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  • MARINA AUGUSTO SILVEIRA

    CONTROLE NEUROENDCRINO DA

    REPRODUO: FATORES QUE MODULAM A

    ATIVIDADE DE NEURNIOS GNRH E

    KISSPEPTINA

    Tese apresentada ao Programa de Ps-

    Graduao em Cincias Morfofuncionais

    da Universidade de So Paulo, para a

    obteno do ttulo de Doutor em Cincias

    So Paulo

    2017

  • MARINA AUGUSTO SILVEIRA

    NEURAL CONTROL OF REPRODUCTION:

    NEUROMODULATORS OF GNRH AND

    KISSPEPTIN NEURONS ACTIVITY

    Thesis presented to the Graduate Program

    in Morphofunctional Science of the

    University of So Paulo to obtain the title

    of Ph. D. in Science

    So Paulo

    2017

  • MARINA AUGUSTO SILVEIRA

    Controle neuroendcrino da reproduo:

    Fatores que modulam a atividade de

    neurnios GnRH e kisspeptina

    Tese apresentada ao Programa de Ps-Graduao

    em Cincias Morfofuncionais do Instituto de

    Cincias Biomdicas da Universidade de So

    Paulo, para a obteno do ttulo de Doutor em

    Cincias

    rea de concentrao: Cincias Morfofuncionais

    Orientadora: Prof. Dra. Renata Frazo

    Verso original

    So Paulo

    2017

  • MARINA AUGUSTO SILVEIRA

    Neural control of reproduction:

    neuromodulators of GnRH and kisspeptin

    neurons activity

    Thesis presented to the Graduate Program of

    Morphofunctional Sciences of the Institute of

    Biomedical Sciences of the University of So Paulo,

    to obtain the title of Ph. D. in Sciences.

    Concentration Area: Morphofunctional Sciences

    Mentor: Prof. Dra. Renata Frazo

    Original Version.

    So Paulo

    2017

  • UNIVERSIDADE DE SO PAULO INSTITUTO DE CINCIAS BIOMDICAS

    Candidato(a): Marina Augusto Silveira

    Ttulo da Tese: Controle neuroendcrino da reproduo: Fatores que modulam a atividade de neurnios GnRH e kisspeptina

    Orientador(a): Renata Frazo

    A Comisso Julgadora dos trabalhos de Defesa da Tese de Doutorado, em sesso

    pblica realizada a ................./................./................., considerou

    ( ) Aprovado(a) ( ) Reprovado(a)

    Examinador(a): Assinatura: ................................................................................ Nome: ........................................................................................

    Instituio: .................................................................................

    Examinador(a): Assinatura: ................................................................................ Nome: .........................................................................................

    Instituio: ..................................................................................

    Examinador(a): Assinatura: .................................................................................. Nome: .........................................................................................

    Instituio: ...................................................................................

    Examinador(a): Assinatura: ................................................................................... Nome: ...........................................................................................

    Instituio: ....................................................................................

    Presidente: Assinatura: ....................................................................................

    Nome: ........................................................................................... Instituio: ...................................................................................

  • DEDICATION

    To my mother, my father, my sister, my grandma and my boyfriend for

    all the affection and support to get here.

  • ACKNOWLEDGEMENTS

    No achievement is made alone. During my years as a PhD student, I received the support of many

    people, who were fundamental to my growth, maturation and that gave me strength to never quit.

    I would like to thank my mother, my father and my sister, for being the most important people in

    my life and for supporting me at all moments. I love you!

    To my grandmothers for being my inspiration to move through life strong and smiling, even with

    all the difficulties.

    To my boyfriend, for all the affection, patience, support and for always being optimistic even in

    the most difficult times.

    To my mentor Renata for believing and investing in my formation; for all the teaching, for the

    patience, for sincerity and especially for always being by my side.

    To me mentor Sue, for receiving me so well in her lab, for everything that Ive learned, for trusting

    me and for the opportunities.

    To Tony, Laura and Beth for everything they taught me: from the most complex experiment to the

    best running shoes.

    To Tova, Caroline, Luhong, Eden, Charlotte, Kasia and Jeff, for all the shared knowledge, for

    showing me the candy machine and for being the best friends I could ever find in Michigan.

    To Salete, who has awakened in me the passion for research, and even today continues to support

    and inspire me. And also to Maira, Luiz and Marcelo, my dearest anatomy professors.

    To professor Donato and all his students for all the help, opportunity and shared knowledge.

    Especially Isadora, Pryscilla and Aninha, who besides being great researchers became big friends.

    To the students of the lab of Neuroelectophysiology: Regina, Tabata, Fernanda, Igor, Larissa, Dani,

    Thais and Naira for all the help, support, coffee and the time we have grown up together.

    To my two friends Milena and Ivson for staying by my side at all times, for all of the empathy,

    fidelity, and for being friends that I will have for the rest of my life.

    To Bia, for being a great friend, understanding me and making me laugh at the most difficult times.

    To Carol Elias, for having trained so well the people who guided me and for being always available

    to help me, talk and advise.

    To professor Cassola for sharing with me your knowledge of electrophysiology.

    To cookies, Mabi, Vanes, Manu, Ivi and Mi for the amazing friendship, for all the laughter, crying

    and for all that we learned together.

    To my dear friends Marina and Amanda for being present even when distant and always remaining

    by my side in every situations.

    To all the employees of Anatomy Department, especially Renivaldo and Patrcia.

  • Gostaria de agradecer ao financiamento da CAPES que foi indispensvel para a realizao

    desse projeto. Agradeo tambm pela grande oportunidade de realizar um perodo de doutorado

    sanduche pelo PDSE na University of Michigan (processo nmero 7028/2015-06).

  • EPIGRAFH

    The experience of life envolves everything.

    Life is like this: it warms and it cools,

    it tightens, and it loosens, quiet and restless.

    What the life wants from us is courage.

    Guimares Rosa

  • RESUMO

    SILVEIRA, M. A. Controle neuroendcrino da reproduo: fatores que modulam a atividade

    de neurnios GnRH e kisspeptina. 2017. 101 f. Tese (Doutorado em Cincias Morfofuncionais)

    Instituto de Cincias Biomdicas, Universidade de So Paulo, So Paulo, 2017.

    Os neurnios GnRH e os neurnios kisspeptina representam as duas populaes neuronais de maior

    importncia no controle da reproduo. Os esteroides sexuais tm um papel essencial na modulao

    da rede de neurnios GnRH. Durante o ciclo reprodutivo feminino, o estradiol liga-se ao seu receptor

    expresso pelos neurnios kisspeptina e, exerce tanto feeddback negativo quanto positivo para modular

    a liberao de GnRH. Muitos estudos sobre os mecanismos neurobiolgicos subjacentes ao feedback

    de estradiol foram feitos em camundongos ovariectomizados com reposio de estradiol (OVX+E).

    Neste modelo, a atividade do neurnio GnRH dependente de estradiol e hora do dia, e o aumento

    da atividade do neurnio GnRH no final da tarde coincide com um pico drio de LH. A amplitude

    desse pico aparenta ser menor em OVX+E comparada com fmeas em proestrus, talvez porque outros

    fatores ovarianos no sejam substitudos nesse modelo. Ns testamos a hiptese de que a atividade

    de neurnios GnRH maior em proestrus comparada com o modelo OVX+E. Nossos resultados

    demonstraram que, embora a taxa de disparo dos neurnios GnRH seja similar entre os camundongos

    em proestrus e OVX+E, o padro dos potenciais de disparo revelou uma mudana para maior durao

    dos bursts em camundongos em proestrus, enquanto os intervalos entre os potenciais de disparo

    foram mais curtos em camundongos OVX+E. O pico de LH em resposta a uma injeo de GnRH no

    incio da tarde foi maior em camundongos em proestrous comparado com diestrous ou OVX+E. Estas

    observaes sugerem que a menor amplitude do pico de LH observada no modelo OVX+E

    provavelmente no devido uma alterao na atividade do neurnio GnRH, mas devido reduo

    da sensibilidade pituitria, mudanas no padro de potencial de disparo e / ou acoplamento excitao-

    secreo em neurnios GnRH. Prolactina outro hormnio com impacto na modulao do eixo HPG.

    Estudos anteriores mostraram que os neurnios de kisspeptina so mediadores importantes dos efeitos

    da prolactina sobre a reproduo. Contudo, os mecanismos celulares recrutados pela prolactina para

    afetar os neurnios kisspeptina permanecem desconhecidos. Observamos que uma pequena

    porcentagem de neurnios kisspeptina no ncleo AVPV foi indiretamente despolari