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Results: 1 to 10 of 21

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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20 MeSH Terms
M muscarinic activation induces long-lasting increase in intrinsic excitability of striatal projection neurons.
Lv X, Dickerson JW, Rook JM, Lindsley CW, Conn PJ, Xiang Z
(2017) Neuropharmacology 118: 209-222
MeSH Terms: Acetylcholine, Action Potentials, Animals, Channelrhodopsins, Choline O-Acetyltransferase, Cholinergic Agents, Corpus Striatum, Cues, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, Female, Gene Expression Regulation, Learning, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Neurons, Photic Stimulation, Receptor, Muscarinic M1
Show Abstract · Added April 6, 2017
The dorsolateral striatum is critically involved in movement control and motor learning. Striatal function is regulated by a variety of neuromodulators including acetylcholine. Previous studies have shown that cholinergic activation excites striatal principal projection neurons, medium spiny neurons (MSNs), and this action is mediated by muscarinic acetylcholine subtype 1 receptors (M) through modulating multiple potassium channels. In the present study, we used electrophysiology techniques in conjunction with optogenetic and pharmacological tools to determine the long-term effects of striatal cholinergic activation on MSN intrinsic excitability. A transient increase in acetylcholine release in the striatum by optogenetic stimulation resulted in a long-lasting increase in excitability of MSNs, which was associated with hyperpolarizing shift of action potential threshold and decrease in afterhyperpolarization (AHP) amplitude, leading to an increase in probability of EPSP-action potential coupling. The M selective antagonist VU0255035 prevented, while the M selective positive allosteric modulator (PAM) VU0453595 potentiated the cholinergic activation-induced persistent increase in MSN intrinsic excitability, suggesting that M receptors are critically involved in the induction of this long-lasting response. This M receptor-dependent long-lasting change in MSN intrinsic excitability could have significant impact on striatal processing and might provide a novel mechanism underlying cholinergic regulation of the striatum-dependent motor learning and cognitive function. Consistent with this, behavioral studies indicate that potentiation of M receptor signaling by VU0453595 enhanced performance of mice in cue-dependent water-based T-maze, a dorsolateral striatum-dependent learning task.
Copyright © 2017. Published by Elsevier Ltd.
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21 MeSH Terms
Heterogeneous transgene expression in the retinas of the TH-RFP, TH-Cre, TH-BAC-Cre and DAT-Cre mouse lines.
Vuong HE, Pérez de Sevilla Müller L, Hardi CN, McMahon DG, Brecha NC
(2015) Neuroscience 307: 319-37
MeSH Terms: Animals, Biotin, Calbindin 2, Choline O-Acetyltransferase, Chromosomes, Artificial, Bacterial, Dopamine Plasma Membrane Transport Proteins, Female, Gene Expression Regulation, Glycine, Integrases, Luminescent Proteins, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, RNA-Binding Proteins, Retina, Tyrosine 3-Monooxygenase, Visual Pathways, gamma-Aminobutyric Acid
Show Abstract · Added February 3, 2017
Transgenic mouse lines are essential tools for understanding the connectivity, physiology and function of neuronal circuits, including those in the retina. This report compares transgene expression in the retina of a tyrosine hydroxylase (TH)-red fluorescent protein (RFP) mouse line with three catecholamine-related Cre recombinase mouse lines [TH-bacterial artificial chromosome (BAC)-, TH-, and dopamine transporter (DAT)-Cre] that were crossed with a ROSA26-tdTomato reporter line. Retinas were evaluated and immunostained with commonly used antibodies including those directed to TH, GABA and glycine to characterize the RFP or tdTomato fluorescent-labeled amacrine cells, and an antibody directed to RNA-binding protein with multiple splicing to identify ganglion cells. In TH-RFP retinas, types 1 and 2 dopamine (DA) amacrine cells were identified by their characteristic cellular morphology and type 1 DA cells by their expression of TH immunoreactivity. In the TH-BAC-, TH-, and DAT-tdTomato retinas, less than 1%, ∼ 6%, and 0%, respectively, of the fluorescent cells were the expected type 1 DA amacrine cells. Instead, in the TH-BAC-tdTomato retinas, fluorescently labeled AII amacrine cells were predominant, with some medium diameter ganglion cells. In TH-tdTomato retinas, fluorescence was in multiple neurochemical amacrine cell types, including four types of polyaxonal amacrine cells. In DAT-tdTomato retinas, fluorescence was in GABA immunoreactive amacrine cells, including two types of bistratified and two types of monostratified amacrine cells. Although each of the Cre lines was generated with the intent to specifically label DA cells, our findings show a cellular diversity in Cre expression in the adult retina and indicate the importance of careful characterization of transgene labeling patterns. These mouse lines with their distinctive cellular labeling patterns will be useful tools for future studies of retinal function and visual processing.
Published by Elsevier Ltd.
1 Communities
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20 MeSH Terms
Persistent sonic hedgehog signaling in adult brain determines neural stem cell positional identity.
Ihrie RA, Shah JK, Harwell CC, Levine JH, Guinto CD, Lezameta M, Kriegstein AR, Alvarez-Buylla A
(2011) Neuron 71: 250-62
MeSH Terms: Age Factors, Animals, Calbindins, Cell Movement, Cerebral Ventricles, Choline O-Acetyltransferase, Cytarabine, Estrogen Antagonists, Gene Expression Regulation, Hedgehog Proteins, Immunosuppressive Agents, Kruppel-Like Transcription Factors, Luminescent Proteins, Mice, Mice, Transgenic, Neural Stem Cells, Neurons, Olfactory Bulb, RNA, Messenger, Receptors, G-Protein-Coupled, S100 Calcium Binding Protein G, Signal Transduction, Smoothened Receptor, Stilbamidines, Tamoxifen, Time Factors, Tyrosine 3-Monooxygenase, Zinc Finger Protein GLI1
Show Abstract · Added August 21, 2012
Neural stem cells (NSCs) persist in the subventricular zone (SVZ) of the adult brain. Location within this germinal region determines the type of neuronal progeny NSCs generate, but the mechanism of adult NSC positional specification remains unknown. We show that sonic hedgehog (Shh) signaling, resulting in high gli1 levels, occurs in the ventral SVZ and is associated with the genesis of specific neuronal progeny. Shh is selectively produced by a small group of ventral forebrain neurons. Ablation of Shh decreases production of ventrally derived neuron types, while ectopic activation of this pathway in dorsal NSCs respecifies their progeny to deep granule interneurons and calbindin-positive periglomerular cells. These results show that Shh is necessary and sufficient for the specification of adult ventral NSCs.
Copyright © 2011 Elsevier Inc. All rights reserved.
1 Communities
1 Members
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28 MeSH Terms
Motor neuron-specific overexpression of the presynaptic choline transporter: impact on motor endurance and evoked muscle activity.
Lund D, Ruggiero AM, Ferguson SM, Wright J, English BA, Reisz PA, Whitaker SM, Peltier AC, Blakely RD
(2010) Neuroscience 171: 1041-53
MeSH Terms: Acetylcholine, Acetylcholinesterase, Action Potentials, Animals, Animals, Newborn, Behavior, Animal, Brain, Choline O-Acetyltransferase, Electric Stimulation, Exercise Test, GPI-Linked Proteins, Gene Expression Regulation, Developmental, Green Fluorescent Proteins, Homeodomain Proteins, Membrane Transport Proteins, Mice, Mice, Transgenic, Motor Activity, Motor Neurons, Muscle, Skeletal, Nerve Tissue Proteins, Neuromuscular Junction, Statistics, Nonparametric, Synapses, Transcription Factors
Show Abstract · Added July 11, 2013
The presynaptic, hemicholinium-3 sensitive, high-affinity choline transporter (CHT) supplies choline for acetylcholine (ACh) synthesis. In mice, a homozygous deletion of CHT (CHT-/-) leads to premature cessation of spontaneous or evoked neuromuscular signaling and is associated with perinatal cyanosis and lethality within 1 h. Heterozygous (CHT+/-) mice exhibit diminished brain ACh levels and demonstrate an inability to sustain vigorous motor activity. We sought to explore the contribution of CHT gene dosage to motor function in greater detail using transgenic mice where CHT is expressed under control of the motor neuron promoter Hb9 (Hb9:CHT). On a CHT-/- background, the Hb9:CHT transgene conferred mice with the ability to move and breath for a postnatal period of ∼24 h, thus increasing survival. Conversely, Hb9:CHT expression on a wild-type background (CHT+/+;Hb9:CHT) leads to an increased capacity for treadmill running compared to wild-type littermates. Analysis of the stimulated compound muscle action potential (CMAP) in these animals under basal conditions established that CHT+/+;Hb9:CHT mice display an unexpected, bidirectional change, producing either elevated or reduced CMAP amplitude, relative to CHT+/+ animals. To examine whether these two groups arise from underlying changes in synaptic properties, we used high-frequency stimulation of motor axons to assess CMAP recovery kinetics. Although CHT+/+; Hb9:CHT mice in the two groups display an equivalent, time-dependent reduction in CMAP amplitude, animals with a higher basal CMAP amplitude demonstrate a significantly enhanced rate of recovery. To explain our findings, we propose a model whereby CHT support for neuromuscular signaling involves contributions to ACh synthesis as well as cholinergic synaptic vesicle availability.
Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.
2 Communities
3 Members
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25 MeSH Terms
Impaired cognition, sensorimotor gating, and hippocampal long-term depression in mice lacking the prostaglandin E2 EP2 receptor.
Savonenko A, Munoz P, Melnikova T, Wang Q, Liang X, Breyer RM, Montine TJ, Kirkwood A, Andreasson K
(2009) Exp Neurol 217: 63-73
MeSH Terms: Analysis of Variance, Animals, Attention, Avoidance Learning, Choline O-Acetyltransferase, Cognition Disorders, Dendrites, Discrimination (Psychology), Disks Large Homolog 4 Protein, Electroshock, Exploratory Behavior, Guanylate Kinases, Hippocampus, In Vitro Techniques, Inhibition (Psychology), Intracellular Signaling Peptides and Proteins, Long-Term Synaptic Depression, Maze Learning, Membrane Proteins, Memory, Mice, Mice, Inbred C57BL, Mice, Knockout, Neuropsychological Tests, Odorants, Receptors, Prostaglandin E, Receptors, Prostaglandin E, EP2 Subtype, Sensory Gating, Social Behavior, Spatial Behavior
Show Abstract · Added December 21, 2013
Cyclooxygenase-2 (COX-2) is a neuronal immediate early gene that is regulated by N-methyl d aspartate (NMDA) receptor activity. COX-2 enzymatic activity catalyzes the first committed step in prostaglandin synthesis. Recent studies demonstrate an emerging role for the downstream PGE(2) EP2 receptor in diverse models of activity-dependent synaptic plasticity and a significant function in models of neurological disease including cerebral ischemia, Familial Alzheimer's disease, and Familial amyotrophic lateral sclerosis. Little is known, however, about the normal function of the EP2 receptor in behavior and cognition. Here we report that deletion of the EP2 receptor leads to significant cognitive deficits in standard tests of fear and social memory. EP2-/- mice also demonstrated impaired prepulse inhibition (PPI) and heightened anxiety, but normal startle reactivity, exploratory behavior, and spatial reference memory. This complex behavioral phenotype of EP2-/- mice was associated with a deficit in long-term depression (LTD) in hippocampus. Our findings suggest that PGE(2) signaling via the EP2 receptors plays an important role in cognitive and emotional behaviors that recapitulate some aspects of human psychopathology related to schizophrenia.
1 Communities
1 Members
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30 MeSH Terms
The high-affinity choline transporter: a critical protein for sustaining cholinergic signaling as revealed in studies of genetically altered mice.
Bazalakova MH, Blakely RD
(2006) Handb Exp Pharmacol : 525-44
MeSH Terms: Acetylcholinesterase, Animals, Choline, Choline O-Acetyltransferase, Membrane Transport Proteins, Mice, Mice, Knockout, Neuronal Plasticity, Presynaptic Terminals, Receptors, Nicotinic, Synaptic Transmission
Show Abstract · Added July 10, 2013
In cholinergic neurons, the presynaptic choline transporter (CHT) mediates high-affinity choline uptake (HACU) as the rate-limiting step in acetylcholine (ACh) synthesis. It has previously been shown that HACU is increased by behaviorally and pharmacologically-induced activity of cholinergic neurons in vivo, but the molecular mechanisms of this change in CHT function and regulation have only recently begun to be elucidated. The recent cloning of CHT has led to the generation of new valuable tools, including specific anti-CHT antibodies and a CHT knockout mouse. These new reagents have allowed researchers to investigate the possibility of a presynaptic, CHT-mediated, molecular plasticity mechanism, regulated by and necessary for sustained in vivo cholinergic activity. Studies in various mouse models of cholinergic dysfunction, including acetylcholinesterase (AChE) transgenic and knockout mice, choline acetyltransferase (ChAT) heterozygote mice, muscarinic (mAChR) and nicotinic (mAChR) receptor knockout mice, as well as CHT knockout and heterozygote mice, have revealed new information about the role of CHT expression and regulation in response to long-term alterations in cholinergic neurotransmission. These mouse models highlight the capacity of CHT to provide for functional compensation in states of cholinergic dysfunction. A better understanding of modes of CHT regulation should allow for experimental manipulation of cholinergic signaling in vivo with potential utility in human disorders of known cholinergic dysfunction such as Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's disease, and dysautonomia.
1 Communities
1 Members
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11 MeSH Terms
Developmental expression of the high affinity choline transporter in cholinergic sympathetic neurons.
Guidry G, Willison BD, Blakely RD, Landis SC, Habecker BA
(2005) Auton Neurosci 123: 54-61
MeSH Terms: Animals, Axons, Blotting, Western, Choline O-Acetyltransferase, Female, Foot, Immunohistochemistry, Membrane Transport Proteins, Mice, Neurons, Pregnancy, Rats, Rats, Sprague-Dawley, Superior Cervical Ganglion, Sweat Glands, Sympathectomy, Chemical, Sympathetic Nervous System, Tyrosine 3-Monooxygenase
Show Abstract · Added July 10, 2013
Choline uptake by the high affinity choline transporter (CHT) is the rate-limiting step in acetylcholine synthesis. Induction of CHT is therefore a critical step in cholinergic differentiation, and we examined the developmental expression of CHT in cholinergic sympathetic neurons that innervate rodent sweat glands. During postnatal development the earliest sympathetic axons in the rear footpads are noradrenergic, containing intense tyrosine hydroxylase immunoreactivity and lacking CHT-immunoreactivity (CHT-IR). By postnatal day 7 (P7) in mouse, and P10 in rat, weak CHT-IR appeared in axons associated with the sweat gland anlagen. CHT staining intensity increased during the following weeks in conjunction with plexus arborization and gland maturation. The pattern of CHT-immunoreactivity (CHT-IR) in the sweat gland innervation was similar to staining for the vesicular acetylcholine transporter and vasoactive intestinal peptide. Immunoblots of tissue from sympathectomized rats confirmed that most of the CHT in footpad was contained in sympathetic neurons. Although CHT expression has been reported in noradrenergic sympathetic neurons of the superior cervical ganglion, these data indicate that in the sympathetic neurons projecting to sweat glands CHT is present at detectable levels only after association with the glands.
1 Communities
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18 MeSH Terms
Lethal impairment of cholinergic neurotransmission in hemicholinium-3-sensitive choline transporter knockout mice.
Ferguson SM, Bazalakova M, Savchenko V, Tapia JC, Wright J, Blakely RD
(2004) Proc Natl Acad Sci U S A 101: 8762-7
MeSH Terms: Acetylcholine, Animals, Brain, Choline O-Acetyltransferase, Cholinergic Agents, Hemicholinium 3, In Vitro Techniques, Membrane Transport Proteins, Mice, Mice, Knockout, Motor Neurons, Neuromuscular Junction, Phenotype, Synaptic Transmission, Synaptosomes
Show Abstract · Added July 10, 2013
Presynaptic acetylcholine (ACh) synthesis and release is thought to be sustained by a hemicholinium-3-sensitive choline transporter (CHT). We disrupted the murine CHT gene and examined CHT-/- and +/- animals for evidence of impaired cholinergic neurotransmission. Although morphologically normal at birth, CHT-/- mice become immobile, breathe irregularly, appear cyanotic, and die within an hour. Hemicholinium-3-sensitive choline uptake and subsequent ACh synthesis are specifically lost in CHT-/- mouse brains. Moreover, we observe a time-dependent loss of spontaneous and evoked responses at CHT-/- neuromuscular junctions. Consistent with deficits in synaptic ACh availability, we also observe developmental alterations in neuromuscular junction morphology reminiscent of changes in mutants lacking ACh synthesis. Adult CHT+/- mice overcome reductions in CHT protein levels and sustain choline uptake activity at wild-type levels through posttranslational mechanisms. Our results demonstrate that CHT is an essential and regulated presynaptic component of cholinergic signaling and indicate that CHT warrants consideration as a candidate gene for disorders characterized by cholinergic hypofunction.
2 Communities
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15 MeSH Terms
The neurotensin agonist PD149163 increases Fos expression in the prefrontal cortex of the rat.
Petrie KA, Bubser M, Casey CD, Davis MD, Roth BL, Deutch AY
(2004) Neuropsychopharmacology 29: 1878-88
MeSH Terms: Animals, Antipsychotic Agents, Body Temperature, Calbindin 2, Calbindins, Cell Count, Choline O-Acetyltransferase, Dose-Response Relationship, Drug, Genes, fos, Immunoblotting, Immunoenzyme Techniques, Interneurons, Male, Neurotensin, Parasympathetic Nervous System, Parvalbumins, Prefrontal Cortex, Pyrazoles, Quinolines, Rats, Rats, Sprague-Dawley, Receptors, Neurotensin, S100 Calcium Binding Protein G
Show Abstract · Added May 27, 2014
Dopaminergic axons innervating the prefrontal cortex (PFC) target both pyramidal cells and GABAergic interneurons. Many of these dopamine (DA) axons in the rat coexpress the peptide neurotransmitter neurotensin. Previous electrophysiological data have suggested that neurotensin activates GABAergic interneurons in the PFC. Activation of D2-like DA receptors increases extracellular GABA levels in the PFC, as opposed to the striatum, where D2 receptor activation inhibits GABAergic neurons. Because activation of presynaptic D2 release-modulating autoreceptors in the PFC suppresses DA release but increases release of the cotransmitter neurotensin, D2 agonists may enhance the activity of GABAergic interneurons via release of neurotensin. In order to determine if neurotensin can activate GABAergic interneurons, we treated rats with the peptide neurotensin agonist, PD149163, and examined Fos expression in PFC neurons. Systemic administration of PD149163 increased overall Fos expression in the PFC, but not in the dorsal striatum. PD149163 induced Fos in PFC interneurons, as defined by the presence of calcium-binding proteins, and in pyramidal cells. Pretreatment with the high-affinity neurotensin antagonist, SR48692, blocked neurotensin agonist-induced Fos expression. These data suggest that neurotensin activates interneurons in the PFC of the rat.
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23 MeSH Terms