Activity In Globus Pallidus Research Articles

Subthalamic nucleus evokes similar long lasting glutamatergic excitations in pallidal, entopeduncular and nigral neurons in the basal ganglia slice

The subthalamic nucleus (STN) modulates the activity of globus pallidus (GP), entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr) neurons via its direct glutamatergic projections. To investigate the mechanism by which STN affects activity in these structures and whether STN induced activity is comparable among STN target neurons, we performed patch clamp recordings in a tilted, parasagittal, basal ganglia slice (BGS) that preserves these functional connections. We report that single, brief stimulation of the STN generates a brief monosynaptic AMPA-mediated excitatory postsynaptic current (EPSC) in GP, EP and SNr neurons. A higher intensity, supra-threshold activation evokes a compound EPSC consisting of an early monosynaptic component followed by a slow inward NMDA-mediated current with an overlying barrage of AMPA-mediated EPSCs. These late EPSCs were polysynaptic and gave rise to bursts of spikes that lasted several hundreds of milliseconds. They were eliminated by surgical removal of the STN from the BGS slice, indicating that the STN is required for their generation. Reconstruction of biocytin-filled STN neurons revealed that a third of STN neurons project intra-STN axon collaterals that may underlie polysynaptic activity. We propose that activation of the STN yields comparable long lasting excitations in its target neurons by means of a polysynaptic network.

Behavioral and electrophysiological effects of 5‐HT in globus pallidus of 6‐hydroxydopamine lesioned rats

Anatomical studies have shown that the globus pallidus receives abundant 5-hydroxytryptamine (5-HT) innervations from raphe nuclei. 5-HT may occupy an important position in the modulation of motor function through its affect on the activity of globus pallidus. In the present study, intrapallidal microinjection of 5-HT (0.1 mM) alone did not induce any motor behavior or postural asymmetry in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. However, when infused concomitantly with a low dose of 3, 4-dihydroxyphenylalanine (L-DOPA, 3 mg/kg i.p.), which itself can induce modest contralateral rotational behavior, 5-HT significantly potentiated the number of contralateral rotations. To elucidate the cellular mechanism, in vivo extracellular recordings were performed to examine the effects of 5-HT on globus pallidus neurons. In normal rats, the predominant effect of micropressure ejection of 5-HT on pallidal neurons was excitation. In 6-OHDA-lesioned rats, although 5-HT increased the firing rate in most pallidal neurons, 5-HT-induced inhibitory effects was stronger than that on the unlesioned side as well as normal rats. Furthermore, 5-HT(1B) receptors are mainly involved in 5-HT-induced excitation while 5-HT(1A) receptors are involved in 5-HT-induced inhibition. The results suggest that 5-HT may potentiate the antiparkinsonian effect of L-DOPA through modulating the activity of globus pallidus.

Intrapallidal injection of 6-hydroxydopamine induced changes in dopamine innervation and neuronal activity of globus pallidus

The globus pallidus (GP) plays an important role in basal ganglia circuitry. In contrast to the well-characterized actions of dopamine on striatal neurons, the functional role of the dopamine innervation of GP is still not clearly determined. The present study aimed to investigate the effects of intrapallidal injection of 6-hydroxydopamine (6-OHDA) on rotational behavior induced by apomorphine, on the loss of dopamine cell bodies in the substantia nigra pars compacta (SNc) and fibers in the GP and striatum and on in vivo extracellularly-recorded GP neurons in the rat. Injection of 6-OHDA into GP induced severe loss of tyrosine hydroxylase–immunoreactive (TH-IR) fibers in GP (−85%) with a reduction in the number of TH-IR cell bodies in the SNc (−52%) and fibers in the striatum (−50%). S.c. injection of apomorphine in these rats induced a moderate number of turns (26±6 turns/5 min). Electrophysiological recordings show that 6-OHDA injection in GP induced a significant decrease of the firing rate of GP neurons (16.02±1.11 versus 24.14±1.58 spikes/sec in control animals and 22.83±1.28 in sham animals, one-way ANOVA , P<0.0001) without any change in the firing pattern (χ 2=1.03, df=4, P=0.90). Our results support the premise of the existence of collaterals of SNc dopaminergic axons projecting to the striatum and GP and that dopamine plays a role in the modulation of the firing rate but not the firing pattern of GP neurons. Our data provide important insights into the functional role of the SNc–GP dopaminergic pathway suggesting that dopamine depletion in GP may participate in the development of motor disabilities.

Involvement of Basal Ganglia Network in Motor Disabilities Induced by Typical Antipsychotics

BackgroundClinical treatments with typical antipsychotic drugs (APDs) are accompanied by extrapyramidal motor side-effects (EPS) such as hypokinesia and catalepsy. As little is known about electrophysiological substrates of such motor disturbances, we investigated the effects of a typical APD, α-flupentixol, on the motor behavior and the neuronal activity of the whole basal ganglia nuclei in the rat.Methods and FindingsThe motor behavior was examined by the open field actimeter and the neuronal activity of basal ganglia nuclei was investigated using extracellular single unit recordings on urethane anesthetized rats. We show that α-flupentixol induced EPS paralleled by a decrease in the firing rate and a disorganization of the firing pattern in both substantia nigra pars reticulata (SNr) and subthalamic nucleus (STN). Furthermore, α-flupentixol induced an increase in the firing rate of globus pallidus (GP) neurons. In the striatum, we recorded two populations of medium spiny neurons (MSNs) after their antidromic identification. At basal level, both striato-pallidal and striato-nigral MSNs were found to be unaffected by α-flupentixol. However, during electrical cortico-striatal activation only striato-pallidal, but not striato-nigral, MSNs were found to be inhibited by α-flupentixol. Together, our results suggest that the changes in STN and SNr neuronal activity are a consequence of increased neuronal activity of globus pallidus (GP). Indeed, after selective GP lesion, α-flupentixol failed to induce EPS and to alter STN neuronal activity.ConclusionOur study reports strong evidence to show that hypokinesia and catalepsy induced by α-flupentixol are triggered by dramatic changes occurring in basal ganglia network. We provide new insight into the key role of GP in the pathophysiology of APD-induced EPS suggesting that the GP can be considered as a potential target for the treatment of EPS.

Functional MRI investigations of emotional processing and autonomic responses in patients with autonomic hyperactivity

Introduction Previous functional imaging studies provide evidence for neural integration of human emotions and autonomic bodily responses. However it remains unclear how primary autonomic disorders influence emotional processing. The present functional MRI study investigates how heightened bodily reactivity shape excessive emotional responses. Methods We recruited patients with autonomic hyperreactivity (postural tachycardia syndrome, POTS) and age-matched normal controls. Participants were scanned with heart rate recording when judging emotional pictures, consisting of five emotion-specific categories of faces and scences (happy, angry, disgust, sad, and neutral) taken from the Karolinska Directed Emotional Faces (KDEF) and the International Affective Picture System (IAPS). After scanning, participants completed questionnaires for anxiety (STAI), depression (BDI-II), and panic disorders (PDSS). Results The scores of the questionnaires indicated that the POTS patients showed significantly higher state and trait anxiety, higher depressive status, and nearly half of the patients had past experience of pacic attacks. At the physiological level, the POTS patients showed an excessive rise in heart rate from onset of each stimulus presentation when compared to controls. The results of the fMRI data showed much greater deactivation within ventromedial prefrontal cortex (VMPFC, BA11, Figure 1 & 2) and right dorsolateral prefrontal cortex (BA9) in the patients compared to controls. In contrast, greater activation in midline structures; precuneus (BA7), anterior prefrontal cortex (BA10), and rostral anterior cingulate cortex, were found in the patients compared to controls. Further investigations showed that globus pallidus (GP), pons, and VMPFC were significantly correlated with higher state anxiety in the patients. Causal mediation analysis revealed that the activation in VMPFC provoked the activation in GP mediated via the level of state anxiety in the patients. Conclusions Overall findings suggest that hyperreactive bodily states trigger disruptive emotional status by increased attenuation of activity within VMPFC impacting on GP function. Our study highlights the possible neural mechanisms for understanding emotional disturbance in autonomic hyperreactivity disorders

Demonstration of disturbed activity of external globus pallidus projecting neurons in depressed patients by the AgNOR staining method

BackgroundThe external globus pallidus (EGP) is thought to play the most important integrating and conveying role in the striatopallidal system involved in the transfer from motivation to action. The aim to find a morphological biomarker of disturbed EGP activity in depression was approached by the karyometric analysis of large projecting neurons. MethodsThe study was performed on paraffin-embedded brains from 19 depressed patients from both the major depressive disorder (MDD) and the bipolar disorder (BD) diagnostic groups encompassing 10 suicides and from 24 controls. The karyometric parameters of EGP neurons bilaterally were evaluated by argyrophilic nucleolar organiser (AgNOR) silver staining method. ResultsA significantly decreased AgNOR area was found in the left EGP neurons in depressed patients compared to controls. The distinctness of the diagnostic groups and suicidal vs non-suicidal patients was not shown in the statistical comparisons. The AgNOR parameter which was decreased correlated positively with the mean dose of benzodiazepines in non-suicidal patients. LimitationsA major limitation of this study is the relatively small number of cases. A further limitation is given by the lack of data on drug exposure across the whole lifespan of patients. ConclusionThe results suggest disturbed, most likely decreased, activity of the left EGP projecting neurons in depressed patients, a disturbed activity that should hypothetically be counteracted by the applied pharmacotherapy in non-suicidal patients.

Identifying the Neurocircuitry Involved in the Exercise Pressor Reflex during Exercise in Humans

The neurocircuitry responsible for the muscle pressor reflex in humans remains incompletely identified. Group III and IV afferents carry sensory information regarding this reflex, although central integration is still poorly defined. Emerging evidence reports that the periaqueductal grey (PAG) in humans could be a major site for controlling the cardiovascular response to exercise. We assessed the spectral changes in local field potentials (LFPs) recorded from deep brain nuclei in patients who had undergone neurosurgery for movement or pain disorders. Patients with electrodes implanted were asked to perform light handgrip exercise, followed by arterial occlusion of the exercised limb in order to maintain the pressor response. We focussed on the PAG, and compared it to control areas, i.e. the internal globus pallidus (GPi) and thalamus. The PAG showed significant increases in LFP power at frequencies from 0‐100Hz (p&lt;0.001) during occlusion. This period was associated with maintained elevated arterial blood pressure. Cuff inflation without prior exercise resulted in a small increase in PAG activity suggesting that the inflation itself may, in part, contribute to the pressor response associated with occlusion. No change in GPi or thalamus activity was observed during occlusion. These data suggest the PAG is a part of the subcortical neurocircuitry involved in the exercise pressor reflex.

The role of the basal ganglia in processing of Chinese writing: evidence from a PET study in Wilson's disease

ObjectiveTo investigate the role of basal ganglia in processing of Chinese writing by Wilson' disease(WD). Methods7 WD patients were divided into two groups which were normal writing group and dysgraphia group. They were scanned by 18F-fluorodeoxyglucose(18F-FDG) positron emission tomography respectively while performing two tasks: 1) pseudo-writing,2) Chinese character writing. Data were analyzed with Statistical Parametric Mapping. ResultsCompared with pseudo-writing,patients in normal writing group showed greater activation of bilateral lateral globus pallidus and right putamen,whereas patients in dysgraphia group showed greater activation of right ventral lateral nucleus,claustrum,left putamen and lateral globus pallidus(P<0.01). Conclusions1) The results indicate that Chinese writing of WD patients involves in bilateral subcortical structure. Right basal ganglia plays more important role. 2) Activated areas in bilateral basal ganglia of WD patients with agraphia are different with WD patients with normal writing and right thalamus play a compensatory role when WD patients with agraphia are writing. Key words: Writing; Chinese character; Wilson's Disease; Positron emission tomography

Neurokinin-1 receptor activation in globus pallidus

The undecapeptide substance P has been demonstrated to modulate neuronal activity in a number of brain regions by acting on neurokinin-1 receptors. Anatomical studies revealed a moderate level of neurokinin-1 receptor in rat globus pallidus. To determine the electrophysiological effects of neurokinin-1 receptor activation in globus pallidus, whole-cell patch-clamp recordings were performed in the present study. Under current-clamp recordings, neurokinin-1 receptor agonist, [Sar9, Met(O2)11] substance P (SM-SP) at 1 μM, depolarized globus pallidus neurons and increased their firing rate. Consistently, SM-SP induced an inward current under voltage-clamp recording. The depolarization evoked by SM-SP persisted in the presence of tetrodotoxin, glutamate and GABA receptor antagonists, indicating its direct postsynaptic effects. The neurokinin-1 receptor antagonist, SR140333B, could block SM-SP-induced depolarization. Further experiments showed that suppression of potassium conductance was the predominant ionic mechanism of SM-SP-induced depolarization. To determine if neurokinin-1 receptor activation exerts any effects on GABAergic and glutamatergic neurotransmission, the action of SM-SP on synaptic currents was studied. SM-SP significantly increased the frequency of spontaneous inhibitory postsynaptic currents, but only induced a transient increase in the frequency of miniature inhibitory postsynaptic currents. No change was observed in both spontaneous and miniature excitatory postsynaptic currents. Based on the direct excitatory effects of SM-SP on pallidal neurons, we hypothesize that neurokinin-1 receptor activation in globus pallidus may be involved in the beneficial effect of substance P in Parkinson's disease.

Behavioral and electrophysiological effects of pallidal GABA B receptor activation and blockade on haloperidol-induced akinesia in rats

The globus pallidus plays an important role in movement regulation. Morphological studies have revealed GABA B receptor expression in the globus pallidus. To investigate the behavioral and electrophysiological effects of pallidal GABA B receptors on haloperidol-induced akinesia, microinjection and extracellular recordings were performed in the present study. Unilateral microinjection of GABA B receptor agonist, baclofen, into globus pallidus produced ipsilateral dystonic posturing in haloperidol-induced akinesia rats. However, microinjection of GABA B receptor antagonist, CGP55845, induced contralateral dystonic posturing, suggesting the tonic activity of pallidal GABAergic neurotransmission. Micro-pressure ejection of baclofen into globus pallidus decreased the spontaneous firing of pallidal neurons. Furthermore, local administration of CGP55845 alone induced a weak but consistent increase in the frequency of pallidal firing. The presence of CGP55845 prevented baclofen-induced effects completely. From the present in vivo findings it may be concluded that pallidal GABA B receptors may contribute to the therapy of parkinsonian akinesia by modulating the activity of globus pallidus.

Pre- and Postsynaptic Serotoninergic Excitation of Globus Pallidus Neurons

The basal ganglia (BG) play a critical role in the pathogenesis and pathophysiology of Parkinson's disease (PD). Recent studies indicate that serotoninergic systems modulate BG activity and may be implicated in the pathophysiology and treatment of PD. The globus pallidus (GP), the rodent homologue of the primate GPe, is the main central nucleus of the basal ganglia, affecting the striatum, the subthalamic nucleus (STN), and BG output structures. We therefore studied the effect of serotonin (5-HT) and specific 5-HT agonists and antagonists on GP neurons from rat brain slices. Using intra- and extracellular recordings of GP neurons we found that serotonin increases the firing rate of GP neurons. Analyzing the effects of specific 5-HT agonists and antagonists on the firing rate of GP neurons showed that the increase in firing rate is due to the activation of 5-HT1B and 5-HT1A receptors. Intracellular recordings in both voltage- and current-clamp modes revealed that serotonin mediates its effect via pre- and postsynaptic mechanisms. The presynaptic effect is mediated by attenuation of gamma-aminobutyric acid release, probably through activation of 5-HT1B receptors. Postsynaptically, serotonin activates a hyperpolarization-activated cation channel, probably via 5-HT1A receptors. Furthermore, serotonin decreases the fast synaptic depression characteristic of the striatal afferent input. The decreased serotonin concentrations in the BG nuclei in PD may contribute to depressed GP activity and enhance the emergence of BG pathological synchronous oscillations. We therefore suggest that future therapeutics of PD should be directed toward restoration of normal serotonin levels in BG nuclei.

Different activation pattern to unattended emotional words in depressed vs.healthy subjects

Objective Depression is thought to be related with either diminished processing of positive stimuli or enhanced processing of negative stimuli.Method Eight depressed patients and 8 healthy controls were required to make a perceptual judgment on two figures representing the backward masks of positive,neutral,or negative words. 2.0 T GE Prestige MRI system was used to collect the fMRI data that were post-processed with the software Statistical Parametric Mapping(SPM2).Results For positive words contrary to neutral words.the depressed subjects exhibited no activation,while the controls showed activation in the right orbitofrontal cortex,right anterior cingulate gyrus,right thalamus,and bilateral caudate that are implicated in the processing of positive emotion.For the negative words vs.neutral words,the depressed subjects showed activation in the left putamen and left lateral globus pallidus,while the controls only showed activation in the insular cortex. No significant difference was found in both positive and negative(relative to neutral)words between the depressed participants and controls. Conclusion These results support the hypothesis that depressed patients are impaired in the processing of positive information.The activation pattern may suggest the neural mechanism underlying the negative bias and social dysfunction in clinical depression under unattended processing. Key words: Depression; Emotion; Unattended; Magnetic Resonance Imaging

Thalamocortical Relay Fidelity Varies Across Subthalamic Nucleus Deep Brain Stimulation Protocols in a Data-Driven Computational Model

The therapeutic effectiveness of deep brain stimulation (DBS) of the subthalamic nucleus (STN) may arise through its effects on inhibitory basal ganglia outputs, including those from the internal segment of the globus pallidus (GPi). Changes in GPi activity will impact its thalamic targets, representing a possible pathway for STN-DBS to modulate basal ganglia-thalamocortical processing. To study the effect of STN-DBS on thalamic activity, we examined thalamocortical (TC) relay cell responses to an excitatory input train under a variety of inhibitory signals, using a computational model. The inhibitory signals were obtained from single-unit GPi recordings from normal monkeys and from monkeys rendered parkinsonian through arterial 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injection. The parkinsonian GPi data were collected in the absence of STN-DBS, under sub-therapeutic STN-DBS, and under therapeutic STN-DBS. Our simulations show that inhibition from parkinsonian GPi activity recorded without DBS-compromised TC relay of excitatory inputs compared with the normal case, whereas TC relay fidelity improved significantly under inhibition from therapeutic, but not sub-therapeutic, STN-DBS GPi activity. In a heterogeneous model TC cell population, response failures to the same input occurred across multiple TC cells significantly more often without DBS than in the therapeutic DBS case and in the normal case. Inhibitory signals preceding successful TC relay were relatively constant, whereas those before failures changed more rapidly. Computationally generated inhibitory inputs yielded similar effects on TC relay. These results support the hypothesis that STN-DBS alters parkinsonian GPi activity in a way that may improve TC relay fidelity.

Motor cortical control of internal pallidal activity through glutamatergic and GABAergic inputs in awake monkeys

The internal segment of the globus pallidus (GPi) receives motor-related cortical signals mainly through the striatum, the external segment of the globus pallidus (GPe) and the subthalamic nucleus (STN). The GPi sends its outputs outside the basal ganglia and plays a key role in motor control. Extracellular unit recordings were performed in awake monkeys to explore how glutamatergic STN inputs and GABAergic striatal and GPe inputs control spontaneous activity and how these inputs contribute to motor cortex stimulation-induced responses of GPi neurons. The typical responses of GPi neurons to cortical stimulation consisted of an early excitation, an inhibition and a late excitation. Local applications of the NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid and/or the AMPA/kainate receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulphonamide in the vicinity of recorded GPi neurons reduced the firing rate, and abolished or attenuated both early and late excitations following cortical stimulation. Local application of the GABA(A) receptor antagonist gabazine increased the firing rate, induced oscillatory firings and diminished the cortically induced inhibition. Muscimol or gabazine injection into the STN or GPe also altered the firing rate, and attenuated the late excitation of GPi neurons. The gabazine injection into the STN occasionally induced dyskinesia with significantly decreased GPi activity. These data suggest that the early and late excitations are glutamatergic and induced by the cortico-STN-GPi and cortico-striato-GPe-STN-GPi pathways, respectively. The inhibition is GABAergic and induced by the cortico-striato-GPi pathway. In addition, these inputs are the main factors governing the spontaneous activity of GPi neurons.

Distinct changes in evoked and resting globus pallidus activity in early and late Parkinson's disease experimental models

The main clinical manifestations of Parkinson's disease are caused by alterations of basal ganglia activity that are tied in with the progressive loss of mesencephalic dopaminergic neurons. Recent theoretical and modeling studies have suggested that changes in resting neuronal activity occurred later in the course of the disease than those evoked by phasic cortical input. However, there is no empirical support for this proposal. Here we report a marked increase in the responsiveness of globus pallidus neurons to electrical motor cortex stimulation, in the absence of noticeable changes in resting activity, in anesthetized rats that had consistently shown a deficit in forelimb use during behavioral testing before the experiments, and had approximately 45% dopamine neurons spared in the substantia nigra. Pallidal neurons were also over-responsive to motor cortex stimulation and lost spatial selectivity for cortical inputs in rats with extensive nigrostriatal damage. After partial lesions, over-responsiveness was mainly due to an increased proportion of neurons showing excitatory responses, while extensive lesions led to an increased likelihood of inhibitory responding neurons. Changes in resting neuronal activity, comprising pauses disrupting tonic discharge, occurred across different global brain states, including an activated condition which shares similarities with natural patterns of cortical activity seen in awake states and rapid eye-movement sleep, but only after massive nigrostriatal degeneration. These results suggest that a loss of functional segregation and an abnormal temporal encoding of phasic cortical inputs by globus pallidus neurons may contribute to inducing early motor impairment in Parkinson's disease.

Effects of motor imagery training after chronic, complete spinal cord injury

Abnormalities in brain motor system function are present following spinal cord injury (SCI) and could reduce effectiveness of restorative interventions. Motor imagery training, which can improve motor behavior and modulate brain function, might address this concern but has not been examined in subjects with SCI. Ten subjects with SCI and complete tetra-/paraplegia plus ten healthy controls underwent assessment before and after 7 days of motor imagery training to tongue and to foot. Motor imagery training significantly improved the behavioral outcome measure, speed of movement, in non-paralyzed muscles. Training was also associated with increased fMRI activation in left putamen, an area associated with motor learning, during attempted right foot movement in both groups, despite foot movements being present in controls and absent in subjects with SCI. This fMRI change was absent in a second healthy control group serially imaged without training. In subjects with SCI, training exaggerated, rather than normalized, baseline derangement of left globus pallidus activation. The current study found that motor imagery training improves motor performance and alters brain function in subjects with complete SCI despite lack of voluntary motor control and peripheral feedback. These effects of motor imagery training on brain function have not been previously described in a neurologically impaired population, and were similar to those found in healthy controls. Motor imagery might be of value as one component of a restorative intervention.

Lesions in monkey globus pallidus externus exacerbate parkinsonian symptoms

To further define the role of the external segment of the globus pallidus (GPe) in the development of parkinsonian motor signs, two rhesus monkeys were made parkinsonian with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Behavioral assessments of bradykinesia and akinesia as well as single neuron recordings in the internal segment of the globus pallidus (GPi) were performed in both monkeys before and after ablating the sensorimotor portion of GPe. The effects of apomorphine on behavior and neuronal activity were also assessed in the parkinsonian monkeys before and after GPe ablation. We found that lesions in GPe exacerbated parkinsonian symptoms, altered neuronal activity in GPi, and reduced the therapeutic effects of apomorphine. These results support the hypothesis that GPe can influence GPi neuronal activity and is directly involved in parkinsonism. In addition, these data suggest that the inclusion of GPe in pallidotomy lesions for the treatment of Parkinson's disease can block the beneficial effects of antiparkinsonian medications and should be avoided.

Excitatory effect of histamine on neuronal activity of rat globus pallidus by activation of H 2 receptors in vitro

Previous studies have revealed distribution of histaminergic fibers and presence of histamine receptors in globus pallidus (GP). In this study, the brain slice preparation of adult rats was used to examine the effect of histamine on the spontaneous unitary discharge of GP neurons and the underlying receptor mechanism. Ninety-five GP neurons were extracellularly recorded from 42 slices containing the GP, of which 87 (91.6%) were excited by the stimulation of histamine. The histamine-induced excitation was concentration-dependent and persisted in low Ca 2+/high Mg 2+ medium ( n = 9), demonstrating that the action of histamine on the GP neurons was postsynaptic. The excitatory effect of histamine on the GP neurons was not blocked by selective histamine H 1 receptor antagonist triprolidine ( n = 16) or chlorpheniramine ( n = 6), but was effectively suppressed by ranitidine, a highly selective histamine H 2 receptor antagonist ( n = 21). On the other hand, highly selective histamine H 2 receptor agonist dimaprit mimicked the excitatory effect of histamine on the GP neurons ( n = 23), while histamine H 1 receptor agonists, including 2-pyridylethylamine ( n = 22), 2-thiazolyethylamine ( n = 9) and betahistine ( n = 9), did not cause GP neurons any response. The dimaprit-induced GP neuronal excitation was effectively antagonized by selective histamine H 2 receptor antagonist ranitidine ( n = 14) but not influenced by selective histamine H 1 receptor antagonist triprolidine ( n = 12). Moreover, adenylate cyclase (AC) activator forskolin ( n = 7) was observed to evoke GP neurons an excitatory response, whereas the histamine-induced excitation was effectively reduced by H-89 ( n = 9), a selective and potent inhibitor of protein kinase A (PK A). Finally, it was noted that neurons of both subdivisions of the GP, the internal (GPi, n = 35) and external (GPe, n = 60) segment, showed no differences in their responses to stimulations of the tested histaminergic reagents. These results demonstrated that histamine excited GP (including GPi and GPe) neurons via histamine H 2 receptors and H 2 receptors linked intracellular G-protein-AC-PK A signaling pathway, suggesting that the hypothalamic histaminergic afferent fibers innervating GP may play an important modulatory role in motor control through its excitatory effect on GP neurons.

Subthalamic Neurons Coordinate Basal Ganglia Function through Differential Neural Pathways

The subthalamic nucleus (STN) is a key component of basal ganglia circuitry that mediates a variety of motor functions. The STN neurons send glutamatergic projections to the output structures of basal ganglia, including the substantia nigra pars reticulata (SNr) and the entopeduncular nucleus, and also innervate the globus pallidus (GP). However, the mechanism by which the STN regulates motor functions in the neural circuitry is not fully understood. Here we performed conditional ablation of the STN neurons by using immunotoxin-mediated cell targeting. We then analyzed dopamine (DA)-mediated motor behavior and firing activity of the SNr and GP neurons. Ablation of the STN neurons increased spontaneous movement and reduced hyperactivity in response to DA stimulation. Ablation of these neurons modulated the pattern and rate of spontaneous firing of the SNr neurons, although it did not substantially affect spontaneous firing of the GP neurons. The ablation attenuated DA-induced suppression of the firing rate of the SNr neurons and inhibited DA-induced elevation of the rate of the GP neurons. In addition, pharmacological blockade of GP activation in response to DA stimulation inhibited the suppression of SNr activity and the resultant motor activation. These results suggest that the STN neurons suppress spontaneous behavior through their direct projection to the output neurons and that, in response to DA, they contribute to expression of behavior by acting on the output neurons mainly through the GP-mediated pathways. We conclude that the STN coordinates motor behavior through differential neural pathways depending on the state of DA transmission.

HCN2 and HCN1 Channels Govern the Regularity of Autonomous Pacemaking and Synaptic Resetting in Globus Pallidus Neurons

The globus pallidus (GP) is a critical component of the basal ganglia circuitry controlling motor behavior. Dysregulation of GP activity has been implicated in a number of psychomotor disorders, including Parkinson's disease (PD), in which a cardinal feature of the pathophysiology is an alteration in the pattern and synchrony of discharge in GP neurons. Yet the determinants of this activity in GP neurons are poorly understood. To help fill this gap, electrophysiological, molecular, and computational approaches were used to identify and characterize GABAergic GP neurons in tissue slices from rodents. In vitro, GABAergic GP neurons generate a regular, autonomous, single-spike pacemaker activity. Hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels make an important contribution to this process: their blockade with ZD7288 significantly slowed discharge rate and decreased its regularity. HCN currents evoked by somatic voltage clamp had fast and slow components. Single-cell RT-PCR and immunohistochemical approaches revealed robust expression of HCN2 subunits as well as significant levels of HCN1 subunits in GABAergic GP neurons. Transient activation of striatal GABAergic input to GP neurons led to a resetting of rhythmic discharge that was dependent on HCN currents. Simulations suggested that the ability of transient striatal GABAergic input to reset pacemaking was dependent on dendritic HCN2/HCN1 channels. Together, these studies show that HCN channels in GABAergic GP neurons are key determinants of the regularity and rate of pacemaking as well as striatal resetting of this activity, implicating HCN channels in the emergence of synchrony in PD.