Roles for globus pallidus externa revealed in a computational model of action selection in the basal ganglia

The basal ganglia are considered vital to action selection - a hypothesis supported by several biologically plausible computational models. Of the several subnuclei of the basal ganglia, the globus pallidus externa (GPe) has been thought of largely as a relay nucleus, and its intrinsic connectivity has not been incorporated in significant detail, in any model thus far. Here, we incorporate newly revealed subgroups of neurons within the GPe into an existing computational model of the basal ganglia, and investigate their role in action selection. Three main results ensued. First, using previously used metrics for selection, the new extended connectivity improved the action selection performance of the model. Second, low frequency theta oscillations were observed in the subpopulation of the GPe (the TA or ‘arkypallidal’ neurons) which project exclusively to the striatum. These oscillations were suppressed by increased dopamine activity - revealing a possible link with symptoms of Parkinson’s disease. Third, a new phenomenon was observed in which the usual monotonic relationship between input to the basal ganglia and its output within an action ‘channel’ was, under some circumstances, reversed. Thus, at high levels of input, further increase of this input to the channel could cause an increase of the corresponding output rather than the more usually observed decrease. Moreover, this phenomenon was associated with the prevention of multiple channel selection, thereby assisting in optimal action selection. Examination of the mechanistic origin of our results showed the so-called ‘prototypical’ GPe neurons to be the principal subpopulation influencing action selection. They control the striatum via the arkypallidal neurons and are also able to regulate the output nuclei directly. Taken together, our results highlight the role of the GPe as a major control hub of the basal ganglia, and provide a mechanistic account for its control function

Value encoding in the globus pallidus: fMRI reveals an interaction effect between reward and dopamine drive

The external part of the globus pallidus (GPe) is a core nucleus of the basal ganglia (BG) whose activity is disrupted under conditions of low dopamine release, as in Parkinson's disease. Current models assume decreased dopamine release in the dorsal striatum results in deactivation of dorsal GPe, which in turn affects motor expression via a regulatory effect on other nuclei of the BG. However, recent studies in healthy and pathological animal models have reported neural dynamics that do not match with this view of the GPe as a relay in the BG circuit. Thus, the computational role of the GPe in the BG is still to be determined. We previously proposed a neural model that revisits the functions of the nuclei of the BG, and this model predicts that GPe encodes values which are amplified under a condition of low striatal dopaminergic drive. To test this prediction, we used an fMRI paradigm involving a within-subject placebo-controlled design, using the dopamine antagonist risperidone, wherein healthy volunteers performed a motor selection and maintenance task under low and high reward conditions. ROI-based fMRI analysis revealed an interaction between reward and dopamine drive manipulations, with increased BOLD activity in GPe in a high compared to low reward condition, and under risperidone compared to placebo. These results confirm the core prediction of our computational model, and provide a new perspective on neural dynamics in the BG and their effects on motor selection and cognitive disorders

Cell-type specific plasticity at intrapallidal synapses in a mouse model of Parkinson's Disease

The cell types that comprise neural networks are critical in determining their function. Within the globus pallidus externa (GPe), a nucleus of the basal ganglia implicated in Parkinsonism, several neuronal subpopulations have been described genetically and anatomically, but functional and physiological studies have been limited. This study examines the previously undescribed collateral connections between two key cell types in the GPe, defined by the genetic expression of parvalbumin (PV) or LIM homeobox 6 (Lhx6). Further investigation of this network in a mouse model of Parkinson’s Disease reveals a selective weakening of synaptic input from PV to Lhx6 neurons following dopamine lesions. This study builds on recent literature elucidating the roles of specific GPe cell types to basal ganglia function in health and disease

Neural Substrates of the Drift-Diffusion Model in Brain Disorders

Many studies on the drift-diffusion model (DDM) explain decision-making based on a unified analysis of both accuracy and response times. This review provides an in-depth account of the recent advances in DDM research which ground different DDM parameters on several brain areas, including the cortex and basal ganglia. Furthermore, we discuss the changes in DDM parameters due to structural and functional impairments in several clinical disorders, including Parkinson's disease, Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorders, Obsessive-Compulsive Disorder (OCD), and schizophrenia. This review thus uses DDM to provide a theoretical understanding of different brain disorders

Modeling Basal Ganglia for understanding Parkinsonian Reaching Movements

We present a computational model that highlights the role of basal ganglia (BG) in generating simple reaching movements. The model is cast within the reinforcement learning (RL) framework with the correspondence between RL components and neuroanatomy as follows: dopamine signal of substantia nigra pars compacta as the Temporal Difference error, striatum as the substrate for the Critic, and the motor cortex as the Actor. A key feature of this neurobiological interpretation is our hypothesis that the indirect pathway is the Explorer. Chaotic activity, originating from the indirect pathway part of the model, drives the wandering, exploratory movements of the arm. Thus the direct pathway subserves exploitation while the indirect pathway subserves exploration. The motor cortex becomes more and more independent of the corrective influence of BG, as training progresses. Reaching trajectories show diminishing variability with training. Reaching movements associated with Parkinson's disease (PD) are simulated by (a) reducing dopamine and (b) degrading the complexity of indirect pathway dynamics by switching it from chaotic to periodic behavior. Under the simulated PD conditions, the arm exhibits PD motor symptoms like tremor, bradykinesia and undershoot. The model echoes the notion that PD is a dynamical disease.Comment: Neural Computation, In Pres

Goal-directed and habitual control in the basal ganglia: implications for Parkinson's disease

Progressive loss of the ascending dopaminergic projection in the basal ganglia is a fundamental pathological feature of Parkinson's disease. Studies in animals and humans have identified spatially segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. In patients with Parkinson's disease the loss of dopamine is predominantly in the posterior putamen, a region of the basal ganglia associated with the control of habitual behaviour. These patients may therefore be forced into a progressive reliance on the goal-directed mode of action control that is mediated by comparatively preserved processing in the rostromedial striatum. Thus, many of their behavioural difficulties may reflect a loss of normal automatic control owing to distorting output signals from habitual control circuits, which impede the expression of goal-directed action. © 2010 Macmillan Publishers Limited. All rights reserved

The External Globus Pallidus: Bidirectional Control Over Anxiety-Related Behavior Mediated by CRFR1

Abstract THE EXTERNAL GLOBUS PALLIDUS: BIDIRECTIONAL CONTROL OVER ANXIETY-RELATED BEHAVIOR MEDIATED BY CRFR1 Albert Lee Joseph Hunt, Jr., B.S. Advisory Professor: Shane Cunha, Ph.D. Corticotropin-releasing factor receptor 1 (CRFR1), the principle receptor responsible for the anxiogenic activity of the stress peptide CRF, is abundantly expressed in the external globus pallidus (GPe) raising the question whether activity in the GPe is altered in response to stress. I show that CRFR1 expressing neurons are of the “prototypic” subtype of GPe neurons. I provide evidence of novel circuits from CRF neurons in stress-responsive nuclei, including the paraventricular nucleus of the hypothalamus (PVN) and the central nucleus of the amygdala (CeA), that provide excitatory input to the GPe. Additionally, I show that activation of CRFR1 neurons using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) increases anxiety-related behavior and movement. I show that anxiety-related behavior and movement are decreased in response to activation of Npas1+ neurons, a class of neuron in the GPe that are primarily of the “arkypallidal” subtype. My evidence indicates that CRF neurons may project to the GPe to modulate anxiety-related behavior and movement through differential synaptic input to distinct GPe neuronal subtypes. CRF to GPe circuits provide possible therapeutic avenues to treat anxiety disorders comorbid with basal ganglia neurodegenerative diseases that cause aberrant activity in the GPe such as Parkinson’s disease

Functional implications of dopamine D1 vs. D2 receptors: A ‘prepare and select’ model of the striatal direct vs. indirect pathways

AbstractThe functions of the D1- and D2-dopamine receptors in the basal ganglia have remained somewhat enigmatic, with a number of competing theories relating to the interactions of the ‘direct’ and ‘indirect pathways’. Computational models have been good at simulating properties of the system, but are typically divorced from the underlying neural architecture. In this article we propose a new model which re-addresses response selection at the level of the basal ganglia. At the core of this response selection system the D1 DA receptor-expressing striatal pathways ‘prepare’ the set of possible appropriate responses. The D2DR-expressing striatal pathways then shape and ‘select’ from this initial response set framework.This article is part of a Special Issue entitled: Ventral Tegmentum & Dopamine