Structural analysis of adult neural stem cells and their niche in the adult hippocampus

175 Pages·2016·19.56 MB·English

Unicentre

CH-1015 Lausanne
http://serval.unil.ch

Year : 2016
R

Structural analysis of adult neural stem cells and their niche in
the adult hippocampus

Gebara Elias Georges

Gebara Elias Georges, 2016, Structural analysis of adult neural stem cells and their niche
in the adult hippocampus

Originally published at : Thesis, University of Lausanne

Posted at the University of Lausanne Open Archive http://serval.unil.ch
Document URN : urn:nbn:ch:serval-BIB_9B66D57D69847

Droits d’auteur
L'Université de Lausanne attire expressément l'attention des utilisateurs sur le fait que tous les
documents publiés dans l'Archive SERVAL sont protégés par le droit d'auteur, conformément à la
loi fédérale sur le droit d'auteur et les droits voisins (LDA). A ce titre, il est indispensable d'obtenir
le consentement préalable de l'auteur et/ou de l’éditeur avant toute utilisation d'une oeuvre ou
d'une partie d'une oeuvre ne relevant pas d'une utilisation à des fins personnelles au sens de la
LDA (art. 19, al. 1 lettre a). A défaut, tout contrevenant s'expose aux sanctions prévues par cette
loi. Nous déclinons toute responsabilité en la matière.

Copyright
The University of Lausanne expressly draws the attention of users to the fact that all documents
published in the SERVAL Archive are protected by copyright in accordance with federal law on
copyright and similar rights (LDA). Accordingly it is indispensable to obtain prior consent from the
author and/or publisher before any use of a work or part of a work for purposes other than
personal use within the meaning of LDA (art. 19, para. 1 letter a). Failure to do so will expose
offenders to the sanctions laid down by this law. We accept no liability in this respect.
Département des Neurosciences Fondamentales

Structural analysis of adult neural stem cells and their
niche in the adult hippocampus

Thèse de doctorat en Neurosciences

présentée à la

Faculté de Biologie et de Médecine
de l’Université de Lausanne

par

Elias Georges Gebara

Neurobiologiste diplômé de l’Université Paris-Est Créteil (UPEC)

Jury

Prof. Jean-Pierre Hornung, Président
Prof. Nicolas Toni, Directeur
Prof. Andrea Volterra, Co-Directeur
Prof. Yvan Arsenijevic, Expert interne
Prof. Carmen Sandi, Expert externe

Lausanne 2016

Programme doctoral interuniversitaire en Neurosciences
des Universités de Lausanne et Genève

« The staircase of science is Jacob's ladder, it ends at the feet of God »

Albert Einstein

« As long as our brain is a mystery, the universe, the reflection of the
structure of the brain will also be a mystery »

Santiago Ramón y Cajal

« Has it ever struck you… that life is all memory, except for the one present
moment that goes by you so quickly you hardly catch it going? It’s really all
memory… except for each passing moment »

Eric kandell

1
Death of a Dogma

“Once development has ended, the fonts of growth of the cells, axons and dendrites dries up
irrevocably. In adult centers, the nerve paths are fixed and immutable: everything may die,
nothing may be regenerated.”

Santiago Ramon y Cajal, 1928

2
ACKNOWLEDGMENTS

…It is impossible to start….
It cannot be argued with that the most influential person in my graduate career has
been my advisor, Nicolas Toni. Nico’s passion, guidance, and discipline have been
indispensable to my growth as a scientist and as a person over these past four and a half
years. I am especially grateful to Nico for his devotion to his students’ education and success.
I have not heard of another professor who goes so far out of his/her way to make sure
students are prepared for whatever the next step in their journeys may be.
I am especially indebted to my thesis committee members. You have been very
gracious and generous with your time. Thank you so much.
I have had the great pleasure of working on my project with Sébastien Sultan,
Fréderic Cassé and Jonathan Moss. Seb was the single most influential person on my
development as a bench scientist. He taught me everything he knew. I am also grateful to
Seb for helping me to learn that there is more than one way to approach a problem. His hard
work and friendship over the past years have been critical. He is a brilliant scientist, and I am
sure he will have a successful carrier. Fred, it was great to know him for the last year of my
thesis. He was always helpful and comforting. The various members of the lab have provided
a diverse, if occasionally tumultuous, environment that has not only shaped me as a
neuroscientist, but also as a person. I wouldn’t replace any of the people I have had the
opportunity to work with in the lab. The early lab members were instrumental to me in
learning techniques and in how to think about neurosciences. I want also to thank my two
students who become friends Florian Udry and Pieter-Jan Gijs.
I am more and more grateful to Michel Keilar every day as I write my thesis. Mitch is
so thoughtful in always trying to make the annoying parts of lab life run more smoothly. His
good mood and his humor were essential for me. He always makes me laugh and has the
most quotable quotes.
A special thanks to Alexandre Pinault. Alex is one of the more unusual (in a good way)
characters I’ve met. I’ve enjoyed getting to know him better over the last two years or so,
3
and I’m sad that it took so long. He is a really thoughtful person. We had so much fun
together with the movie shooting and especially in Barcelona.
I want to thank also my training buddies Ossama, Paul, Ludo, Mitch (again), Flo
(again), Gil, Tamara, and Kim without your support and our crazy running competitions I
wouldn’t be able to pass the writing obstacle. I believe that writing my thesis was the
hardest obstacle to pass.
I need to make a separate paragraph here for the best secretary team ever. Maria,
Francine and Kim, I want to thank you for being here, for all the hard work you did for me
(residents permit, contract, bills...) and especially for the great time we spent together
laughing.
I want to take the opportunity to thank the Department of Fundamental
neurosciences for their support and the warm family atmosphere. A special thanks to the
animal facility and the CIF.
Finally, to thank the people who shaped me into who I am. Toufic Saad, Pierre
Boufayssal and Bahaa Roustom have been my best friends since I can remember, and it is
always awesome to spend great time with you Bros. I am very happy to have you around. It’s
really nice to have some extended family nearby.
Mom, dad, I wish I could see you more, but I wanted to take this chance to thank you
for working so hard to keep the family together over the years. I know it was challenging
raising me as a kid and a teenage, and I’m amazed that you managed to do it so successfully.
I want take the advantage to thank Maïté and Regis for being here, and being
supportive for all these years.
My two love life, Sophie and Nathanael. I love you both. Without your love and your
support I would not have been able to accomplish all this. Sophie your support through all
these years has been treasured. Your encouragement, quiet patience and unwavering love
were undeniably the bedrock upon which the past ten years of my life have been built. Your
tolerance of my occasional vulgar moods is a testament in itself of your unyielding devotion
and love.
I cannot thank you enough.
4
TABLE OF CONTENTS

ACKNOWLEDGMENTS ............................................................................................................................. 3
TABLE OF CONTENTS .............................................................................................................................. 5
LIST OF FIGURES ...................................................................................................................................... 7
LIST OF APPENDICES ............................................................................................................................... 8
English abstract ....................................................................................................................................... 9
French abstract ..................................................................................................................................... 10
CHAPTER 1: PREAMBLE ......................................................................................................................... 11
CHAPTER 2: GENERAL INTRODUCTION ................................................................................................ 13
2.1 Introduction ................................................................................................................................ 14
2.2 Neurogenesis in the adult brain ................................................................................................. 14
2.2.1 The Sub-ventricular Zone .................................................................................................... 14
2.2.1.1 Proliferation and production of neural precursors ....................................................... 14
2.2.1.2 Migration of neuroblasts to the olfactory bulb ............................................................. 15
2.2.1.3 Maturation and integration of newly generated interneurons .................................... 17
2.2.2 The dentate gyrus and the hippocampus ........................................................................... 18
2.2.2.1 Anatomy and function of the hippocampus.................................................................. 18
2.2.2.2 Adult neurogenesis in the dentate gyrus: The process ................................................. 21
2.3 Regulation of adult neurogenesis in the DG .............................................................................. 27
2.3.1 Regulation of adult neurogenesis by neuronal activity ..................................................... 30
2.3.2 Regulation of adult neurogenesis by glia............................................................................ 31
2.3.2.1 Microglia ........................................................................................................................ 31
2.3.2.2 Astrocytes ...................................................................................................................... 33
2.4 Aim of the study ......................................................................................................................... 36
CHAPTER 3: STRUCTURE OF THE ADULT NEURAL STEM CELL ............................................................. 37
3.1 Introduction ................................................................................................................................ 38
3.2 Results ......................................................................................................................................... 40
Article 1 ..................................................................................................................................... 40
Contribution to article 1 ............................................................................................................ 42
Article 2 ..................................................................................................................................... 43
Contribution to article 2 ............................................................................................................ 45
CHAPTER 4: REGULATION OF ADULT NEUROGENESIS BY THE NEUROGENIC NICHE ......................... 46
4.1 General Introduction .................................................................................................................. 47
4.2 Regulation of adult neurogenesis by microglia ......................................................................... 47
5