Striatonigral Pathway Research Articles

Immunohistochemical Localization of DARPP-32 in the Brain of Two Lungfishes: Further Assessment of Its Relationship with the Dopaminergic System

The distribution of DARPP-32 (a phosphoprotein related to the dopamine D₁ receptor) has been widely used as a means to clarify the brain regions with dopaminoceptive cells, primarily in representative species of tetrapods. The relationship between dopaminergic and dopaminoceptive elements is frequently analyzed using the catecholamine marker tyrosine hydroxylase (TH). In the present study, by means of combined immunohistochemistry, we have analyzed these relationships in lungfishes, the only group of sarcopterygian fishes represented by 6 extant species that are the phylogenetically closest living relatives of tetrapods. We used the Australian lungfish Neoceratodus forsteri and the African lungfish Protopterus dolloi. The DARPP-32 antibody yields a distinct and consistent pattern of neuronal staining in brain areas that, in general, coincide with areas that are densely innervated by TH-immunoreactive fibers. The striatum, thalamus, optic tectum, and torus semicircularis contain intensely DARPP-32-immunoreactive cell bodies and fibers. Cells are also located in the olfactory bulbs, amygdaloid complex, lateral septum, pallidum, preoptic area, suprachiasmatic nucleus, tuberal hypothalamic region, rostral rhombencephalic reticular formation, superior raphe nucleus, octavolateral area, solitary tract nucleus, and spinal cord. Remarkably, DARPP-32-immunoreactive fibers originating in the striatum reach the region of the dopaminergic cells in the mesencephalic tegmentum and represent a well-established striatonigral pathway in lungfishes. Double immunolabeling reveals that DARPP-32 is present in neurons that most likely receive TH input, but it is absent from the catecholaminergic neurons themselves, with the only exception of a few cells in the suprachiasmatic nucleus of Neoceratodus and the solitary tract nucleus of Protopterus. In addition, some species differences exist in the localization of DARPP-32 cells in the pallium, lateral amygdala, thalamus, prethalamus, and octavolateral area. In general, the present study demonstrates that the distribution pattern of DARPP-32, and its relationship with TH, is largely comparable to those reported for tetrapods, highlighting a shared situation among all sarcopterygians.

CK2 Oppositely Modulates l-DOPA-Induced Dyskinesia via Striatal Projection Neurons Expressing D1 or D2 Receptors.

We have previously shown that casein kinase 2 (CK2) negatively regulates dopamine D1 and adenosine A2A receptor signaling in the striatum. Ablation of CK2 in D1 receptor-positive striatal neurons caused enhanced locomotion and exploration at baseline, whereas CK2 ablation in D2 receptor-positive neurons caused increased locomotion after treatment with A2A antagonist, caffeine. Because both, D1 and A2A receptors, play major roles in the cellular responses to l-DOPA in the striatum, these findings prompted us to examine the impact of CK2 ablation on the effects of l-DOPA treatment in the unilateral 6-OHDA lesioned mouse model of Parkinson's disease. We report here that knock-out of CK2 in striatonigral neurons reduces the severity of l-DOPA-induced dyskinesia (LID), a finding that correlates with lowered pERK but unchanged pPKA substrate levels in D1 medium spiny neurons as well as in cholinergic interneurons. In contrast, lack of CK2 in striatopallidal neurons enhances LID and ERK phosphorylation. Coadministration of caffeine with a low dose of l-DOPA reduces dyskinesia in animals with striatopallidal knock-out to wild-type levels, suggesting a dependence on adenosine receptor activity. We also detect reduced Golf levels in the striatonigral but not in the striatopallidal knock-out in response to l-DOPA treatment.Our work shows, in a rodent model of PD, that treatment-induced dyskinesia and striatal ERK activation are bidirectionally modulated by ablating CK2 in D1- or D2-positive projection neurons, in male and female mice. The results reveal that CK2 regulates signaling events critical to LID in each of the two main populations of striatal neurons.SIGNIFICANCE STATEMENT To date, l-DOPA is the most effective treatment for PD. Over time, however, its efficacy decreases, and side effects including l-DOPA-induced dyskinesia (LID) increase, affecting up to 78% of patients within 10 years of therapy (Hauser et al., 2007). It is understood that supersensitivity of the striatonigral pathway underlies LID, however, D2 agonists were also shown to induce LID (Bezard et al., 2001; Delfino et al., 2004). Our work implicates a novel player in the expression of LID, the kinase CK2: knock-out of CK2 in striatonigral and striatopallidal neurons has opposing effects on LID. The bidirectional modulation of dyskinesia reveals a central role for CK2 in striatal physiology and indicates that both pathways contribute to LID.

Striatonigral direct pathway activation is sufficient to induce repetitive behaviors

Pharmacological intervention in the substantia nigra is known to induce repetitive behaviors in rodents, but a direct causal relationship between a specific neural circuit and repetitive behavior has not yet been established. Here we demonstrate that optogenetic activation of dopamine D1 receptor-expressing MSNs terminals in the substantia nigra pars reticulata resulted in sustained and chronic repetitive behaviors. These data show for the first time that activation of the striatonigral direct pathway is sufficient to generate motor stereotypies.

Imaging neuronal pathways with 52Mn PET: Toxicity evaluation in rats

Manganese in its divalent state (Mn2+) has features that make it a unique tool for tracing neuronal pathways. It is taken up and transported by neurons in an activity-dependent manner and it can cross synapses. It also acts as a contrast agent for magnetic resonance imaging (MRI) enabling visualization of neuronal tracts. However, due to the limited sensitivity of MRI systems relatively high Mn2+ doses are required. This is undesirable, especially in long-term studies, because of the known toxicity of the metal.In order to overcome this limitation, we propose 52Mn as a positron emission tomography (PET) neuronal tract tracer. We used 52Mn for imaging dopaminergic pathways after a unilateral injection into the ventral tegmental area (VTA), as well as the striatonigral pathway after an injection into the dorsal striatum (STR) in rats. Furthermore, we tested potentially noxious effects of the radioactivity dose with a behavioral test and histological staining.24 h after 52Mn administration, the neuronal tracts were clearly visible in PET images and statistical analysis confirmed the observed distribution of the tracer. We noticed a behavioral impairment in some animals treated with 170 kBq of 52Mn, most likely caused by dysfunction of dopaminergic cells. Moreover, there was a substantial DNA damage in the brain tissue after applying 150 kBq of the tracer. However, all those effects were completely eliminated by reducing the 52Mn dose to 20–30 kBq. Crucially, the reduced dose was still sufficient for PET imaging.

Striatal activation by optogenetics induces dyskinesias in the 6-hydroxydopamine rat model of Parkinson disease.

Long-term levodopa (l-dopa) treatment is associated with the development of l-dopa-induced dyskinesias in the majority of patients with Parkinson disease (PD). The etiopathogonesis and mechanisms underlying l-dopa-induced dyskinesias are not well understood. We used striatal optogenetic stimulation to induce dyskinesias in a hemiparkinsonian model of PD in rats. Striatal dopamine depletion was induced unilaterally by 6-hydroxydopamine injection into the medial forebrain bundle. For the optogenetic manipulation, we injected adeno-associated virus particles expressing channelrhodopsin to stimulate striatal medium spiny neurons with a laser source. Simultaneous optical activation of medium spiny neurons of the direct and indirect striatal pathways in the 6-hydroxydopamine lesion but l-dopa naïve rats induced involuntary movements similar to l-dopa-induced dyskinesias, labeled here as optodyskinesias. Noticeably, optodyskinesias were facilitated by l-dopa in animals that did not respond initially to the laser stimulation. In general, optodyskinesias lasted while the laser stimulus was applied, but in some instances remained ongoing for a few seconds after the laser was off. Postmortem tissue analysis revealed increased FosB expression, a molecular marker of l-dopa-induced dyskinesias, primarily in medium spiny neurons of the direct pathway in the dopamine-depleted hemisphere. Selective optogenetic activation of the dorsolateral striatum elicits dyskinesias in the 6-hydroxydopamine rat model of PD. This effect was associated with a preferential activation of the direct striato-nigral pathway. These results potentially open new avenues in the understanding of mechanisms involved in l-dopa-induced dyskinesias. © 2017 International Parkinson and Movement Disorder Society.

Dopamine-Induced Changes in Gαolf Protein Levels in Striatonigral and Striatopallidal Medium Spiny Neurons Underlie the Genesis of l-DOPA-Induced Dyskinesia in Parkinsonian Mice.

The dopamine precursor, l-3,4-dihydroxyphenylalanine (l-DOPA), exerts powerful therapeutic effects but eventually generates l-DOPA-induced dyskinesia (LID) in patients with Parkinson’s disease (PD). LID has a close link with deregulation of striatal dopamine/cAMP signaling, which is integrated by medium spiny neurons (MSNs). Olfactory type G-protein α subunit (Gαolf), a stimulatory GTP-binding protein encoded by the GNAL gene, is highly concentrated in the striatum, where it positively couples with dopamine D1 (D1R) receptor and adenosine A2A receptor (A2AR) to increase intracellular cAMP levels in MSNs. In the striatum, D1Rs are mainly expressed in the MSNs that form the striatonigral pathway, while D2Rs and A2ARs are expressed in the MSNs that form the striatopallidal pathway. Here, we examined the association between striatal Gαolf protein levels and the development of LID. We used a hemi-parkinsonian mouse model with nigrostriatal lesions induced by 6-hydroxydopamine (6-OHDA). Using quantitative immunohistochemistry (IHC) and a dual-antigen recognition in situ proximity ligation assay (PLA), we here found that in the dopamine-depleted striatum, there appeared increased and decreased levels of Gαolf protein in striatonigral and striatopallidal MSNs, respectively, after a daily pulsatile administration of l-DOPA. This leads to increased responsiveness to dopamine stimulation in both striatonigral and striatopallidal MSNs. Because Gαolf protein levels serve as a determinant of cAMP signal-dependent activity in striatal MSNs, we suggest that l-DOPA-induced changes in striatal Gαolf levels in the dopamine-depleted striatum could be a key event in generating LID.

Functional role of new striatopallidal specific genes in motor and motivational behavior

Event Abstract Back to Event Functional role of new striatopallidal specific genes in motor and motivational behavior Deniz Karadurmus1*, Daniel Rial1, Alban De Kerchove D'Exaerde1 and Serge N. Schiffmann1 1 Université Libre de Bruxelles, Belgium Basal ganglia are a set of interconnected nuclei involved in motor control and motivation. The striatum is the main input of basal ganglia and is mainly composed of medium spiny neurons, subdivided into striatopallidal (STP) and striatonigral (STN) neurons. STP and STN neurons give rise respectively to the indirect and the direct pathways of basal ganglia, with opposite effects at both motor and motivational levels. Cellular mechanisms involving these pathways in disorders such as Huntington's and Parkinson's diseases and addiction, are still poorly understood. Our laboratory has previously identified gene expression profiles of STN and STP neurons using microarray (Ena et al., 2013). The present work consists in the identification and functional study of genes differentially expressed in STN and STP neurons, selected on their potential involvement in striatal functions. Using floxed mice, shRNA interference mediated by lentivirus and CRISPR/Cas9 techniques, we generated knockdown and/or knockout models for these genes. We are now assessing the effect of gene deletion using a multi technique approach, combining 3D reconstruction, electrophysiology and behavioral tests. Acknowledgements D.K.. was supported by a Research Fellow grant of the Fonds National de la Recherche Scientifique (FRS-FNRS) (Belgium). Keywords: Striatum, striatopallidal pathway, cell-type-specific gene, knockdown model, striatonigral pathway Conference: 12th National Congress of the Belgian Society for Neuroscience, Gent, Belgium, 22 May - 22 May, 2017. Presentation Type: Poster Presentation Topic: Cognition and Behavior Citation: Karadurmus D, Rial D, De Kerchove D'Exaerde A and Schiffmann SN (2019). Functional role of new striatopallidal specific genes in motor and motivational behavior. Front. Neurosci. Conference Abstract: 12th National Congress of the Belgian Society for Neuroscience. doi: 10.3389/conf.fnins.2017.94.00074 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: 24 Apr 2017; Published Online: 25 Jan 2019. * Correspondence: Ms. Deniz Karadurmus, Université Libre de Bruxelles, Brussels, Belgium, denizkaradurmus@hotmail.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 Deniz Karadurmus Daniel Rial Alban De Kerchove D'Exaerde Serge N Schiffmann Google Deniz Karadurmus Daniel Rial Alban De Kerchove D'Exaerde Serge N Schiffmann Google Scholar Deniz Karadurmus Daniel Rial Alban De Kerchove D'Exaerde Serge N Schiffmann PubMed Deniz Karadurmus Daniel Rial Alban De Kerchove D'Exaerde Serge N Schiffmann 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.

Involvement of Striatal Cholinergic Interneurons and M1 and M4 Muscarinic Receptors in Motor Symptoms of Parkinson's Disease

Over the last decade, striatal cholinergic interneurons (ChIs) have reemerged as key actors in the pathophysiology of basal-ganglia-related movement disorders. However, the mechanisms involved are still unclear. In this study, we address the role of ChI activity in the expression of parkinsonian-like motor deficits in a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion model using optogenetic and pharmacological approaches. Dorsal striatal photoinhibition of ChIs in lesioned ChAT(cre/cre) mice expressing halorhodopsin in ChIs reduces akinesia, bradykinesia, and sensorimotor neglect. Muscarinic acetylcholine receptor (mAChR) blockade by scopolamine produces similar anti-parkinsonian effects. To decipher which of the mAChR subtypes provides these beneficial effects, systemic and intrastriatal administration of the selective M1 and M4 mAChR antagonists telenzepine and tropicamide, respectively, were tested in the same model of Parkinson's disease. The two compounds alleviate 6-OHDA lesion-induced motor deficits. Telenzepine produces its beneficial effects by blocking postsynaptic M1 mAChRs expressed on medium spiny neurons (MSNs) at the origin of the indirect striatopallidal and direct striatonigral pathways. The anti-parkinsonian effects of tropicamide were almost completely abolished in mutant lesioned mice that lack M4 mAChRs specifically in dopamine D1-receptor-expressing neurons, suggesting that postsynaptic M4 mAChRs expressed on direct MSNs mediate the antiakinetic action of tropicamide. The present results show that altered cholinergic transmission via M1 and M4 mAChRs of the dorsal striatum plays a pivotal role in the occurrence of motor symptoms in Parkinson's disease. The striatum, where dopaminergic and cholinergic systems interact, is the pivotal structure of basal ganglia involved in pathophysiological changes underlying Parkinson's disease. Here, using optogenetic and pharmacological approaches, we investigated the involvement of striatal cholinergic interneurons (ChIs) and muscarinic receptor subtypes (mAChRs) in the occurrence of a wide range of motor deficits such as akinesia, bradykinesia, motor coordination, and sensorimotor neglect after unilateral nigrostriatal 6-hydroxydopamine lesion in mice. Our results show that photoinhibition of ChIs in the dorsal striatum and pharmacological blockade of muscarinic receptors, specifically postsynaptic M1 and M4 mAChRs, alleviate lesion-induced motor deficits. The present study points to these receptor subtypes as potential targets for the symptomatic treatment of parkinsonian-like motor symptoms.

Basal Ganglia: Pathways for action.

Patterns of coordinated activity in the direct, striatonigral pathway and the indirect, striatopallidal pathway regulate action performance.

Complementary Contributions of Striatal Projection Pathways to Action Initiation and Execution

The performance of an action relies on the initiation andexecution of appropriate movement sequences. Two basal ganglia pathways have been classically hypothesized to regulate this process via opposing roles in movement facilitation and suppression. By using a series of state-dependent optogenetic manipulations, we dissected the contributions of each pathway and found that both the direct striatonigral pathway and the indirect striatopallidal pathway are necessary for smooth initiation and the execution oflearned action sequences. Optogenetic inhibition or stimulation of each pathway before sequence initiation increased the latency for initiation: manipulations of the striatonigral pathway activity slowed action initiation, and those of the striatopallidal pathway aborted action initiation. Theinhibition of each pathway after initiation also impaired ongoing execution. Furthermore, the subtle activation of striatonigral neurons sustained the performance of learned sequences, while striatopallidal manipulations aborted ongoing performance. These results suggest a supportive versus permissive model, where patterns of coordinated activity, rather than the relative amount of activity in these pathways, regulate movement initiation and execution.

Susceptibility Sensitive Magnetic Resonance Imaging Displays Pallidofugal and Striatonigral Fiber Tracts.

The pallidofugal and striatonigral fiber tracts form a functional part of the basal ganglionic neuronal networks. For deep brain stimulation, a surgical procedure applied in the treatment of Parkinson disease and dystonia, precise localization of pallidofugal pathways may be of particular clinical relevance for correct electrode positioning. To investigate whether the pallidofugal and striatonigral pathways can be visualized with magnetic resonance imaging in vivo by exploiting their intrinsic magnetic susceptibility. Three-dimensional gradient-echo imaging of 5 volunteers was performed on a 7 T magnetic resonance imaging system. To demonstrate that the displayed tubular structures in the vicinity of the subthalamic nucleus and substantia nigra truly represent fiber tracts rather than veins, gradient-echo data of a formalin-fixated brain and a volunteer during inhalation of ambient air and carbogen were collected at 3 T. Susceptibility weighted images, quantitative susceptibility maps, and effective transverse relaxation maps were reconstructed and the depiction of fiber tracts was qualitatively assessed. High-resolution susceptibility-based magnetic resonance imaging contrasts enabled visualization of pallidofugal and striatonigral fiber tracts noninvasively at 3 T and 7 T. We verified that the stripe-like pattern observed on susceptibility-sensitive images is not caused by veins crossing the internal capsule but by fiber tracts traversing the internal capsule. Pallidofugal and striatonigral fiber tracts have been visualized in vivo for the first time by using susceptibility-sensitive image contrasts. Considering the course of pallidofugal pathways, in particular for deep brain stimulation procedures in the vicinity of the subthalamic nucleus, could provide landmarks for optimal targeting during stereotactic planning.

Striatonigral control of movement velocity in mice.

The basal ganglia have long been implicated in action initiation. Using three-dimensional motion capture, we quantified the effects of optogenetic stimulation of the striatonigral (direct) pathway on movement kinematics. We generated transgenic mice with channelrhodopsin-2 expression in striatal neurons that express the D1-like dopamine receptor. With optic fibres placed in the sensorimotor striatum, an area known to contain movement velocity-related single units, photo-stimulation reliably produced movements that could be precisely quantified with our motion capture programme. A single light pulse was sufficient to elicit movements with short latencies (< 30 ms). Increasing stimulation frequency increased movement speed, with a highly linear relationship. These findings support the hypothesis that the sensorimotor striatum is part of a velocity controller that controls rate of change in body configurations.

Overexpression of α-synuclein in oligodendrocytes does not increase susceptibility to focal striatal excitotoxicity.

BackgroundMultiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disease characterized by α-synuclein (α-syn) positive oligodendroglial cytoplasmic inclusions. The latter are associated with a neuronal multisystem neurodegeneration targeting central autonomic, olivopontocerebellar and striatonigral pathways, however the underlying mechanisms of neuronal cell death are poorly understood. Previous experiments have shown that oligodendroglial α-syn pathology increases the susceptibility to mitochondrial stress and proteasomal dysfunction leading to enhanced MSA-like neurodegeneration. Here we analyzed whether oligodendroglial α-syn overexpression in a transgenic mouse model of MSA synergistically interacts with focal neuronal excitotoxic damage generated by a striatal injection of quinolinic acid (QA) to affect the degree of striatal neuronal loss.ResultsQA injury led to comparable striatal neuronal loss and optical density of astro- and microgliosis in the striatum of transgenic and control mice. Respectively, no differences were identified in drug-induced rotation behavior or open field behavior between the groups.ConclusionsThe failure of oligodendroglial α-syn pathology to exacerbate striatal neuronal loss resulting from QA excitotoxicity contrasts with enhanced striatal neurodegeneration due to oxidative or proteolytic stress, suggesting that enhanced vulnerability to excitotoxicity does not occur in oligodendroglial α-synucleinopathy like MSA.

Coordinated Regulation of Synaptic Plasticity at Striatopallidal and Striatonigral Neurons Orchestrates Motor Control.

The basal ganglia play a critical role in shaping motorbehavior. For this function, the activity of medium spiny neurons (MSNs) of the striatonigral and striatopallidal pathways must be integrated. It remains unclear whether the activity of the two pathways is primarily coordinated by synaptic plasticity mechanisms. Using a model of Parkinson's disease, we determined the circuit and behavioral effects of concurrently regulating cell-type-specific forms of corticostriatal long-term synaptic depression (LTD) by inhibiting small-conductance Ca(2+)-activated K(+) channels (SKs) of the dorsolateral striatum. At striatopallidal synapses, SK channel inhibition rescued the disease-linked deficits in endocannabinoid (eCB)-dependent LTD. At striatonigral cells, inhibition of these channels counteracted a form of adenosine-mediated LTD by activating the ERK cascade. Interfering with eCB-, adenosine-, and ERK signaling invivo alleviated motor abnormalities, which supports that synaptic modulation of striatal pathways affects behavior. Thus, our results establish a central role of coordinated synaptic plasticity at MSN subpopulations in motor control.

Retinoic Acid Receptor β Controls Development of Striatonigral Projection Neurons through FGF-Dependent and Meis1-Dependent Mechanisms.

The mammalian striatum controls sensorimotor and psychoaffective functions through coordinated activities of its two striatonigral and striatopallidal output pathways. Here we show that retinoic acid receptor β (RARβ) controls development of a subpopulation of GABAergic, Gad65-positive striatonigral projection neurons. In Rarb(-/-) knock-out mice, concomitant reduction of Gad65, dopamine receptor D1 (Drd1), and substance P expression at different phases of prenatal development was associated with reduced number of Drd1-positive cells at birth, in contrast to normal numbers of striatopallidal projection neurons expressing dopamine receptor D2. Fate mapping using BrdU pulse-chase experiments revealed that such deficits may originate from compromised proliferation of late-born striosomal neurons and lead to decreased number of Drd1-positive cells retaining BrdU in postnatal day (P) 0 Rarb(-/-) striatum. Reduced expression of Fgf3 in the subventricular zone of the lateral ganglionic eminence (LGE) at embryonic day 13.5 may underlie such deficits by inducing premature differentiation of neuronal progenitors, as illustrated by reduced expression of the proneural gene Ascl1 (Mash1) and increased expression of Meis1, a marker of postmitotic LGE neurons. In agreement with a critical role of FGF3 in this control, reduced number of Ascl1-expressing neural progenitors, and a concomitant increase of Meis1-expressing cells, were observed in primary cell cultures of Rarb(-/-) LGE. This defect was normalized by addition of fibroblast growth factor (FGF). Such data point to role of Meis1 in striatal development, also supported by reduced neuronal differentiation in the LGE of Meis1(-/-) embryos. Our data unveil a novel mechanism of development of striatonigral projection neurons involving retinoic acid and FGF, two signals required for positioning the boundaries of Meis1-expressing cells.

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.

Endocannabinoid signaling mechanisms in the substantia nigra pars reticulata modulate GABAergic nigrotectal pathways in mice threatened by urutu-cruzeiro venomous pit viper

The substantia nigra pars reticulata (SNpr) is rich in γ-aminobutyric acid (GABA)-ergic neurons and connected to the mesencephalic tectum (MT) structures, such as the superior colliculus and dorsal periaqueductal gray matter. The SNpr presents a high density of cannabinoid receptors (CBRs), suggesting a possible regulatory role that is played by endocannabinoids (eCBs) in the ventral mesencephalon. The present study investigated the involvement of SNpr eCB mechanisms in nigrotectal pathways in the expression of defensive behavior associated with instinctive fear and panic reactions in mice that are confronted with the venomous Viperidae snake Bothrops alternatus. The localization of CB1 receptors (CB1RS) and synaptophysin glycoprotein in the SNpr was also evaluated. Administration of the GABAA receptor antagonist bicuculline in the MT increased defensive responses to the snake that are related to panic, such as freezing and non-oriented escape reactions, sometimes toward the snake itself. Mice that were pretreated with anandamide (5 or 50pmol) in the SNpr, followed by an injection of physiological saline or bicuculline in the MT, exhibited significant decreases in the expression of alertness, freezing, and escape responses. Immunofluorescence showed the presence of fibers that were rich in CB1RS and synaptophysin in the SNpr, indicating that these receptors appear to be located mainly in presynaptic terminals in the striatonigral pathway. These findings suggest that eCB mechanisms in the SNpr facilitate the activity of nigrotectal GABAergic pathways, modulating the activity of striatonigral links during the elaboration and organization of innate fear and panic-like responses in threatening situations.

The PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents

Phosphodiesterase 10A (PDE10A) has garnered attention as a potential therapeutic target for schizophrenia due to its prominent striatal expression and ability to modulate striatal signaling. The present study used the selective PDE10A inhibitor MP-10 and the dopamine D2 antagonist haloperidol to compare effects of PDE10A inhibition and dopamine D2 blockade on striatopallidal (D2) and striatonigral (D1) pathway activation. Our studies confirmed that administration of MP-10 significantly elevates expression of the immediate early genes (IEG) c-fos, egr-1, and arc in rat striatum. Furthermore, we demonstrated that MP-10 induced egr-1 expression was distributed evenly between enkephalin-containing D2-neurons and substance P-containing D1-neurons. In contrast, haloperidol (3 mg/kg) selectively activated egr-1 expression in enkephalin neurons. Co-administration of MP-10 and haloperidol (0.5 mg/kg) increased IEG expression to a greater extent than either compound alone. Similarly, in a rat catalepsy assay, administration of haloperidol (0.5 mg/kg) or MP-10 (3–30 mg/kg) did not produce cataleptic behavior when dosed alone, but co-administration of haloperidol with MP-10 (3 and 10 mg/kg) induced cataleptic behaviors. Interestingly, co-administration of haloperidol with a high dose of MP-10 (30 mg/kg) failed to produce cataleptic behavior. These findings are important for understanding the neural circuits involved in catalepsy and suggest that the behavioral effects produced by PDE10A inhibitors may be influenced by concomitant medication and the level of PDE10A inhibition achieved by the dose of the inhibitor.

Loss of the preferential control over the striato-nigral direct pathway by striatal NMDA receptors in a rat model of Parkinson's disease.

By using multi-probe microdialysis we previously demonstrated that endogenous glutamate differentially regulates the activity of the striatal output pathways in vivo, through N-methyl-d-aspartate (NMDA) receptors containing the GluN2A or GluN2B subunits. Using the same approach, we presently investigate whether reverse dialysis of NMDA in the striatum differentially affects GABA release in the striatum and in striatal target areas, i.e. globus pallidus (GP) and substantia nigra reticulata (SNr). Moreover, we ask whether this control is altered under parkinsonian conditions. Intrastriatal NMDA perfusion (10 min) evoked GABA release more potently in SNr (1-100 μM) than in other regions (10-100 μM), suggesting preferential control over striato-nigral projection neurons. Intrastriatal NMDA more potently stimulated glutamate levels in the striatum (1-100 μM) and SNr (1-10 μM) than in GP (10 μM). Striatal dopamine denervation with 6-hydroxydopamine caused a leftward shift in the NMDA concentration-response curve. Intrastriatal NMDA elevated GABA levels at 0.1 μM (all regions) and 1 μM (striatum and GP only), but not at higher concentrations, indicating that, compared to naïve animals, the GABA response in SNr was attenuated. Attenuation of the glutamate response was also observed in SNr (NMDA effective only at 0.1 μM). Conversely, the glutamate response in GP was widened (NMDA effective in the 0.1-1 μM range). We conclude that NMDA preferentially stimulates the activity of the striato-nigral direct pathway under physiological conditions. In Parkinson's disease, dopamine loss compromises the NMDA ability to stimulate striato-nigral neurons, thus shifting the NMDA control towards the striato-pallidal ones.

Functional role of PDGFRb, a striatopallidal specific gene, in motor and motivational behavior

Event Abstract Back to Event Functional role of PDGFRb, a striatopallidal specific gene, in motor and motivational behavior Deniz Karadurmus1*, Sabrina L. Ena1, Laurie Lambot1, Alban De Kerchove D'Exaerde1 and Serge N. Schiffmann1 1 Université Libre de Bruxelles, ULB Neuroscience Institute, Belgium Basal ganglia are a set of interconnected nuclei involved in motor control and motivation. The striatum is the main input of basal ganglia and is mainly composed of medium spiny neurons, subdivided into striatopallidal (STP) and striatonigral (STN) neurons. STP and STN neurons give rise respectively to the indirect and the direct pathways of basal ganglia, with opposite effects at both motor and motivational levels. Cellular mechanisms involving these pathways in disorders such as Huntington's and Parkinson's diseases and addiction, are still poorly understood. Our laboratory has previously identified gene expression profiles of STN and STP neurons using microarray (Ena, 2013). Our project consists in the study of STP or STN specific genes function in locomotor control and addiction behavior. To this end, specific repression of genes of interest in STP or STN pathway is generated using floxed mice or shRNA interference mediated by lentivirus. Phenotypic analysis is then achieved through behavioral tests to assess the effect of gene deletion. Moreover, different experimental strategies based on molecular biology and electrophysiology are used to determine molecular mechanisms responsible for observed phenotypes. We first focused on PDGFRb because of its enrichment in STP neurons and its potential function in striatal neurons according to the literature. STP specific expression of PDGFRb has been validated, and the activation pathway of PDGFRb in STP neurons has been investigated in primary striatal cultures. We are now generating mouse model repressing PDGFRb in striatal neurons to study PDGFRb deletion effects in vivo. References Ena, S. L., De Backer, J. F., Schiffmann, S. N., de Kerchove d'Exaerde, A. (2013). FACS array profiling identifies Ecto-5' nucleotidase as a striatopallidal neuron-specific gene involved in striatal-dependent learning. J Neurosci 33, 8794-809, DOI:10.1523/JNEUROSCI.2989-12.2013 Keywords: Striatum, PDGFRB, striatopallidal pathway, striatonigral pathway, cell-type-specific gene Conference: 11th National Congress of the Belgian Society for Neuroscience, Mons, Belgium, 22 May - 22 May, 2015. Presentation Type: Poster presentation Topic: Neuroscience Citation: Karadurmus D, Ena SL, Lambot L, De Kerchove D'Exaerde A and Schiffmann SN (2015). Functional role of PDGFRb, a striatopallidal specific gene, in motor and motivational behavior. Front. Neurosci. Conference Abstract: 11th National Congress of the Belgian Society for Neuroscience. doi: 10.3389/conf.fnins.2015.89.00045 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: 29 Apr 2015; Published Online: 05 May 2015. * Correspondence: Ms. Deniz Karadurmus, Université Libre de Bruxelles, ULB Neuroscience Institute, Bruxelles, 1070, Belgium, denizkaradurmus@hotmail.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 Deniz Karadurmus Sabrina L Ena Laurie Lambot Alban De Kerchove D'Exaerde Serge N Schiffmann Google Deniz Karadurmus Sabrina L Ena Laurie Lambot Alban De Kerchove D'Exaerde Serge N Schiffmann Google Scholar Deniz Karadurmus Sabrina L Ena Laurie Lambot Alban De Kerchove D'Exaerde Serge N Schiffmann PubMed Deniz Karadurmus Sabrina L Ena Laurie Lambot Alban De Kerchove D'Exaerde Serge N Schiffmann 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.