Chat

Summary

Gene Symbol: Chat
Description: choline acetyltransferase
Alias: B230380D24Rik, choline O-acetyltransferase, CHOACTase, choline acetylase
Species: mouse

Top Publications

  1. ncbi Complementary expression and regulation of cadherins 6 and 11 during specific steps of motoneuron differentiation
    Veronique Marthiens
    Signalisation et Différenciation Cellulaires dans les Systèmes Nerveux et Musculaire, INSERM U440 Université Paris 6, Institut du Fer a Moulin, Paris, France
    Mol Cell Neurosci 20:458-75. 2002
  2. pmc Amyolid precursor protein mediates presynaptic localization and activity of the high-affinity choline transporter
    Baiping Wang
    Huffington Center on Aging and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
    Proc Natl Acad Sci U S A 104:14140-5. 2007
  3. pmc Pet-1 is required across different stages of life to regulate serotonergic function
    Chen Liu
    Case Western Reserve University, School of Medicine, Department of Neurosciences, Cleveland, Ohio, USA
    Nat Neurosci 13:1190-8. 2010
  4. ncbi Loss of leukemia inhibitory factor receptor beta or cardiotrophin-1 causes similar deficits in preganglionic sympathetic neurons and adrenal medulla
    Stephan Oberle
    Neuroanatomy and Interdisciplinary Center for Neurosciences, University of Heidelberg, D 69120 Heidelberg, Germany
    J Neurosci 26:1823-32. 2006
  5. ncbi Choline transporter 1 maintains cholinergic function in choline acetyltransferase haploinsufficiency
    Eugene P Brandon
    Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA
    J Neurosci 24:5459-66. 2004
  6. doi Characterization of the null murine sodium/myo-inositol cotransporter 1 (Smit1 or Slc5a3) phenotype: myo-inositol rescue is independent of expression of its cognate mitochondrial ribosomal protein subunit 6 (Mrps6) gene and of phosphatidylinositol levels
    Roberto Buccafusca
    Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA
    Mol Genet Metab 95:81-95. 2008
  7. pmc Insm1 (IA-1) is an essential component of the regulatory network that specifies monoaminergic neuronal phenotypes in the vertebrate hindbrain
    John Jacob
    MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK
    Development 136:2477-85. 2009
  8. doi Dynamic expression patterns of Nkx6.1 and Nkx6.2 in the developing mes-diencephalic basal plate
    Juan Antonio Moreno-Bravo
    Instituto de Neurociencias de Alicante, Consejo Superior de Investigaciones Cientificas, and Universidad Miguel Hernandez, Sant Joan d Alacant, Spain
    Dev Dyn 239:2094-101. 2010
  9. ncbi Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation
    S L Pfaff
    Howard Hughes Medical Institute, Department of Biochemistry and Molecule Biophysics, Columbia University, New York, New York 10032, USA
    Cell 84:309-20. 1996
  10. ncbi The expression pattern of the transcription factor Phox2 delineates synaptic pathways of the autonomic nervous system
    M C Tiveron
    Institut de Biologie du Developpement de Marseille, Centre National dela Recherche Scientifique Institut National de la Santé et de la Recherche Médicale Université de la Mediterranée, Marseille, France
    J Neurosci 16:7649-60. 1996

Research Grants

  1. SODIUM PUMP AND REGULATION OF NEURONAL EXCITABILITY
    Bradley Alger; Fiscal Year: 2002
  2. Does cortex kill striatum in HD?
    CHRISTOPHER MEADE; Fiscal Year: 2004

Scientific Experts

Detail Information

Publications146 found, 100 shown here

  1. ncbi Complementary expression and regulation of cadherins 6 and 11 during specific steps of motoneuron differentiation
    Veronique Marthiens
    Signalisation et Différenciation Cellulaires dans les Systèmes Nerveux et Musculaire, INSERM U440 Université Paris 6, Institut du Fer a Moulin, Paris, France
    Mol Cell Neurosci 20:458-75. 2002
    ..These results strongly implicate cadherins 6 and 11 in the control of spinal motoneuron differentiation and segregation and in axoaxonal, axoglial, and glio-glial interactions during sensory-motor nerve progression...
  2. pmc Amyolid precursor protein mediates presynaptic localization and activity of the high-affinity choline transporter
    Baiping Wang
    Huffington Center on Aging and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
    Proc Natl Acad Sci U S A 104:14140-5. 2007
    ..These results identify a physiological activity of APP in cholinergic neurons, and our data indicate that deregulation of APP function may contribute to cholinergic impairment and AD pathogenesis...
  3. pmc Pet-1 is required across different stages of life to regulate serotonergic function
    Chen Liu
    Case Western Reserve University, School of Medicine, Department of Neurosciences, Cleveland, Ohio, USA
    Nat Neurosci 13:1190-8. 2010
    ..These findings indicate that Pet-1 is required across the lifespan of the mouse and that behavioral pathogenesis can result from both developmental and adult-onset alterations in serotonergic transcription...
  4. ncbi Loss of leukemia inhibitory factor receptor beta or cardiotrophin-1 causes similar deficits in preganglionic sympathetic neurons and adrenal medulla
    Stephan Oberle
    Neuroanatomy and Interdisciplinary Center for Neurosciences, University of Heidelberg, D 69120 Heidelberg, Germany
    J Neurosci 26:1823-32. 2006
    ..Thus, both somatic motoneurons and PSNs in the spinal cord depend on LIFRbeta signaling for their development and maintenance, although PSNs seem to be overall less affected than somatic motoneurons by LIFRbeta deprivation...
  5. ncbi Choline transporter 1 maintains cholinergic function in choline acetyltransferase haploinsufficiency
    Eugene P Brandon
    Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA
    J Neurosci 24:5459-66. 2004
    Choline acetyltransferase (ChAT), the enzyme that synthesizes the neurotransmitter acetylcholine (ACh), is thought to be present in kinetic excess in cholinergic neurons...
  6. doi Characterization of the null murine sodium/myo-inositol cotransporter 1 (Smit1 or Slc5a3) phenotype: myo-inositol rescue is independent of expression of its cognate mitochondrial ribosomal protein subunit 6 (Mrps6) gene and of phosphatidylinositol levels
    Roberto Buccafusca
    Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA
    Mol Genet Metab 95:81-95. 2008
    ..In conclusion, in neonatal brain tissue, Mrps6 gene expression may not be contingent on function of its embedded Slc5a3 gene, while inositide deficiency may not be the mechanism of lethal apnea in null Slc5a3 mice...
  7. pmc Insm1 (IA-1) is an essential component of the regulatory network that specifies monoaminergic neuronal phenotypes in the vertebrate hindbrain
    John Jacob
    MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK
    Development 136:2477-85. 2009
    ..Thus, Insm1 regulates the synthesis of distinct monoaminergic neurotransmitters by acting combinatorially with, or independently of, Ascl1 in specific monoaminergic populations...
  8. doi Dynamic expression patterns of Nkx6.1 and Nkx6.2 in the developing mes-diencephalic basal plate
    Juan Antonio Moreno-Bravo
    Instituto de Neurociencias de Alicante, Consejo Superior de Investigaciones Cientificas, and Universidad Miguel Hernandez, Sant Joan d Alacant, Spain
    Dev Dyn 239:2094-101. 2010
    ..The nuclei integrated in this domain would be the rostral interstitial nucleus, the interstitial nucleus of Cajal, and a mesencephalic equivalent to these nuclei...
  9. ncbi Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation
    S L Pfaff
    Howard Hughes Medical Institute, Department of Biochemistry and Molecule Biophysics, Columbia University, New York, New York 10032, USA
    Cell 84:309-20. 1996
    ..These results show that ISL1 is required for the generation of motor neurons and suggest that motor neuron generation is required for the subsequent differentiation of certain interneurons...
  10. ncbi The expression pattern of the transcription factor Phox2 delineates synaptic pathways of the autonomic nervous system
    M C Tiveron
    Institut de Biologie du Developpement de Marseille, Centre National dela Recherche Scientifique Institut National de la Santé et de la Recherche Médicale Université de la Mediterranée, Marseille, France
    J Neurosci 16:7649-60. 1996
    ..e., that of the medullary control reflexes of autonomic functions. This suggests that Phox2 could be involved in the establishment of these circuits...
  11. ncbi Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis
    A Pattyn
    Laboratoire de Genetique et Physiologie du Developpement, Institut de Biologie du Developpement de Marseille, CNRS Inserm Université de la Méditerranée, France
    Development 124:4065-75. 1997
    ..This suggests that Phox2b links early patterning events to the differentiation of defined neuronal populations in the hindbrain...
  12. ncbi The cholinergic gene locus
    L E Eiden
    Section of Molecular Neuroscience, Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892 4090, USA
    J Neurochem 70:2227-40. 1998
    Messenger RNAs and the cognate gene(s) encoding choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT) have been cloned from mammals and several other animal classes in the last decade...
  13. ncbi LIM homeodomain factors Lhx3 and Lhx4 assign subtype identities for motor neurons
    K Sharma
    Gene Expression Laboratory, The Salk Institute, La Jolla, California 92037, USA
    Cell 95:817-28. 1998
    ..Thus, Lhx3 and Lhx4 act in a binary fashion during a brief period in development to specify the trajectory of motor axons from the neural tube...
  14. ncbi Requirement for the homeobox gene Hb9 in the consolidation of motor neuron identity
    S Arber
    Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Center for Neurobiology and Behavior, Columbia University, New York, New York 10032, USA
    Neuron 23:659-74. 1999
    ..These findings show that HB9 has an essential function in consolidating the identity of postmitotic MNs...
  15. ncbi Aberrant patterning of neuromuscular synapses in choline acetyltransferase-deficient mice
    Eugene P Brandon
    Laboratory of Genetics and Peptide Biology Laboratories, The Salk Institute for Biological Studies, La Jolla, California 92037, USA
    J Neurosci 23:539-49. 2003
    ..developmental roles of acetylcholine (ACh) by establishing and analyzing mice lacking choline acetyltransferase (ChAT), the biosynthetic enzyme for ACh...
  16. pmc The LIM-homeobox gene Lhx8 is required for the development of many cholinergic neurons in the mouse forebrain
    Yangu Zhao
    Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, MD 20892, USA
    Proc Natl Acad Sci U S A 100:9005-10. 2003
    ..These results provide genetic evidence supporting an important role for Lhx8 in development of cholinergic neurons in the forebrain...
  17. ncbi Role of Phox2b and Mash1 in the generation of the vestibular efferent nucleus
    M C Tiveron
    CNRS UMR 6156, NMDA IBDM, Case 907 Parc Scientifique de Luminy, 13288, Marseille Cedex 9, France
    Dev Biol 260:46-57. 2003
    ....
  18. pmc ATP-citrate lyase deficiency in the mouse
    Anne P Beigneux
    Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94141, USA
    J Biol Chem 279:9557-64. 2004
    ..The Acly knockout allele is useful for identifying cell types with a high demand for acetyl-CoA synthesis...
  19. ncbi The LIM homeobox gene, L3/Lhx8, is necessary for proper development of basal forebrain cholinergic neurons
    Tetsuji Mori
    Department of Cell Science, Institute of Biomedical Sciences, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, Fukushima, 960 1295 Japan
    Eur J Neurosci 19:3129-41. 2004
    ..Neurotransmitter phenotypes other than cholinergic in the basal forebrain appeared intact. From these results, we suggested that L3/Lhx8 has a pivotal and specific role in the development and/or maintenance of BFCNs...
  20. ncbi c-ret regulates cholinergic properties in mouse sympathetic neurons: evidence from mutant mice
    K Burau
    Interdisciplinary Center for Neurosciences, Department of Neuroanatomy, University of Heidelberg, INF 307, D 69120 Heidelberg, Germany
    Eur J Neurosci 20:353-62. 2004
    ..of the c-ret receptor in mice dramatically reduces numbers of cells positive for choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT) in stellate ganglia of homozygous newborn animals...
  21. ncbi Neurotransmitter acetylcholine negatively regulates neuromuscular synapse formation by a Cdk5-dependent mechanism
    Weichun Lin
    The Salk Institute, La Jolla, California 92037, USA
    Neuron 46:569-79. 2005
    ..Genetic elimination of Cdk5 or blocking ACh production prevents the dispersion of AChR clusters in agrin mutants. Therefore, we propose that ACh negatively regulates neuromuscular synapse formation through a Cdk5-dependent mechanism...
  22. ncbi Loss of forebrain cholinergic neurons and impairment in spatial learning and memory in LHX7-deficient mice
    Apostolia Fragkouli
    Division of Molecular Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK
    Eur J Neurosci 21:2923-38. 2005
    ..Overall our experiments demonstrate that Lhx7 expression is required for the specification or differentiation of cholinergic forebrain neurons involved in the processing of spatial information...
  23. pmc Agrin promotes synaptic differentiation by counteracting an inhibitory effect of neurotransmitter
    Thomas Misgeld
    Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA
    Proc Natl Acad Sci U S A 102:11088-93. 2005
    ..Similar interactions between neurotransmitters and synaptic organizing molecules may operate at synapses in the central nervous system...
  24. ncbi Identification of lynx2, a novel member of the ly-6/neurotoxin superfamily, expressed in neuronal subpopulations during mouse development
    Eric Dessaud
    INSERM UMR 623, Developmental Biology Institute of Marseille INSERM, CNRS, Case 907, 13288 Marseille Cedex 09, France
    Mol Cell Neurosci 31:232-42. 2006
    ..Comparison of its spatio-temporal expression pattern with that of two other members of this family, lynx1 and ly-6h, shows that these genes are detected both in distinct and overlapping neuron populations...
  25. pmc Requirement for Bhlhb5 in the specification of amacrine and cone bipolar subtypes in mouse retina
    Liang Feng
    Center for Aging and Developmental Biology, University of Rochester, Rochester, NY 14642, USA
    Development 133:4815-25. 2006
    ..Our results reveal that a bHLH transcription factor cascade is involved in regulating retinal cell differentiation and imply that Bhlhb5 functions downstream of retinogenic factors to specify bipolar and amacrine subtypes...
  26. pmc The LIM-homeobox gene Islet-1 is required for the development of restricted forebrain cholinergic neurons
    Yasser Elshatory
    Medical Scientist Training Program, Department of Ophthalmology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    J Neurosci 28:3291-7. 2008
    ..Together, these results demonstrate the requirement for Isl1 in the development of restricted telencephalic cholinergic neurons and link the development of cholinergic neurons in anatomically disparate sites to Isl1 function...
  27. pmc Single-neuron labeling with inducible Cre-mediated knockout in transgenic mice
    Paul Young
    Department of Neurobiology, Duke University Medical Center, Research Drive, Durham, North Carolina 27710, USA
    Nat Neurosci 11:721-8. 2008
    ..Our results provide evidence for the long-term stability of inactive neuromuscular synapses in adult animals and demonstrate a Cre-loxP compatible system for dissecting gene functions in single identifiable neurons...
  28. pmc Gene regulation logic in retinal ganglion cell development: Isl1 defines a critical branch distinct from but overlapping with Pou4f2
    Xiuqian Mu
    Department of Biochemistry and Molecular Biology, M D Anderson Cancer Center and Graduate Training Program in Genes and Development, Graduate School of Biomedical Sciences, University of Texas, Houston, TX 77030, USA
    Proc Natl Acad Sci U S A 105:6942-7. 2008
    ..They also reveal that identical RGC expression patterns are achieved by different combinations of divergent inputs from upstream transcription factors...
  29. doi Altered visual function and interneuron survival in Atrx knockout mice: inference for the human syndrome
    Chantal F Medina
    Regenerative Medicine, Ottawa Health Research Institute, Ottawa, Ontario, Canada K1H 8L6
    Hum Mol Genet 18:966-77. 2009
    ..These results implicate a role for Atrx in interneuron survival and differentiation...
  30. pmc Genetically-directed, cell type-specific sparse labeling for the analysis of neuronal morphology
    Thomas Rotolo
    Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    PLoS ONE 3:e4099. 2008
    ....
  31. pmc The vesicular acetylcholine transporter is required for neuromuscular development and function
    Braulio M de Castro
    Molecular Brain Research Group, Robarts Research Institute, University of Western Ontario, P O Box 5015, 100 Perth Drive, London, Ontario N6A 5K8, Canada
    Mol Cell Biol 29:5238-50. 2009
    ..The abnormalities are similar to those of mice that cannot synthesize ACh due to a lack of choline acetyltransferase. Our results indicate that VAChT is essential to the normal development of motor neurons and the release of ACh...
  32. pmc LIM homeodomain transcription factor-dependent specification of bipotential MGE progenitors into cholinergic and GABAergic striatal interneurons
    Apostolia Fragkouli
    MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK
    Development 136:3841-51. 2009
    ..These studies suggest that a LIM homeodomain transcriptional code confers cell-fate specification and neurotransmitter identity in neuronal subpopulations of the ventral forebrain...
  33. pmc New mouse lines for the analysis of neuronal morphology using CreER(T)/loxP-directed sparse labeling
    Tudor C Badea
    Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    PLoS ONE 4:e7859. 2009
    ..Pharmacologic control of Cre-mediated recombination using tamoxifen-dependent activation of a Cre-estrogen receptor ligand binding domain fusion protein [CreER(T)] is widely used to modify and/or visualize cells in the mouse...
  34. pmc DSCAM and DSCAML1 function in self-avoidance in multiple cell types in the developing mouse retina
    Peter G Fuerst
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    Neuron 64:484-97. 2009
    ..Therefore, DSCAM and DSCAML1 function similarly in self-avoidance, and are not essential for synaptic specificity in the mouse retina...
  35. pmc A robust and high-throughput Cre reporting and characterization system for the whole mouse brain
    Linda Madisen
    Allen Institute for Brain Science, Seattle, Washington, USA
    Nat Neurosci 13:133-40. 2010
    ..Our expression data are displayed in a public online database to help researchers assess the utility of various Cre-driver lines for cell-type-specific genetic manipulation...
  36. pmc Dysautonomia due to reduced cholinergic neurotransmission causes cardiac remodeling and heart failure
    Aline Lara
    Department of Physiology, Institute of Biological Sciences, Federal University of Minas Gerais, Av Antonio Carlos 6627, Belo Horizonte, MG CEP 31270 901, Brazil
    Mol Cell Biol 30:1746-56. 2010
    ..Our findings provide direct evidence that decreased cholinergic neurotransmission and underlying autonomic imbalance cause plastic alterations that contribute to heart dysfunction...
  37. pmc Genetic dissection of the function of hindbrain axonal commissures
    Nicolas Renier
    INSERM, U968, Paris, F 75012, France
    PLoS Biol 8:e1000325. 2010
    ..To our knowledge, this study is one of the first to link defects in commissural axon guidance with specific cellular and behavioral phenotypes...
  38. doi Teashirt 3 regulates development of neurons involved in both respiratory rhythm and airflow control
    Xavier Caubit
    Unité Mixte de Recherche UMR 6216, Centre National de la Recherche Scientifique CNRS, Universite de la Mediterranee, Institut de Biologie du Developpement de Marseille Luminy, Parc Scientifique de Luminy, Marseille Cedex 9, France
    J Neurosci 30:9465-76. 2010
    ..Thus, a single gene, Tshz3, controls the development of diverse components of the circuitry required for breathing...
  39. pmc Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis
    Jari Rossi
    Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Cell Metab 13:195-204. 2011
    ..Re-expression of MC4Rs in cholinergic neurons (ChAT-Cre, loxTB MC4R mice) modestly reduced body weight gain without altering food intake and was sufficient to ..
  40. pmc Novel strains of mice deficient for the vesicular acetylcholine transporter: insights on transcriptional regulation and control of locomotor behavior
    Cristina Martins-Silva
    Molecular Brain Research Group, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada
    PLoS ONE 6:e17611. 2011
    ..VAChT gene is embedded within the first intron of the choline acetyltransferase (ChAT) gene, which provides a unique arrangement and regulation for these two genes...
  41. pmc Cholinergic interneurons mediate fast VGluT3-dependent glutamatergic transmission in the striatum
    Michael J Higley
    Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, United States of America
    PLoS ONE 6:e19155. 2011
    ..Our results indicate that CINs are capable of mediating fast glutamatergic transmission, suggesting a new role for these cells in regulating striatal activity...
  42. pmc Elimination of the vesicular acetylcholine transporter in the striatum reveals regulation of behaviour by cholinergic-glutamatergic co-transmission
    Monica S Guzman
    Molecular Brain Research Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
    PLoS Biol 9:e1001194. 2011
    ..The data also raise the possibility of using VAChT as a target to boost dopaminergic function and decrease high striatal cholinergic activity, common neurochemical alterations in individuals affected with Parkinson's disease...
  43. doi Overexpression of the vesicular acetylcholine transporter increased acetylcholine release in the hippocampus
    P M Nagy
    Brain Sciences Program, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5
    Neuroscience 218:1-11. 2012
    ..It remains to be established whether, in cases of cholinergic deficits, increasing VAChT expression would re-establish adequate levels of cholinergic neurotransmission, thereby providing a valid therapeutic target...
  44. pmc Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy
    Tara L Martinez
    Department of Neurology, Johns Hopkins University, Baltimore, Maryland 21205, USA
    J Neurosci 32:8703-15. 2012
    ..Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power...
  45. pmc Wnt7A identifies embryonic γ-motor neurons and reveals early postnatal dependence of γ-motor neurons on a muscle spindle-derived signal
    Soha Ashrafi
    Neuroscience Program, Weill Cornell Medical College, New York, New York 10065, USA
    J Neurosci 32:8725-31. 2012
    ..Furthermore, using Wnt7a expression as an early marker of γ-MN identity, we demonstrate a previously unknown dependence of γ-MNs on a muscle spindle-derived, GDNF-independent signal during the first postnatal week...
  46. pmc Opposing regulation of dopaminergic activity and exploratory motor behavior by forebrain and brainstem cholinergic circuits
    Jyoti C Patel
    Department of Neurosurgery, Physiology and Neuroscience, New York, New York 10016, USA
    Nat Commun 3:1172. 2012
    ..These results support a model in which forebrain and brainstem cholinergic systems act in tandem to regulate striatal dopamine signalling for proper control of motor activity...
  47. pmc New modules are added to vibrissal premotor circuitry with the emergence of exploratory whisking
    Jun Takatoh
    Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
    Neuron 77:346-60. 2013
    ..Thus, neural modules that are well suited to facilitate the bilateral coordination and cortical control of whisking are added to the premotor circuitry in parallel with the emergence of this exploratory behavior...
  48. pmc Melanocortin 4 receptors reciprocally regulate sympathetic and parasympathetic preganglionic neurons
    Jong Woo Sohn
    Department of Internal Medicine, Division of Hypothalamic Research, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
    Cell 152:612-9. 2013
    ....
  49. doi ChAT-ChR2-EYFP mice have enhanced motor endurance but show deficits in attention and several additional cognitive domains
    Benjamin Kolisnyk
    Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5K8
    J Neurosci 33:10427-38. 2013
    ..transgenic mice expressing channelrhodopsin-2 (ChR2) protein under the control of the choline acetyltransferase (ChAT) promoter (ChAT-ChR2-EYFP) to dissect cholinergic circuit connectivity and function using optogenetic approaches...
  50. doi Forebrain deletion of the vesicular acetylcholine transporter results in deficits in executive function, metabolic, and RNA splicing abnormalities in the prefrontal cortex
    Benjamin Kolisnyk
    Robarts Research Institute, Graduate Program in Neuroscience, Department of Physiology and Pharmacology, Department of Anatomy and Cell Biology, Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada, N6A 5K8, and Department of Biological Chemistry and The Edmond and Lily Safra Center of Brain Science, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
    J Neurosci 33:14908-20. 2013
    ..We propose that VAChT-targeted mice can be used to model and to dissect the neurochemical basis of executive abnormalities. ..
  51. pmc Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy
    Shingo Kariya
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
    Hum Mol Genet 17:2552-69. 2008
    ..We suggest that SMA might best be described as a NMJ synaptopathy and that one promising means of treating it could involve maintaining function at the NMJ...
  52. ncbi Roles of neurotransmitter in synapse formation: development of neuromuscular junctions lacking choline acetyltransferase
    Thomas Misgeld
    Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO 63110, USA
    Neuron 36:635-48. 2002
    ..At subsequent stages, neurotransmission delays some steps in synaptic maturation but accelerates others. Thus, neurotransmission affects synaptogenesis from early stages and coordinates rather than drives synaptic maturation...
  53. ncbi GFR alpha3, a component of the artemin receptor, is required for migration and survival of the superior cervical ganglion
    J Nishino
    Division of Molecular Biology, Institute for Molecular and Cellular Biology, Osaka University, Japan
    Neuron 23:725-36. 1999
    ..These observations suggest that GFR alpha3-mediated signaling is required both for the rostral migration of SCG precursors and for the survival of mature SCG neurons...
  54. pmc Targeted deletion of Hand2 in enteric neural precursor cells affects its functions in neurogenesis, neurotransmitter specification and gangliogenesis, causing functional aganglionosis
    Jun Lei
    Department of Neurosciences and Program in Neurosciences and Neurodegenerative Diseases, University of Toledo Health Sciences Campus, Toledo, OH 43614, USA
    Development 138:4789-800. 2011
    ..Thus, Hand2 is essential for neurogenesis, neurotransmitter specification and neural network patterning in the developing ENS...
  55. pmc Luminal cholinergic signalling in airway lining fluid: a novel mechanism for activating chloride secretion via Ca²⁺-dependent Cl⁻ and K⁺ channels
    Monika I Hollenhorst
    Institute of Animal Physiology, Justus Liebig University Giessen, Giessen, Germany
    Br J Pharmacol 166:1388-402. 2012
    ..Thus, this study focused on the effect of luminal ACh as a regulator of transepithelial ion transport in epithelial cells...
  56. doi Mice with selective elimination of striatal acetylcholine release are lean, show altered energy homeostasis and changed sleep/wake cycle
    Monica S Guzman
    Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
    J Neurochem 124:658-69. 2013
    ..These new insights on how cholinergic neurons influence homeostasis open new avenues for the search of drug targets to treat obesity...
  57. pmc Prickle1 is expressed in distinct cell populations of the central nervous system and contributes to neuronal morphogenesis
    Chunqiao Liu
    Neurobiology Neurodegeneration and Repair Laboratory N NRL, National Eye Institute, MSC0610, 6 Center Drive, Bethesda, MD 20892, USA
    Hum Mol Genet 22:2234-46. 2013
    ..Our studies implicate Pk1 function in axonal-dendritic development associated with the maturation of CNS neurons...
  58. pmc Survey on amacrine cells coupling to retrograde-identified ganglion cells in the mouse retina
    Ji Jie Pang
    Department of Ophthalmology, Baylor College of Medicine, Houston, Texas 77030, USA
    Invest Ophthalmol Vis Sci 54:5151-62. 2013
    ..The total number and subtypes of ACs coupled to the entire GC population were investigated in wild-type and three lines of transgenic mice...
  59. pmc BLT-humanized C57BL/6 Rag2-/-γc-/-CD47-/- mice are resistant to GVHD and develop B- and T-cell immunity to HIV infection
    Kerry J Lavender
    Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT
    Blood 122:4013-20. 2013
    ..The lack of GVHD makes the TKO-BLT mouse a significantly improved model for long-term studies of pathogenesis, immune responses, therapeutics, and vaccines to human pathogens. ..
  60. pmc The LIM homeobox gene Isl1 is required for the correct development of the striatonigral pathway in the mouse
    Lisa A Ehrman
    Divisions of Developmental Biology, Neurosurgery, Experimental Hematology and Cancer Biology and Neurology, Cincinnati Children s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati OH 45229
    Proc Natl Acad Sci U S A 110:E4026-35. 2013
    ....
  61. doi Cholinergic signals in mouse barrel cortex during active whisker sensing
    Emmanuel Eggermann
    Laboratory of Sensory Processing, Brain Mind Institute, Faculty of Life Sciences, Ecole Polytechnique Federale de Lausanne EPFL, Lausanne 1015, Switzerland
    Cell Rep 9:1654-60. 2014
    ....
  62. pmc Feedback in the brainstem: an excitatory disynaptic pathway for control of whisking
    David W Matthews
    Graduate Program in Neuroscience, University of California, San Diego, La Jolla, CA, 92093, USA Department of Physics, University of California, San Diego, La Jolla, CA, 92093, USA
    J Comp Neurol 523:921-42. 2015
    ..These anatomical results suggest a general role of disynaptic architecture in fast positive feedback for motor output that drives active sensation...
  63. pmc Silencing of Cholinergic Basal Forebrain Neurons Using Archaerhodopsin Prolongs Slow-Wave Sleep in Mice
    Yu feng Shi
    Department of Neurobiology and Physiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
    PLoS ONE 10:e0130130. 2015
    ..Our results indicate that the main effect of these neurons is to terminate SWS, whereas wakefulness or REM sleep may be determined by co-operation of the cholinergic BF neurons with other arousal-sleep control systems. ..
  64. pmc Dorsal Medial Habenula Regulation of Mood-Related Behaviors and Primary Reinforcement by Tachykinin-Expressing Habenula Neurons
    Yun Wei A Hsu
    Center for Integrative Brain Research, Seattle Children s Research Institute, Seattle, Washington 98101
    Eneuro 3:. 2016
    ..Together, our data show that the dMHb is involved in the regulation of multiple mood-related behaviors, but also support the idea that these behaviors do not reflect a single functional pathway. ..
  65. pmc Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit
    Mauricio Rosas-Ballina
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, New York 11030, USA
    Science 334:98-101. 2011
    ..Thus, action potentials originating in the vagus nerve regulate T cells, which in turn produce the neurotransmitter, acetylcholine, required to control innate immune responses...
  66. pmc Transcription factor LIM homeobox 7 (Lhx7) maintains subtype identity of cholinergic interneurons in the mammalian striatum
    Rita Lopes
    Division of Molecular Neurobiology, Medical Research Council, National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom
    Proc Natl Acad Sci U S A 109:3119-24. 2012
    ....
  67. pmc A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing
    Linda Madisen
    Allen Institute for Brain Science, Seattle, Washington, USA
    Nat Neurosci 15:793-802. 2012
    ..When combined with the hundreds of available Cre driver lines, this optimized toolbox of reporter mice will enable widespread investigations of neural circuit function with unprecedented reliability and accuracy...
  68. pmc Genetic dissection of midbrain dopamine neuron development in vivo
    Debra Ellisor
    Department of Molecular Biology, Cell Biology and Biochemistry, Division of Biology and Medicine, Brown University, 70 Ship St, Providence, RI 02903, USA
    Dev Biol 372:249-62. 2012
    ..By placing Wnt1, Fgf8, and En1/2 in the context of their temporal requirement for MbDA neuron development, we further deciphered the developmental program underpinning MbDA neuron progenitors...
  69. pmc Elimination of the vesicular acetylcholine transporter in the forebrain causes hyperactivity and deficits in spatial memory and long-term potentiation
    Amanda C Martyn
    Molecular Brain Research Group, Robarts Research Institute, and Department of Anatomy and Cell Biology and Physiology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada N6A 5K8
    Proc Natl Acad Sci U S A 109:17651-6. 2012
    ..These data uncover the specific contribution of forebrain cholinergic tone for synaptic plasticity and behavior. Moreover, these experiments define specific cognitive functions that could be targeted by cholinergic replacement therapy...
  70. pmc Sustained Hox5 gene activity is required for respiratory motor neuron development
    Polyxeni Philippidou
    Howard Hughes Medical Institute, New York University School of Medicine, Smilow Neuroscience Program, Department of Physiology and Neuroscience, New York, New York, USA
    Nat Neurosci 15:1636-44. 2012
    ..These findings indicate that Hox5 genes orchestrate PMC development through deployment of temporally distinct wiring programs...
  71. pmc Egr2::cre mediated conditional ablation of dicer disrupts histogenesis of mammalian central auditory nuclei
    Elena Rosengauer
    Department of Neurogenetics, Carl von Ossietzky University Oldenburg, Oldenburg, Germany
    PLoS ONE 7:e49503. 2012
    ..Together our data identify a critical role of Dicer activity during embryonic development of the auditory brainstem...
  72. pmc Nerve growth factor scales endocannabinoid signaling by regulating monoacylglycerol lipase turnover in developing cholinergic neurons
    Erik Keimpema
    European Neuroscience Institute at Aberdeen, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom
    Proc Natl Acad Sci U S A 110:1935-40. 2013
    ..These data indicate that NGF can orchestrate endocannabinoid signaling to promote cholinergic differentiation and implicate BRCA1 in determining neuronal morphology...
  73. pmc Heart-specific overexpression of choline acetyltransferase gene protects murine heart against ischemia through hypoxia-inducible factor-1α-related defense mechanisms
    Yoshihiko Kakinuma
    Department of Cardiovascular Control, Kochi Medical School, Nankoku, Japan
    J Am Heart Assoc 2:e004887. 2013
    ..Such a mismatch and missing link suggest the existence of a nonneuronal cholinergic system in ventricular myocardium...
  74. pmc The transcription factor Hmx1 and growth factor receptor activities control sympathetic neurons diversification
    Alessandro Furlan
    Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden
    EMBO J 32:1613-25. 2013
    ....
  75. ncbi NCAM in the organ of Corti of the developing mouse
    D S Whitlon
    Department of Neurology, University of Wisconsin, Madison
    J Neurocytol 19:970-7. 1990
    ..NCAM is also present along the growth path of the nerve fibres. These studies suggest that NCAM is properly positioned in the cochlea for possible roles in axon guidance and nerve-target interactions...
  76. ncbi Analysis of CAG trinucleotide repeats from mouse cDNA sequences
    C Abbott
    MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK
    Ann Hum Genet 58:87-94. 1994
    ..containing variable length CAG repeats, seven in absentia homologue 1b (Sinh1b), and choline acetyl transferase (Chat), which had not previously been mapped in the mouse genome, were mapped by linkage analysis in an interspecific ..
  77. ncbi Segmental and neuronal architecture of the hindbrain of Krox-20 mouse mutants
    S Schneider-Maunoury
    Unité 368 de l Institut National de la Santé et de la Recherche Médicale, Biologie Moléculaire du Développement, Ecole Normale Superieure, Paris, France
    Development 124:1215-26. 1997
    ..This navigational error could explain the disappearance, at around 17.5 dpc, of the trigeminal motor nucleus in Krox-20(-/-) embryos by inadequate supply of essential, possibly arch-specific survival factors...
  78. pmc Acetylcholinesterase-transgenic mice display embryonic modulations in spinal cord choline acetyltransferase and neurexin Ibeta gene expression followed by late-onset neuromotor deterioration
    C Andres
    Department of Biological Chemistry, The Hebrew University of Jerusalem, 91904 Israel
    Proc Natl Acad Sci U S A 94:8173-8. 1997
    ....
  79. ncbi Molecular characterization of the mouse vesicular acetylcholine transporter gene
    J M Naciff
    Department of Molecular and Cellular Physiology, University of Cincinnati, College of Medicine, OH 45267 0576, USA
    Neuroreport 8:3467-73. 1997
    The organization of the mouse choline acetyltransferase (ChAT) gene has been previously analyzed. Here we show that the first intron of the mouse ChAT gene contains an uninterrupted open reading frame...
  80. ncbi The origin and development of the vagal and spinal innervation of the external muscle of the mouse esophagus
    Q Sang
    Department of Anatomy and Cell Biology, University of Melbourne, Victoria, Australia
    Brain Res 809:253-68. 1998
    ....
  81. ncbi Impaired extrapyramidal function caused by the targeted disruption of retinoid X receptor RXRgamma1 isoform
    Y Saga
    Banyu Tsukuba Research Institute Merck Tsukuba, Ibaraki, 300 33 Japan
    Genes Cells 4:219-28. 1999
    ..In contrast to the widespread expression of RXRalpha and RXRbeta, the expression of RXRgamma is restricted to particular tissues in which RXRgamma1 is the major isoform expressed in the mouse corpus striatum...
  82. ncbi Identification of quantitative trait loci for haloperidol-induced catalepsy on mouse chromosome 14
    E Rasmussen
    Department of Psychiatry and Psychology, State University of New York at Stony Brook, Stony Brook, New York, USA
    J Pharmacol Exp Ther 290:1337-46. 1999
    ..A second QTL was detected on chromosome 14 (peak LOD = 6.9), which was located more proximally and included the Chat locus...
  83. ncbi Cloning of a novel murine gene Sfmbt, Scm-related gene containing four mbt domains, structurally belonging to the Polycomb group of genes
    H Usui
    Department of Molecular Neuropathology, Brain Research Institute, Niigata University, 1 757 Asahimachi, Niigata, Japan
    Gene 248:127-35. 2000
    ..Northern blot analysis showed that the Sfmbt mRNAs were expressed most abundantly in the adult testis, and less intensively in all other tissues examined...
  84. pmc Formation of brainstem (nor)adrenergic centers and first-order relay visceral sensory neurons is dependent on homeodomain protein Rnx/Tlx3
    Y Qian
    The Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
    Genes Dev 15:2533-45. 2001
    ....
  85. ncbi Mitogen-activated protein kinase kinase negatively modulates ciliary neurotrophic factor-activated choline acetyltransferase gene expression
    Tiffany Mellott
    Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA
    Eur J Biochem 269:850-8. 2002
    The expression of the choline acetyltransferase (ChAT) enzyme that synthesizes the neurotransmitter acetylcholine (ACh) is upregulated by ciliary neurotrophic factor (CNTF)...
  86. ncbi Evidence for a cell-specific action of Reelin in the spinal cord
    Patricia E Phelps
    Department of Physiological Science, UCLA, Los Angeles, California 90095 1527, USA
    Dev Biol 244:180-98. 2002
    ..These results suggest that Reelin acts in a cell-specific manner on the migration of cholinergic spinal cord neurons...
  87. ncbi Developmental timing of hair follicle and dorsal skin innervation in mice
    Eva M J Peters
    Department of Dermatology, University Hospital Eppendorf, University of Hamburg, Hamburg D 20246, Germany
    J Comp Neurol 448:28-52. 2002
    ..This sequence of developing innervation consistently correlates with hair follicle development, indicating a close interdependence of neuronal and epithelial morphogenesis...
  88. ncbi Cyclin-dependent kinase 5/p35 contributes synergistically with Reelin/Dab1 to the positioning of facial branchiomotor and inferior olive neurons in the developing mouse hindbrain
    Toshio Ohshima
    Laboratory for Developmental Neurobiology, The Institute of Physical and Chemical Research RIKEN, Wako, Saitama 351 0198, Japan
    J Neurosci 22:4036-44. 2002
    ..These results indicate that Cdk5/p35 and Reelin signaling regulates the selective mode of neuronal migration in the developing mouse hindbrain...
  89. pmc FGFR1 is independently required in both developing mid- and hindbrain for sustained response to isthmic signals
    Ras Trokovic
    Institute of Biotechnology, Viikki Biocenter, PO Box 56, 00014 University of Helsinki, Finland
    EMBO J 22:1811-23. 2003
    ..In addition, FGFR1 appears to modify cell adhesion properties critical for maintaining a coherent organizing center. This may be achieved by regulating expression of specific cell-adhesion molecules at the midbrain-hindbrain border...
  90. pmc Lethal impairment of cholinergic neurotransmission in hemicholinium-3-sensitive choline transporter knockout mice
    Shawn M Ferguson
    Neuroscience Graduate Program, Vanderbilt University, Nashville, TN 37232, USA
    Proc Natl Acad Sci U S A 101:8762-7. 2004
    ..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...
  91. ncbi Analysis of neuronal subpopulations in mice over-expressing suppressor of cytokine signaling-2
    M I Ransome
    Neural Regeneration Laboratory, Centre for Neuroscience, University of Melbourne, Melbourne, Victoria 3010, Australia
    Neuroscience 132:673-87. 2005
    ..Therefore, over-expression of SOCS2 variably affects different cortical regions and neuronal populations, with the predominant effect appearing to be on interneurons and neuronal connectivity in the cortex...
  92. pmc Developmental abnormalities of neuronal structure and function in prenatal mice lacking the prader-willi syndrome gene necdin
    Silvia Pagliardini
    Department of Physiology, Centre of Neuroscience, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada
    Am J Pathol 167:175-91. 2005
    ....
  93. ncbi Disruption and recovery of patterned retinal activity in the absence of acetylcholine
    Rebecca C Stacy
    Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Neurosci 25:9347-57. 2005
    ..of cholinergic transmission by using a conditional mutant in which the gene encoding choline acetyltransferase (ChAT), the sole synthetic enzyme for acetylcholine (ACh), was deleted from large retinal regions...
  94. ncbi V1 spinal neurons regulate the speed of vertebrate locomotor outputs
    Simon Gosgnach
    Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
    Nature 440:215-9. 2006
    ....
  95. ncbi Spatiotemporal definition of neurite outgrowth, refinement and retraction in the developing mouse cochlea
    Lin Chien Huang
    Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand
    Development 134:2925-33. 2007
    ..This reorganization also establishes the cochlea as a model system for studying CNS synapse development, plasticity and elimination...
  96. ncbi Expression of the homeodomain transcription factor Meis2 in the embryonic and postnatal retina
    Keely M Bumsted-O'Brien
    Department of Neuroanatomy, Max Planck Institute for Brain Research, Deutschordenst 46, 60218 Frankfurt, Germany
    J Comp Neurol 505:58-72. 2007
    ....
  97. pmc Histogenetic compartments of the mouse centromedial and extended amygdala based on gene expression patterns during development
    Margarita García-López
    Department of Human Anatomy, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain
    J Comp Neurol 506:46-74. 2008
    ..Our study provides a molecular and morphological foundation for understanding the complex embryonic origins and adult organization of the centromedial and extended amygdala...
  98. doi Mice lacking the transcription factor Ikaros display behavioral alterations of an anti-depressive phenotype
    Tim Rasmus Kiehl
    Department of Pathology, University Health Network, 610 University Avenue, Toronto, Ontario, Canada
    Exp Neurol 211:107-14. 2008
    ....
  99. doi Neuronal 3',3,5-triiodothyronine (T3) uptake and behavioral phenotype of mice deficient in Mct8, the neuronal T3 transporter mutated in Allan-Herndon-Dudley syndrome
    Eva K Wirth
    Neuroscience Research Center, Charite Universitatsmedizin Berlin, Berlin, Germany
    J Neurosci 29:9439-49. 2009
    ....
  100. pmc Seizure-related gene 6 (Sez-6) in amacrine cells of the rodent retina and the consequence of gene deletion
    Jenny M Gunnersen
    Brain Development, Howard Florey Institute, University of Melbourne, Parkville, Victoria, Australia
    PLoS ONE 4:e6546. 2009
    ..Seizure-related gene 6 (Sez-6) is expressed in neurons of the mouse brain, retina and spinal cord. In the cortex, Sez-6 plays a role in specifying dendritic branching patterns and excitatory synapse numbers during development...
  101. pmc MSC p43 required for axonal development in motor neurons
    Xiaodong Zhu
    Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China
    Proc Natl Acad Sci U S A 106:15944-9. 2009
    ..Thus, MSC p43 is indispensable in maintaining axonal integrity. Its dysfunction may underlie the NF disorganization and axon degeneration associated with motor neuron degenerative diseases...

Research Grants3

  1. SODIUM PUMP AND REGULATION OF NEURONAL EXCITABILITY
    Bradley Alger; Fiscal Year: 2002
    ..This proposal is a step towards filling the gap. ..
  2. Does cortex kill striatum in HD?
    CHRISTOPHER MEADE; Fiscal Year: 2004
    ..These studies will validate the in oculo technique as an effective HD model system, which might be useful in further testing hypotheses of mutant Ht mechanism of action and in testing possible drug therapies. ..