scholarly journals Opponent regulation of action performance and timing by striatonigral and striatopallidal pathways

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Konstantin I Bakhurin ◽  
Xiaoran Li ◽  
Alexander D Friedman ◽  
Nicholas A Lusk ◽  
Glenn DR Watson ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Reinforcement Schedule ◽  
Action Selection ◽  
Fixed Time ◽  
Indirect Pathway ◽  
Optogenetic Stimulation ◽  
Direct Pathway ◽  
Stimulation Of

The basal ganglia have been implicated in action selection and timing, but the relative contributions of the striatonigral (direct) and striatopallidal (indirect) pathways to these functions remain unclear. We investigated the effects of optogenetic stimulation of D1+ (direct) and A2A+ (indirect) neurons in the ventrolateral striatum in head-fixed mice on a fixed time reinforcement schedule. Direct pathway stimulation initiates licking, whereas indirect pathway stimulation suppresses licking and results in rebound licking after stimulation. Moreover, direct and indirect pathways also play distinct roles in timing. Direct pathway stimulation produced a resetting of the internal timing process, whereas indirect pathway stimulation transiently paused timing, and proportionally delayed the next bout of licking. Our results provide evidence for the continuous and opposing contributions of the direct and indirect pathways in the production and timing of reward-guided behavior.

scholarly journals Opponent regulation of action performance and timing by striatonigral and striatopallidal pathways

2019 ◽  
Author(s):  
Konstantin I. Bakhurin ◽  
Xiaoran Li ◽  
Alexander D. Friedman ◽  
Nicholas A. Lusk ◽  
Glenn D.R. Watson ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Reinforcement Schedule ◽  
Action Selection ◽  
Fixed Time ◽  
Indirect Pathway ◽  
Optogenetic Stimulation ◽  
Direct Pathway ◽  
Stimulation Of

AbstractThe basal ganglia have been implicated in action selection and timing, but the relative contributions of the striatonigral (direct) and striatopallidal (indirect) pathways to these functions remain unclear. We investigated the effects of optogenetic stimulation of D1+ (direct) and A2A+ (indirect) neurons in the ventrolateral striatum in head-fixed mice on a fixed time reinforcement schedule. Direct pathway stimulation initiates licking, whereas indirect pathway stimulation suppresses licking and results in rebound licking after stimulation. Moreover, direct and indirect pathways also play distinct roles in timing. Direct pathway stimulation produced a resetting of the internal timing process, whereas indirect pathway stimulation transiently paused timing, and proportionally delayed the next bout of licking. Our results provide evidence for the continuous and opposing contributions of the direct and indirect pathways in the production and timing of reward-guided behavior.

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

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.

scholarly journals Key Modulatory Role of Presynaptic Adenosine A2AReceptors in Cortical Neurotransmission to the Striatal Direct Pathway

2009 ◽  
Vol 9 ◽  
pp. 1321-1344 ◽  
Author(s):  
César Quiroz ◽  
Rafael Luján ◽  
Motokazu Uchigashima ◽  
Ana Patrícia Simoes ◽  
Talia N. Lerner ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Neuropsychiatric Disorders ◽  
Receptor Function ◽  
Striatal Neurons ◽  
Indirect Pathway ◽  
Direct Pathway ◽  
Selective Modulation ◽  
Efferent Pathways

Basal ganglia processing results from a balanced activation of direct and indirect striatal efferent pathways, which are controlled by dopamine D1and D2receptors, respectively. Adenosine A2Areceptors are considered novel antiparkinsonian targets, based on their selective postsynaptic localization in the indirect pathway, where they modulate D2receptor function. The present study provides evidence for the existence of an additional, functionally significant, segregation of A2Areceptors at the presynaptic level. Using integrated anatomical, electrophysiological, and biochemical approaches, we demonstrate that presynaptic A2Areceptors are preferentially localized in cortical glutamatergic terminals that contact striatal neurons of the direct pathway, where they exert a selective modulation of corticostriatal neurotransmission. Presynaptic striatal A2Areceptors could provide a new target for the treatment of neuropsychiatric disorders.

scholarly journals The effects of chloride dynamics on substantia nigra pars reticulata responses to pallidal and striatal inputs

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Ryan S Phillips ◽  
Ian Rosner ◽  
Aryn H Gittis ◽  
Jonathan E Rubin
Keyword(s):  
Substantia Nigra ◽  
Low Frequency ◽  
Operating Mode ◽  
Impact Behavior ◽  
Substantia Nigra Pars Reticulata ◽  
Indirect Pathway ◽  
Optogenetic Stimulation ◽  
Low Frequency Oscillations ◽  
Computational Work ◽  
Stimulation Of

As a rodent basal ganglia (BG) output nucleus, the substantia nigra pars reticulata (SNr) is well positioned to impact behavior. SNr neurons receive GABAergic inputs from the striatum (direct pathway) and globus pallidus (GPe, indirect pathway). Dominant theories of action selection rely on these pathways’ inhibitory actions. Yet, experimental results on SNr responses to these inputs are limited and include excitatory effects. Our study combines experimental and computational work to characterize, explain, and make predictions about these pathways. We observe diverse SNr responses to stimulation of SNr-projecting striatal and GPe neurons, including biphasic and excitatory effects, which our modeling shows can be explained by intracellular chloride processing. Our work predicts that ongoing GPe activity could tune the SNr operating mode, including its responses in decision-making scenarios, and GPe output may modulate synchrony and low-frequency oscillations of SNr neurons, which we confirm using optogenetic stimulation of GPe terminals within the SNr.

scholarly journals Parallel Movement-suppressing Striatal Output Pathways

2020 ◽  
Author(s):  
Qiaoling Cui ◽  
Xixun Du ◽  
Isaac Y. M. Chang ◽  
Arin Pamukcu ◽  
Varoth Lilascharoen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Basal Ganglia ◽  
Body Movement ◽  
Disease Model ◽  
Projection Neurons ◽  
Indirect Pathway ◽  
Direct Pathway ◽  
Striatal Projection Neurons ◽  
6 Hydroxydopamine

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.

scholarly journals Multiple neuronal circuits for variable object–action choices based on short- and long-term memories

2019 ◽  
Vol 116 (52) ◽  
pp. 26313-26320 ◽  
Author(s):  
Okihide Hikosaka ◽  
Masaharu Yasuda ◽  
Kae Nakamura ◽  
Masaki Isoda ◽  
Hyoung F. Kim ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Basic Mechanism ◽  
Indirect Pathway ◽  
Value Judgment ◽  
Direct Pathway ◽  
Caudate Head ◽  
Parallel Circuits ◽  
Parallel Circuit ◽  
Short And Long Term

At each time in our life, we choose one or few behaviors, while suppressing many other behaviors. This is the basic mechanism in the basal ganglia, which is done by tonic inhibition and selective disinhibition. Dysfunctions of the basal ganglia then cause 2 types of disorders (difficulty in initiating necessary actions and difficulty in suppressing unnecessary actions) that occur in Parkinson’s disease. The basal ganglia generate such opposite outcomes through parallel circuits: The direct pathway for initiation and indirect pathway for suppression. Importantly, the direct pathway processes good information and the indirect pathway processes bad information, which enables the choice of good behavior and the rejection of bad behavior. This is mainly enabled by dopaminergic inputs to these circuits. However, the value judgment is complex because the world is complex. Sometimes, the value must be based on recent events, thus is based on short-term memories. Or, the value must be based on historical events, thus is based on long-term memories. Such memory-based value judgment is generated by another parallel circuit originating from the caudate head and caudate tail. These circuit-information mechanisms allow other brain areas (e.g., prefrontal cortex) to contribute to decisions by sending information to these basal ganglia circuits. Moreover, the basal ganglia mechanisms (i.e., what to choose) are associated with cerebellum mechanisms (i.e., when to choose). Overall, multiple levels of parallel circuits in and around the basal ganglia are essential for coordinated behaviors. Understanding these circuits is useful for creating clinical treatments of disorders resulting from the failure of these circuits.

scholarly journals A computational model explains and predicts substantia nigra pars reticulata responses to pallidal and striatal inputs

2020 ◽  
Author(s):  
Ryan S. Phillips ◽  
Ian Rosner ◽  
Aryn H. Gittis ◽  
Jonathan E. Rubin
Keyword(s):  
Substantia Nigra ◽  
Low Frequency ◽  
Operating Mode ◽  
Impact Behavior ◽  
Substantia Nigra Pars Reticulata ◽  
Indirect Pathway ◽  
Optogenetic Stimulation ◽  
Low Frequency Oscillations ◽  
Computational Work ◽  
Stimulation Of

AbstractAs a rodent basal ganglia (BG) output nucleus, the substantia nigra pars reticulata (SNr) is well positioned to impact behavior. SNr neurons receive GABAergic inputs from the striatum (direct pathway) and globus pallidus (GPe, indirect pathway). Dominant theories of action selection rely on these pathways’ inhibitory actions. Yet, experimental results on SNr responses to these inputs are limited and include excitatory effects. Our study combines experimental and computational work to characterize, explain, and make predictions about these pathways. We observe diverse SNr responses to stimulation of SNr-projecting striatal and GPe neurons, including biphasic and excitatory effects, which our modeling shows can be explained by intracellular chloride processing. Our work predicts that ongoing GPe activity could tune the SNr operating mode, including its responses in decision-making scenarios, and GPe output may modulate synchrony and low-frequency oscillations of SNr neurons, which we confirm using optogenetic stimulation of GPe terminals within the SNr.

scholarly journals Aversion encoded in the subthalamic nucleus

2020 ◽  
Author(s):  
Gian Pietro Serra ◽  
Adriane Guillaumin ◽  
Jérome Baufreton ◽  
François Georges ◽  
Åsa Wallén-Mackenzie
Keyword(s):  
Basal Ganglia ◽  
Subthalamic Nucleus ◽  
Place Preference ◽  
Ventral Pallidum ◽  
Lateral Habenula ◽  
Place Aversion ◽  
Optogenetic Stimulation ◽  
Ongoing Behavior ◽  
Aversive Behavior ◽  
Stimulation Of

AbstractActivation of the subthalamic nucleus (STN) is associated with the stopping of ongoing behavior via the basal ganglia. However, we recently observed that optogenetic STN excitation induced a strong jumping/escaping behavior. We hypothesized that STN activation is aversive. To test this, place preference was assessed. Optogenetic excitation of the STN caused potent place aversion. Causality between STN activation and aversion has not been demonstrated previously. The lateral habenula (LHb) is a critical hub for aversion. Optogenetic stimulation of the STN indeed caused firing of LHb neurons, but with delay, suggesting the involvement of a polysynaptic circuit. To unravel a putative pathway, the ventral pallidum (VP) was investigated. VP receives projections from the STN and in turn projects to the LHb. Optogenetic excitation of STN-VP terminals caused firing of VP neurons and induced aversive behavior. This study identifies the STN as critical hub for aversion, potentially mediated via an STN-VP-LHb pathway.

scholarly journals Motor thalamus supports striatum-driven reinforcement

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Arnaud L Lalive ◽  
Anthony D Lien ◽  
Thomas K Roseberry ◽  
Christopher H Donahue ◽  
Anatol C Kreitzer
Keyword(s):  
Synaptic Plasticity ◽  
Basal Ganglia ◽  
Substantia Nigra ◽  
Projection Neurons ◽  
Direct Pathway ◽  
Substantia Nigra Reticulata ◽  
Motor Thalamus ◽  
Self Stimulation ◽  
Stimulation Of

Reinforcement has long been thought to require striatal synaptic plasticity. Indeed, direct striatal manipulations such as self-stimulation of direct-pathway projection neurons (dMSNs) are sufficient to induce reinforcement within minutes. However, it’s unclear what role, if any, is played by downstream circuitry. Here, we used dMSN self-stimulation in mice as a model for striatum-driven reinforcement and mapped the underlying circuitry across multiple basal ganglia nuclei and output targets. We found that mimicking the effects of dMSN activation on downstream circuitry, through optogenetic suppression of basal ganglia output nucleus substantia nigra reticulata (SNr) or activation of SNr targets in the brainstem or thalamus, was also sufficient to drive rapid reinforcement. Remarkably, silencing motor thalamus—but not other selected targets of SNr—was the only manipulation that reduced dMSN-driven reinforcement. Together, these results point to an unexpected role for basal ganglia output to motor thalamus in striatum-driven reinforcement.

scholarly journals Physiology of Basal Ganglia Disorders: An Overview

1993 ◽  
Vol 20 (3) ◽  
pp. 177-183 ◽  
Author(s):  
Mark Hallett
Keyword(s):  
Basal Ganglia ◽  
Movement Disorders ◽  
Voluntary Movement ◽  
Good Theory ◽  
Indirect Pathway ◽  
Anatomy And Physiology ◽  
Direct Pathway ◽  
Motor Synergies ◽  
Recent Advances ◽  
Basal Ganglia Disorders

ABSTRACT:The pathophysiology of the movement disorders arising from basal ganglia disorders has been uncertain, in part because of a lack of a good theory of how the basal ganglia contribute to normal voluntary movement. An hypothesis for basal ganglia function is proposed here based on recent advances in anatomy and physiology. Briefly, the model proposes that the purpose of the basal ganglia circuits is to select and inhibit specific motor synergies to carry out a desired action. The direct pathway is to select and the indirect pathway is to inhibit these synergies. The clinical and physiological features of Parkinson's disease, L-DOPA dyskinesias, Huntington's disease, dystonia and tic are reviewed. An explanation of these features is put forward based upon the model.

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