Basal Ganglia Output Structures Research Articles

Targeting parvalbumin-expressing neurons in the substantia nigra pars reticulata restores motor function in parkinsonian mice

The activity of substantia nigra pars reticulata (SNr) neurons, the main output structure of basal ganglia, is altered in Parkinson's disease (PD). However, neither the underlying mechanisms nor the type of neurons responsible for PD-related motor dysfunctions have been elucidated yet. Here, we show that parvalbumin-expressing SNr neurons (SNr-PV+) occupy dorsolateral parts and possess specific electrophysiological properties compared with other SNr cells. We also report that only SNr-PV+ neurons' intrinsic excitability is reduced by downregulation of sodium leak channels in a PD mouse model. Interestingly, in anesthetized parkinsonian mice invivo, SNr-PV+ neurons display a bursty pattern of activity dependent on glutamatergic tone. Finally, we demonstrate that chemogenetic inhibition of SNr-PV+ neurons is sufficient to alleviate motor impairments in parkinsonian mice. Overall, our findings establish cell-type-specific dysfunction in experimental parkinsonism in the SNr and provide a potential cellular therapeutic target to alleviate motor symptoms in PD.

Direct-Pathway Spiny Projection Neuron Inhibition Evokes Transient Circuit Imbalance Manifested as Rotational Behavior

The striatum collects and integrates information from many different areas of the brain and propels this forward to the basal ganglia (BG) output structures. In this way, the striatum is playing a pivotal role in control of voluntary movements and is implicated in debilitating movement disorders such as Parkinson’s disease. The functional backbone of the striatum is represented by direct pathway (dSPN) Drd1-expressing and indirect pathway (iSPN) Drd2-expressing spiny projection neurons (SPN), exerting opposite effects on movement. In rodent models of striatal function, unilateral dopamine deprivation is known to induce ipsilateral rotational behavior. To further study imbalance of the BG circuit and striatal domain influence on behavioral outcome, we employed a viral approach based on tetanus toxin light chain (TeLC) activity for permanent inhibition of dSPN activity in dorsomedial striatum (DMS). Cre-dependent TeLC injected unilaterally into the DMS of Drd1-Cre mice resulted in robust expression of TeLC in the dSPN cell populations as shown by immunohistochemistry. In the TeLC expressing mice, but not in control mice, we observed ipsilateral rotations that were enhanced upon administration of amphetamine to augment striatal dopamine levels. We argue that the observed single turns of ipsilateral rotations occur because of TeLC-mediated silencing of dSPN activity in one hemisphere, causing unresponsiveness to dopamine transients during movement initiation. This evokes a temporal BG circuit imbalance manifested as short bursts of rotations, particular evident during extrinsic dopaminergic modulation.

Spike discharge characteristic of the caudal mesencephalic reticular formation and pedunculopontine nucleus in MPTP-induced primate model of Parkinson disease

The pedunculopontine nucleus (PPN) included in the caudal mesencephalic reticular formation (cMRF) plays a key role in the control of locomotion and wake state. Regarding its involvement in the neurodegenerative process observed in Parkinson disease (PD), deep brain stimulation of the PPN was proposed to treat levodopa-resistant gait disorders. However, the precise role of the cMRF in the pathophysiology of PD, particularly in freezing of gait and other non-motor symptoms is still not clear.Here, using micro electrode recording (MER) in 2 primates, we show that dopamine depletion did not alter the mean firing rate of the overall cMRF neurons, particularly the putative non-cholinergic ones, but only a decreased activity of the regular neurons sub-group (though to be the cholinergic PPN neurons). Interestingly, a significant increase in the relative proportion of cMRF neurons with a burst pattern discharge was observed after MPTP intoxication. The present results question the hypothesis of an over-inhibition of the CMRF by the basal ganglia output structures in PD. The decreased activity observed in the regular neurons could explain some non-motor symptoms in PD regarding the strong involvement of the cholinergic neurons on the modulation of the thalamo-cortical system. The increased burst activity under dopamine depletion confirms that this specific spike discharge pattern activity also observed in other basal ganglia nuclei and in different pathologies could play a mojor role in the pathophysiology of the disease and could explain several symptoms of PD including the freezing of gait. The present data will have to be replicated in a larger number of animals and will have to investigate more in details how the modification of the spike discharge of the cMRF neurons in the parkinsonian state could alter functions such as locomotion and attentional state. This will ultimely allow a better comprehension of the pathophysiology of freezing of gait.

Targeted upregulation of uncoupling protein 2 within the basal ganglia output structure ameliorates dyskinesia after severe liver failure

Impaired motor function, due to the dysfunction of the basal ganglia, is the most common syndrome of hepatic encephalopathy (HE), and its etiology remains poorly understood. Neural oxidative stress is shown to be the major cellular defects contributing to HE pathogenesis. Mitochondrial uncoupling protein 2 (UCP2) has been implicated in neuroprotection in several neurological disorders. We explored the neuroprotective role of UCP2 within the substantia nigra pars reticulate (SNr), the output structure of the basal ganglia, in HE. The toxin thioacetamide (TAA) induced HE mice showed hypolocomotion, which was associated with decreased ATP levels and loss of antioxidant substances SOD and GSH within the SNr. Stable overexpression of UCP2 via AAV-UCP2 under the control of the UCP2 promoter in bilateral SNr preserved local ATP level, increased antioxidant substances, and ameliorated locomotion defects after severe liver failure. Contrary to UCP2 overexpression, targeted knockdown of UCP2 within bilateral SNr via AAV-UCP2 shRNA exacerbated the impaired mitochondrial dysfunction and hypokinesia in HE mice. The modulatory effects of UCP2 was due to mediation of K+-Cl− cotransporter-2 (KCC2) expression on GABAergic neurons of SNr. Taken together, our results demonstrate that UCP2 exerts a neural protective role at the subcortical level by increasing the resistance of neurons to oxidative stress, which may offer a novel therapeutic target for the treatment of motor dysfunction diseases.

Seq-ing the Circuit Logic of the Basal Ganglia

Recently, Wallace et al. (2017) provide an unprecedented view of the layers of molecular, cellular and circuit complexity involving a basal ganglia output structure, the entopeduncular nucleus. Their findings lend order to chaos by revealing how molecularly and functionally defined cellular subsets are organized into distinct circuitry.

92. Brainstem reflexes: New tools for differential diagnosis between idiopathic and psychogenic cervical dystonia?

Cervical idiopathic dystonia (CID) is the most common kind of primary dystonia, but its pathogenesis remains still unclear. As in other movement disorders, the major challenge is to recognize the organic from the psychogenic phenotype. Our objective was to evaluate the reliability of blink reflex test (BRT) in detecting powerful differences in patients with diagnosis of CID or (clinically presumed) psychogenic dystonia (PD). Twelve subjects were enrolled (6 CID, 6 PD), and BRT was assessed in term of R1 and R2 latencies and habituation phenomenon (trains of 10 stimulus, 1 Hz of frequency, 200 ms of duration). Electrodes were placed over the orbicular inferior muscle (recording electrode) and lateral canthus (reference). CID patients showed both an enhanced latency of polysynaptic R2 responses and a lack of habituation compared with subjects diagnosed as PD (t-test: p < 0.001). Our results support the hypothesis of a dysfunction of brainstem reflex circuits on the basis of CID. As in Parkinson Disease, one could speculate that this phenomenon relies on changes in the inhibitory drive from basal ganglia output structures, via tecto-reticular projections, to the superior colliculus.

Bee Venom Alleviates Motor Deficits and Modulates the Transfer of Cortical Information through the Basal Ganglia in Rat Models of Parkinson's Disease.

Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson’s disease (PD). Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure) in pharmacological (neuroleptic treatment) and lesional (unilateral intranigral 6-hydroxydopamine injection) PD models. In the hemi-parkinsonian 6-hydroxydopamine lesion model, subchronic bee venom treatment significantly alleviates contralateral forelimb akinesia and apomorphine-induced rotations. Moreover, a single injection of bee venom reverses haloperidol-induced catalepsy, a pharmacological model reminiscent of parkinsonian akinetic deficit. This effect is mimicked by apamin, a blocker of small conductance Ca2+-activated K+ (SK) channels, and blocked by CyPPA, a positive modulator of these channels, suggesting the involvement of SK channels in the bee venom antiparkinsonian action. In vivo electrophysiological recordings in the substantia nigra pars reticulata (basal ganglia output structure) showed no significant effect of BV on the mean neuronal discharge frequency or pathological bursting activity. In contrast, analyses of the neuronal responses evoked by motor cortex stimulation show that bee venom reverses the 6-OHDA- and neuroleptic-induced biases in the influence exerted by the direct inhibitory and indirect excitatory striatonigral circuits. These data provide the first evidence for a beneficial action of bee venom on the pathological functioning of the cortico-basal ganglia circuits underlying motor PD symptoms with potential relevance to the symptomatic treatment of this disease.

Striatal Cholinergic Interneurons Control Motor Behavior and Basal Ganglia Function in Experimental Parkinsonism.

Despite evidence showing that anticholinergic drugs are of clinical relevance in Parkinson's disease (PD), the causal role of striatal cholinergic interneurons (CINs) in PD pathophysiology remains elusive. Here, we show that optogenetic inhibition of CINs alleviates motor deficits in PD mouse models, providing direct demonstration for their implication in parkinsonian motor dysfunctions. As neural correlates, CIN inhibition in parkinsonian mice differentially impacts the excitability of striatal D1 and D2 medium spiny neurons, normalizes pathological bursting activity in the main basal ganglia output structure, and increases the functional weight of the direct striatonigral pathway in cortical information processing. By contrast, CIN inhibition in non-lesioned mice does not affect locomotor activity, equally modulates medium spiny neuron excitability, and does not modify spontaneous or cortically driven activity in the basal ganglia output, suggesting that the role of these interneurons in motor function is highly dependent on dopamine tone.

Anticonvulsant Effects by Bilateral and Unilateral Transplantation of GABA-Producing Cells into the Subthalamic Nucleus in an Acute Seizure Model

Neural transplantation of GABA-producing cells into key structures within seizure-suppressing circuits holds promise for medication-resistant epilepsy patients not eligible for resection of the epileptic focus. The substantia nigra pars reticulata (SNr), a basal ganglia output structure, is well known to modulate different seizure types. A recent microinjection study by our group indicated that the subthalamic nucleus (STN), which critically regulates nigral activity, might be a more promising target for focal therapy in epilepsies than the SNr. As a proof of principle, we therefore assessed the anticonvulsant efficacy of bilateral and unilateral allografting of GABA-producing cell lines into the STN using the timed intravenous pentylenetetrazole seizure threshold test, which allows repeated seizure threshold determinations in individual rats. We observed (a) that grafted cells survived up to the end of the experiments, (b) that anticonvulsant effects can be induced by bilateral transplantation into the STN using immortalized GABAergic cells derived from the rat embryonic striatum and cells additionally transfected to obtain higher GABA synthesis than the parent cell line, and (c) that anticonvulsant effects were observed even after unilateral transplantation into the STN. Neither grafting of control cells nor transplantation outside the STN induced anticonvulsant effects, emphasizing the site and cell specificity of the observed anticonvulsant effects. To our knowledge, the present study is the first showing anticonvulsant effects by grafting of GABA-producing cells into the STN. The STN can be considered a highly promising target region for modulation of seizure circuits and, moreover, has the advantage of being clinically established for functional neurosurgery.

Long-term depression at distinct glutamatergic synapses in the basal ganglia.

Long-term adaptations of synaptic transmission are believed to be the cellular basis of information storage in the brain. In particular, long-term depression of excitatory neurotransmission has been under intense investigation since convergent lines of evidence support a crucial role for this process in learning and memory. Within the basal ganglia, a network of subcortical nuclei forming a key part of the extrapyramidal motor system, plasticity at excitatory synapses is essential to the regulation of motor, cognitive, and reward functions. The striatum, the main gateway of the basal ganglia, receives convergent excitatory inputs from cortical areas and transmits information to the network output structures and is a major site of activity-dependent plasticity. Indeed, long-term depression at cortico-striatal synapses modulates the transfer of information to basal ganglia output structures and affects voluntary movement execution. Cortico-striatal plasticity is thus considered as a cellular substrate for adaptive motor control. Downstream in this network, the subthalamic nucleus and substantia nigra nuclei also receive glutamatergic innervation from the cortex and the subthalamic nucleus, respectively. Although these connections have been less investigated, recent studies have started to unravel the molecular mechanisms that contribute to adjustments in the strength of cortico-subthalamic and subthalamo-nigral transmissions, revealing that adaptations at these synapses governing the output of the network could also contribute to motor planning and execution. Here, we review our current understanding of long-term depression mechanisms at basal ganglia glutamatergic synapses and emphasize the common and unique plastic features observed at successive levels of the network in healthy and pathological conditions.

Inhibiting subthalamic D5 receptor constitutive activity alleviates abnormal electrical activity and reverses motor impairment in a rat model of Parkinson's disease.

Burst firing has been reported as a pathological activity of subthalamic nucleus (STN) neurons in Parkinson's disease. However, the origin of bursts and their causal link with motor deficits remain unknown. Here we tested the hypothesis that dopamine D5 receptors (D5Rs), characterized by a high constitutive activity, may contribute to the emergence of burst firing in STN. We tested whether inhibiting D5R constitutive activity depresses burst firing and alleviates motor impairments in the 6-OHDA rat model of Parkinson's disease. Intrasubthalamic microinjections of either an inverse agonist of D5Rs, flupenthixol, or a D2R antagonist, raclopride, were applied. Behavioral experiments, in vivo and in vitro electrophysiological recordings, and ex vivo functional neuroanatomy studies were performed. Using [(5)S]GTPγ binding autoradiography, we show that application of flupenthixol inhibits D5R constitutive activity within the STN. Furthermore, flupenthixol reduced evoked burst in brain slices and converted pathological burst firing into physiological tonic, single-spike firing in 6-OHDA rats in vivo. This later action was mimicked by calciseptine, a Cav1 channel blocker. Moreover, the same treatment dramatically attenuated motor impairment in this model and normalized metabolic hyperactivity in both STN and substantia nigra pars reticulata, the main output structure of basal ganglia in rats. In contrast, raclopride as well as saline did not reverse burst firing and motor deficits, confirming the selective action of flupenthixol on D5Rs. These results are the first to demonstrate that subthalamic D5Rs are involved in the pathophysiology of Parkinson's disease and that administering an inverse agonist of these receptors may lessen motor symptoms.

The enhanced oral response to the 5-HT2 agonist Ro 60-0175 in parkinsonian rats involves the entopeduncular nucleus: electrophysiological correlates

Lesions of nigrostriatal dopaminergic neurons as seen in Parkinson's disease (PD) increase orofacial responses to serotonergic (5-HT) agonists in rodents. Although this response to 5-HT agonists has been related to aberrant signalling in the basal ganglia, a group a subcortical structures involved in the control of motor behaviours, it deserves additional studies with respect to the specific loci involved. Using measurements of orofacial activity, as well as single-cell recordings in vivo, we have studied the role of the entopeduncular nucleus (EPN; equivalent to the internal globus pallidus of primates), an output structure of basal ganglia, in the hypersensitized responses to a 5-HT agonist in sham- or unilaterally dopamine-depleted rats. Intra-EPN injections of Ro 60-0175 (0.3 and 1μg/100nl) promoted robust oral movements in 6-OHDA rats without affecting oral activity in sham-depleted rats. Peripheral administration of Ro 60-0175 (3mg/kg ip) decreased EPN neuronal firing rate in 6-OHDA rats compared to sham-depleted rats. Such an effect was also observed when the agonist (0.2μg/20nl) was locally applied onto EPN neurons. These data demonstrate the contribution of EPN to hypersensitized responses to 5-HT agonists in a rat model of PD.

The subcortical hidden side of focal motor seizures: evidence from micro-recordings and local field potentials

Focal motor seizures are characterized by transient motor behaviour that occurs simultaneously with paroxystic activity in the controlateral motor cortex. The implication of the basal ganglia has already been shown for generalized seizure but the propagation pathways from the motor cortex towards the basal ganglia during focal motor seizures are largely unknown. With a better knowledge of those pathways, a therapeutic modulation for reducing drug resistant motor epilepsy could be considered. Here, we recorded single-unit activities and local field potentials in the basal ganglia of two Macaca fascicularis in which acute focal motor seizures were induced by the injection of penicillin over the arm motor cortex territory. Each neuron was characterized using its mean firing rate and its type of firing pattern during interictal periods and seizures. Time-frequency analyses of local field potentials and electroencephalographic signals were used to assess dynamic changes occurring during seizure at a larger spatial level. The firing rate of neurons of input stages of basal ganglia (subthalamic nucleus and putamen) and those from the external part of the globus pallidus were significantly higher during seizures as compared to interictal periods. During seizures, the proportion of oscillatory neurons in subthalamic nucleus (71%), external globus pallidus (45%) and putamen (53%) significantly increased in comparison to interictal periods. Rhythmic activity was synchronized with ictal cortical spikes in external globus pallidus and subthalamic nucleus, but not in the putamen which oscillated faster than motor cortex. In contrast, no significant modification of the firing rate of the output stages of basal ganglia (internal part of the globus pallidus, substantia nigra pars reticulata) could be found during seizures. The local field potentials of subthalamic nucleus and external globus pallidus changed abruptly at the onset of the seizure, showing synchronization with the cortical activity throughout the seizure. In putamen, the synchronization appeared only by the end of seizures and for the two output structures, despite some increase of the oscillatory activity, the synchronization with the cortex was not significant. Our results suggest that the subthalamo-(external)-pallidal pathway is the main subcortical route involved during ictal motor seizures. Surprisingly, ictal activity did not propagate to the output structure of basal ganglia in that model. This finding may be important for clinical decisions of targeting when considering anti-epileptic neuromodulation in human beings suffering from disabling, drug resistant motor epilepsy.

Vigabatrin for focal drug delivery in epilepsy: Bilateral microinfusion into the subthalamic nucleus is more effective than intranigral or systemic administration in a rat seizure model

Vigabatrin is a rationally developed antiepileptic drug, which acts by increasing GABA levels in the brain by irreversibly inhibiting GABA degradation. However, its clinical use in epilepsy is restricted by severe side effects, including vision loss, which is thought to be a consequence of drug exposure of the retina and nonepileptic brain regions. Targeted delivery into brain regions involved in seizure generation and propagation would overcome this problem. Previous studies in rat models of seizures or epilepsy have shown that anticonvulsant effects can be achieved by bilateral microinjection of vigabatrin into the substantia nigra pars reticulata (SNr), a basal ganglia output structure that plays an important role in the modulation of seizures. In the present study, we compared the anticonvulsant efficacy of vigabatrin after systemic and intranigral administration in a rat model, in which seizure susceptibility can be determined by timed intravenous infusion of pentylenetetrazol (PTZ) before and after drug injection in individual animals. Furthermore, because the subthalamic nucleus (STN) plays a crucial role as a regulator of basal ganglia outflow by providing excitatory glutamatergic input into the two output nuclei of the basal ganglia, SNr and entopeduncular nucleus, we evaluated the effects of bilateral focal delivery of vigabatrin into the STN on PTZ seizure threshold. A significant increase in seizure threshold was observed following systemic (i.p.) administration of high (600 or 1200mg/kg) doses of vigabatrin. Bilateral microinjection of vigabatrin (10μg) into either the anterior or posterior SNr also increased seizure threshold, but less markedly than systemic treatment. In contrast, focal delivery into the STN increased seizure threshold more markedly than either intranigral or systemic administration of vigabatrin. Furthermore, focal inhibition of STN was not associated with the severe adverse effects associated with systemic treatment. The data demonstrate that vigabatrin is an interesting substance for focal drug delivery in epilepsy and may be advantageous compared to more commonly evaluated compounds such as muscimol.

The Anticonvulsant Response to Valproate in Kindled Rats Is Correlated with Its Effect on Neuronal Firing in the Substantia Nigra Pars Reticulata: A New Mechanism of Pharmacoresistance

Resistance to antiepileptic drugs (AEDs) is a major problem in epilepsy treatment. However, mechanisms of resistance are only incompletely understood. We have recently shown that repeated administration of the AED phenytoin allows selecting resistant and responsive rats from the amygdala kindling model of epilepsy, providing a tool to study mechanisms of AED resistance. We now tested whether individual amygdala-kindled rats also differ in their anticonvulsant response to the major AED valproate (VPA) and which mechanism may underlie the different response to VPA. VPA has been proposed to act, at least in part, by reducing spontaneous activity in the substantia nigra pars reticulata (SNr), a main basal ganglia output structure involved in seizure propagation, seizure control, and epilepsy-induced neuroplasticity. Thus, we evaluated whether poor anticonvulsant response to VPA is correlated with low efficacy of VPA on SNr firing rate and pattern in kindled rats. We found (1) that good and poor VPA responders can be selected in kindled rats by repeatedly determining the effect of VPA on the electrographic seizure threshold, and (2) a significant correlation between the anticonvulsant response to VPA in kindled rats and its effect on SNr firing rate and pattern. The less VPA was able to raise seizure threshold, the lower was the VPA-induced reduction of SNr firing rate and the VPA-induced regularity of SNr firing. The data demonstrate for the first time an involvement of the SNr in pharmacoresistant experimental epilepsy and emphasize the relevance of the basal ganglia as target structures for new treatment options.

Imaging mass spectrometry reveals elevated nigral levels of dynorphin neuropeptides in L-DOPA-induced dyskinesia in rat model of Parkinson's disease.

L-DOPA-induced dyskinesia is a troublesome complication of L-DOPA pharmacotherapy of Parkinson's disease and has been associated with disturbed brain opioid transmission. However, so far the results of clinical and preclinical studies on the effects of opioids agonists and antagonists have been contradictory at best. Prodynorphin mRNA levels correlate well with the severity of dyskinesia in animal models of Parkinson's disease; however the identities of the actual neuroactive opioid effectors in their target basal ganglia output structures have not yet been determined. For the first time MALDI-TOF imaging mass spectrometry (IMS) was used for unbiased assessment and topographical elucidation of prodynorphin-derived peptides in the substantia nigra of a unilateral rat model of Parkinson's disease and L-DOPA induced dyskinesia. Nigral levels of dynorphin B and alpha-neoendorphin strongly correlated with the severity of dyskinesia. Even if dynorphin peptide levels were elevated in both the medial and lateral part of the substantia nigra, MALDI IMS analysis revealed that the most prominent changes were localized to the lateral part of the substantia nigra. MALDI IMS is advantageous compared with traditional molecular methods, such as radioimmunoassay, in that neither the molecular identity analyzed, nor the specific localization needs to be predetermined. Indeed, MALDI IMS revealed that the bioconverted metabolite leu-enkephalin-arg also correlated positively with severity of dyskinesia. Multiplexing DynB and leu-enkephalin-arg ion images revealed small (0.25 by 0.5 mm) nigral subregions with complementing ion intensities, indicating localized peptide release followed by bioconversion. The nigral dynorphins associated with L-DOPA-induced dyskinesia were not those with high affinity to kappa opioid receptors, but consisted of shorter peptides, mainly dynorphin B and alpha-neoendorphin that are known to bind and activate mu and delta opioid receptors. This suggests that mu and/or delta subtype-selective opioid receptor antagonists may be clinically relevant for reducing L-DOPA-induced dyskinesia in Parkinson's disease.

Contribution of astrocytic glutamate and GABA uptake to corticostriatal information processing

The astrocytes, active elements of the tripartite synapse, remove most of the neurotransmitter that spills over the synaptic cleft. Neurotransmitter uptake operated by astrocytes contributes to the strength and timing of synaptic inputs. The striatum, the main input nucleus of basal ganglia, extracts pertinent cortical signals from the background noise and relays cortical information toward basal ganglia output structures. We investigated the role of striatal astrocytic uptake in the shaping of corticostriatal transmission.We performed dual patch-clamp recordings of striatal output neuron (the medium-sized spiny neurons, MSNs)–astrocyte pairs while stimulating the somatosensory cortex. Cortical activity evoked robust synaptically activated transporter-mediated currents (STCs) in 78% of the recorded astrocytes. STCs originated equally from the activities of glutamate transporters and GABA transporters (GATs). Astrocytic STCs reflected here a presynaptic release of neurotransmitters. STCs displayed a large magnitude associated with fast kinetics, denoting an efficient neurotransmitter clearance at the corticostriatal pathway. Inhibition of glutamate transporters type-1 (GLT-1) and GATs decreased the corticostriatal synaptic transmission, through, respectively, desensitization of AMPA receptors and activation of GABAA receptor. STCs displayed a bidirectional short-term plasticity (facilitation for paired-pulse intervals less than 100 ms and depression up to 1 s).We report a genuine facilitation of STCs for high-frequency cortical activity, which could strengthen the detection properties of cortical activity operated by MSNs. MSN EPSCs showed a triphasic short-term plasticity, which was modified by the blockade of GLT-1 or GATs. We show here that neurotransmitter uptake by astrocytes plays a key role in the corticostriatal information processing.

Dissecting Inhibitory Control of Striatal Projection Neurons

Event Abstract Back to Event Dissecting Inhibitory Control of Striatal Projection Neurons Damodaran Sriraman1* and Kim Blackwell1 1 George Mason University, United States The striatum is the main input nucleus of the basal ganglia and is involved in processing inputs from the cortex and thalamus. This processing is carried out by GABAergic medium spiny projection neurons (MSPN) that comprise 90-95% of the neuronal population in the rodent striatum (Bolam and Bennett, 1993). These neurons project to the basal ganglia output structures, the globus pallidus and substantia nigra; therefore understanding striatal processing will help elucidate further the factors affecting basal ganglia function. GABAergic inhibition plays a very important role in the modulation of the MSPN network (Tepper et al., 2008). Among the different GABAergic interneurons in the striatum, the fast-spiking interneurons (FSIs) provide strong feedforward inhibition of the MSPNs (Koos & Tepper, 1999; Tepper et al., 2008), whereas MSPNs provide widespsread but weak feedback inhibition of each other. The FSIs are interconnected through electrical synapses/gap junctions (Galarreta and Hestrin, 2001) and GABAergic synapses (Gittis et al., 2010). It has been hypothesized that gap junctions are involved in coordinating synchronous activity in populations of the MSPN network (Berke et al., 2004, Galarreta and Hestrin, 2002). However, recent experiments (Berke, 2008) suggest that FSIs do not fire synchronously, and recent simulations (Hjorth et al., 2009) have shown that gap junctions alone are not sufficient to synchronize FSI network activity in the striatum, except transiently in response to synchronous cortical activity. The function of the widespread but weak feedback loop of the MSPNs is also not clear (Plenz, 2002). The present study constructs a network of the realistic multi-compartmental model MSPNs receiving both realistic synaptic input from a model FSI network and simulated input trains from the cortex. The FSI network, which also receives cortical input trains, is connected by both gap junctions (Hjorth et al., 2009) and chemical synapses (Gittis et al., 2010). The simulations address the role of chemical synapses and gap junctions in the FSI network in controlling activity in the MSPN network of the striatum. The simulations also parse out the contributions of the feedforward and feedback connections on the MSN output thus addressing the functional contribution of each type of connection to the network activity. Keywords: computational neuroscience Conference: 4th INCF Congress of Neuroinformatics, Boston, United States, 4 Sep - 6 Sep, 2011. Presentation Type: Poster Presentation Topic: Computational neuroscience Citation: Sriraman D and Blackwell K (2011). Dissecting Inhibitory Control of Striatal Projection Neurons. Front. Neuroinform. Conference Abstract: 4th INCF Congress of Neuroinformatics. doi: 10.3389/conf.fninf.2011.08.00031 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 17 Oct 2011; Published Online: 19 Oct 2011. * Correspondence: Dr. Damodaran Sriraman, George Mason University, Fairfax, United States, dsriraman@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Damodaran Sriraman Kim Blackwell Google Damodaran Sriraman Kim Blackwell Google Scholar Damodaran Sriraman Kim Blackwell PubMed Damodaran Sriraman Kim Blackwell Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Effects of pharmacological entopeduncular manipulations on idiopathic dystonia in the dt sz mutant hamster

The pathophysiology of idiopathic dystonias is still unknown, but it is regarded as a basal ganglia disorder. Previous experiments in the dt(sz) hamster, a model of primary paroxysmal dystonia, demonstrated reduced discharge rates and an abnormal pattern within the entopeduncular nucleus (EPN), a basal ganglia output structure. To clarify if this is based on abnormal gamma-aminobutyric acid(GABA)ergic or glutamatergic input, microinjections into the EPN were done in mutant hamsters in the present study. The GABA(A) receptor antagonists pentylenetetrazole and bicuculline exerted moderate antidystonic effects, while previous systemic administrations worsened dystonia in the dt(sz) mutant. GABA-potentiating drugs, i.e., the GABA(A) receptor agonist muscimol and the GABA transporter inhibitor 1,2,5,6-tetrahydro-1-[2-[[(diphenylmethylene)amino]oxy]ethyl]-3-pyridinecarboxy-lic acid (NNC-711), which are known to improve dystonia after systemic treatment in mutant hamsters, did not exert significant effects after EPN injections, but NNC-711 tended to increase the severity at the highest dose (2.5 ng bilateral). The NMDA receptor antagonist D(-)-2-amino-5-phosphopentanoic acid (AP-5) retarded the onset of a dystonic attack. However, this effect was not dose dependent and the AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzol(f)quinoxaline (NBQX) alone or in combination with AP-5 and NNC-711, also failed to show any effects on dystonia. The present data do not provide clear evidence for an enhanced striatal GABAergic input or a reduced glutamatergic activation of the EPN via the subthalamic nucleus, i.e., more pronounced antidystonic effects of GABA(A) receptor antagonists and stronger prodystonic effects of GABAmimetics and glutamate receptor antagonists were expected. Nevertheless, previously found changes in entopeduncular activity probably play a critical pathophysiological role in dystonic hamsters.

Fos after single and repeated self-administration of cocaine and saline in the rat: emphasis on the Basal forebrain and recalibration of expression.

The effects of addictive psychostimulant drugs on the brain change over repeated administrations. We evaluated a large sample of brain structures, particularly ones comprising basal forebrain macrosystems, and determined in which the immediate-early gene product, Fos, is expressed following a single and repeated self-administrations of cocaine. The caudate-putamen and accumbens, comprising the basal ganglia input structures, and the hypothalamic supraoptic and paraventricular nuclei, lateral and medial habenula, mesopontine rostromedial tegmental nucleus and anterior cingulate cortex exhibited Fos expression enhanced by acute self-administration of cocaine (SAC), but desensitized after repeated administrations. Fos expression was mainly enhanced by acutely self-administered cocaine in basal ganglia output and intrinsic structures and the intermediate nucleus of lateral septum, medial division of the central amygdaloid nucleus and zona incerta, but, in contrast, was sensitized in these structures after repeated administrations. Acute and repeated SAC left Fos expression unaffected or marginally enhanced in most extended amygdala structures, of which nearly all, however, exhibited robustly increased Fos expression after repeated saline self-administration, occasionally to levels exceeding those elicited by cocaine. Thus, self-administered cocaine mainly elicits Fos expression, which persists or increases with repeated administrations in some structures, but declines in others. In addition, Fos expression is sensitized in most extended amygdala structures merely by the act of repeated self-administering. Similar spatiotemporal patterns of cocaine- or saline-elicited Fos expression characterize functionally related clusters of structures, such as, eg, basal ganglia input structures, basal ganglia output structures, extended amygdala and structures in the brainstem to which forebrain macrosystems project.