Rapid target-specific remodeling of fast-spiking inhibitory circuits after loss of dopamine

In Parkinson's disease (PD), dopamine depletion alters neuronal activity in the direct and indirect pathways and leads to increased synchrony in the basal ganglia network. However, the origins of these?changes remain elusive. Because GABAergic interneurons regulate activity of projection neurons and?promote neuronal synchrony, we recorded from pairs of striatal fast-spiking (FS) interneurons and direct- or indirect-pathway MSNs after dopamine depletion with 6-OHDA. Synaptic properties of?FS-MSN connections remained similar, yet within 3?days of dopamine depletion, individual FS cells doubled their connectivity to indirect-pathway MSNs, whereas connections to direct-pathway MSNs remained unchanged. A model of the striatal microcircuit revealed that such increases in FS innervation were effective at enhancing synchrony within targeted cell populations. These data suggest that after dopamine depletion, rapid target-specific microcircuit organization in the striatum may lead to increased synchrony of indirect-pathway MSNs that contributes to pathological network oscillations and motor symptoms of PD.     

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.     

Striatal D2 receptors and LTD: yes, but not where you thought they were

D1 and D2 dopamine receptors are expressed in disjoint subsets of striatal projection neurons, the direct and indirect pathways, respectively. This differential distribution of receptors forms the basis for explanations of many aspects of basal ganglia function and dysfunction, but it seems incompatible with some other important properties of striatal neurons. In this issue of Neuron, Wang et al. discover the mechanism of D2 sensitivity of long term depression at synapses on the striatal projection neuron. They show that D2 dependence of LTD does not depend on dopamine receptors of on the projection cell but is mediated by dopamine-induced changes in release of acetylcholine by interneurons that contact projection cells of both types.     

Anatomical funneling, sparse connectivity and redundancy reduction in the neural networks of the basal ganglia

The major anatomical characteristics of the main axis of the basal ganglia are: (1) Numerical reduction in the number of neurons across layers of the feed-forward network, (2) lateral inhibitory connections within the layers, and (3) neuro-modulatory effects of dopamine and acetylcholine, both on the basal ganglia neurons and on the efficacy of information transmission along the basal ganglia axis. We recorded the simultaneous activity of neurons in the output stages of the basal ganglia as well as the activity of dopaminergic and cholinergic neurons during the performance of a probability decision-making task. We found that the functional messages of the cholinergic and dopaminergic neurons differ, and that the cholinergic message is less specific than that of the dopaminergic neurons. The output stage of the basal ganglia showed uncorrelated neuronal activity. We conclude that despite the huge numerical reduction from the cortex to the output nuclei of the basal ganglia, the activity of these nuclei represents an optimally compressed (uncorrelated) version of distinctive features of cortical information.     

Chronic corticotropin-releasing factor type 1 receptor antagonism with antalarmin regulates the dopaminergic system of Fawn-Hooded rats

Corticotropin-releasing factor is a neuropeptide associated with the integration of physiological and behavioural responses to stress and also in the modulation of affective state and drug reward. The selective, centrally acting corticotropin-releasing factor type 1 receptor antagonist, antalarmin, is a potent anxiolytic and reduces volitional ethanol consumption in Fawn-Hooded rats. The efficacy of antalarmin to reduce ethanol consumption increased with time, suggestive of adaptation to reinforcement processes and goal-directed behaviour. The aim of the present study was to examine the effects of chronic antalarmin treatment on reward-related regions of Fawn-Hooded rat brain. Bi-daily antalarmin treatment (20 mg/kg, i.p.) for 10 days increased tyrosine hydroxylase messenger RNA expression throughout the ventral mesencephalon. Following chronic antalarmin the density of dopaminergic terminals within the basal ganglia and amygdaloid complex were reduced, as was dopamine transporter binding within the striatum. Receptor autoradiography indicated an up-regulation of dopamine D2, but no change in D1, binding in striatum, and Golgi-Cox analysis of striatal medium spiny neurones indicated that chronic antalarmin treatment increased spine density. Thus, chronic antalarmin treatment modulates dopaminergic pathways and implies that chronic treatment with drugs of this class may ultimately alter postsynaptic signaling mechanisms within the basal ganglia.     

Nanomolar concentrations of kynurenic acid reduce extracellular dopamine levels in the striatum

Precise regulation of dopaminergic activity is of obvious importance for the physiology and pathology of basal ganglia. We report here that nanomolar concentrations of the astrocyte-derived neuroinhibitory metabolite kynurenic acid (KYNA) potently reduce the extracellular levels of striatal dopamine in unanesthetized rats in vivo. This effect, which is initiated by the KYNA-induced blockade of alpha7 nicotinic acetylcholine receptors, highlights the functional relevance of glia-neuron interactions in the striatum and indicates that even modest increases in the brain levels of endogenous KYNA are capable of interfering with dopaminergic neurotransmission.     

Neural mechanisms of reward-related motor learning

The analysis of the neural mechanisms responsible for reward-related learning has benefited from recent studies of the effects of dopamine on synaptic plasticity. Dopamine-dependent synaptic plasticity may lead to strengthening of selected inputs on the basis of an activity-dependent conjunction of sensory afferent activity, motor output activity, and temporally related firing of dopamine cells. Such plasticity may provide a link between the reward-related firing of dopamine cells and the acquisition of changes in striatal cell activity during learning. This learning mechanism may play a special role in the translation of reward signals into context-dependent response probability or directional bias in movement responses.     

CaMKIIα interacts with M4 muscarinic receptors to control receptor and psychomotor function

Muscarinic acetylcholine receptors (mAChRs) are widely expressed in the mammalian brain and are essential for neuronal functions. These receptors are believed to be actively regulated by intracellular signals, although the underlying mechanisms are largely unknown. In this study, we show that Ca²⁺/calmodulin‐dependent protein kinase II (CaMKII) binds directly and selectively to one of five mAChR subtypes, M4 receptors (M4Rs), at their C‐terminal regions of second intracellular loops. This binding relies on Ca²⁺ activation of the kinase and leads to the phosphorylation of M4Rs at a specific threonine site (Thr145). Complementary in vivo studies in rat striatal neurons enriched with M4Rs confirm that rising Ca²⁺ recruits CaMKIIα to M4Rs to potentiate receptor signalling, which controls behavioural sensitivity to dopamine stimulation in an activity‐dependent manner. Our data identify a new model of protein–protein interactions. In a Ca²⁺‐sensitive manner, CaMKIIα regulates M4R efficacy and controls the acetylcholine–dopamine balance in the basal ganglia and also the dynamics of movement.     

Human immunodeficiency virus-1 Tat protein and methamphetamine interact synergistically to impair striatal dopaminergic function

The human immunodeficiency virus (HIV)-1 transactivating protein Tat may be pathogenically relevant in HIV-1-induced neuronal injury. The abuse of methamphetamine (MA), which is associated with behaviors that may transmit HIV-1, may damage dopaminergic afferents to the striatum. Since Tat and MA share common mechanisms of injury, we examined whether co-exposure to these toxins would lead to enhanced dopaminergic toxicity. Animals were treated with either saline, a threshold dose of MA, a threshold concentration of Tat injected directly into the striatum, or striatal injections of Tat followed by exposure to MA. Threshold was defined as the highest concentration of toxin that would not result in a significant loss of striatal dopamine levels. One week later, MA-treated animals demonstrated a 7% decline in striatal dopamine levels while Tat-treated animals showed an 8% reduction. Exposure to both MA + Tat caused an almost 65% reduction in striatal dopamine. This same treatment caused a 56% reduction in the binding capacity to the dopamine transporter. Using human fetal neurons, enhanced toxicity was also observed when cells were exposed to both Tat and MA. Mitochondrial membrane potential was disrupted and could be prevented by treatment with antioxidants. This study demonstrates that the HIV-1 'virotoxin' Tat enhances MA-induced striatal damage and suggests that HIV-1-infected individuals who abuse MA may be at increased risk of basal ganglia dysfunction.     

Comparison of responses by striatonigral substance P and neurokinin A systems to methamphetamine treatment

Multiple administrations of high doses of methamphetamine (METH) previously have been shown to significantly elevate the concentrations of substance P-like immunoreactivity in CNS regions associated with the basal ganglia. Recently, another tachykinin, neurokinin A (NKA), has been found to be closely associated with substance P (SP). While both neuropeptides exert comparable effects when locally injected, there are significant differences in their potencies apparently based on the relative concentrations of their unique receptors. Due to the controversy which has arisen as to their respective roles within the basal ganglia, we have evaluated and compared the responses of the striatal and nigral SP and NKA systems to METH treatment. We observed that multiple high doses of this stimulant increased the nigral and striatal concentrations of both neuropeptides in an identical fashion. Our observation that METH treatment did not alter the relative concentrations of SP and NKA suggests that responses of both transmitter systems, associated with the basal ganglia, parallel each other and are sensitive to the same regulatory mechanisms.     

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.     

Influence of Age and Strain on Striatal Dopamine Loss in a Genetic Mouse Model of Lesch-Nyhan Disease

Abstract : Lesch-Nyhan disease is a neurogenetic disorder caused by deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Affected individuals exhibit a characteristic pattern of neurological and behavioral features attributable in part to dysfunction of basal ganglia dopamine systems. In the current studies, striatal dopamine loss was investigated in five different HPRT-deficient strains of mice carrying one of two different HPRT gene mutations. Caudoputamen dopamine concentrations were significantly reduced in all five of the strains, with deficits ranging from 50.7 to 61.1%. Mesolimbic dopamine was significantly reduced in only three of the five strains, with a range of 31.6-38.6%. The reduction of caudoputamen dopamine was age dependent, emerging between 4 and 12 weeks of age. Tyrosine hydroxylase and aromatic amino acid decarboxylase, two enzymes responsible for the synthesis of dopamine, were reduced by 22.4-37.3 and 22.2-43.1%, respectively. These results demonstrate that HPRT deficiency is strongly associated with a loss of basal ganglia dopamine. The magnitude of dopamine loss measurable is dependent on the genetic background of the mouse strain used, the basal ganglia sub-region examined, and the age of the animals at assessment.     

A network representation of response probability in the striatum

The striatum of the basal ganglia is considered a key structure in the learning circuitry of the brain. To analyze neural signals that underlie striatal plasticity, we recorded from an identifiable class of striatal interneurons as macaque monkeys underwent training in a range of conditioning and non-associative learning paradigms, and recorded eyeblink electromyographs as the measure of behavioral response. We found that the responses of these striatal interneurons were modifiable under all training conditions and that their population responses were tightly correlated with the probability that a given stimulus would evoke a behavioral response. Such a network signal, proportional to current response probability, could be crucial to the learning and decision functions of the basal ganglia.     

A contribution of synaptic plasticity in the basal ganglia to processing of visual information

The mechanism of involvement of the basal ganglia in processing of visual information on the basis of dopamine-dependent modulation of efficacy of synaptic transmission in interconnected parallel associative and limbic loops (cortex--basal ganglia--thalamus--cortex) is proposed. Each loop consists of one of the visual or prefrontal cortical areas connected with the thalamic nucleus and corresponding loci in different nuclei of the basal ganglia. Circulation of activity in such a loop provides reentrance of information into the thalamus and neocortex. Dopamine releasing in response to a visual stimulus oppositely modulates the efficacy of "strong" and "weak" corticostriatal inputs. Subsequent reorganization of activity in the loop leads to a disinhibition (inhibition) of activity of those cortical neurons that were "strongly" ("weakly)" excited by the visual stimulus simultaneously with activation of dopaminergic cells. A selected neuronal pattern in each cortical area represents a property of the visual stimulus processed by this area. Excitation of dopaminergic cells by the visual stimulus via the superior colliculi requires parallel activation of a disinhibitory input to the superior colliculi via the thalamus and a "direct" pathway through the basal ganglia. The prefrontal cortex excited by the visual stimulus via the mediodorsal thalamic nucleus performs a top-down control over the dopaminergic cell activity, supervising simultaneous dopamine release in different striatal loci and thus promotes the interconnected selection of neuronal representations of individual properties of the visual stimulus and their binding in an integrated image.     

Dichotomous organization of the external globus pallidus

Different striatal projection neurons are the origin of?a?dual organization essential for basal ganglia function. We have defined an analogous division of labor in the external globus pallidus (GPe) of Parkinsonian rats, showing that the distinct temporal activities of two populations of GPe neuron in?vivo are?underpinned by distinct molecular profiles and axonal connectivities. A first population of prototypic GABAergic GPe neurons fire antiphase to subthalamic nucleus (STN) neurons, often express parvalbumin, and target downstream basal ganglia nuclei, including STN. In contrast, a second population (arkypallidal neurons) fire in-phase with STN neurons, express preproenkephalin, and only innervate the striatum. This novel cell type provides the largest extrinsic GABAergic innervation of striatum, targeting both projection neurons and interneurons. We conclude that GPe exhibits several core components of?a dichotomous organization as fundamental as?that in striatum. Thus, two populations of GPe neuron?together orchestrate activities across all basal ganglia nuclei in a cell-type-specific manner.     

Effects of cyclo (Leu-Gly) on neurochemical indices of striatal dopaminergic supersensitivity induced by prolonged haloperidol treatment

The effects of a prolonged treatment with cyclo (Leu-Gly) and/or haloperidol on biochemical parameters indicative of striatal dopamine target cell supersensitivity have been investigated in the rat. When given acutely, cyclo (Leu-Gly) (2 mg/kg sc) did not affect striatal homovanillic acid, dihydroxyphenylacetic acid and acetylcholine levels both under basal conditions or after acute haloperidol (1 mg/kg ip) treatment. When given concomitantly with haloperidol (infused by means of osmotic minipumps at a rate of 2.5 μg/h sc) for 14 days, cyclo (Leu-Gly) (2 mg/kg sc once daily) failed to prevent the fall of striatal dopamine metabolites observed 2 days following withdrawal and the tolerance to the elevation of dopamine metabolites which occurs in response to challenge with the neuroleptic during withdrawal. Prolonged treatment with cyclo (Leu-Gly) also failed to affect the tolerance to the decrease of striatal acetylcholine levels which occurs under chronic haloperidol treatment. These data suggest that the mechanism whereby cyclo (Leu-Gly) inhibits the development of neuroleptic-induced dopaminergic supersensitivity does not involve an action of the peptide on nigro-striatal dopaminergic and striatal cholinergic neurons and is probably exerted distally to both dopaminergic and cholinergic synapses.     

A neural model of basal ganglia-thalamocortical relations in normal and parkinsonian movement

 Anatomical, neurophysiological, and neurochemical evidence supports the notion of parallel basal ganglia–thalamocortical motor systems. We developed a neural network model for the functioning of these systems during normal and parkinsonian movement. Parkinson’s disease (PD), which results predominantly from nigrostriatal pathway damage, is used as a window to examine basal ganglia function. Simulations of dopamine depletion produce motor impairments consistent with motor deficits observed in PD that suggest the basal ganglia play a role in motor initiation and execution, and sequencing of motor programs. Stereotaxic lesions in the model’s globus pallidus and subthalamic nucleus suggest that these lesions, although reducing some PD symptoms, may constrain the repertoire of available movements. It is proposed that paradoxical observations of basal ganglia responses reported in the literature may result from regional functional neuronal specialization, and the non-uniform distributions of neurochemicals in the basal ganglia. It is hypothesized that dopamine depletion produces smaller-than-normal pallidothalamic gating signals that prevent rescalability of these signals to control variable movement speed, and that in PD can produce smaller-than-normal movement amplitudes. Received: 1 September 1994/Accepted in revised form: 16 May 1995     

Motor actions of cannabinoids in the basal ganglia output nuclei.

The levels of CB1 cannabinoid receptors in the basal ganglia are the highest in the brain, comparable to the levels of dopamine receptors, a major transmitter in the basal ganglia. This localization of receptors is consistent with the profound effects on motor function exerted by cannabinoids. The output nuclei of the basal ganglia, the globus pallidus (GP) and substantia nigra reticulata (SNr), apparently lack intrinsic cannabinoid receptors. Rather, the receptors are located on afferent terminals, the striatum being the major source. Cannabinoids blocked the inhibitory action of the striatal input in the SNr. Furthermore, cannabinoids blocked the excitatory effect of stimulation of the subthalamic input to the SNr revealing, along with data from in situ hybridization studies, that this input is another likely source of cannabinoid receptors to the SNr. Similar actions of cannabinoids were observed in the GP. Behavioral studies further revealed that the action of cannabinoids differs depending upon which input to the output nuclei of the basal ganglia is active. The inhibitory striatal input is quiescent and the cannabinoid action is observable only upon stimulation of the striatum, while the noticeable effect of cannabinoids under basal conditions would be on the tonically active subthalamic input. These data suggest that the recently discovered endogenous cannabinergic system exerts a major modulatory action in the basal ganglia by its ability to block both the major excitatory and inhibitory inputs to the SNr and GP.     

Mean-field modeling of the basal ganglia-thalamocortical system. I: Firing rates in healthy and parkinsonian states

Parkinsonism leads to various electrophysiological changes in the basal ganglia-thalamocortical system (BGTCS), often including elevated discharge rates of the subthalamic nucleus (STN) and the output nuclei, and reduced activity of the globus pallidus external (GPe) segment. These rate changes have been explained qualitatively in terms of the direct/indirect pathway model, involving projections of distinct striatal populations to the output nuclei and GPe. Although these populations partly overlap, evidence suggests dopamine depletion differentially affects cortico-striato-pallidal connection strengths to the two pallidal segments. Dopamine loss may also decrease the striatal signal-to-noise ratio, reducing both corticostriatal coupling and striatal firing thresholds. Additionally, nigrostriatal degeneration may cause secondary changes including weakened lateral inhibition in the GPe, and mesocortical dopamine loss may decrease intracortical excitation and especially inhibition. Here a mean-field model of the BGTCS is presented with structure and parameter estimates closely based on physiology and anatomy. Changes in model rates due to the possible effects of dopamine loss listed above are compared with experiment. Our results suggest that a stronger indirect pathway, possibly combined with a weakened direct pathway, is compatible with empirical evidence. However, altered corticostriatal connection strengths are probably not solely responsible for substantially increased STN activity often found. A lower STN firing threshold, weaker intracortical inhibition, and stronger striato-GPe inhibition help explain the relatively large increase in STN rate. Reduced GPe-GPe inhibition and a lower GPe firing threshold can account for the comparatively small decrease in GPe rate frequently observed. Changes in cortex, GPe, and STN help normalize the cortical rate, also in accord with experiments. The model integrates the basal ganglia into a unified framework along with an existing thalamocortical model that already accounts for a wide range of electrophysiological phenomena. A companion paper discusses the dynamics and oscillations of this combined system.