FREE ELECTRONIC LIBRARY - Dissertations, online materials

Pages:   || 2 | 3 | 4 | 5 |   ...   | 11 |

«Bonnie Gale Garcia Dissertation Submitted to the faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements ...»

-- [ Page 1 ] --




Bonnie Gale Garcia


Submitted to the faculty of the

Graduate School of Vanderbilt University

in partial fulfillment of the requirements for

the degree of




May, 2010

Nashville, Tennessee


Professor Ariel Y. Deutch Professor Randy D. Blakely Professor Danny G. Winder Professor Eugenia V. Gurevich Professor P. Jeffrey Conn Copyright © 2010 by Bonnie Gale Garcia All Rights Reserved


This dissertation would not have been possible without the help of so many people in so many ways. First I would like to thank my doctoral advisor, Dr. Ariel Y.

Deutch for having faith in me and accepting me into his lab. Ariel has been a great scientific role model, instilling in me the qualities of being not only a good scientist.

I am grateful for his unwavering patience and guidance, especially with the development of my communication and writing skills, and my overall growth as a scientist throughout all these years in his laboratory.

I am grateful for the professional and personal guidance from all of my committee members. Drs. Eugenia V. Gurevich (chair), Randy D. Blakely, P. Jeff Conn, and Danny G. Winder all have made committee meetings a very valuable and pleasurable experience.

My doctoral research was conducted with the support of an NRSA predoctoral award (F31 NS060174) from the National Institutes of Neurological Disorders and Stroke.

I would also like to thank Dr. M. Diana Neely for teaching me how to prepare organotypic slice cultures and for our scientific and personal discussions. I would also like to thank Dr. Michael Bubser for showing me how to perfuse a rat, and for all his immunohistochemical expertise. I would also like to thank all members of the Deutch lab both past and present. Special thanks to Michael Bubser, Brian Mathur, and Sheila Kusnoor for insightful discussions. I thank Lorelei Reinhardt and Dr.

Dennis Schmidt who have provided much needed humor in the lab.

iii I am also grateful to Dr. Aurelio Galli who inspired me to become a scientist and join the graduate program at Vanderbilt University.

I would also like to thank my family and friends who have always been there for me. Finally I owe my deepest gratitude to my husband, Sergio Coffa,for his support especially in these last few months.

–  –  –




Chapter I. INTRODUCTION The striatum and movement

Diseases of the basal ganglia

Striatal cell morphology

Defining MSNs by non-morphological criteria


Synaptic architecture of MSNs

Regulation of MSNs



Striatal afferents from M1 cortex



















VI. CONCLUSIONS Introduction

Relation to motor deficits in parkinsonism


–  –  –

1. Illustration of the dorsal and ventral striatum of the rat

2. Schematic illustrating dopaminergic innervation of the striatum

3. Medium spiny neuron reconstruction

4. Schematic illustrating medium spiny neuron afferents

5. Schematic illustrating medium spiny neuron synaptic triad

6. Dopamine D2 receptor localization on the striatal triad

7. Corticostriatal tract tracing using an anterograde tracer deposited into the motor cortex (IP)

8. Corticostriatal tract tracing using an anterograde tracer deposited into the motor cortex (IF)

9. Fluorogold-positive cells in the cortex using a retrograde tracer deposited into the striatum

10. Sholl analysis of spine density as function of distance from the soma

11. Control spine density as a function of distance from soma

12. Tyrosine hydroxylase immunoreactivity in the striatum and substantia nigra (IHC)

13. Tyrosine hydroxylase immunoreactivity in the striatum as measured by western blot

14. Golgi-impregnated MSNs from sham and dopamine denervated animals

15. Time course of dopamine depletion-induced dendritic spine loss

–  –  –

17. Dopamine denervation effects on neuronal dendritic field as assessed by longest dendrite

18. Schematic illustrating the morphologies of dendritic spines

19. Dopamine denervation alters MSN spine types

20. Schematic illustrating M1 and non-M1recipient zones of striatum analyzed

21. Characterization of motor cortex lesions

22. FluoroJade C stain for degenerating cells

23. Cortical lesions in vivo reverse spine loss

24. Photomicrographs of representative MSN dendrites from each treatment group

25. Cortical lesions in vivo prevent dendritic spine loss

26. Cortical lesions cause compensatory corticostriatal sprouting

27. Representative organotypic triple slice culture stained with toluidine blue

28. mGluR 2/3 agonist prevents MSN spine loss in vitro in dopamine denervated cultures

29. Representative photomicrographs of ballistically-labeled dendrites from each culture treatment condition

30. mGluR 2/3 antagonist, blocks the effects of LY379268 on preventing spine loss

31. mGluR 5 antagonist does not prevent spine loss in dopamine denervated cultures

–  –  –

mGluR Metabotropic Glutamate Receptor MPP+ 1-methyl-4-phenyl-2,3-dihydropyridinium Ion MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine MSN Medium Spiny Neuron NMDA N-methyl-D-aspartate

–  –  –

The striatum and movement. The collection of nuclei referred to as the ―basal ganglia‖ was previously called the great cerebral nucleus by David Ferrier in 1876 (see Swanson 2000). The basal ganglia are an ill-defined group of subcortical nuclei, which consist of the neostriatum (caudate nucleus and putamen), globus pallidus, substantia nigra, and subthalamic nucleus. The striatum is the largest nucleus of the basal ganglia and is so named because it has a striated appearance due to the dense fiber bundles of axons that course through the region (Willis T et al. 1965). This ‖striped‖ structure was first illustrated by Andreas Vesalius in 1543 and later described by the seventeenth century physician, Thomas Willis, who designated the structure ―corpus

striatum‖ in 1664 (Sarikcioglu et al. 2008). Willis noted:

―These bodies, if they should be dissected along the middle, appear marked, with medullar streak, as it were rays or beams;

which sort of chamferings or streaks have a double aspect or tendency; to wit, some descend from the top of this body, as if they were tracts from the brain into the oblong marrow; and others ascend from the lower part, and meet aforesaid, as if they were paths of spirits from the oblong marrow into the brain.

And it is worth observation, that in the whole head besides there is no part found chamfered or streaked after the like manner.‖ In primates the striatum is composed of the caudate nucleus and the putamen, the two nuclei being separated by the white matter of the internal capsule. However in rodents a single structure is observed, with fascicles of

–  –  –

striatum is functionally divided into the dorsal striatum and the ventral striatum (see Figure 1). Whereas the dorsal striatum is implicated in voluntary movement, as well as habit-based learning, the ventral striatum plays an important role in the translation of motivation to movement.

Modulation of movement processes is mainly what the striatum is known for, but it also plays important roles in procedural learning and reward pathways.

The basal ganglia were suggested to be involved in movement at the beginning of the 20th century, based on the observation that damage to these structures resulted in movement disorders (Wilson SAK 1914; Mettler R and Mettler C 1942; Mettler FA 1945; Divac et al. 1967; Denny-Brown D and Yanagisawa N 1972). Simplistically, the motor cortex sends information to the basal ganglia and the cerebellum; both areas of the brain send information back to the cortex via the thalamus.

Diseases of the basal ganglia. Disturbances in the basal ganglia result in a myriad of movement disorders, both hypokinetic and hyperkinetic. Hyperkinetic disorders, or disorders of increased motor function, include Huntington’s disease (HD), dystonia, and hemiballismus. HD is a genetic, neurodegenerative disease in which striatal MSNs degenerate as a result of a mutation in the Huntington protein. Dystonia involves sustained muscle contractions that cause twisting and abnormal postures. Hemiballismus (―half jumping‖) is a rare disorder usually

–  –  –


3 Figure 1. The striatum is divided into the dorsal striatum (caudate and putamen) shown in blue and the ventral striatum (nucleus accumbens) shown in orange.

Although illustrated is a distinct border between dorsal and ventral striatum, no such delineation truly exits in vivo. Abbreviations: CPu, caudate and putamen;

Acb, accumbens. Image from Voorn et al. 2004.

–  –  –

(PD). Parkinson’s Disease is a hypokinetic disorder, in which there is reduced motor function. The pathology of PD involves the degeneration of the pigmented dopamine cells in the substantia nigra (black substance, referring to the heavily pigmented dopamine neurons). The degeneration of the substantia nigra (SN) dopamine neurons results in a decrease in the amount of striatal dopamine (see Figure 2), and the appearance of the cardinal symptoms of PD: bradykinesia, resting tremor, and rigidity. Postural instability is also observed, but usually presents somewhat later in the course of the disease.

The gold standard of treatment for PD is administration of the dopamine precursor L-dihydroxyphenylalanine (levodopa, L-DOPA). Direct dopamine agonists have increasingly been used in the treatment of PD. Although levodopa is incredibly beneficial in treating the symptoms of PD, after 3-7 years patients develop on-off effects and abnormal involuntary movements (dyskinesias). Later in the course of PD, the full symptomatic responsive to L-DOPA treatment is decreased.

5 Figure 2. Dopaminergic innervation of the striatum (caudate and putamen).

A.) Normal nigrostriatal innervation is schematized in red. B.) In Parkinson’s disease the substantia nigra dopamine cells degenerate with a resultant loss of striatal dopamine levels illustrated by the hatched and thinned red lines). Image from Dauer et al. 2003.

–  –  –

medium-sized cells and large cells (interneurons). The cells of medium size are the projection neurons of the striatum. These cells were subsequently termed the medium spiny neurons (MSNs) by Kemp and Powell (1971), which are richly invested with dendritic spines. MSNs account for approximately 90-95% of all striatal neurons and utilize γ-aminobutyric acid (GABA) as their classical neurotransmitter (Gerfen 1992). As the name suggests, MSNs have a mediumsized soma (8-17 µm in diameter) possess dendrites that radially emanate and of which are densely studded with dendritic spines (see Figure 3), the sites of excitatory synapses.

The geometries of dendritic spines suggest that they are independent compartments that ―protect‖ dendrites from sharp, rapid rises in intracellular

calcium (Segal M 1993, 1995). Segal noted:

―I should like to take this a step further, and propose a novel function for spines: by isolating the synapse from the dendrite, the spine protects the neurons from toxic insults associated with the raised [Ca2+], that follows synaptic activity.‖ For example spines with large heads and thin necks sequester calcium in the spine head, whereas in spines with a low spine head: neck diameter ratio calcium may frequently invade the neck of the spine and the dendritic shaft (Sabatini et al. 2002; Noguchi et al. 2005).

As originally suggested by Vogt and Vogt (1920), there are several types of MSNs. Studies of Golgi-impregnated MSNs have revealed subtle differences in the location and density of dendritic spines on MSNs, with five different classes

–  –  –

so-called type I class, which possess aspiny proximal dendrites and somata with distal dendrites that are densely studded with dendritic spines. Type II MSNs differ in that their somata occasionally possess spines and their dendrites have significantly fewer spines compared to that of the type I class. Type III MSNs have less branched dendrites that are relatively aspiny and smooth. Type IV MSN somata are aspiny and have dendrites that branch repeatedly with a very sparse labeling of spines. Finally type V MSNs are similar to type IV in having aspiny somata, but differ in that the secondary dendrites branch significantly less and are very long (Chang et al. 1982). There have been no studies examining functional, genetic, or neurochemical differences between the five types of MSNs.

–  –  –

There are no data on physiological differences across the five morphologically defined MSNs. We will discuss MSNs as a single class.

Defining MSNs by non-morphological criteria. MSNs can also be defined on the basis of efferent projections, peptide content, and receptor expression. Two

Pages:   || 2 | 3 | 4 | 5 |   ...   | 11 |

Similar works:

«Animal Health Trust Diagnostic Laboratory Services Lanwades Park, Kentford, Newmarket, Suffolk CB8 7UU Tel: 01638 552993 Fax: 01638 555643 Strangles: Identification of carriers of Streptococcus equi Identification of Animal Carriers Streptococcus equi (S. equi) is the bacterium that causes Strangles in horses. Some horses are carriers of S. equi, meaning that they are infected with S. equi but do not show any signs of the disease, and these animals can be a source of ‘Strangles’ in...»

«September 4, 2013 CURRICULUM VITAE Noah L. Weisleder Professional Address: Home Address: Department of Physiology and Cell Biology 55 N Roosevelt Ave Davis Heart and Lung Research Institute Room 611A Bexley, OH 43209 The Ohio State University Medical Center (908)358-7248 473 W. 12th Ave. Columbus, OH 43210-1252 Phone (614) 292-5321 Fax (614) 247-7799 noah.weisleder@osumc.edu PERSONAL INFORMATION Date of Birth: July 5, 1974 Place of Birth: Corinth, ME Citizenship: USA EDUCATION Baylor College of...»

«JOHN QUINTNER, DAVID BUCHANAN, MILTON COHEN and ANDREW TAYLOR SIGNIFICATION AND PAIN: A SEMIOTIC READING OF FIBROMYALGIA ABSTRACT. Patients with persistent pain who lack a detectable underlying disease challenge the theories supporting much of biomedical body-mind discourse. In this context, diagnostic labeling is as inherently vulnerable to the same pitfalls of uncertainty that beset any other interpretative endeavour. The end point is often no more than a name rather than the discovered...»

«www.tricountyeye.com Richard B. Prince, MD Mona L. Nedjar, MD Joel M. Wolinsky, OD Jeffrey A. Gordon, MD Emily A. DeCarlo, MD Glen E. Loeser, OD Scott M. Goldstein, MD, FASOPRS Jocelyn T. Kuryan, MD Avital L. Feldman, OD Sheryl J. Menacker, MD Jessica Prince Wolfish, MD Dear New Patient, Welcome! Thank you for choosing Tri-County Eye for your eye health care. To expedite your visit, please complete the enclosed forms and bring them when you come for your first appointment. Your eyes may be...»

«Vietnam Evacuation : Operation FREQUENT WIND Daniel L. Haulman DATES: April 4-September 16, 1975 LOCATION : Republic of Vietnam (South Vietnam) OVERSEAS BASES USED : Tan Son Nhut Air Base (AB), Saigon, Vung Tau, South Vietnam; U-Tapao Royal Thailand Air Base (RTAB), Thailand ; Clark AB, Philippines ; Andersen Air Force Base (AFB), Guam; Wake Island AIR FORCE ORGANIZATIONS: DIVISION : WINGS : (con't.) 3d Air 436th Military Airlift 437th Military Airlift WINGS: 438th Military Airlift 3d Tactical...»

«GEPI 707 Genetic Epidemiology 14:17–33 (1997) Genetic Factors in the Aetiology of Mouth Ulcers Robert I.E. Lake, 1* Steve J. Thomas,1,2 and Nicholas G. Martin1 1 Queensland Institute of Medical Research, Brisbane, Australia 2 College of Medicine, University of Wales, Cardiff, Wales The aetiology of mouth ulcers is uncertain, and prior research has indicated both environmental and genetic factors. In this study, information on mouth ulcer incidence was collected for 290 twin pairs—127...»

«J. Pers. Med. 2015, 5, 341-353; doi:10.3390/jpm5040341 OPEN ACCESS Journal of Personalized Medicine ISSN 2075-4426 www.mdpi.com/journal/jpm/ Article Measurement Issues in Anthropometric Measures of Limb Volume Change in Persons at Risk for and Living with Lymphedema: A Reliability Study Dorit Tidhar 1,*, Jane M. Armer 2, Daniel Deutscher 1, Chi-Ren Shyu 3, Josef Azuri 4,5 and Richard Madsen 6 1 Physical Therapy Service, Maccabi Healthcare Services, Tel-Aviv 6812511, Israel; E-Mail:...»

«PUBLISHED BY World's largest Science, Technology & Medicine Open Access book publisher 96,000+ 2750+ 89+ MILLION INTERNATIONAL AUTHORS AND EDITORS OPEN ACCESS BOOKS DOWNLOADS AUTHORS AMONG 12.2% BOOKS TOP 1% AUTHORS AND EDITORS DELIVERED TO MOST CITED SCIENTIST FROM TOP 500 UNIVERSITIES 151 COUNTRIES Selection of our books indexed in the Book Citation Index in Web of Science™ Core Collection (BKCI) Chapter from the book Amyloidosis Downloaded from: http://www.intechopen.com/books/amyloidosis...»

«SIXTY-FOURTH WORLD HEALTH ASSEMBLY A64/8 5 May 2011 Provisional agenda item 13.1 Pandemic influenza preparedness: sharing of influenza viruses and access to vaccines and other benefits Report by the Open-Ended Working Group of Member States on Pandemic Influenza Preparedness: sharing of influenza viruses and access to vaccines and other benefits The Director-General has the honour to transmit to the Sixty-fourth World Health Assembly the report of the Open-Ended Working Group of Member States...»

«5 2. HEALTH EFFECTS 2.1 INTRODUCTION The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective of the toxicology of thallium and a depiction of significant exposure levels associated with various adverse health effects. It contains descriptions and evaluations of studies and presents levels of significant exposure for thallium based on toxicological studies and epidemiological...»

«Sociology of Health & Illness Vol. 31 No. 3 2009 ISSN 0141–9889, pp. 441–455 doi: 10.1111/j.1467-9566.2009.01161.x Health-related Original Articlestigma XXX Graham © 2009 UK 1467-9566 0141-9889of Health Ltd Sociology Publishing& the Sociology of Health & Illness/Blackwell Publishing Ltd SHIL Foundation forIllness Oxford, Scambler Blackwell Review article Health-related stigma Graham Scambler Centre for Sociological Theory and Research on Health, UCL, London The concept of stigma, denoting...»

«© Bård S. Lundeland, 2012 Series of dissertations submitted to the Faculty of Medicine, University of Oslo No. 1458 ISBN 978-82-8264-492-1 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Inger Sandved Anfinsen. Printed in Norway: AIT Oslo AS. Produced in co-operation with Akademika publishing. The thesis is produced by Akademika publishing merely in connection with the thesis defence. Kindly direct all...»

<<  HOME   |    CONTACTS
2016 www.dissertation.xlibx.info - Dissertations, online materials

Materials of this site are available for review, all rights belong to their respective owners.
If you do not agree with the fact that your material is placed on this site, please, email us, we will within 1-2 business days delete him.