patients with MMD-induced chorea highlighting the corticostriatal pathway plays an important role in the pathogenesis of MMD-induced chorea.

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18F-fluorodeoxyglucose positron emission tomography and magnetic resonance imaging evaluation of chorea

Neurology International ◽

10.4081/ni.2018.7780 ◽

2018 ◽

Vol 10 (3) ◽

Cited By ~ 1

Author(s):

Nobuyuki Ishii ◽

Hitoshi Mochizuki ◽

Miyuki Miyamoto ◽

Yuka Ebihara ◽

Kazutaka Shiomi ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Positron Emission Tomography ◽

Basal Ganglia ◽

Magnetic Resonance ◽

Emission Tomography ◽

Fluorodeoxyglucose Positron Emission Tomography ◽

Resonance Imaging ◽

Indirect Pathway ◽

Positron Emission ◽

Fluorodeoxyglucose Positron Emission

Chorea is thought to be caused by deactivation of the indirect pathway in the basal ganglia circuit. However, few imaging studies have evaluated the basal ganglia circuit in actual patients with chorea. We investigated the lesions and mechanisms underlying chorea using brain magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). This retrospective case series included three patients with chorea caused by different diseases: hyperglycemic chorea, Huntington’s disease, and subarachnoid hemorrhage. All the patients showed dysfunction in the striatum detected by both MRI and FDG-PET. These neuroimaging findings confirm the theory that chorea is related to an impairment of the indirect pathway of basal ganglia circuit.

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Dynamic Changes in the Cortex-Basal Ganglia Network After Dopamine Depletion in the Rat

Journal of Neurophysiology ◽

10.1152/jn.90466.2008 ◽

2008 ◽

Vol 100 (1) ◽

pp. 385-396 ◽

Cited By ~ 56

Author(s):

Cyril Dejean ◽

Christian E. Gross ◽

Bernard Bioulac ◽

Thomas Boraud

Keyword(s):

Basal Ganglia ◽

Local Field ◽

Signal Transmission ◽

Local Field Potentials ◽

Cellular Level ◽

Cortical Activation ◽

Field Potentials ◽

Dopamine Depletion ◽

Indirect Pathway ◽

Before And After

It is well established that parkinsonian syndrome is associated with alterations in the temporal pattern of neuronal activity and local field potentials in the basal ganglia (BG). An increase in synchronized oscillations has been observed in different BG nuclei in parkinsonian patients and animal models of this disease. However, the mechanisms underlying this phenomenon remain unclear. This study investigates the functional connectivity in the cortex-BG network of a rodent model of Parkinson's disease. Single neurons and local field potentials were simultaneously recorded in the motor cortex, the striatum, and the substantia nigra pars reticulata (SNr) of freely moving rats, and high-voltage spindles (HVSs) were used to compare signal transmission before and after dopaminergic depletion. It is shown that dopaminergic lesion results in a significant enhancement of oscillatory synchronization in the BG: the coherence between pairs of structures increased significantly and the percentage of oscillatory auto- and cross-correlograms. HVS episodes were also more numerous and longer. These changes were associated with a shortening of the latency of SNr response to cortical activation, from 40.5 ± 4.8 to 10.2 ± 1.07 ms. This result suggests that, in normal conditions, SNr neurons are likely to be driven by late inputs from the indirect pathway; however, after the lesion, their shorter latency also indicates an overactivation of the hyperdirect pathway. This study confirms that neuronal signal transmission is altered in the BG after dopamine depletion but also provides qualitative evidence for these changes at the cellular level.

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Bursting in Substantia Nigra Pars Reticulata Neurons In Vitro: Possible Relevance for Parkinson Disease

Journal of Neurophysiology ◽

10.1152/jn.00620.2007 ◽

2007 ◽

Vol 98 (4) ◽

pp. 2311-2323 ◽

Cited By ~ 32

Author(s):

Osvaldo Ibáñez-Sandoval ◽

Luis Carrillo-Reid ◽

Elvira Galarraga ◽

Dagoberto Tapia ◽

Ernesto Mendoza ◽

...

Keyword(s):

Substantia Nigra ◽

Parkinson Disease ◽

Temporal Structure ◽

Projection Neurons ◽

Rate Model ◽

Indirect Pathway ◽

Bath Application ◽

Pattern Generators ◽

Oscillatory Model

Projection neurons of the substantia nigra reticulata (SNr) convey basal ganglia (BG) processing to thalamocortical and brain stem circuits responsible for movement. Two models try to explain pathological BG performance during Parkinson disease (PD): the rate model, which posits an overexcitation of SNr neurons due to hyperactivity in the indirect pathway and hypoactivity of the direct pathway, and the oscillatory model, which explains PD as the product of pathological pattern generators disclosed by dopamine reduction. These models are, apparently, incompatible. We tested the predictions of the rate model by increasing the excitatory drive and reducing the inhibition on SNr neurons in vitro. This was done pharmacologically with bath application of glutamate agonist N-methyl-d-aspartate and GABAA receptor blockers, respectively. Both maneuvers induced bursting behavior in SNr neurons. Therefore synaptic changes forecasted by the rate model induce the electrical behavior predicted by the oscillatory model. In addition, we found evidence that CaV3.2 Ca2+ channels are a critical step in generating the bursting firing pattern in SNr neurons. Other ion channels involved are: hyperpolarization-activated cation channels, high-voltage-activated Ca2+ channels, and Ca2+-activated K+ channels. However, although these channels shape the temporal structure of bursting, only CaV3.2 Ca2+ channels are indispensable for the initiation of the bursting pattern.

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A selective projection from the subthalamic nucleus to parvalbumin-expressing interneurons of the striatum

10.1101/2020.11.26.400242 ◽

2020 ◽

Author(s):

Krishnakanth Kondabolu ◽

Natalie M. Doig ◽

Olaoluwa Ayeko ◽

Bakhtawer Khan ◽

Alexandra Torres ◽

...

Keyword(s):

Basal Ganglia ◽

Subthalamic Nucleus ◽

Ex Vivo ◽

Cell Types ◽

Projection Neurons ◽

Striatal Neurons ◽

Primary Input ◽

Cholinergic Interneurons ◽

Axonal Connections ◽

Excitatory Responses

AbstractThe striatum and subthalamic nucleus (STN) are considered to be the primary input nuclei of the basal ganglia. Projection neurons of both striatum and STN can extensively interact with other basal ganglia nuclei, and there is growing anatomical evidence of direct axonal connections from the STN to striatum. There remains, however, a pressing need to elucidate the organization and impact of these subthalamostriatal projections in the context of the diverse cell types constituting the striatum. To address this, we carried out monosynaptic retrograde tracing from genetically-defined populations of dorsal striatal neurons in adult male and female mice, quantifying the connectivity from STN neurons to spiny projection neurons, GABAergic interneurons, and cholinergic interneurons. In parallel, we used a combination of ex vivo electrophysiology and optogenetics to characterize the responses of a complementary range of dorsal striatal neuron types to activation of STN axons. Our tracing studies showed that the connectivity from STN neurons to striatal parvalbumin-expressing interneurons is significantly higher (~ four-to eight-fold) than that from STN to any of the four other striatal cell types examined. In agreement, our recording experiments showed that parvalbumin-expressing interneurons, but not the other cell types tested, commonly exhibited robust monosynaptic excitatory responses to subthalamostriatal inputs. Taken together, our data collectively demonstrate that the subthalamostriatal projection is highly selective for target cell type. We conclude that glutamatergic STN neurons are positioned to directly and powerfully influence striatal activity dynamics by virtue of their enriched innervation of GABAergic parvalbumin-expressing interneurons.

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#3101 Imbalanced basal ganglia connectivity is associated with motor deficits and apathy in Huntingtons disease: first evidence from human in vivo neuroimaging

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2021-bnpa.15 ◽

2021 ◽

Vol 92 (8) ◽

pp. A6.1-A6

Author(s):

Akshay Nair ◽

Adeel Razi ◽

Sarah Gregory ◽

Robb Rutledge ◽

Geraint Rees ◽

...

Keyword(s):

Basal Ganglia ◽

Bayesian Model ◽

Empirical Bayes ◽

Model Comparison ◽

De Novo ◽

Effective Connectivity ◽

Indirect Pathway ◽

Direct Pathway ◽

Bayesian Model Comparison

BackgroundThe gating of movement in humans is thought to depend on activity within the cortico-striato-thalamic loops. Within these loops, emerging from the cells of the striatum, run two opponent pathways the direct and indirect pathway. Both are complex and polysynaptic but the overall effect of activity within these pathways is to encourage and inhibit movement respectively. In Huntingtons disease (HD), the preferential early loss of striatal neurons forming the indirect pathway is thought to lead to disinhibition that gives rise to the characteristic motor features of the condition. But early HD is also specifically associated with apathy, a failure to engage in goal-directed movement. We hypothesised that in HD, motor signs and apathy may be selectively correlated with indirect and direct pathway dysfunction respectively.MethodsUsing a novel technique for estimating dynamic effective connectivity of the basal ganglia, we tested both of these hypotheses in vivo for the first time in a large cohort of patients with prodromal HD (n = 94). We used spectral dynamic casual modelling of resting state fMRI data to model effective connectivity in a model of these cortico-striatal pathways. We used an advanced approach at the group level by combining Parametric Empirical Bayes and Bayesian Model Reduction procedure to generate large number of competing models and compare them by using Bayesian model comparison.ResultsWith this fully Bayesian approach, associations between clinical measures and connectivity parameters emerge de novo from the data. We found very strong evidence (posterior probability > 0.99) to support both of our hypotheses. Firstly, more severe motor signs in HD were associated with altered connectivity in the indirect pathway and by comparison, loss of goal-direct behaviour or apathy, was associated with changes in the direct pathway component of our model.ConclusionsThe empirical evidence we provide here is the first in vivo demonstration that imbalanced basal ganglia connectivity may play an important role in the pathogenesis of some of commonest and disabling features of HD and may have important implications for therapeutics.

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