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University of Groningen

Biological interactions in depression: Insights from preclinical studies Moraga Amaro, Rodrigo

DOI:

10.33612/diss.165782986

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.

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Publication date: 2021

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):

Moraga Amaro, R. (2021). Biological interactions in depression: Insights from preclinical studies. University of Groningen. https://doi.org/10.33612/diss.165782986

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Chapter 13

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As I am writing these lines, I just feel very grateful to be where I am now. As for some people doing a PhD abroad is just “the next step”, for me it was a unique opportunity that I had to fight for. I always felt like I was not living my real life, like this all was a dream. Well, of course I know is not a dream, and I feel immensely privileged for the stage in life that I am now. More than a “PhD abroad”, this was a life experience, and I would like to thank this opportunity. I can totally say that I am completely fulfill with everything experienced, the huge amount of nice people that I met, accomplishments and failures, and for the learned lessons from both the good and the bad things.

As a trained scientist, I think it is important to make some disclosures. First, due to the vast amount of people mentioned here, I cannot say all I would like to say, so hopefully I did already in person. Second, the order of appearance does not necessarily means importance (I just let my consciousness flow). And third, linked to the aforementioned, I can really write a lot (just ask my supervisors), meaning more pages to print and more money to pay, so I will try to make it as short as possible (although this is the section that everyone actually reads). So here we go.

First of all, I would like to thank my supervisors. Erik, you are the reason I am here. I feel glad that we met and that you wanted to take me as your PhD student here in Groningen. I see you as a great scientist and I really see you as a role model. Thank you for challenging me and for shaping my rational thinking. Janine, I think you are great. Somehow I reflect myself in you, as we may be the more practical people in our supervisors-PhD student relationship. Thank you very much for always being available for me, and for calming my confused mind when all these (technical) problems appeared, and for your guidance through them. Jimmy, we know each other since the beginning of my career. I probably said all of these things to you. Thank you for pushing me to the limit, for giving me these bunch of opportunities that gave me the scholarship, and formed as a scientist. Thanks for walking by my side even in this stage. I owe you so much!. Rudi, I really enjoyed our short meetings. You always took me out of my comfort zone and open up my mind to a whole new world of possibilities. Thank you all for letting me develop my ideas and to explore them.

In addition, I would like to thank my colleagues with whom I have the opportunity to work shoulder to shoulder, who are part of what I always called “the preclinical team”. Thanks for making me feel that you were always there when I needed you. Anna, we started together our period in Groningen, and we quickly became friends. I still consider you a good friend, and I am happy for all the experiences we shared together (from tears to successful moments). Thanks for the office sweets and breaks once in a while. Bruno, once you told me

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that you deserve at least 2 lines, I will try to keep it short then. You were one of my best friends in here, and I really missed you when you left. But not only that, we also worked together for so long, and I really feel like you were the person with whom I wanted to talked about science, as we challenged each other but also were in the same level of thinking. I still admire your critical thinking ability. Thank you so much for everything, there are so many moments that I will keep, and so many others that we will create in the future (hope this was enough). Lara, since we met we had this instant chemistry, like we were meant to be best

friends. There is so much I want to tell you (which I think I already did). You are such a special person, easy to love and to get along with. We really had tons of experiences of all kind, which strengthen our bonds. I have to say that this experience (specially the 2020) would have definitively been different without you. Daniel, I think I learned to meet you over

time and realized that you have a huge heart. Thank you very much for all the experiences and for being there. Thank you also for all the gifts that you gave me, including the nice food and other nice details. Kavya, my little sys! I think our bond grew stronger and stronger. From

silly conversations to very deep and personal conversations. I love you so much and I am sure that all the effort you are doing right now will lead to many beautiful experiences in your life. Thank you also for your delightful indian cooking and treats. Nafiseh, it was very nice to

work together. Thank you for the conversations in the surgery room and for the dinner. I wish you the best in whatever you do. Jurgen, you are like our godfather. Probably you don’t

realize how important you are for all the people who work in the preclinical section. You are like this important piece of the machine that when is missing, the machine just stop working. It was very nice to share with you. You are a very nice and kind person. I also enjoyed our Pokemon raids once in a while. Luiza, you come later ;).

I have to say that I am quite happy with all the people I came across in the department. I will always remember the borrels, the secret santa, the Friday drinks, the coffee breaks, and many more fruitful experiences. Elli, my ice cream mate. We also started together and were

office mates for more than 2 years and I really had a good time with you. Thank you very much for opening your heart and your house to me. We grew up together and forged this amazing friendship bond, that we don’t need to speak so often to know that we are still friends and that it is like time hasn’t pass. Thank you very much for the nice conversations with coffee, ice creams or dinner, and more importantly, for letting me see how little Maya was growing. I am sure we will not lose the contact, and hope we can visit each other in Germany. Debora, as others, we came from the same batch, when all of this was weird and unfamiliar. You are a very good friend. I admire your tenacity and your protectiveness with the people

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you love. Thank you very much for all the crazy moments and for the suuuuuuuuper tasty cakes. It was always a pleasure to have you around. Ines, I really enjoyed every opportunity we were together. Thank you so much for the energy, the long conversations and dinners, I always felt very comfortable around you. Bruna, it felt like we were twins. Thank you for the energy, the unconditional support, for always being there up for any kind of social activities. I am really going to miss you. Pascalle, although we met at the second half of my period, it was a pleasant surprise to become such friends. Although rainbow team evolved into an error (404), our friendship still continued to grow. I really enjoyed our going outs and other activities. Dik, same story. I really feel we created a very nice friendship bond. It was very nice to share many hobbies and preferences. Thanks for the openness and for all the funny and interesting facts that always taught me a lot. We really have to repeat karaoke! Andrea querida! Thank you for letting me be part of important processes of your life. Thanks for the nice friendship and everything that came included. I really enjoyed our time together. Also thank you very much for your support and kindness in one of the most difficult moments that I had here. I am sure we will meet more in the future.

(break…I really need to make another paragraph)

David, since the beginning you were an important influence in my staying in Groningen. Thank you for your kindness, friendship and guidance in all senses. Thanks for all the support and the friendship. Paula, thank you for your constant kindness and willingness to help, and for all the supports and smiles in all of these 4 years. Khaled, I always enjoyed our coffee break conversations, the Friday drinks and all the meetings. Thank you very much for your compromise with my work, and also for the tips about Egypt. Verena and Gonçalo, when I just arrived and I was a lonely biologist, you adopted me in your funny chemist group and made me feel welcome. I really appreciate that. Marta, we met later, but doesn’t make you less important. I always enjoyed having you around. Thank you for the good energy and for all those random funny moments that we shared together. Hugo, I have to say that I was always scared about our building up enthusiasm for parties (ahahahah), but I did enjoyed our time together. Thanks for the chemistry (not the (radio)-chemistry) and for all the nice moments we spent together. Joyce, it was always nice to chitchat with you and to see your big smile around, thank you. Ananthi, also thanks for the chitchat, and for the amazing Diwali experience. I wish you the best in the rest of your period in here. Dana (Wejdan), thank you for always been up for the coffee breaks and the meetings. Thanks for all the chitchats.

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Maaike, my first dutch friend ahahaha. Thanks for the good moments. Special thanks for the Bandidos. Bruno, not again sorry ahhaa, Kars, no worries, you come later. Gui, according to

Carlos, you were the most Brazilian person of the group and I think I know why ahaha. Thanks for the gatherings, casual conversations, funny facts, crazy talks about physics and the good moments. Filipe, although you were hidden somewhere, I always feel a good vibe with

you and it was very nice and funto be around you when we meet. Aljosa, our time was short

but enjoyable, and as you would say: “Bosnia has the best people in the world”. Well, I don’t know if that is true but you did left a good impression. Bart (tinho), thanks for all the beers

and conversations. Thanks for your trust. Although you just disappeared at some point from the world, I still call you friend.

In addition, I had the opportunity to lead students during my PhD, whom each one taught me something, helping me to become better. Elisa, you were my first student as a PhD

student. I will always remember your energy and laughs. You put great effort in everything you did, and I really appreciated that. Thank you for all the time spent together. Cyprien, it

was a real pleasure to work with you. Thank you for showing me that I could completely trust and delegate in you. You are a great person with such energy and will. I was a witness of your growth, and I am sure you will accomplish with success all the issues of your PhD now.

Benjamin, it was very nice to have a Chilean as a student, it made me feel at home. Thanks

for the trust you had in me and for keeping in contact. For all of you, I really wish the best in whatever you do.

I also wanted to thank the people working in the department. Gerda, you were always

very enthusiastic about the department activities and always acted as a bridge between us, the PhD students, and the department. Sarita, thank you for your kindness and willingness to

help. Aren, I admired you for your vast knowledge and practical approaches. Was very useful

to work with you on my first manuscript from the PhD. Rolf, thanks for being there whenever

I had questions. Thanks for the help and the talks. Same goes for Bram, the Picanha master!.

Thanks for all the help support, nice moments and nice weekend barbecues. Chantal, I got

the opportunity to meet you a bit more in the conference. I think you are a great person. Thank you for all the help and commitment with my tracers, you really deserve a special mention for that. Additional thanks to Michel, Gina and Janet for helping me with the tracers

too. Also special thanks to Hans, Carlos, Ming, Luis, Isadora, Sabine, Anne-Sophie, Magdalena, Gerben, Pieter, Emile and many other people from the department that I had

the pleasure to meet and share with. Also to all the researchers and professors I didn’t had the chance to directly work with.

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Thanks to all the collaborators. Laura, I owe you a lot. Thank you very much for your time and effort. Thank you for your compromise in our project, even if it didn´t go the way we expected. It was a real pleasure to work with you. I find you a nice person and very professional. Your inputs and points of view were always important to me. Bart Eggen, thank you for letting us to collaborate with you. Lara Barazzuol, thanks for your kindness and for always be willing to help me in whatever I need. Same goes for you Daniëlle, thanks for your trusting in what we were doing and for getting involved. This work will be not complete without your help.

To the CDP personeel. All of these people play an important role in the preclinical research of the whole university, so of course they deserve special aknowledgements. Thanks to Ar, Miriam, Catriene, Minke, Gerward, Annemieke, Daryll for making this possible and for the trust. I want to specially thank Michel. Thanks for the good humor, the jokes, the willingness to help and the involvement in my projects. You played a major role in my thesis.

I also would like to mention the people from the PhD councils. I had the opportunity to work with so many people who were involved and caredabout PhD matters. Thank you for trusting me as the chair of these councils. Thanks to the GSMS PhD council people Ioana, Francisco, Vasilena, Jeroen, Matthijs, Sonya, Rita, Johanna, Frits, Jing, and Luc. Also thanks to the BCN PhD council group Sebastián, Mayra, Emile, Hermine, Alejandro, Tiago and Magdalini. It was a great experience to work with all of you. Thanks for the commitment for the change. In addition I wanted to thank the BCN board, but letting us to have a voice and opinion in all the decisions of the research school. In addition, a special mention to Diana Koopmans. I really enjoyed working with you, and thank you for all the support and the trust you had in us, and specially in me.

Changing a bit the focus, I would like to thank all of the people that I met besides work. To my chilean Friends in Groningen. Natalia and Cesar. You were the first people I could call friends when I arrived. Natalia, you were the very first person with whom I had such a strong connection, and I am glad to have you in my life, and I am very happy that our friendship is growing stronger every day. I loved how much we trusted each other and I love that we can feel ourselves and be transparent when we are together. Cesar, you were the first Chilean I met, and I am glad to have met you, I think we both share many life experiences and we can really understand each other’s very well, thanks for the nice conversations and the good moments. Mel and Ale, I never imagined that we could share so many beautiful experiences. Also, I learned to love you both (even with all your special issues ahaha), which made our bond stronger. Mel, we became naturally very friends from the beginning, and I

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really appreciate having someone so genuine as my friend, you taught me a lot. Thanks for giving me the feeling of being there for whenever I need you. Ale, the more I shared with you,

the more I liked you, because you are this really nice guy with a huge heart, whom everyone who knows you with tiem will think the same about. Thanks for all the kindness and laughs and weird conversations. Dani y Pablo (Gato), I wish we had more time together, but I think

it was enough to form a tight bond. For sure we will visit each other again when back in Chile. Clau, my temporal roomie and friend. We shared some very special moments. As

country side comrades we had a lot in common and it was nice living together and being accompanied by you. Eli, Lupe, Felipe, Rodrigo, it was very nice to share so many moments

with you. You were always adding this “missing thing” that only our cultural bond can provide. Thank you for the nice moments. And thanks also to all the (“caleta de”) wonderful people from Chile with whom we share many “dieciochos”, “sopaipillas”, “pastel de choclo”, “pisco sour”, “pebre” and many other Chilean things that we love and miss when abroad. Solo nos falto bailar cueca!.

Moreover, I wanted to mention all the nice (not Chilean) people that made my staying in Groningen a great experience. Miguel (Santin), you were the first latino I talked with, and

you kindly introduced me to other people when I just arrived and I was lonely. I will never forget that. You have a special place in my heart. Miguel (Souto), thank you for your

closeness, for the dinner invitations (specially the callos jajaja) and for always be there willing to help in any matter. Thank you for always inviting us and having us into consideration .

Oscar thank you very much for the good moments and nice talks, it was always fun to see

you. Bob, thank you for all the laughs, and conversations of the many many subjects we could

talk about. Also thanks for your kindness and niceness always, your support was very much appreciated. Sonso, although we couldn’t see each other much lately, I really enjoyed our

time together and I am gonna miss you. Alfredo (Parce), it was very nice meeting you, and

thanks for all the food and the moments. Menno, thank you very much for being there in the

worst moments.

A special mention also to the many kind people I met in this journey including the latino group, the Spanish people, the dutch people and the fellow PhD students from GSMS and BCN, the “Cochifriends” and the EURON team.

As it seems, I met a considerable amount of people during this adventure. However, I also have to thank the people that keeps me connected with my roots. I wanted to thank “los chicos de la vecindad” (Tania, Hugo, Daria, Fabian, Michelle, Jose, Tahi) for being always

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country. I just love that over all of these years we are still very good friends. Special thanks to Daria, because our unconditional love across continents is unbreakable. Thank you for the long conversations and for always being there in one way or another, we were always each other’s rock. To my cute Carito! We also know each other’s since so long and have so many experiences together! I couldn’t be more happy with you being the designer of my cover. Thank you to all my other good friends in Chile for their support and company at the distance. To my paranymphs, whom play a major role in this work. I really have a lot to write about you both in here. Instead, I will just try to summarize some stuff. Chris Willemsen Jacobson (known by his fictional name Kars), you were my first dutch friend. People always have a stereotype of dutch people, and you are the living proof that it is wrong (or that you are not dutch hahaha). I never thought that I would meet such a special person like you. You were always there for me. I always enjoyed when you appeared at my office’s door with a cup of coffee (or without it) and your big, loud and contagious laugh. I hope you keep your passion for what you do, and to never lose that weird and contagious sense of humor. Luiza (lulu, luizhinha), when I first met you, it really felt like we knew each other since a long time. The love was immediate. I don’t even remember if we became friends or if we were already. I feel like we shared so many different moments together, from crying to laughs, projects, ideas, that for some reason I don’t think I will be able to share with anyone else. Keep that big heart of yours. I am looking forward for your invitations for dinner prepared with your magic hands.

For the following paragraph, I apologize for the Spanish sentences. I would like everyone who read this section to know what I feel, but I prefer that the message can be understandable for the receivers. Me gustaría dedicarle esta tesis a mi familia. Mama, no solo me diste la vida, pero me entregaste las mejores herramientas para vivirla. Eres una mujer muy fuerte y te admiro mucho. Me enseñaste a no rendirme y a ser fiel a mis principios. Quiero que sepas que todos los esfuerzos que hiciste para sacarnos adelante, los que sabemos y también los que no sabemos, no fueron en vano. Gracias por enseñarme que el trabajo duro puede llegar a algo fructífero. Te quiero mucho y eres mi modelo a seguir. Papa, gracias por la fe que siempre tuviste en mí. Gracias por esforzarte por darnos la oportunidad de estudiar y sacar una carrera. Gracias por siempre impulsarme al siguiente paso. Quiero que sepas que estoy agradecido de tus esfuerzos y que estoy en una buena posición en mi vida y que soy feliz. Hermano, el cariño que te tengo es inexplicable. Quizás no somos de las personas que hablan todos los días, pero de alguna forma siempre sabemos que el cariño y apoyo incondicional está ahí. Me encanta nuestra conexión de memes y de videojuegos, y quiero que

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sepas que te he extrañado caleta durante estos años. Te agradezco mucho por el apoyo que siempre me diste, a pesar de que este viaje significaría el no estar para ti en los momentos importantes de tu vida. Al final, sin ti, sin tu preocupación por nuestra mama, no estaría tranquilo. Muchísimas gracias por hacerte cargo, por ser el que está ahí presente mientras yo no lo estoy. Finally to Felipe (Guau Guau), mi “compañero de vida”. I never thought that I

would be together with such an amazing person for 5 years already. You are the one with whom I shared my days, my success and failures, laughs and tears. There are so much things that you give me that I don’t really know where to start. Thanks for taking me out of my comfort zone, for walking with me side by side and for your unconditional love and support. Thanks for the funny faces and voices, for all the adventures and the songs. Just thanks for staying in my life. You are the main reason for me to keep going and keep smiling.

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263

- First author publications

1) Khayum MA1, Moraga-Amaro R1, Buwalda B, Koole M, den Boer JA, Dierckx

RAJO, Doorduin J, de Vries EFJ. (2020) Ovariectomy-induced depressive-like behavior and brain glucose metabolism changes in female rats are not affected by chronic mild stress. Psychoneuroendocrinology 115:104610.

2) Moraga-Amaro R, van Waarde A, Doorduin J, de Vries EFJ. (2018) Sex steroid hormones and brain function: PET imaging as a tool of research. Journal of Neuroendocrinology 30(2).

3) Moraga-Amaro R, González H, Ugalde V, Donoso-Ramos JP, Quintana-Donoso D, Lara M, Morales B, Rojas P, Pacheco R, Stehberg J. (2016) Dopamine receptor D5 deficiency results in a selective reduction of hippocampal NMDA receptor subunit NR2B expression and impaired memory. Neuropharmacology 103:222-235.

4) Moraga-Amaro R, Jerez-Baraona JM, Simon F, Stehberg J. (2014). Role of astrocytes in memory and psychiatric disorders. Journal of Physiology-Paris 108, 240-251.

5) Moraga-Amaro R, Gonzalez H, Pacheco R, Stehberg J. (2014) Dopamine receptor D3 deficiency results in chronic depression and anxiety. Behavioural Brain Research 274, 186-193.

6) Moraga-Amaro R, Cortés-Rojas A, Simon F, Stehberg J. (2014) Role of the insular cortex in taste familiarity. Neurobiology of Learning and Memory 109:37-45.

- Other publications

1) Giacobbo BL, Doorduin J, Moraga-Amaro R, Nazario LR, Schildt A, Bromberg E, Dierckx RAJO, de Vries EFJ. (2020) Chronic harmine treatment has a delayed effect on mobility in control and socially defeated rats. Psychopharmacology (Berl). 237(6):1595-1606.

2) Schildt A, de Vries EFJ, Willemsen ATM, Giacobbo BL, Moraga-Amaro R, Sijbesma JWA, van Waarde A, Sossi V, Dierckx RAJO, Doorduin J. Effect of Dopamine D2 Receptor Antagonists on [18F]-FEOBV Binding. Mol Pharm. 2020 Mar

2;17(3):865-872.

3) Schildt A, de Vries EFJ, Willemsen ATM, Moraga-Amaro R, Lima-Giacobbo B, Sijbesma JWA, Sossi V, Dierckx RAJO, Doorduin J. (2020) Modeling of [18F]FEOBV Pharmacokinetics in Rat Brain. Molecular Imaging Biology (in press).

4) Méndez-Ruette M, Linsambarth S, Moraga-Amaro R, Quintana-Donoso D, Méndez L, Tamburini G, Cornejo F, Torres RF, Stehberg J. (2019) The Role of the Rodent Insula in Anxiety. Frontiers in Physiology 10:330.

5) Retamal MA, Orellana VP, Arévalo NJ, Rojas CG, Arjona RJ, Alcaíno CA, González W, Canan JG, Moraga-Amaro R, Stehberg J, Reuss L, Altenberg GA. (2019) Cx46

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hemichannel modulation by nitric oxide: Role of the fourth transmembrane helix cysteine and its possible involvement in cataract formation. Nitric Oxide 86:54-62. 6) Orellana JA, Retamal MA, Moraga-Amaro R, Stehberg J. (2016) Role of astroglial

hemichannels and pannexons in memory and neurodegenerative diseases. Frontiers in Integrative Neurosciences 10:26.

7) Torres F, Villalón E, Poblete P, Moraga-Amaro R, Linsambarth S, Riquelme R, Zangen A, Stehberg J. (2015) Retrospective Evaluation of Deep Transcranial Magnetic Stimulation (dTMS) as Add-On Treatment for Parkinson's Disease. Frontiers in Neurology 6:210.

8) Rojas S, Díaz-Galarce R, Jerez-Baraona JM, Quintana-Donoso D, Moraga-Amaro R, Stehberg J. (2015) The insula modulates arousal-induced reluctance to try novel tastes through adrenergic transmission in the rat. Frontiers in Behavioral Neuroscience 9: 164.

9) Orellana JA, Moraga-Amaro R, Díaz-Galarce R, Rojas S, Maturana CJ, Stehberg J and Sáez JC. (2015) Restraint stress increases hemichannel activity in hippocampal glial cells and neurons. Frontiers in Cellular Neuroscience 9:102.

10) Stehberg J, Moraga-Amaro R, Salazar C, Becerra A, Echeverría C, Orellana JA, Bultynck G, Ponsaerts R, Leybaert L, Simon F, Sáez JC, Retamal MA. (2012) Release of gliotransmitters through astroglial connexin 43 hemichannels is necessary for fear memory consolidation in the basolateral amygdala. FASEB J. 26: 3649-3657.

11) Retamal MA, León-Paravic CG, Verdugo CA, Alcaino CA, Moraga-Amaro R, Stehberg J. (2011) Connexin in Lens Physiology and Cataract Formation. Journal of Clinical and Experimental Ophthalmology S1:001.

Book chapters

1) Linsambarth S, Moraga-Amaro R, Quintana-Donoso D, Rojas-Silva S, Stehberg J 2017. The Amygdala in anxiety. (2017) InTech editorial. DOI: 10.5772/intechopen.68618

2) Stehberg J. and Moraga-Amaro R. 2012. The Insular Cortex and the Amygdala: Shared functions and interactions. InTech editorial. ISBN 980-953-307-188-1.

3) Moraga-Amaro R, Doorduin J, Dierckx RAJO, de Vries EFJ.(2020) PET and SPECT Imaging of Steroid Hormone Receptors in the Brain. PET and SPECT of Neurobiological Systems. Springer editorial. ISBN 978-3-030-53175-1.

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