Basal Ganglia Pathways Research Articles

Reduction of repetitive behavior by co-administration of adenosine receptor agonists in C58 mice

Repetitive behaviors are diagnostic for autism spectrum disorder (ASD) and commonly observed in other neurodevelopmental disorders. Currently, there are no effective pharmacological treatments for repetitive behavior in these clinical conditions. This is due to the lack of information about the specific neural circuitry that mediates the development and expression of repetitive behavior. Our previous work in mouse models has linked repetitive behavior to decreased activation of the subthalamic nucleus, a brain region in the indirect and hyperdirect pathways in the basal ganglia circuitry. The present experiments were designed to further test our hypothesis that pharmacological activation of the indirect pathway would reduce repetitive behavior. We used a combination of adenosine A1 and A2A receptor agonists that have been shown to alter the firing frequency of dorsal striatal neurons within the indirect pathway of the basal ganglia. This drug combination markedly and selectively reduced repetitive behavior in both male and female C58 mice over a six-hour period, an effect that required both A1 and A2A agonists as neither alone reduced repetitive behavior. The adenosine A1 and A2A receptor agonist combination also significantly increased the number of Fos transcripts and Fos positive cells in dorsal striatum. Fos induction was found in both direct and indirect pathway neurons suggesting that the drug combination restored the balance of activation across these complementary basal ganglia pathways. The adenosine A1 and A2A receptor agonist combination also maintained its effectiveness in reducing repetitive behavior over a 7-day period. These findings point to novel potential therapeutic targets for development of drug therapies for repetitive behavior in clinical disorders.

Strategies of selective changing: Preparatory neural processes seem to be responsible for differences in complex inhibition.

Selective inhibition describes the stopping of an action while other actions are further executed. It can be differentiated between two strategies to stop selectively: the fast but global stop all, then discriminate strategy and the slower but more selective first discriminate, then stop strategy. It is assumed that the first discriminate, then stop strategy is especially used when information regarding which action might have to be stopped is already available beforehand. Moreover, it is supposed that both strategies differ in matters of basal ganglia pathways used for their execution. Aim of the present study was to investigate the use of the two strategies in situations requiring selective changing of an action. Eighteen healthy male participants performed a selective stop-change task with informative and uninformative cues during fMRI. Behavioral results show that informative cues led to a benefit in both inhibition times and selectivity. FMRI data revealed that the same cortico-subcortical pathway was used with informative and uninformative cues. Behavioral and neuronal results indicate that participants used the first discriminate, then stop strategy for selective inhibition irrespective of the amount of previously available information. Moreover, the neural activity data indicate that the benefit in the informed condition was produced by an efficient preparation for the concrete change process. Possible factors that might affect which strategy is used for selective stopping are the level of previously available information (foreknowledge) and the experimental set-up, as e.g. task complexity.

Targeting Dopamine D2, Adenosine A2A, and Glutamate mGlu5 Receptors to Reduce Repetitive Behaviors in Deer Mice.

Repetitive behaviors are seemingly purposeless patterns of behavior that vary little in form and are characteristic of many neurodevelopmental, psychiatric, and neurologic disorders. Our work has identified an association between hypofunctioning of the indirect basal ganglia pathway and the expression of repetitive behavior in the deer mouse model. In this study, we targeted indirect pathway cells of the striatum with single drugs and drug combinations that bind to dopamine D2, adenosine A2A, and glutamate mGlu5 receptors. These receptors function both individually and as receptor heteromers. We found that only the triple drug cocktail (L-741,626+CGS21680+CDPPB) that was designed to increase striatal indirect basal ganglia pathway cell function reduced repetitive behavior in adult male deer mice. No single drug or double drug combinations were effective at selectively reducing repetitive behavior. We found this triple drug cocktail reduced repetitive behavior in both short-acting and long-acting formulations and was effective throughout 7 days of daily administration. Conversely, another triple drug cocktail (quinpirole+SCH58261+MTEP) that was designed to further reduce striatal indirect basal ganglia pathway cell function caused a significant increase in repetitive behavior. Significant and behaviorally selective effects on repetitive behavior were only achieved with the triple drug cocktails that included doses of L-741,626 and quinpirole that have off-target effects (e.g., dopamine D3 receptors). These data further a role for decreased indirect basal ganglia pathway activation in repetitive behavior and suggest that targeting these receptors and/or heteromeric complexes on the indirect pathway neurons of the striatum may offer pharmacotherapeutic benefit for individuals with repetitive behavior disorders.

The effect of dopamine on response inhibition in Parkinson's disease relates to age-dependent patterns of nigrostriatal degeneration

IntroductionMotor but also non-motor effects are modulated by dopamine (DA) in Parkinson's disease (PD). Impaired inhibition has been related to dopamine overdosing of the associative striatum. We compared effects of dopaminergic medication on inhibitory control in patients with young (age at onset <50 years, YOPD) and late onset PD (LOPD) and related them to nigrostriatal degeneration. Methods27 patients (10 YOPD, 17 LOPD) underwent a Go/NoGo paradigm comprising a global and specific NoGo condition ON and OFF DA. The ratio of dopamine transporter availability (DAT) in the associative relative to the sensorimotor striatum according to [123I]FP-CIT SPECT was compared between YOPD and LOPD (n = 8/12). Neuro-computational modeling was used to identify pathway activation during Go/NoGo performance. ResultsPatients made more errors ON compared to OFF in the global NoGo. This DA effect on global NoGo errors correlated with disease duration (r = 0.489, p = 0.010). YOPD made more errors in the specific NoGo ON-OFF compared to LOPD (p = 0.015). YOPD showed higher associative-to-sensorimotor DAT ratios compared to LOPD (p < 0.001). Neuro-computational modeling revealed DA overdosing of the associative striatum in YOPD resulting in excess activation of the direct basal ganglia pathway triggering incorrect responses. ConclusionsDepending on the age of symptom onset, DA differentially modulated inhibition in PD with detrimental effects on specific NoGo performance in YOPD but increased performance in LOPD. YOPD showed relatively less degeneration in the associative striatum suggesting DA overdosing that is supported by our neuro-computational model. Reduced inhibition in the global NoGo condition suggests different pathway activation.

A Dual Role Hypothesis of the Cortico-Basal-Ganglia Pathways: Opponency and Temporal Difference Through Dopamine and Adenosine.

The hypothesis that the basal-ganglia direct and indirect pathways represent goodness (or benefit) and badness (or cost) of options, respectively, explains a wide range of phenomena. However, this hypothesis, named the Opponent Actor Learning (OpAL), still has limitations. Structurally, the OpAL model does not incorporate differentiation of the two types of cortical inputs to the basal-ganglia pathways received from intratelencephalic (IT) and pyramidal-tract (PT) neurons. Functionally, the OpAL model does not describe the temporal-difference (TD)-type reward-prediction-error (RPE), nor explains how RPE is calculated in the circuitry connecting to the DA neurons. In fact, there is a different hypothesis on the basal-ganglia pathways and DA, named the Cortico-Striatal-Temporal-Difference (CS-TD) model. The CS-TD model differentiates the IT and PT inputs, describes the TD-type RPE, and explains how TD-RPE is calculated. However, a critical difficulty in this model lies in its assumption that DA induces the same direction of plasticity in both direct and indirect pathways, which apparently contradicts the experimentally observed opposite effects of DA on these pathways. Here, we propose a new hypothesis that integrates the OpAL and CS-TD models. Specifically, we propose that the IT-basal-ganglia pathways represent goodness/badness of current options while the PT-indirect pathway represents the overall value of the previously chosen option, and both of these have influence on the DA neurons, through the basal-ganglia output, so that a variant of TD-RPE is calculated. A key assumption is that opposite directions of plasticity are induced upon phasic activation of DA neurons in the IT-indirect pathway and PT-indirect pathway because of different profiles of IT and PT inputs. Specifically, at PT→indirect-pathway-medium-spiny-neuron (iMSN) synapses, sustained glutamatergic inputs generate rich adenosine, which allosterically prevents DA-D2 receptor signaling and instead favors adenosine-A2A receptor signaling. Then, phasic DA-induced phasic adenosine, which reflects TD-RPE, causes long-term synaptic potentiation. In contrast, at IT→iMSN synapses where adenosine is scarce, phasic DA causes long-term synaptic depression via D2 receptor signaling. This new Opponency and Temporal-Difference (OTD) model provides unique predictions, part of which is potentially in line with recently reported activity patterns of neurons in the globus pallidus externus on the indirect pathway.

The Effect of Rhythmic Auditory Cueing on Functional Gait Performance in Parkinson's Disease Patients

Purpose: Parkinson’s disease is a progressive neurological movement disorder. Gait and its related dysfunctions cause a lot of disability to the patient. The common objective for all therapeutic intervention aims to preserve a patient’s independence and quality of life. There are established benefits of exercises to maintain functional independence including gait, prevent falls and decrease disease progression. External cueing such as rhythmic auditory cueing is a strategy that can be used in adjunct with traditional gait training intervention to facilitate movement, gait initiation and continuation. The external auditory cue training rerouted the movement through a non-automatic pathway, removing it from automatic basal ganglia pathway. There has been some evidence which suggests the positive effect of application of rhythmic auditory cueing on gait and balance performance of Parkinson’s patient, but it still remains ambiguous, hence, this study is planned to gather more evidence, on the effect of external auditory cues on gait performance in Parkinson’s disease patients. Aim: To study the effects of rhythmic auditory cueing on functional gait performance in individuals diagnosed with Parkinson’s disease. Objectives: To assess and compare the effect of conventional rehabilitation exercises combined with rhythmic auditory cueing and conventional rehabilitation exercises on functional gait performance using freezing of gait questionnaire(FOGQ), modified gait efficacy scale(MGES) and figure of eight walk test(FO8WT) in Parkinson’s disease patients. METHOD- Prospective randomized controlled trial. Results: The study results show that there is a significant improvement in functional gait performance in Parkinson’s disease patients after auditory cueing reflected by the significant p values of respective tests. Conclusion: The above study concludes that application of rhythmic auditory cueing has beneficial effects on the functional gait performance primarily on freezing of gait, MGES and the time component of FO8WT in Parkinson’s disease patients.

Predominant Striatal Input to the Lateral Habenula in Macaques Comes from Striosomes

Striosomes, neurochemically specialized modules in the striatum, are thought to be nodes in circuits extending, via basal ganglia pathways, from mood-related neocortical regions to dopamine-containing neurons of the substantia nigra. Yet striosomes have remained beyond the reach of electrophysiological methods to identify them, especially in non-human primates. Such work is needed for translational as well as for basic science. Here we introduce a method to identify striosomes on-line in awake, behaving macaques. We combined electrical microstimulation of the striatum with simultaneous electrophysiological recording in the lateral habenula (LHb) followed by immunohistochemistry. We demonstrate that striosomes provide the predominant striatal input to the macaque pallido-habenular circuit, which is known to function in relation to reinforcement signaling. Further, our experiments suggest that striosomes from different striatal regions may convergently influence the lateral habenula. This work now opens the way to defining the functions of striosomes in behaving primates in relation to mood, motivation, and action.

Oxytocin differentially modulates specific dorsal and ventral striatal functional connections with frontal and cerebellar regions

Interactions between oxytocin and the basal ganglia are central in current overarching conceptualizations of its broad modulatory effects on behavior. Whereas evidence from animal models emphasizes the critical role of the ventral striatum in the behavioral effects of oxytocin, region-specific contributions of the basal ganglia have not been systematically explored in humans. The present study combined the randomized placebo-controlled administration of oxytocin versus placebo in healthy men (n = 144) with fMRI-based resting-state functional connectivity to determine the modulatory role of oxytocin on the major basal ganglia pathways. Oxytocin specifically increased connectivity between ventral striatal and pallidal nodes with upstream frontal regions, whereas it decreased the strengths of downstream pathways between the dorsal striatum and posterior cerebellum. These pathways have previously been implicated in salience, reward and behavioral flexibility, thus shaping goal-directed behavior. Given the importance of aberrant striatal intrinsic organization in autism, addiction and schizophrenia the present findings may suggest new mechanistic perspectives for the therapeutic potential of oxytocin in these disorders.

Antagonism of the D2 dopamine receptor enhances tremor but reduces voluntary muscle activation in humans

Neural circuits that comprise the indirect pathway in the basal ganglia have been implicated in tremor genesis, and possibly play a role in the voluntary activation of muscles. However, an absence of in vivo human studies that target striatal D2 dopamine receptors of the indirect pathway have prevented causal links being made between the D2 receptor and motor control. Healthy individuals ingested 3 mg of the competitive D2 antagonist haloperidol in a double-blinded, placebo-controlled, two-way, cross-over study. Two experiments were performed to examine involuntary and voluntary movement. The first experiment (n = 10) assessed time- and frequency-domain measures of force tremor during isometric elbow flexions, and the second experiment (n = 8) examined voluntary activation of the elbow flexors during unfatigued and fatigued maximum contractions. Blockade of the D2 receptor had no effect on tremor frequency, but increased the amplitude of force variability and 8–12 Hz power during moderate intensity isometric elbow flexions. These findings provide direct evidence that D2 receptors relate to physiological tremor generation during muscle contractions, whereby the gain of tremor is increased after D2 antagonism. The ability to voluntarily activate the elbow flexors was compromised under both non-fatigued and fatigued conditions. Consequently, the duration that maximum contractions could be sustained was reduced with D2 antagonism. These results provide further support that the D2 receptor has a critical role in skeletal muscle activation, where central fatigue is exacerbated by enhancing activity of the indirect basal ganglia pathway during maximum muscle contractions.

Functional segregation of basal ganglia pathways in Parkinson's disease.

Dopamine exerts modulatory signals on cortex-basal ganglia circuits to enable flexible motor control. Parkinson's disease is characterized by a loss of dopaminergic innervation in the basal ganglia leading to complex motor and non-motor symptoms. Clinical symptom alleviation through dopaminergic medication and deep brain stimulation in the subthalamic nucleus likely depends on a complex interplay between converging basal ganglia pathways. As a unique translational research platform, deep brain stimulation allows instantaneous investigation of functional effects of subthalamic neuromodulation in human patients with Parkinson's disease. The present study aims at disentangling the role of the inhibitory basal ganglia pathways in cognitive and kinematic aspects of automatic and controlled movements in healthy and parkinsonian states by combining behavioural experiments, clinical observations, whole-brain deep brain stimulation fibre connectivity mapping and computational modelling. Twenty patients with Parkinson's disease undergoing subthalamic deep brain stimulation and 20 age-matched healthy controls participated in a visuomotor tracking task requiring normal (automatic) and inverted (controlled) reach movements. Parkinsonian patients on and off deep brain stimulation presented complex patterns of reaction time and kinematic changes, when compared to healthy controls. Stimulation of cortico-subthalamic fibres was correlated with reduced reaction time adaptation to task demand, but not kinematic aspects of motor control or alleviation of Parkinson's disease motor signs. By using clinically, behaviourally and fibre tracking informed computational models, our study reveals that loss of cognitive adaptation can be attributed to modulation of the hyperdirect pathway, while kinematic depends on suppression of indirect pathway activity. Our findings suggest that hyperdirect and indirect pathways, converging in the subthalamic nucleus, are differentially involved in cognitive aspects of cautious motor preparation and kinematic gain control during motor performance. Subthalamic deep brain stimulation modulates but does not restore these functions. Intelligent stimulation algorithms could re-enable flexible motor control in Parkinson's disease when adapted to instantaneous environmental demand. Our results may inspire new innovative pathway-specific approaches to reduce side effects and increase therapeutic efficacy of neuromodulation in patients with Parkinson's disease.

Optogenetic Editing Reveals the Hierarchical Organization of Learned Action Sequences

The organization of action into sequences underlies complex behaviors that are essential for organismal survival and reproduction. Despite extensive studies of innate sequences in relation to central pattern generators, how learned action sequences are controlled and whether they are organized as a chain or a hierarchy remain largely unknown. By training mice to perform heterogeneous action sequences, we demonstrate that striatal direct and indirect pathways preferentially encode different behavioral levels of sequence structure. State-dependent closed-loop optogenetic stimulation of the striatal direct pathway can selectively insert a single action element into the sequence without disrupting the overall sequence length. Optogenetic manipulation of the striatal indirect pathway completely removes the ongoing subsequence while leaving the following subsequence to be executed with the appropriate timing and length. These results suggest that learned action sequences are not organized in a serial but rather a hierarchical structure that is distinctly controlled by basal ganglia pathways.

Chronic alcohol exposure disrupts top-down control over basal ganglia action selection to produce habits

Addiction involves a predominance of habitual control mediated through action selection processes in dorsal striatum. Research has largely focused on neural mechanisms mediating a proposed progression from ventral to dorsal lateral striatal control in addiction. However, over reliance on habit striatal processes may also arise from reduced cortical input to striatum, thereby disrupting executive control over action selection. Here, we identify novel mechanisms through which chronic intermittent ethanol exposure and withdrawal (CIE) disrupts top-down control over goal-directed action selection processes to produce habits. We find CIE results in decreased excitability of orbital frontal cortex (OFC) excitatory circuits supporting goal-directed control, and, strikingly, selectively reduces OFC output to the direct output pathway in dorsal medial striatum. Increasing the activity of OFC circuits restores goal-directed control in CIE-exposed mice. Our findings show habitual control in alcohol dependence can arise through disrupted communication between top-down, goal-directed processes onto basal ganglia pathways controlling action selection.

Beta-band oscillations in the supplementary motor cortex are modulated by levodopa and associated with functional activity in the basal ganglia.

We investigated the effect of acute levodopa administration on movement-related cortical oscillations and movement velocity in Parkinson's disease (PD). Patients with PD on and off medication and age- and sex-matched healthy controls performed a ballistic upper limb flexion movement as fast and accurately as possible while cortical oscillations were recorded with high-density electroencephalography. Patients off medication were also studied using task-based functional magnetic resonance imaging (fMRI) using a force control paradigm. Percent signal change of functional activity during the force control task was calculated for the putamen and subthalamic nucleus (STN) contralateral to the hand tested. We found that patients with PD off medication had an exaggerated movement-related beta-band (13–30 Hz) desynchronization in the supplementary motor area (SMA) compared to controls. In PD, spectral power in the beta-band was correlated with movement velocity. Following an acute dose of levodopa, we observed that the beta-band desynchronization in the SMA was reduced in PD, and was associated with increased movement velocity and increased voltage of agonist muscle activity. Further, using fMRI we found that the functional activity in the putamen and STN in the off medication state, was related to how responsive that cortical oscillations in the SMA of PD were to levodopa. Collectively, these findings provide the first direct evaluation of how movement-related cortical oscillations relate to movement velocity during the ballistic phase of movement in PD and demonstrate that functional brain activity in the basal ganglia pathways relate to the effects of dopaminergic medication on cortical neuronal oscillations during movement.

Altered functional connectivity of the subthalamic nucleus during self-initiated movement in Parkinson's disease

Background and purposePatients with Parkinson's disease (PD) have difficulty performing self-initiated movements. The neural mechanism of this deficiency remains unclear. In the present study, we used functional magnetic resonance imaging (fMRI) to investigate the functional connectivity of the subthalamic nucleus (STN) during self-initiated movement in patients with PD. Materials and methodsfMRI were acquired from patients with PD and age- and sex-matched healthy control subjects during a self-initiated right hand tapping task. We selected the bilateral sensorimotor subregions of the STN as regions of interest for our connectivity analysis. Results and conclusionsWe found that the STN contralateral to voluntary hand movement exhibited enhanced connectivity with the midbrain, thalamus, putamen, and so on in patients with PD compared to control subjects. In contrast, the STN ipsilateral to the hand movement exhibited enhanced connectivity with the midbrain and insula in PD patients compared to control subjects. Connectivity between the STN contralateral to the hand movement and the primary motor cortex and supplementary motor area was positively correlated with the severity of bradykinesia. Our findings suggest that STN-related connectivity in the hyperdirect and indirect basal ganglia pathways is strengthened during self-initiated movement in patients with PD. These disrupted network connections may contribute to bradykinesia.

The role of cortical oscillations in a spiking neural network model of the basal ganglia.

Although brain oscillations involving the basal ganglia (BG) have been the target of extensive research, the main focus lies disproportionally on oscillations generated within the BG circuit rather than other sources, such as cortical areas. We remedy this here by investigating the influence of various cortical frequency bands on the intrinsic effective connectivity of the BG, as well as the role of the latter in regulating cortical behaviour. To do this, we construct a detailed neural model of the complete BG circuit based on fine-tuned spiking neurons, with both electrical and chemical synapses as well as short-term plasticity between structures. As a measure of effective connectivity, we estimate information transfer between nuclei by means of transfer entropy. Our model successfully reproduces firing and oscillatory behaviour found in both the healthy and Parkinsonian BG. We found that, indeed, effective connectivity changes dramatically for different cortical frequency bands and phase offsets, which are able to modulate (or even block) information flow in the three major BG pathways. In particular, alpha (8–12Hz) and beta (13–30Hz) oscillations activate the direct BG pathway, and favour the modulation of the indirect and hyper-direct pathways via the subthalamic nucleus—globus pallidus loop. In contrast, gamma (30–90Hz) frequencies block the information flow from the cortex completely through activation of the indirect pathway. Finally, below alpha, all pathways decay gradually and the system gives rise to spontaneous activity generated in the globus pallidus. Our results indicate the existence of a multimodal gating mechanism at the level of the BG that can be entirely controlled by cortical oscillations, and provide evidence for the hypothesis of cortically-entrained but locally-generated subthalamic beta activity. These two findings suggest new insights into the pathophysiology of specific BG disorders.

The direct basal ganglia pathway is hyperfunctional in focal dystonia.

See Fujita and Eidelberg (doi:10.1093/brain/awx305) for a scientific commentary on this article. Focal dystonias are the most common type of isolated dystonia. Although their causative pathophysiology remains unclear, it is thought to involve abnormal functioning of the basal ganglia-thalamo-cortical circuitry. We used high-resolution research tomography with the radioligand 11C-NNC-112 to examine striatal dopamine D1 receptor function in two independent groups of patients, writer’s cramp and laryngeal dystonia, compared to healthy controls. We found that availability of dopamine D1 receptors was significantly increased in bilateral putamen by 19.6–22.5% in writer’s cramp and in right putamen and caudate nucleus by 24.6–26.8% in laryngeal dystonia (all P ≤ 0.009). This suggests hyperactivity of the direct basal ganglia pathway in focal dystonia. Our findings paralleled abnormally decreased dopaminergic function via the indirect basal ganglia pathway and decreased symptom-induced phasic striatal dopamine release in writer’s cramp and laryngeal dystonia. When examining topological distribution of dopamine D1 and D2 receptor abnormalities in these forms of dystonia, we found abnormal separation of direct and indirect pathways within the striatum, with negligible, if any, overlap between the two pathways and with the regions of phasic dopamine release. However, despite topological disorganization of dopaminergic function, alterations of dopamine D1 and D2 receptors were somatotopically localized within the striatal hand and larynx representations in writer’s cramp and laryngeal dystonia, respectively. This finding points to their direct relevance to disorder-characteristic clinical features. Increased D1 receptor availability showed significant negative correlations with dystonia duration but not its severity, likely representing a developmental endophenotype of this disorder. In conclusion, a comprehensive pathophysiological mechanism of abnormal basal ganglia function in focal dystonia is built upon upregulated dopamine D1 receptors that abnormally increase excitation of the direct pathway, downregulated dopamine D2 receptors that abnormally decrease inhibition within the indirect pathway, and weakened nigro-striatal phasic dopamine release during symptomatic task performance. Collectively, these aberrations of striatal dopaminergic function underlie imbalance between direct and indirect basal ganglia pathways and lead to abnormal thalamo-motor-cortical hyperexcitability in dystonia.

Evidence for a task-dependent switch in subthalamo-nigral basal ganglia signaling

Basal ganglia (BG) can either facilitate or inhibit movement through excitatory and inhibitory pathways; however whether these opposing signals are dynamically regulated during healthy behavior is not known. Here, we present compelling neurophysiological evidence from three complimentary experiments in non-human primates, indicating task-specific changes in tonic BG pathway weightings during saccade behavior with different cognitive demands. First, simultaneous local field potential recording in the subthalamic nucleus (STN; BG input) and substantia nigra pars reticulata (SNr; BG output) reveals task-dependent shifts in subthalamo-nigral signals. Second, unilateral electrical stimulation of the STN, SNr, and caudate nucleus results in strikingly different saccade directionality and latency biases across the BG. Third, a simple artificial neural network representing canonical BG signaling pathways suggests that pathway weightings can be altered by cortico-BG input activation. Overall, inhibitory pathways (striato-pallidal-subthalamo-nigral) dominate during goal-driven behavior with instructed rewards, while facilitatory pathways (striato-nigral and subthalamo-pallidal-nigral) dominate during unconstrained (free reward) conditions.

A Pause-then-Cancel model of stopping: evidence from basal ganglia neurophysiology.

Many studies have implicated the basal ganglia in the suppression of action impulses ('stopping'). Here, we discuss recent neurophysiological evidence that distinct hypothesized processes involved in action preparation and cancellation can be mapped onto distinct basal ganglia cell types and pathways. We examine how movement-related activity in the striatum is related to a 'Go' process and how going may be modulated by brief epochs of beta oscillations. We then describe how, rather than a unitary 'Stop' process, there appear to be separate, complementary 'Pause' and 'Cancel' mechanisms. We discuss the implications of these stopping subprocesses for the interpretation of the stop-signal reaction time-in particular, some activity that seems too slow to causally contribute to stopping when assuming a single Stop processes may actually be fast enough under a Pause-then-Cancel model. Finally, we suggest that combining complementary neural mechanisms that emphasize speed or accuracy respectively may serve more generally to optimize speed-accuracy trade-offs.This article is part of the themed issue 'Movement suppression: brain mechanisms for stopping and stillness'.

The development of repetitive motor behaviors in deer mice: Effects of environmental enrichment, repeated testing, and differential mediation by indirect basal ganglia pathway activation.

Little is known about the mechanisms mediating the development of repetitive behaviors in human or animals. Deer mice reared with environmental enrichment (EE) exhibit fewer repetitive behaviors and greater indirect basal ganglia pathway activation as adults than those reared in standard cages. The developmental progression of these behavioral and neural circuitry changes has not been characterized. We assessed the development of repetitive behavior in deer mice using both a longitudinal and cohort design. Repeated testing negated the expected effect of EE, but cohort analyses showed that progression of repetitive behavior was arrested after 1 week of EE and differed significantly from controls after 3 weeks. Moreover, EE reductions in repetitive behavior were associated with increasing activation of indirect pathway nuclei in males across adolescence, but not females. These findings provide the first assessment of developmental trajectories within EE and support indirect pathway mediation of repetitive behavior in male deer mice.

Dorsal striatum D1-expressing neurons are involved with sensorimotor gating on prepulse inhibition test.

Prepulse inhibition (PPI) is a behavioral test in which the startle reflex response to a high-intensity stimulus (pulse) is inhibited by the prior presentation of a weak stimulus (prepulse). The classic neural circuitry that mediates startle response is localized in the brainstem; however, recent studies point to the contribution of structures involved in higher cognitive functions in regulating the sensorimotor gating, particularly forebrain regions innervated by dopaminergic nuclei. The aim of the present study was to verify the role of dorsal striatum (DS) and dopaminergic transmitting mediated by D1 and D2 receptors on PPI test in rats. DS inactivation induced by muscimol injection did not affect PPI (%PPI and startle response), although it impaired the locomotor activity and caused catalepsy. Infusion of D1-like antagonist SCH23390 impaired %PPI but did not disturb the startle response and locomotor activity evaluated immediately after PPI test. D2 antagonist microinjection (sulpiride) did not affect %PPI and startle response, but impaired motor activity. These results point to an important role of DS, probably mediated by direct basal ganglia pathway, on modulation of sensorimotor gating, in accordance with clinical studies showing PPI deficits in schizophrenia, Tourette syndrome, and compulsive disorders - pathologies related to basal ganglia dysfunctions.