Models Of Basal Ganglia Function Research Articles

Striosomes control dopamine via dual pathways paralleling canonical basal ganglia circuits.

Balanced activity of canonical direct D1 and indirect D2 basal ganglia pathways is considered a core requirement for normal movement, and their imbalance is an etiologic factor in movement and neuropsychiatric disorders. We present evidence for a conceptually equivalent pair of direct D1 and indirect D2 pathways that arise from striatal projection neurons (SPNs) of the striosome compartment rather than from SPNs of the matrix, as do the canonical pathways. These striosomal D1 (S-D1) and D2 (S-D2) pathways target substantia nigra dopamine-containing neurons instead of basal ganglia motor output nuclei. They modulate movement with net effects opposite to those exerted by the canonical pathways: S-D1 is net inhibitory and S-D2 is net excitatory. The S-D1 and S-D2 circuits likely influence motivation for learning and action, complementing and reorienting canonical pathway modulation. A major conceptual reformulation of the classic direct-indirect pathway model of basal ganglia function is needed, as well as reconsideration of the effects of D2-targeting therapeutic drugs.

Striosomes Target Nigral Dopamine-Containing Neurons via Direct-D1 and Indirect-D2 Pathways Paralleling Classic Direct-Indirect Basal Ganglia Systems.

Direct S-D1 and Indirect S-D2 striosomal pathways target SNpc dopamine cellsThe S-D2 indirect pathway targets a distinct central external pallidal zone (cGPe)Stimulation of S-D2 increases, of S-D1 decreases, striatal dopamine and movementS-D1 SPNs activity brackets task, inverse to a mid-task peak of dopamine release.

Updating the striatal-pallidal wiring diagram.

The striatal and pallidal complexes are basal ganglia structures that orchestrate learning and execution of flexible behavior. Models of how the basal ganglia subserve these functions have evolved considerably, and the advent of optogenetic and molecular tools has shed light on the heterogeneity of subcircuits within these pathways. However, a synthesis of how molecularly diverse neurons integrate into existing models of basal ganglia function is lacking. Here, we provide an overview of the neurochemical and molecular diversity of striatal and pallidal neurons and synthesize recent circuit connectivity studies in rodents that takes this diversity into account. We also highlight anatomical organizational principles that distinguish the dorsal and ventral basal ganglia pathways in rodents. Future work integrating the molecular and anatomical properties of striatal and pallidal subpopulations may resolve controversies regarding basal ganglia network function.

Abundance Compensates Kinetics: Similar Effect of Dopamine Signals on D1 and D2 Receptor Populations.

The neuromodulator dopamine plays a key role in motivation, reward-related learning, and normal motor function. The different affinity of striatal D1 and D2 dopamine receptor types has been argued to constrain the D1 and D2 signaling pathways to phasic and tonic dopamine signals, respectively. However, this view assumes that dopamine receptor kinetics are instantaneous so that the time courses of changes in dopamine concentration and changes in receptor occupation are basically identical. Here we developed a neurochemical model of dopamine receptor binding taking into account the different kinetics and abundance of D1 and D2 receptors in the striatum. Testing a large range of behaviorally-relevant dopamine signals, we found that the D1 and D2 dopamine receptor populations responded very similarly to tonic and phasic dopamine signals. Furthermore, because of slow unbinding rates, both receptor populations integrated dopamine signals over a timescale of minutes. Our model provides a description of how physiological dopamine signals translate into changes in dopamine receptor occupation in the striatum, and explains why dopamine ramps are an effective signal to occupy dopamine receptors. Overall, our model points to the importance of taking into account receptor kinetics for functional considerations of dopamine signaling.SIGNIFICANCE STATEMENT Current models of basal ganglia function are often based on a distinction of two types of dopamine receptors, D1 and D2, with low and high affinity, respectively. Thereby, phasic dopamine signals are believed to mostly affect striatal neurons with D1 receptors, and tonic dopamine signals are believed to mostly affect striatal neurons with D2 receptors. This view does not take into account the rates for the binding and unbinding of dopamine to D1 and D2 receptors. By incorporating these kinetics into a computational model we show that D1 and D2 receptors both respond to phasic and tonic dopamine signals. This has implications for the processing of reward-related and motivational signals in the basal ganglia.

Understanding Parkinson’s disease and deep brain stimulation: Role of monkey models

Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder affecting over 10 million people worldwide. In the 1930s and 1940s there was little understanding regarding what caused PD or how to treat it. In a desperate attempt to improve patients’ lives different regions of the neuraxis were ablated. Morbidity and mortality were common, but some patients’ motor signs improved with lesions involving the basal ganglia or thalamus. With the discovery of l-dopa the advent of medical therapy began and surgical approaches became less frequent. It soon became apparent, however, that medical therapy was associated with side effects in the form of drug-induced dyskinesia and motor fluctuations and surgical therapies reemerged. Fortunately, during this time studies in monkeys had begun to lay the groundwork to understand the functional organization of the basal ganglia, and with the discovery of the neurotoxin MPTP a monkey model of PD had been developed. Using this model scientists were characterizing the physiological changes that occurred in the basal ganglia in PD and models of basal ganglia function and dysfunction were proposed. This work provided the rationale for the return of pallidotomy, and subsequently deep brain stimulation procedures. In this paper we describe the evolution of these monkey studies, how they provided a greater understanding of the pathophysiology underlying the development of PD and provided the rationale for surgical procedures, the search to understand mechanisms of DBS, and how these studies have been instrumental in understanding PD and advancing the development of surgical therapies for its treatment.

Dynamics of human subthalamic neuron phase-locking to motor and sensory cortical oscillations during movement.

Coupled oscillatory activity recorded between sensorimotor regions of the basal ganglia-thalamocortical loop is thought to reflect information transfer relevant to movement. A neuronal firing-rate model of basal ganglia-thalamocortical circuitry, however, has dominated thinking about basal ganglia function for the past three decades, without knowledge of the relationship between basal ganglia single neuron firing and cortical population activity during movement itself. We recorded activity from 34 subthalamic nucleus (STN) neurons, simultaneously with cortical local field potentials and motor output, in 11 subjects with Parkinson's disease (PD) undergoing awake deep brain stimulator lead placement. STN firing demonstrated phase synchronization to both low- and high-beta-frequency cortical oscillations, and to the amplitude envelope of gamma oscillations, in motor cortex. We found that during movement, the magnitude of this synchronization was dynamically modulated in a phase-frequency-specific manner. Importantly, we found that phase synchronization was not correlated with changes in neuronal firing rate. Furthermore, we found that these relationships were not exclusive to motor cortex, because STN firing also demonstrated phase synchronization to both premotor and sensory cortex. The data indicate that models of basal ganglia function ultimately will need to account for the activity of populations of STN neurons that are bound in distinct functional networks with both motor and sensory cortices and code for movement parameters independent of changes in firing rate.NEW & NOTEWORTHY Current models of basal ganglia-thalamocortical networks do not adequately explain simple motor functions, let alone dysfunction in movement disorders. Our findings provide data that inform models of human basal ganglia function by demonstrating how movement is encoded by networks of subthalamic nucleus (STN) neurons via dynamic phase synchronization with cortex. The data also demonstrate, for the first time in humans, a mechanism through which the premotor and sensory cortices are functionally connected to the STN.

Freezing of Gait in Parkinson's Disease: Its Pathophysiology and Pragmatic Approaches to Management.

Freezing of gait (FOG) in Parkinson's disease (PD) is poorly understood; however, with the established understanding of basal ganglia function, its manifestations should be more easily interpretable. This review examines freezing of gait (FOG) from such a perspective. A search of the MEDLINE and EMBASE databases from the year 2000 onward for review articles, focused on the pathophysiology of FOG, was used to determine current concepts. A previously established model of basal ganglia function was used to determine the concepts' validities. At the core of the model are deficits in motor set maintenance and timing cue production for automatic movement. It includes the shift between attention and automation to the predominant attention control of gait in PD. The difficulties of the found concepts to explain FOG stem from failure to characterize different FOG components, from the assumption that all components share a similar pathophysiology, from a failure to separate basic deficits from compensatory mechanisms, and from the assumption that cognitive deficits are the cause of FOG rather than representing an inadequate compensation to FOG. Pragmatic approaches to management use the attention shift, with the provision of visual information about correct amplitude of step to correct initiation deficits, and motor blocks during gait. It also emphasizes the need to prevent step length reduction on turns, environmental situations, and cognitive overload. The concept of automatic deficits in set maintenance and cue production best describe FOG manifestations in PD and, with the use of attention, the concept also provides pragmatic strategies for management.

The Histamine H3 Receptor Differentially Modulates Mitogen-activated Protein Kinase (MAPK) and Akt Signaling in Striatonigral and Striatopallidal Neurons

The basal ganglia have a central role in motor patterning, habits, motivated behaviors, and cognition as well as in numerous neuropsychiatric disorders. Receptors for histamine, especially the H3 receptor (H3R), are highly expressed in the striatum, the primary input nucleus of the basal ganglia, but their effects on this circuitry have been little explored. H3R interacts with dopamine (DA) receptors ex vivo; the nature and functional importance of these interactions in vivo remain obscure. We found H3R activation with the agonist R-(-)-α-methylhistamine to produce a unique time- and cell type-dependent profile of molecular signaling events in the striatum. H3 agonist treatment did not detectably alter extracellular DA levels or signaling through the cAMP/DARPP-32 signaling pathway in either D1- or D2-expressing striatal medium spiny neurons (MSNs). In D1-MSNs, H3 agonist treatment transiently activated MAPK signaling and phosphorylation of rpS6 and led to phosphorylation of GSK3β-Ser9, a novel effect. Consequences of H3 activation in D2-MSNs were completely different. MAPK signaling was unchanged, and GSK3β-Ser9 phosphorylation was reduced. At the behavioral level, two H3 agonists had no significant effect on locomotion or stereotypy, but they dramatically attenuated the locomotor activation produced by the D1 agonist SKF82958. H3 agonist co-administration blocked the activation of MAPK signaling and the phosphorylation of rpS6 produced by D1 activation in D1-MSNs, paralleling behavioral effects. In contrast, GSK3β-Ser9 phosphorylation was seen only after H3 agonist treatment, with no interactive effects. H3R signaling has been neglected in models of basal ganglia function and has implications for a range of pathophysiologies.

Activation of Direct and Indirect Pathway Medium Spiny Neurons Drives Distinct Brain-wide Responses

A central theory of basal ganglia function is that striatal neurons expressing the D1 and D2 dopamine receptors exert opposing brain-wide influences. However, the causal influence of each population has never been measured at the whole-brain scale. Here, we selectively stimulated D1 or D2 receptor-expressing neurons while visualizing whole-brain activity with fMRI. Excitation of either inhibitory population evoked robust positive BOLD signals within striatum, while downstream regions exhibited significantly different and generally opposing responses consistent with-though not easily predicted from-contemporary models of basal ganglia function. Importantly, positive and negative signals within the striatum, thalamus, GPi, and STN were all associated with increases and decreases in single-unit activity, respectively. These findings provide direct evidence for the opposing influence of D1 and D2 receptor-expressing striatal neurons on brain-wide circuitry and extend the interpretability of fMRI studies by defining cell-type-specific contributions to the BOLD signal.

Eye movements and deep brain stimulation.

Deep brain stimulation (DBS) is an established treatment for several neurological conditions, and is most commonly used to treat Parkinson's disease by implanting electrodes in the basal ganglia. Despite the fact that circuits involved in eye movement control traverse the basal ganglia and are thus likely to be affected by DBS, studies combining DBS with eye movement analysis have been infrequent. This review focuses on recent research studies that examine the relationship between DBS and various types of eye movements and which highlight the potential of this approach. Recent work shows that DBS in the subthalamic nucleus (STN) can improve smooth pursuit in Parkinson's disease. STN DBS has also been shown to modulate visuospatial attention, and has provided experimental evidence backing a Bayesian model of basal ganglia function. DBS in the pallidum can improve antisaccadic performance in Parkinson's disease, suggesting improvement in higher control of oculomotor function, and implying retrograde striatal stimulation as part of the mechanism of action. These studies show that the combination of DBS with eye movement analysis is a powerful research tool. It may be used to study oculomotor physiology, basal ganglia pathophysiology, and the mechanism of action of DBS.

Reassessing models of basal ganglia function and dysfunction.

The basal ganglia are a series of interconnected subcortical nuclei. The function and dysfunction of these nuclei have been studied intensively in motor control, but more recently our knowledge of these functions has broadened to include prominent roles in cognition and affective control. This review summarizes historical models of basal ganglia function, as well as findings supporting or conflicting with these models, while emphasizing recent work in animals and humans directly testing the hypotheses generated by these models.

Working together: basal ganglia pathways in action selection

Jin, Tecuapetla, and Costa combined in vivo electrophysiology with optogenetic-identification to examine firing in multiple basal ganglia nuclei during rapid motor sequences. Their results support a model of basal ganglia function in which co-activation of the direct and indirect pathways facilitate appropriate, while inhibiting competing, motor programs.

Changes in GABA and glutamate concentrations during memory tasks in patients with Parkinson’s disease undergoing DBS surgery

Until now direct neurochemical measurements during memory tasks have not been accomplished in the human basal ganglia. It has been proposed, based on both functional imaging studies and psychometric testing in normal subjects and in patients with Parkinson’s disease (PD), that the basal ganglia is responsible for the performance of feedback-contingent implicit memory tasks. To measure neurotransmitters, we used in vivo microdialysis during deep brain stimulation (DBS) surgery. We show in the right subthalamic nucleus (STN) of patients with PD a task-dependent change in the concentrations of glutamate and GABA during an implicit memory task relative to baseline, while no difference was found between declarative memory tasks. The five patients studied had a significant decrease in the percent concentration of GABA and glutamate during the performance of the weather prediction task (WPT). We hypothesize, based on current models of basal ganglia function, that this decrease in the concentration is consistent with expected dysfunction in basal ganglia networks in patients with PD.

Emergent structured transition from variation to repetition in a biologically-plausible model of learning in basal ganglia

Often, when animals encounter an unexpected sensory event, they transition from executing a variety of movements to repeating the movement(s) that may have caused the event. According to a recent theory of action discovery (Redgrave and Gurney, 2006), repetition allows the animal to represent those movements, and the outcome, as an action for later recruitment. The transition from variation to repetition often follows a non-random, structured, pattern. While the structure of the pattern can be explained by sophisticated cognitive mechanisms, simpler mechanisms based on dopaminergic modulation of basal ganglia (BG) activity are thought to underlie action discovery (Redgrave and Gurney, 2006). In this paper we ask the question: can simple BG-mediated mechanisms account for a structured transition from variation to repetition, or are more sophisticated cognitive mechanisms always necessary? To address this question, we present a computational model of BG-mediated biasing of behavior. In our model, unlike most other models of BG function, the BG biases behavior through modulation of cortical response to excitation; many possible movements are represented by the cortical area; and excitation to the cortical area is topographically-organized. We subject the model to simple reaching tasks, inspired by behavioral studies, in which a location to which to reach must be selected. Locations within a target area elicit a reinforcement signal. A structured transition from variation to repetition emerges from simple BG-mediated biasing of cortical response to excitation. We show how the structured pattern influences behavior in simple and complicated tasks. We also present analyses that describe the structured transition from variation to repetition due to BG-mediated biasing and from biasing that would be expected from a type of cognitive biasing, allowing us to compare behavior resulting from these types of biasing and make connections with future behavioral experiments.

The Organization of Prefrontal-Subthalamic Inputs in Primates Provides an Anatomical Substrate for Both Functional Specificity and Integration: Implications for Basal Ganglia Models and Deep Brain Stimulation

The identification of a hyperdirect cortico-subthalamic nucleus connection highlighted the important role of the subthalamic nucleus (STN) in regulating behavior. However, this pathway was shown primarily from motor areas. Hyperdirect pathways associated with cognitive and motivational cortical regions are particularly relevant given recent data from deep brain stimulation, both for neurologic and psychiatric disorders. Our experiments were designed to demonstrate the existence and organization of prefrontal-STN projections, help delineate the "limbic" STN, and determine whether convergence between cortico-STN fibers from functionally diverse cortical areas exists in the STN. We injected anterograde tracers in the ventromedial prefrontal, orbitofrontal, anterior cingulate, and dorsal prefrontal cortices of Macaca nemestrina and Macaca fascicularis to analyze the organization of terminals and passing fibers in the STN. Results show a topographically organized prefrontal hyperdirect pathway in primates. Limbic areas project to the medial tip of the nucleus, straddling its border and extending into the lateral hypothalamus. Associative areas project to the medial half, motor areas to the lateral half. Limbic projections terminated primarily rostrally and motor projections more caudally. The extension of limbic projections into the lateral hypothalamus, suggests that this region be included in the STN. A high degree of convergence exists between projections from functionally diverse cortical areas, creating potentially important interfaces between terminal fields. Taken together, the results provide an anatomical substrate to extend the role of the hyperdirect pathway in models of basal ganglia function, and new keys for understanding deep brain stimulation effects on cognitive and motivational aspects of behavior.

Striatal Activity during Intentional Switching Depends on Pattern Stability

The theoretical framework of coordination dynamics posits complementary neural mechanisms to maintain complex behavioral patterns under circumstances that may render them unstable and to voluntarily switch between behaviors if changing internal or external conditions so demand. A candidate neural structure known to play a role in both the selection and maintenance of intentional behavior is the basal ganglia. Here, we use functional magnetic resonance imaging to explore the role of basal ganglia in intentional switching between bimanual coordination patterns that are known to differ in their stability as a function of movement rate. Key measures of pattern dynamics and switching were used to map behavior onto the associated neural circuitry to determine the relation between specific behavioral variables and activated brain areas. Results show that putamen activity is highly sensitive to pattern stability: greater activity was observed in bilateral putamen when subjects were required to switch from a more to a less stable pattern than vice versa. Since putamen activity correlated with pattern stability both before and during the switching process, its role may be to select desired actions and inhibit competing ones through parametric modulation of the intrinsic dynamics. Though compatible with recent computational models of basal ganglia function, our results further suggest that pattern stability determines how the basal ganglia efficiently and successfully select among response alternatives.

Update on models of basal ganglia function and dysfunction

Circuit models of basal ganglia function and dysfunction have undergone significant changes over time. The previous view that the basal ganglia are centers in which massive convergence of cortical information occurred has now been replaced by a view in which these structures process information in a highly specific manner, participating in anatomical and functional modules that also involve cortex and thalamus. In addition, much has been learned about the intrinsic connections of the basal ganglia. While the basal ganglia-thalamocortical circuitry was originally seen almost exclusively in its relationship to the control of movement, these structures are now viewed as essential for higher level behavioral control, for instance in the regulation of habit learning or action selection. Probably the greatest benefit of these models has been that they have motivated a wealth of studies of the pathophysiology of movement disorders of basal ganglia origin, such as Parkinson's disease. Such studies, in turn, have helped to reshape the existing circuit models. In this paper we review these fascinating changes of our appreciation of the basal ganglia circuitry, and comment on the current state of our knowledge in this field.

Cortically activated interneurons shape spatial aspects of cortico-accumbens processing.

Basal ganglia circuits are organized as parallel loops that have been proposed to compete in a winner-take-all fashion to determine the appropriate behavioral outcome. However, limited experimental support for strong lateral inhibition mechanisms within striatal regions questions this model. Here, stimulation of the prefrontal cortex (PFC) using naturally occurring bursty patterns inhibited firing in most nucleus accumbens (NA) projection neurons. When an excitatory response was observed for one stimulation site, neighboring PFC sites evoked inhibition in the same neuron. Furthermore, PFC stimulation activated interneurons, and PFC-evoked inhibition was blocked by GABA(A) antagonists in corticoaccumbens slice preparations. Thus bursting PFC activity recruits local inhibition in the NA, shaping responses of projection neurons with a topographical arrangement that allows inhibition among parallel corticoaccumbens channels. The data indicate a high order of information processing within striatal circuits that should be considered in models of basal ganglia function and disease.

Bradykinesia is not a “systematic” feature of adult-onset Huntington's disease; implications for basal ganglia pathophysiology

Our goal was to determine whether bradykinesia is present in choreic adult-onset Huntington's disease (HD) patients, and determine the impact of chorea on their voluntary movements. We recorded whole-body involuntary movements (WBIM) and voluntary motor acts simultaneously, using a magnetic tracker system, in 15 choreic HD patients and 15 healthy age- and gender-matched control subjects. Participants were asked to perform two distinct tasks; a manual-tracking (MT) task yielding a measure of chorea intrusion during accurate movements, and a rapid alternating movement (RAM) task, yielding measures of bradykinesia. Results show that patients with HD presented with deviations from the target that hindered their ability to match the target velocity during the MT task. Furthermore, error in performance was correlated with the amplitude of whole-body chorea ( Rho = 0.67), illustrating the deleterious effect of chorea during accurate movements. However, patients with choreic HD presented with significantly higher RAM range and velocity than matched controls, therefore ruling out the idea that bradykinesia is a systematic feature of HD even when chorea is predominant. The present results imply that patients may have benefited from an intact direct pathway (“select ON” pathway in the focused attention model of basal ganglia function) that allowed them to supersede any dysfunctions associated with the progressive alteration of the “control function“ (striatal–globus pallidus–subthalamic) pathway responsible for generating the chorea. Finally, the present results suggest that patients with adult-onset HD having chorea would greatly benefit from improved treatments aiming at reducing their involuntary movements while maintaining proper motor function.

Effects of Dopaminergic Modulation on the Integrative Properties of the Ventral Striatal Medium Spiny Neuron

Dopaminergic modulation produces a variety of functional changes in the principal cell of the striatum, the medium spiny neuron (MSN). Using a 189-compartment computational model of a ventral striatal MSN, we simulated whole cell D1- and D2-receptor-mediated modulation of both intrinsic (sodium, calcium, and potassium) and synaptic currents (AMPA and NMDA). Dopamine (DA) modulations in the model were based on a review of published experiments in both ventral and dorsal striatum. To objectively assess the net effects of DA modulation, we combined reported individual channel modulations into either D1- or D2-receptor modulation conditions and studied them separately. Contrary to previous suggestions, we found that D1 modulation had no effect on MSN nonlinearity and could not induce bistability. In agreement with previous suggestions, we found that dopaminergic modulation leads to changes in input filtering and neuronal excitability. Importantly, the changes in neuronal excitability agree with the classical model of basal ganglia function. We also found that DA modulation can alter the integration time window of the MSN. Interestingly, the effects of DA modulation of synaptic properties opposed the effects of DA modulation of intrinsic properties, with the synaptic modulations generally dominating the net effect. We interpret this lack of synergy to suggest that the regulation of whole cell integrative properties is not the primary functional purpose of DA. We suggest that D1 modulation might instead primarily regulate calcium influx to dendritic spines through NMDA and L-type calcium channels, by both direct and indirect mechanisms.