Metabotropic glutamate receptors in the basal ganglia motor circuit

In recent years there have been tremendous advances in our understanding of the circuitry of the basal ganglia and our ability to predict the behavioural effects of specific cellular changes in this circuit on voluntary movement. These advances, combined with a new understanding of the rich distribution and diverse physiological roles of metabotropic glutamate receptors in the basal ganglia, indicate that these receptors might have a key role in motor control and raise the exciting possibility that they might provide therapeutic targets for the treatment of Parkinson's disease and related disorders.     

Comprehensive in vivo mapping of the human basal ganglia and thalamic connectome in individuals using 7T MRI

Basal ganglia circuits are affected in neurological disorders such as Parkinson's disease (PD), essential tremor, dystonia and Tourette syndrome. Understanding the structural and functional connectivity of these circuits is critical for elucidating the mechanisms of the movement and neuropsychiatric disorders, and is vital for developing new therapeutic strategies such as deep brain stimulation (DBS). Knowledge about the connectivity of the human basal ganglia and thalamus has rapidly evolved over recent years through non-invasive imaging techniques, but has remained incomplete because of insufficient resolution and sensitivity of these techniques. Here, we present an imaging and computational protocol designed to generate a comprehensive in vivo and subject-specific, three-dimensional model of the structure and connections of the human basal ganglia. High-resolution structural and functional magnetic resonance images were acquired with a 7-Tesla magnet. Capitalizing on the enhanced signal-to-noise ratio (SNR) and enriched contrast obtained at high-field MRI, detailed structural and connectivity representations of the human basal ganglia and thalamus were achieved. This unique combination of multiple imaging modalities enabled the in-vivo visualization of the individual human basal ganglia and thalamic nuclei, the reconstruction of seven white-matter pathways and their connectivity probability that, to date, have only been reported in animal studies, histologically, or group-averaged MRI population studies. Also described are subject-specific parcellations of the basal ganglia and thalamus into sub-territories based on their distinct connectivity patterns. These anatomical connectivity findings are supported by functional connectivity data derived from resting-state functional MRI (R-fMRI). This work demonstrates new capabilities for studying basal ganglia circuitry, and opens new avenues of investigation into the movement and neuropsychiatric disorders, in individual human subjects.     

Role of Cdk5 in neuronal signaling, plasticity, and drug abuse

Functional and structural neuronal plasticity are mediated by a complex network of biochemical signal transduction pathways that control the strength of specific synapses and the formation of new synapses de novo. The neuronal protein kinase Cdk5 has been implicated as being involved in numerous aspects of both functional and structural plasticity through its regulation of signal transduction pathways. In this review the findings of a number of studies are summarized that have advanced our understanding of how Cdk5 may be involved in these processes. We focus on the modulation of protein phosphatase activity in both the hippocampus and basal ganglia, and review findings that indicate Cdk5 is likely to regulate neuronal plasticity in these brain regions. Studies showing involvement of Cdk5 in reward and motor-based plasticity, which are thought to underlie drug abuse, are discussed.     

Complementary 'bottom-up' and 'top-down' approaches to basal ganglia function

Recently, two quite different approaches exemplifying 'bottom-up' and 'top-down' philosophies have shed new light on basal ganglia function. In vitro work using organotypic co-cultures has implicated the subthalamic nucleus (STN) and the external segment of the globus pallidus (GP(e)) as pacemakers for low-frequency bursting that is reminiscent of the activity produced in Parkinsonian tremor. A circuit essential for avian song learning has been identified as part of the basal ganglia with surprisingly well conserved cellular details; investigation of this system may help to address general issues of basal ganglia function.     

Modulation by dopamine of human basal ganglia involvement in feedback control of movement

We learn new motor tasks by trial and error, repeating what works best and avoiding past mistakes. To repeat what works best we must register a satisfactory outcome, and in a study [1] we showed the existence of an evoked activity in the basal ganglia that correlates with accuracy of task performance and is associated with reiteration of successful motor parameters in subsequent movements. Here we report evidence that the signaling of positive trial outcome relies on dopaminergic input to the basal ganglia, by recording from the subthalamic nucleus (STN) in patients with nigrostriatal denervation due to Parkinson's Disease (PD) who have undergone functional neurosurgery. Correlations between subthalamic evoked activities and trial accuracy were weak and behavioral performance remained poor while patients were untreated; however, both improved after the dopamine prodrug levodopa was re-introduced. The results suggest that the midbrain dopaminergic system may be important, not only in signaling explicit positive outcomes or rewards in tasks requiring choices between options [2,3], but also in trial-to-trial learning and in reinforcing the selection of optimal parameters in more automatic motor control.     

Are we ready for a natural history of motor learning?

Here we argue that general principles with regard to the contributions of the cerebellum, basal ganglia, and primary motor cortex to motor learning can begin to be inferred from explicit comparison across model systems and consideration of phylogeny. Both the cerebellum and the basal ganglia have highly conserved circuit architecture in vertebrates. The cerebellum has consistently been shown to be necessary for adaptation of eye and limb movements. The precise contribution of the basal ganglia to motor learning remains unclear but one consistent finding is that they are necessary for early acquisition of novel sequential actions. The primary motor cortex allows independent control of joints and construction of new movement synergies. We suggest that this capacity of the motor cortex implies that it is a necessary locus for motor skill learning, which we argue is the ability to execute selected actions with increasing speed and precision.     

The mouse 5HT5 receptor reveals a remarkable heterogeneity within the 5HT1D receptor family.

Serotonin (5-HT) is a neuromodulator that mediates a wide range of physiological functions by activating multiple receptors. Using a strategy based on amino acid sequence homology between 5-HT receptors that interact with G proteins, we have isolated a cDNA encoding a new serotonin receptor from a mouse brain library. Amino acid sequence comparisons revealed that this receptor was a distant relative of all previously identified 5-HT receptors; we therefore named it 5HT5. When expressed in Cos-7 cells and NIH-3T3 cells, the 5HT5 receptor displayed a high affinity for the serotonergic radioligand [125I]LSD. Surprisingly, its pharmacological profile resembled that of the 5HT1D receptor, which is a 5-HT receptor subtype which has been shown to inhibit adenylate cyclase and which is predominantly expressed in basal ganglia. However, unlike 5HT1D receptors, the 5HT5 receptor did not inhibit adenylate cyclase and its mRNA was not found in basal ganglia. On the contrary, in situ hybridization experiments revealed that the 5HT5 mRNA was expressed predominantly in cerebral cortex, hippocampus, habenula, olfactory bulb and granular layer of the cerebellum. Our results therefore demonstrate that the 5HT1D receptors constitute a heterogeneous family of receptors with distinct intracellular signalling properties and expression patterns.     

A computational model of action selection in the basal ganglia. II. Analysis and simulation of behaviour

 In a companion paper a new functional architecture was proposed for the basal ganglia based on the premise that these brain structures play a central role in behavioural action selection. The current paper quantitatively describes the properties of the model using analysis and simulation. The decomposition of the basal ganglia into selection and control pathways is supported in several ways. First, several elegant features are exposed – capacity scaling, enhanced selectivity and synergistic dopamine modulation – which might be expected to exist in a well designed action selection mechanism. The discovery of these features also lends support to the computational premise of selection that underpins our model. Second, good matches between model globus pallidus external segment output and globus pallidus internal segment and substantia nigra reticulata area output, and neurophysiological data, have been found which are indicative of common architectural features in the model and biological basal ganglia. Third, the behaviour of the model as a signal selection mechanism has parallels with some kinds of action selection observed in animals under various levels of dopaminergic modulation. Received: 16 July 2000 / Accepted in revised form: 30 October 2000     

Striatal information signaling and integration in globus pallidus: timing matters

Advances in research on globus pallidus (GP) suggest that this 'long thought to be' relay in the 'indirect pathway' plays a unique and critical role in basal ganglia function. The traditional idea of parallel processing within the basal ganglia is also challenged by recent findings. It is now clear that axons of GP neurons form large, perisomatic baskets around target neurons in all major basal ganglia nuclei, thereby exerting a profound influence on the output of the entire basal ganglia. GP neurons are autonomously active both in vivo and in vitro. It is believed that temporal information carried along the corticostriatopallidal pathway is critical for proper motor execution. The importance of appropriately controlled discharge of GP neurons is highlighted by psychomotor disorders such as Parkinson's disease, in which alterations in the pattern and synchrony of discharge in GP neurons are thought to contribute to motor symptoms. Several lines of evidence suggest that the aberrant activity of GP neurons following dopamine depletion is caused by alteration in the synaptic input from both striatum and subthalamic nucleus. In normal subjects, the capability of striatal input in translating cortical input into precisely timed responses in GP neurons is mediated by (1) the expression of postsynaptic GABA(A) receptor composed of subunits with fast kinetic properties; (2) an effective GABA reuptake system in terminating the action of synaptically released GABA, and (3) the existence of dendritic HCN channels that actively abbreviate the time course of the inhibitory postsynaptic potentials and reset rhythmic discharge. Despite the rapid pace in uncovering the elements that shape the activity along the striatopallidosubthalamic pathway, the origin of rhythmic, synchronized bursting of GP neurons seen in parkinsonism has not been fully established experimentally. Further elucidation of the factors that control the information transfer in the striatopallidal synapses is thus critical to our understanding of basal ganglia function and establishing treatment for Parkinson's disease and other basal ganglia disorders.     

Complementary ‘bottom-up’ and ‘top-down’ approaches to basal ganglia function

Recently, two quite different approaches exemplifying ‘bottom-up’ and ‘top-down’ philosophies have shed new light on basal ganglia function. In vitro work using organotypic co-cultures has implicated the subthalamic nucleus (STN) and the external segment of the globus pallidus (GP_e) as pacemakers for low-frequency bursting that is reminiscent of the activity produced in Parkinsonian tremor. A circuit essential for avian song learning has been identified as part of the basal ganglia with surprisingly well conserved cellular details; investigation of this system may help to address general issues of basal ganglia function.     

Changes in the content and distribution of sialic acid on the basal surface of isoproterenol-stimulated mouse parotid acinar cells

The presence, distribution and content of sialic acid on the cell surface in collagenase-dispersed acini obtained both from unstimulated as well as from in vivo isoproterenol-stimulated mouse parotid have been studied. To this end, sialic acid residues have been qualitatively and quantitatively analyzed by 1) cytochemical labeling by wheat germ agglutinin (WGA), 2) biochemical procedures and 3) isotopic labeling by [3H]WGA (WGA-N-[acetyl-3H]-acetylated). Electron microscopy revealed striking differences in the binding of ferritin-conjugated WGA at the basal, lateral and apical cell surface. Unstimulated acinar cells showed a heavy patch-distributed binding of ferritin-conjugate on the basal cell surface while it was homogeneous and very scarce on the lateral one and absent on the apical cell surface. During the first few hours after isoproterenol, the WGA binding sites at the basal cell surface became homogeneously distributed. This fact was coincident with a loss of about 60 to 70% both in the content of neuraminidase-releasable sialic acid and in the binding of [3H]WGA to the acinar surface. These findings suggest that the release of sialic acid as free residues, which has been involved in the isoproterenol-triggered cell proliferation-inducing mechanism in the mouse parotid, would occur at the glycocalyx corresponding to the basal plasma membrane of the acinar cells.     

Downstream mechanisms triggered by mitochondrial dysfunction in the basal ganglia: From experimental models to neurodegenerative diseases

Mitochondrial dysfunctions have been implicated in the cellular processes underlying several neurodegenerative disorders affecting the basal ganglia. These include Huntington's chorea and Parkinson's disease, two highly debilitating motor disorders for which recent research has also involved gene mutation linked to mitochondrial deficits. Experimental models of basal ganglia diseases have been developed by using toxins able to disrupt mitochondrial function: these molecules act by selectively inhibiting mitochondrial respiratory complexes, uncoupling cellular respiration. This in turn leads to oxidative stress and energy deficit that trigger critical downstream mechanisms, ultimately resulting in neuronal vulnerability and loss. Here we review the molecular and cellular downstream effects triggered by mitochondrial dysfunction, and the different experimental models that are obtained by the administration of selective mitochondrial toxins or by the expression of mutant genes.     

Input to the lateral habenula from the basal ganglia is excitatory, aversive, and suppressed by serotonin

The lateral habenula (LHb) has recently been identified as a key regulator of the reward system by driving inhibition onto dopaminergic neurons. However, the nature and potential modulation of the major input to the LHb originating from the basal ganglia are poorly understood. Although the output of the basal ganglia is thought to be primarily inhibitory, here we show that transmission from the basal ganglia to the LHb is excitatory, glutamatergic, and suppressed by serotonin. Behaviorally, activation of this pathway is aversive, consistent with its role as an "antireward" signal. Our demonstration of an excitatory projection from the basal ganglia to the LHb explains how LHb-projecting basal ganglia neurons can have similar encoding properties as LHb neurons themselves. Our results also provide a link between antireward excitatory synapses and serotonin,?a neuromodulator implicated in depression.     

3-[18F]Acetylcyclofoxy: a useful probe for the visualization of opiate receptors in living animals

A fluoro-analogue of the potent narcotic antagonist, naltrexone, was synthesized and shown to bind with high affinity to opiate receptors in vitro. 3-[18F]acetylcyclofoxy was prepared via a one-step triflate displacement reaction with the positron emitting 18F ion from tetraethylammonium [18F] fluoride. 3-[18F]acetylcyclofoxy accumulation in opiate receptor rich brain regions of both rat and baboon is shown to be completely displaced by the active enantiomer of naloxone [-)-naloxone) while the identical dose of the pharmacologically inert (+)-naloxone has no detectable effect. Moreover, both rat and baboon brain showed the well documented, typical opiate receptor distribution so that basal ganglia and thalamus are clearly visible in the living baboon brain up to 95 min after intravenous injection of 3-[18F] acetylcyclofoxy. We expect that 3-[18F )acetylcyclofoxy will be a useful probe for visualizing opiate receptors in living humans.     

A dynamical model for the basal ganglia-thalamo-cortical oscillatory activity and its implications in Parkinson’s disease

We propose to investigate brain electrophysiological alterations associated with Parkinson’s disease through a novel adaptive dynamical model of the network of the basal ganglia, the cortex and the thalamus. The model uniquely unifies the influence of dopamine in the regulation of the activity of all basal ganglia nuclei, the self-organised neuronal interdependent activity of basal ganglia-thalamo-cortical circuits and the generation of subcortical background oscillations. Variations in the amount of dopamine produced in the neurons of the substantia nigra pars compacta are key both in the onset of Parkinson’s disease and in the basal ganglia action selection. We model these dopamine-induced relationships, and Parkinsonian states are interpreted as spontaneous emergent behaviours associated with different rhythms of oscillatory activity patterns of the basal ganglia-thalamo-cortical network. These results are significant because: (1) the neural populations are built upon single-neuron models that have been robustly designed to have eletrophysiologically-realistic responses, and (2) our model distinctively links changes in the oscillatory activity in subcortical structures, dopamine levels in the basal ganglia and pathological synchronisation neuronal patterns compatible with Parkinsonian states, this still remains an open problem and is crucial to better understand the progression of the disease.Electronic supplementary materialThe online version of this article (10.1007/s11571-020-09653-y) contains supplementary material, which is available to authorized users.     

Evidences for shared features in the organization of the basal ganglia in tetrapods: studies in amphibians.

In a series of recent studies, the organization of the basal ganglia of amphibians, more in particular their connectivity and chemoarchitecture, has been thoroughly analyzed. The pattern of organization found for the amphibian basal ganglia includes dorsal and ventral striatopallidal systems, reciprocal connections between the striatopallidal complex and structures derived from the diencephalic and mesencephalic parts of the basal plate (striatonigral and nigrostriatal projections), and descending pathways from the striatopallidal system to the midbrain tectum and the reticular formation of the brain stem. A comparative analysis of the organization of the basal ganglia in tetrapods strongly supports the notion that a primitive pattern was most likely present in ancestral tetrapods, and that many features can still be recognized in extant amphibians and amniotes.     

Restructuring of basal ganglia circuitry and associated behaviors triggered by low striatal D2 receptor expression: implications for substance use disorders

Dopamine D2 receptors (D2Rs) consistently emerge as a critical substrate for the etiology of some major psychiatric disorders. Indeed, a central theory of substance use disorders (SUDs) postulates that a reduction in D2R levels in the striatum is a determining factor that confers vulnerability to abuse substances. A large number of clinical and preclinical studies strongly support this link between SUDs and D2Rs; however, identifying the mechanism by which low D2Rs facilitate SUDs has been hindered by the complexity of circuit connectivity, the heterogeneity of D2R expression and the multifaceted constellation of phenotypes observed in SUD patient. Animal models are well‐suited for understanding the mechanisms because they allow access to the circuitry and the genetic tools that enable a dissection of the D2R heterogeneity. This review discusses recent findings on the functional role of D2Rs and highlights the distinctive contributions of D2Rs expressed on specific neuronal subpopulations to the behavioral responses to stimulant drugs. A circuit‐wide restructuring of local and long‐range inhibitory connectivity within the basal ganglia is observed in response to manipulation of striatal D2R levels and is accompanied by multiple alterations in dopamine‐dependent behaviors. Collectively, these new findings provide compelling evidence for a critical role of striatal D2Rs in shaping basal ganglia connectivity; even among neurons that do not express D2Rs. These findings from animal models have deep clinical implications for SUD patients with low levels D2R availability where a similar restructuring of basal ganglia circuitry is expected to take place.     

Genetic mechanisms specifying cortical connectivity: let's make some projections together

Great neuroanatomists of the twentieth century recognized that the cerebral cortex of mammals is the single most complex structure of the central nervous system both in terms of neuronal diversity and connectivity. Understanding the cellular and molecular mechanisms specifying the afferent and efferent connectivity in the neocortex may seem like a daunting task. However, recent technical advances have greatly improved our ability to (1) profile gene expression of neuronal populations isolated based on their connectional properties, (2) manipulate gene expression in specific neuronal populations, and (3) visualize their axonal projections in vivo. These new tools are revolutionizing our ability to identify the molecular mechanisms patterning afferent and efferent cortical projections.     

Localization and physiological roles of metabotropic glutamate receptors in the direct and indirect pathways of the basal ganglia

Summary.  Our current understanding of the circuitry of the basal ganglia, and the pathophysiology of Parkinson's disease has led to major breakthroughs in the treatment of this debilitating movement disorder. Unfortunately, there are significant problems with the currently available pharmacological therapies that focus on dopamine replacement or dopaminergic agonists. Because of this, much effort has been focused on developing novel targets for the treatment of Parkinson's disease. The metabotropic glutamate receptors are a family of G-protein coupled receptors activated by glutamate. These receptors are differentially distributed throughout the basal ganglia in a manner suggesting that they may provide novel targets for the treatment of movement disorders. In this review we summarize anatomical and physiological data from our work and the work of other laboratories describing the distribution and physiological roles of metabotropic glutamate receptors in the basal ganglia with emphasis on possible therapeutic targets. Received July 2, 2001 Accepted August, 6, 2001 Published online June 26, 2002     

Complementary roles of basal ganglia and cerebellum in learning and motor control

The classical notion that the basal ganglia and the cerebellum are dedicated to motor control has been challenged by the accumulation of evidence revealing their involvement in non-motor, cognitive functions. From a computational viewpoint, it has been suggested that the cerebellum, the basal ganglia, and the cerebral cortex are specialized for different types of learning: namely, supervised learning, reinforcement learning and unsupervised learning, respectively. This idea of learning-oriented specialization is helpful in understanding the complementary roles of the basal ganglia and the cerebellum in motor control and cognitive functions.