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Publication Record


Cholinergic Projections to the Substantia Nigra Pars Reticulata Inhibit Dopamine Modulation of Basal Ganglia through the M Muscarinic Receptor.
Moehle MS, Pancani T, Byun N, Yohn SE, Wilson GH, Dickerson JW, Remke DH, Xiang Z, Niswender CM, Wess J, Jones CK, Lindsley CW, Rook JM, Conn PJ
(2017) Neuron 96: 1358-1372.e4
MeSH Terms: Acetylcholine, Animals, Basal Ganglia, Channelrhodopsins, Choline O-Acetyltransferase, Cholinergic Agents, Cholinergic Neurons, Dopamine, Inhibitory Postsynaptic Potentials, Locomotion, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurotransmitter Agents, Oxygen, Pars Reticulata, Pedunculopontine Tegmental Nucleus, Receptor, Muscarinic M4, Receptors, Dopamine D1, Signal Transduction
Show Abstract · Added March 14, 2018
Cholinergic regulation of dopaminergic inputs into the striatum is critical for normal basal ganglia (BG) function. This regulation of BG function is thought to be primarily mediated by acetylcholine released from cholinergic interneurons (ChIs) acting locally in the striatum. We now report a combination of pharmacological, electrophysiological, optogenetic, chemogenetic, and functional magnetic resonance imaging studies suggesting extra-striatal cholinergic projections from the pedunculopontine nucleus to the substantia nigra pars reticulata (SNr) act on muscarinic acetylcholine receptor subtype 4 (M) to oppose cAMP-dependent dopamine receptor subtype 1 (D) signaling in presynaptic terminals of direct pathway striatal spiny projections neurons. This induces a tonic inhibition of transmission at direct pathway synapses and D-mediated activation of motor activity. These studies provide important new insights into the unique role of M in regulating BG function and challenge the prevailing hypothesis of the centrality of striatal ChIs in opposing dopamine regulation of BG output.
Copyright © 2017 Elsevier Inc. All rights reserved.
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4 Members
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20 MeSH Terms
OCD candidate gene /EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior.
Zike ID, Chohan MO, Kopelman JM, Krasnow EN, Flicker D, Nautiyal KM, Bubser M, Kellendonk C, Jones CK, Stanwood G, Tanaka KF, Moore H, Ahmari SE, Veenstra-VanderWeele J
(2017) Proc Natl Acad Sci U S A 114: 5719-5724
MeSH Terms: Amphetamines, Animals, Basal Ganglia, Cell Line, Central Nervous System Stimulants, Dopamine, Excitatory Amino Acid Transporter 3, Glutamic Acid, Grooming, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Obsessive-Compulsive Disorder, Receptors, Dopamine D1, Reflex, Startle
Show Abstract · Added March 18, 2020
Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to , which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in () locomotor activity, () stereotypy, and () immediate early gene induction in the dorsal striatum following amphetamine administration. Further, -STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCD-like grooming behavior. This reduced grooming is accompanied by reduced dopamine D receptor binding in the dorsal striatum of -STOP mice. -STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. Viral-mediated restoration of /EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine-induced locomotion and stereotypy in -STOP mice, consistent with an impact of EAAT3 loss on presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.
0 Communities
1 Members
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MeSH Terms
G protein-coupled receptor kinases as regulators of dopamine receptor functions.
Gurevich EV, Gainetdinov RR, Gurevich VV
(2016) Pharmacol Res 111: 1-16
MeSH Terms: Animals, Basal Ganglia, Central Nervous System Stimulants, G-Protein-Coupled Receptor Kinases, Humans, Parkinsonian Disorders, Phosphorylation, Receptors, Dopamine, Signal Transduction
Show Abstract · Added March 14, 2018
Actions of the neurotransmitter dopamine in the brain are mediated by dopamine receptors that belong to the superfamily of G protein-coupled receptors (GPCRs). Mammals have five dopamine receptor subtypes, D1 through D5. D1 and D5 couple to Gs/olf and activate adenylyl cyclase, whereas D2, D3, and D4 couple to Gi/o and inhibit it. Most GPCRs upon activation by an agonist are phosphorylated by GPCR kinases (GRKs). The GRK phosphorylation makes receptors high-affinity binding partners for arrestin proteins. Arrestin binding to active phosphorylated receptors stops further G protein activation and promotes receptor internalization, recycling or degradation, thereby regulating their signaling and trafficking. Four non- visual GRKs are expressed in striatal neurons. Here we describe known effects of individual GRKs on dopamine receptors in cell culture and in the two in vivo models of dopamine-mediated signaling: behavioral response to psychostimulants and L-DOPA- induced dyskinesia. Dyskinesia, associated with dopamine super-sensitivity of striatal neurons, is a debilitating side effect of L-DOPA therapy in Parkinson's disease. In vivo, GRK subtypes show greater receptor specificity than in vitro or in cultured cells. Overexpression, knockdown, and knockout of individual GRKs, particularly GRK2 and GRK6, have differential effects on signaling of dopamine receptor subtypes in the brain. Furthermore, deletion of GRK isoforms in select striatal neuronal types differentially affects psychostimulant-induced behaviors. In addition, anti-dyskinetic effect of GRK3 does not require its kinase activity: it is mediated by the binding of its RGS-like domain to Gαq/11, which suppresses Gq/11 signaling. The data demonstrate that the dopamine signaling in defined neuronal types in vivo is regulated by specific and finely orchestrated actions of GRK isoforms.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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1 Members
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9 MeSH Terms
Cortical hierarchy governs rat claustrocortical circuit organization.
White MG, Cody PA, Bubser M, Wang HD, Deutch AY, Mathur BN
(2017) J Comp Neurol 525: 1347-1362
MeSH Terms: Animals, Basal Ganglia, Immunohistochemistry, Male, Neural Pathways, Neurons, Rats, Rats, Sprague-Dawley
Show Abstract · Added February 22, 2016
The claustrum is a telencephalic gray matter structure with various proposed functions, including sensory integration and attentional allocation. Underlying these concepts is the reciprocal connectivity of the claustrum with most, if not all, areas of the cortex. What remains to be elucidated to inform functional hypotheses further is whether a pattern exists in the strength of connectivity between a given cortical area and the claustrum. To this end, we performed a series of retrograde neuronal tract tracer injections into rat cortical areas along the cortical processing hierarchy, from primary sensory and motor to frontal cortices. We observed that the number of claustrocortical projections increased as a function of processing hierarchy; claustrum neurons projecting to primary sensory cortices were scant and restricted in distribution across the claustrum, whereas neurons projecting to the cingulate cortex were densely packed and more evenly distributed throughout the claustrum. This connectivity pattern suggests that the claustrum may preferentially subserve executive functions orchestrated by the cingulate cortex. J. Comp. Neurol. 525:1347-1362, 2017. © 2016 Wiley Periodicals, Inc.
© 2016 Wiley Periodicals, Inc.
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1 Members
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8 MeSH Terms
Epidemiology of MRI-defined vascular depression: A longitudinal, community-based study in Korean elders.
Park JH, Lee SB, Lee JJ, Yoon JC, Han JW, Kim TH, Jeong HG, Newhouse PA, Taylor WD, Kim JH, Woo JI, Kim KW
(2015) J Affect Disord 180: 200-6
MeSH Terms: Aged, Aged, 80 and over, Basal Ganglia, Brain, Cerebral Ventricles, Cerebrovascular Disorders, Comorbidity, Cross-Sectional Studies, Depression, Depressive Disorder, Female, Follow-Up Studies, Geriatric Assessment, Health Status, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Republic of Korea
Show Abstract · Added February 4, 2016
BACKGROUND - There are no cross-sectional or longitudinal epidemiological studies present on MRI-defined vascular depression in community populations. The purpose of this study was to estimate the prevalence rates of both vascular and non-vascular late life depression (LLD) at baseline, to examine the natural course of LLD, and to investigate the influence of White matter hyperintensities (WMHs) on depression after three years.
METHOD - The baseline study employed a two-stage design, Phase I population survey (n=783) and Phase II diagnostic evaluation (n=122). In the 3-year follow-up study, baseline participants completing the second phase were reassessed with the same methodology. WMHs severity was rated visually by the modified Fazekas scale and WMHs volume was calculated using an automated method.
RESULTS - The prevalence rates of vascular major depressive disorder (MDD) and vascular non-major depressive disorder (nMDD) were 2.39% (56.2% of MDD) and 4.24% (34.0% of nMDD). Subjects with a score of 2 or more on the modified Fazekas scale in either deep white matter hyperintensities or subcortical gray matter ratings had an 8.1 times greater risk of developing a depressive disorder in the 3-year follow-up study. Greater Log WMHs volume (odds ratio=5.78, 95% CI, 1.04-31.72) at baseline was an independent predictor for depressive disorder in the 3-year assessment.
LIMITATIONS - Response rate and follow-up rate were relatively low.
CONCLUSIONS - Vascular depression is common and makes up about a half of MDD in elders. Greater WMHs severity is a crucial factor predicting future depression risk, which supports the previous vascular depression hypothesis.
Copyright © 2015 Elsevier B.V. All rights reserved.
0 Communities
2 Members
0 Resources
19 MeSH Terms
Substantia nigra hyperactivity in schizophrenia.
Heckers S, Konradi C
(2013) Biol Psychiatry 74: 82-3
MeSH Terms: Basal Ganglia, Female, Humans, Male, Prefrontal Cortex, Schizophrenia, Substantia Nigra
Added May 27, 2014
0 Communities
2 Members
0 Resources
7 MeSH Terms
Resting-state networks in schizophrenia.
Karbasforoushan H, Woodward ND
(2012) Curr Top Med Chem 12: 2404-14
MeSH Terms: Basal Ganglia, Brain, Humans, Magnetic Resonance Imaging, Prefrontal Cortex, Schizophrenia
Show Abstract · Added February 15, 2016
Schizophrenia has been conceptualized as a disorder of altered brain connectivity (i.e. dysconnectivity). Until relatively recently, it was not feasible to test dysconnectivity hypotheses of schizophrenia in vivo. Resting-state functional magnetic resonance imaging (fMRI) is a powerful tool for mapping functional networks of the brain, such as the default mode network (DMN), and investigating the systems-level pathology of neurological and psychiatric disorders. In this article, we review the latest findings from resting-state fMRI studies on schizophrenia. Despite the wide array of methods used and heterogeneity of patient samples, several tentative conclusions may be drawn from the existing literature. 1) Connectivity of the DMN is altered in schizophrenia. Findings vary across studies; however, a majority of investigations reported hyper-connectivity of the DMN. 2) Resting-state connectivity of the prefrontal cortex (PFC) is reduced in schizophrenia, particularly intra-PFC connectivity. 3) Cortical-subcortical networks, including thalamocortical, frontolimbic, and cortico-cerebellar networks are altered in schizophrenia. 4) Preliminary findings indicate that functional connectivity within auditory/language networks and the basal ganglia is related to specific clinical symptoms, including auditory- verbal hallucinations and delusions. 5) Whole-brain network topology measures based on graph theory indicate that functional brain networks in schizophrenia are characterized by reduced small-worldness, lower degree connectivity of brain hubs, and decreased modularity. 6) Some of the alterations in functional connectivity observed in probands are present in unaffected relatives, raising the possibility that functional dysconnectivity is an endophenotype related to genetic risk for schizophrenia. Combined, these findings provide broad support for dysconnectivity theories of schizophrenia. We conclude our review with a discussion of the limitations of the existing literature and potentially important areas of future research.
0 Communities
1 Members
0 Resources
6 MeSH Terms
Relationship of dopamine type 2 receptor binding potential with fasting neuroendocrine hormones and insulin sensitivity in human obesity.
Dunn JP, Kessler RM, Feurer ID, Volkow ND, Patterson BW, Ansari MS, Li R, Marks-Shulman P, Abumrad NN
(2012) Diabetes Care 35: 1105-11
MeSH Terms: Adult, Basal Ganglia, Body Mass Index, Fasting, Female, Ghrelin, Humans, Insulin Resistance, Leptin, Middle Aged, Obesity, Positron-Emission Tomography, Receptors, Dopamine D2
Show Abstract · Added December 5, 2013
OBJECTIVE - Midbrain dopamine (DA) neurons, which are involved with reward and motivation, are modulated by hormones that regulate food intake (insulin, leptin, and acyl ghrelin [AG]). We hypothesized that these hormones are associated with deficits in DA signaling in obesity.
RESEARCH DESIGN AND METHODS - We assessed the relationships between fasting levels of insulin and leptin, and AG, BMI, and insulin sensitivity index (S(I)) with the availability of central DA type 2 receptor (D2R). We measured D2R availability using positron emission tomography and [(18)F]fallypride (radioligand that competes with endogenous DA) in lean (n = 8) and obese (n = 14) females. Fasting hormones were collected prior to scanning and S(I) was determined by modified oral glucose tolerance test.
RESULTS - Parametric image analyses revealed associations between each metabolic measure and D2R. The most extensive findings were negative associations of AG with clusters involving the striatum and inferior temporal cortices. Regional regression analyses also found extensive negative relationships between AG and D2R in the caudate, putamen, ventral striatum (VS), amygdala, and temporal lobes. S(I) was negatively associated with D2R in the VS, while insulin was not. In the caudate, BMI and leptin were positively associated with D2R availability. The direction of associations of leptin and AG with D2R availability are consistent with their opposite effects on DA levels (decreasing and increasing, respectively). After adjusting for BMI, AG maintained a significant relationship in the VS. We hypothesize that the increased D2R availability in obese subjects reflects relatively reduced DA levels competing with the radioligand.
CONCLUSIONS - Our findings provide evidence for an association between the neuroendocrine hormones and DA brain signaling in obese females.
1 Communities
0 Members
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13 MeSH Terms
Roles of the M1 muscarinic acetylcholine receptor subtype in the regulation of basal ganglia function and implications for the treatment of Parkinson's disease.
Xiang Z, Thompson AD, Jones CK, Lindsley CW, Conn PJ
(2012) J Pharmacol Exp Ther 340: 595-603
MeSH Terms: Animals, Basal Ganglia, Male, Mice, Mice, Inbred C57BL, Parkinson Disease, Rats, Rats, Sprague-Dawley, Receptor, Muscarinic M1, Substantia Nigra, Subthalamic Nucleus, Synaptic Transmission
Show Abstract · Added February 19, 2015
Antagonists of the muscarinic acetylcholine receptors (mAChRs) were among the first treatments for Parkinson's disease. However, the clinical utility of mAChR antagonists is limited by adverse effects associated with the blockade of multiple mAChR subtypes. Understanding the roles of specific mAChR subtypes in regulating basal ganglia and motor function could lead to the development of novel agents that have antiparkinsonian activity with fewer adverse effects. Using the novel, highly selective M1 antagonist N-[3-oxo-3-[4-(4-pyridinyl)-1-piperazinyl]propyl]-2,1,3-benzothiadiazole-4-sulfonamide (VU0255035) and the M1 positive allosteric modulator benzylquinolone carboxylic acid, we investigated the roles of M1 receptors in cholinergic excitation and regulation of synaptic transmission in striatal medium spiny neurons (MSNs) and neurons in the subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr). Electrophysiological studies demonstrate that M1 activation has excitatory effects on MSNs but plays little or no role in mAChR-mediated increases in firing frequency or the regulation of synaptic transmission in STN and SNr neurons. On the basis of this profile, M1-selective antagonists may have weak antiparkinsonian activity but would not have the full efficacy observed in nonselective mAChR antagonists. Consistent with this, the M1-selective antagonist VU0255035 partially reversed reserpine-induced akinesia and decreased haloperidol-induced catalepsy in rats but did not have the full efficacy observed with the nonselective mAChR antagonist scopolamine. These results suggest that the M1 receptor participates in the overall regulation of basal ganglia function and antiparkinsonian effects of mAChR antagonists but that other mAChR subtype(s) also play important roles at multiple levels of the basal ganglia motor circuit.
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2 Members
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12 MeSH Terms
Activation of group II metabotropic glutamate receptors induces long-term depression of excitatory synaptic transmission in the substantia nigra pars reticulata.
Johnson KA, Niswender CM, Conn PJ, Xiang Z
(2011) Neurosci Lett 504: 102-106
MeSH Terms: Amino Acids, Animals, Basal Ganglia, Bridged Bicyclo Compounds, Heterocyclic, Data Interpretation, Statistical, Dose-Response Relationship, Drug, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, Mice, Mice, Knockout, Neuronal Plasticity, Patch-Clamp Techniques, Rats, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate, Substantia Nigra, Synaptic Transmission, Xanthenes, gamma-Aminobutyric Acid
Show Abstract · Added February 19, 2015
Activation of group II metabotropic glutamate receptors (mGlu2 and mGlu3) has been implicated as a potential therapeutic strategy for treating both motor symptoms and progressive neurodegeneration in Parkinson's disease (PD). Modulation of excitatory transmission in the basal ganglia represents a possible mechanism by which group II mGlu agonists could exert antiparkinsonian effects. Previous studies have identified reversible effects of mGlu2/3 activation on excitatory transmission at various synapses in the basal ganglia, including the excitatory synapse between the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr). Using whole-cell patch clamp studies of GABAergic SNr neurons in rat midbrain slices, we have found that a prolonged activation of group II mGlus by the selective agonist LY379268 induces a long-term depression (LTD) of evoked excitatory postsynaptic current (EPSC) amplitude. Bath application of LY379268 (100nM, 10min) induced a marked reduction in EPSC amplitude, and excitatory transmission remained depressed for at least 40min after agonist washout. The effect of LY379268 was concentration-dependent and was completely blocked by the group II mGlu-preferring antagonist LY341495 (500nM). To determine the relative contributions of mGlu2 and mGlu3 to the LTD induced by LY379268, we tested the ability of LY379268 (100nM) to induce LTD in wild type mice and mice lacking mGlu2 or mGlu3. LY379268 induced similar LTD in wild type mice and mGlu3 knockout mice, whereas LTD was absent in mGlu2 knockout mice, indicating that mGlu2 activation is necessary for the induction of LTD in the SNr. These studies suggest a novel role for mGlu2 in the long-term regulation of excitatory transmission in the SNr and invite further exploration of mGlu2 as a therapeutic target for treating the motor symptoms of PD.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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2 Members
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19 MeSH Terms