Causal role for the subthalamic nucleus in interrupting behavior

Fife, Kathryn H; Gutierrez‐Reed, Navarre; Zell, Vivien; Bailly, Julie; Lewis, Catherine E.; Aron, Adam R.; Hnasko, Thomas S.

doi:10.7554/elife.27689

Cited by 85 publications

(85 citation statements)

References 32 publications

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“…In agreement with the established relationship between STN activity and movement suppression [35, [100][101][102][103], both direct recordings and theoretical models assert that the hypokinetic symptoms of PD are a result of excessive STN activity [6,15,[104][105][106][107][108][109][110][111]. Importantly, lesioning and inactivation studies from animal models of PD further support this idea [112,113] but see [114].…”

Section: Stimulation Of Pv + Neurons Lessens Hypokinetic Symptoms 390supporting

confidence: 60%

“…We previously observed strengthening of the GABAergic 490 GPe input to the STN with chronic 6-OHDA lesion [140]; it is now clear that this input arises from PV + neurons as PV + neurons are the primary source of inhibitory input to the STN [36,41,42]. As the activity of the STN negatively regulates motor output [35, 100,101], a decrease in the ambient glutamate content in the GPe [134], along with a reduction in the STN-PV + input, would disinhibit the STN and suppress motor output in the parkinsonian state, thus explaining the hypokinetic symptoms of PD. On the other hand, a strengthening of the inhibitory PV + input 495 to the STN [141] would promote movement and may act as a compensatory mechanism against the hypokinetic effects of the abnormal glutamatergic signaling in the GPe in PD.…”

Section: Stn-gpe Network Function and Its Dysfunction In The Context mentioning

confidence: 99%

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Parvalbumin⁺and Npas1⁺Pallidal Neurons Have Distinct Circuit Topology and Function

Pamukcu¹,

Cui²,

Xenias³

et al. 2020

Preprint

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The external globus pallidus (GPe) is a critical node within the basal ganglia circuit. Phasic changes in the activity of GPe neurons during movement and their alterations in Parkinson’s disease (PD) argue that the GPe is important in motor control. PV+ neurons and Npas1+ neurons are the two principal neuron classes in the GPe. The distinct electrophysiological properties and axonal projection patterns argue that these two neuron classes serve different roles in regulating motor output. However, the causal relationship between GPe neuron classes and movement remains to be established. Here, by using optogenetic approaches in mice (both males and females), we showed that PV+ neurons and Npas1+ neurons promoted and suppressed locomotion, respectively. Moreover, PV+ neurons and Npas1+ neurons are under different synaptic influences from the subthalamic nucleus (STN). Additionally, we found a selective weakening of STN inputs to PV+ neurons in the chronic 6-hydroxydopamine lesion model of PD. This finding reinforces the idea that the reciprocally connected GPe-STN network plays a key role in disease symptomatology and thus provides the basis for future circuit-based therapies.Significance StatementThe external pallidum is a key, yet an understudied component of the basal ganglia. Neural activity in the pallidum goes awry in neurological diseases, such as Parkinson’s disease. While this strongly argues that the pallidum plays a critical role in motor control, it has been difficult to establish the causal relationship between pallidal activity and motor (dys)function. This was in part due to the cellular complexity of the pallidum. Here, we showed that the two principal neuron types in the pallidum have opposing roles in motor control. In addition, we described the differences in their synaptic influence. Importantly, our research provides new insights into the cellular and circuit mechanisms that explain the hypokinetic features of Parkinson’s disease.

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Section: Stimulation Of Pv + Neurons Lessens Hypokinetic Symptoms 390supporting

confidence: 60%

Section: Stn-gpe Network Function and Its Dysfunction In The Context mentioning

confidence: 99%

Parvalbumin⁺and Npas1⁺Pallidal Neurons Have Distinct Circuit Topology and Function

Pamukcu¹,

Cui²,

Xenias³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…This works also follows from the rich literature on the role of the STN in behavioral inhibition. Normal function of the STN is thought to be important for inhibiting behaviors that are inconsistent with goal‐directed behavior and increasing STN firing rate with optogenetic stimulation can inhibit even goal‐directed behaviors . Furthermore, lesioning the STN impairs stopping behavior in a go‐trial reaction time task and increases spontaneous locomotion .…”

Section: Discussionmentioning

confidence: 99%

“…Normal function of the STN is thought to be important for inhibiting behaviors that are inconsistent with goal-directed behavior 69,70 and increasing STN firing rate with optogenetic stimulation can inhibit even goal-directed behaviors. 71 Furthermore, lesioning the STN impairs stopping behavior in a go-trial reaction time task and increases spontaneous locomotion. 72 Taken together, these findings and the ones reported here suggest an important role for the STN in the mediation of repetitive behavior, which may be a product of a generalized deficit of behavioral inhibition.…”

Section: Discussionmentioning

confidence: 99%

Subthalamic nucleus pathology contributes to repetitive behavior expression and is reversed by environmental enrichment

Lewis

Lindenmaier

Boswell

et al. 2018

Genes Brain and Behavior

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Repetitive motor behaviors are common in neurodevelopmental, psychiatric and neurological disorders. Despite their prevalence in certain clinical populations, our understanding of the neurobiological cause of repetitive behavior is lacking. Likewise, not knowing the pathophysiology has precluded efforts to find effective drug treatments. Our comparisons between mouse strains that differ in their expression of repetitive behavior showed an important role of the subthalamic nucleus (STN). In mice with high rates of repetitive behavior, we found significant differences in dendritic spine density, gene expression and neuronal activation in the STN. Taken together, these data show a hypoglutamatergic state. Furthermore, by using environmental enrichment to reduce repetitive behavior, we found evidence of increased glutamatergic tone in the STN with our measures of spine density and gene expression. These results suggest the STN is a major contributor to repetitive behavior expression and highlight the potential of drugs that increase STN function to reduce repetitive behavior in clinical populations.

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“…A recent study from nonhuman animals provides further causal evidence for this association. Artificially de‐activating STN via optogenetics after an unexpected event reduced the inhibitory motor effects that unexpected events had on ongoing behavior—in this case, interrupting licking bouts (Fife et al, ). Most importantly for the current theory, suppression of CSE has been found after both errors (Amengual et al, ) and unexpected events in general (Wessel & Aron, ).…”

Section: Section Iii: An Adaptive Orienting Theory Of Error Processingmentioning

confidence: 99%

An adaptive orienting theory of error processing

2017

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The ability to detect and correct action errors is paramount to safe and efficient goaldirected behaviors. Existing work on the neural underpinnings of error processing and post-error behavioral adaptations has led to the development of several mechanistic theories of error processing. These theories can be roughly grouped into adaptive and maladaptive theories. While adaptive theories propose that errors trigger a cascade of processes that will result in improved behavior after error commission, maladaptive theories hold that error commission momentarily impairs behavior. Neither group of theories can account for all available data, as different empirical studies find both impaired and improved post-error behavior. This article attempts a synthesis between the predictions made by prominent adaptive and maladaptive theories. Specifically, it is proposed that errors invoke a nonspecific cascade of processing that will rapidly interrupt and inhibit ongoing behavior and cognition, as well as orient attention toward the source of the error. It is proposed that this cascade follows all unexpected action outcomes, not just errors. In the case of errors, this cascade is followed by error-specific, controlled processing, which is specifically aimed at (re) tuning the existing task set. This theory combines existing predictions from maladaptive orienting and bottleneck theories with specific neural mechanisms from the wider field of cognitive control, including from error-specific theories of adaptive post-error processing. The article aims to describe the proposed framework and its implications for post-error slowing and post-error accuracy, propose mechanistic neural circuitry for post-error processing, and derive specific hypotheses for future empirical investigations. K E Y W O R D Sattention, cognitive control, error processing, inhibitory control, orienting, performance monitoring | IN TRO DUCT IO NThe ability to adapt behavior after erroneous actions is one of the key components of human cognitive control. Correcting current and avoiding future errors is paramount to survival. These abilities are the centerpiece of the scientific field of performance monitoring. Research into the neurophysiological and behavioral changes associated with error processing has generated several influential theories over the past few decades, which seek to explain how the human brain reacts to error commission. While many existing theories entail unique mechanisms and propose specific corollaries, one factor by which all theories can be roughly classified is whether they propose that psychological and neural processes triggered by error commission are maladaptive or adaptive. Empirically, this classification can be made based on whether a theory predicts that error commission is ultimately beneficial or detrimental to post-error behavior. Specifically, adaptive theories propose that errors trigger a cascade of neural processes that represents a remedial effort of the cognitive system, which is explicitly targeted at avoiding f...

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Causal role for the subthalamic nucleus in interrupting behavior

Cited by 85 publications

References 32 publications

Parvalbumin⁺and Npas1⁺Pallidal Neurons Have Distinct Circuit Topology and Function

Parvalbumin⁺and Npas1⁺Pallidal Neurons Have Distinct Circuit Topology and Function

Subthalamic nucleus pathology contributes to repetitive behavior expression and is reversed by environmental enrichment

An adaptive orienting theory of error processing

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Causal role for the subthalamic nucleus in interrupting behavior

Cited by 85 publications

References 32 publications

Parvalbumin+and Npas1+Pallidal Neurons Have Distinct Circuit Topology and Function

Parvalbumin+and Npas1+Pallidal Neurons Have Distinct Circuit Topology and Function

Subthalamic nucleus pathology contributes to repetitive behavior expression and is reversed by environmental enrichment

An adaptive orienting theory of error processing

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Product

Resources

About

Parvalbumin⁺and Npas1⁺Pallidal Neurons Have Distinct Circuit Topology and Function

Parvalbumin⁺and Npas1⁺Pallidal Neurons Have Distinct Circuit Topology and Function