Congratulations Erica Littlejohn, PhD
On Tuesday, May 29 2018 Erica Littlejohn successfully defended her dissertation and was awarded her doctoral degree. Congratulations Erica!
INSULIN-LIKE GROWTH FACTOR-1 OVEREXPRESSION MEDIATES HIPPOCAMPAL REMODELING AND PLASTICITY FOLLOWING TBI
Doctoral Committee
Dr. Kathryn Saatman/ Department of Physiology, Mentor
Dr. Bret Smith / Department of Neuroscience
Dr. John Gensel / Department of Physiology
Dr. Kim Nixon / Department of Pharmaceutical Sciences
Outside Examiner: Dr. Deshana Collett / Division of Physician Assistant Studies
Abstract
Every year over 2.5 million traumatic brain injuries (TBI) occur and are the leading cause ofdeath and disability among adolescents. There are no approved therapeutic treatments for TBI. Survivors suffer from persistent cognitive impairment due to posttraumatic tissue damage and disruption of neural networks which significantly detract from their quality of life. Posttraumatic cognitive impairment depends in part to the brains limited ability to repair or replace damaged cells. Immature neurons in the hippocampus dentate gyrus, a brain region required for learning and memory, are particularly vulnerable to TBI. Insulin-like growth factor-1 (IGF1) is a potential therapeutic for TBI because it is a potent neurotrophic factor capable of mediating neuroprotection, neuro-repair, and neurogenesis. We hypothesized that conditional IGF1 overexpression in the mouse hippocampus following experimental controlled cortical impact injury (CCI) would enhanced posttraumatic neurogenesis chronically. To this end, astrocyte-specific IGF1 conditionally overexpressing mice (IGFtg) and wild-type (WT) mice received controlled cortical impact or sham injury. The proliferation marker, BrdU was used to label neurons born the first week after injury. Six weeks after injury, when surviving posttrauma-born neurons would be fully developed we counted proliferated cells (BrdU+) and the subset expressing a mature neuronal marker (NeuN+/BrdU+) in the hippocampus. We also assessed cognitive performance during radial arm water-maze reversal (RAWM-R) testing, a neurogenesis-sensitive assay. IGF1 promoted end-stage maturity and decreased mis-migration of neurons born after trauma. These affects coincide with IGF1 induced improve performance on neurogenesis sensitive cognition following TBI.
Mammalian target of rapamycin (mTOR), an early signaling molecule downstream of IGF1, has been identified as a potential target for TBI interventions because of its regulatory role in neuronal plasticity and neurogenesis. However, recent studies have also reported maladaptive plasticity and recovery associated with posttraumatic mTOR activation. It is imperative to elucidate the mechanism of action of IGF1 during pre-clinical evaluations. We hypothesized that IGF1 posttraumatic neurogenic effects were mediated through IGF1 induction of mTOR activation. We injured cohorts of IGFtg and WT mice and harvested their brains for immunohistochemistry to assess IGF1 overexpression effects on posttraumatic mTOR activation at 1, 3, and 10 days post-injury (dpi). We found that IGF1 upregulated mTOR activation following TBI in a region-specific manner at 1 and 3dpi. To determine if IGF1 regulated differentiation and arborization through the mTOR pathway, injured WT and IGFtg mice received daily i.p. injections of rapamycin (10mg/kg), the inhibitor of mTOR or it’s vehicle for 7 days. Vehicle and rapamycin administration began after dividing cells were labeled with BRDU at 3dpi (the peak of posttraumatic proliferation). IGF1 enhancement of posttraumatic neurogenesis was not dependent on mTOR activation.
In summary, IGF1 directs newborn neuron localization, promotes end-stage maturation, and chronically improves cognition. IGF1 can stimulate posttraumatic neurogenesis and plasticity independent of mTOR activation. These data suggest that IGF1 can neuron replacement following trauma-induced hippocampal neuron loss and cognitive improvement. Further studies should investigate IGF1 and mTOR inhibition as a combination therapies for neurorehabilitation.
Acknowledgements
I am very grateful for the journey to my Doctorate in Physiology. In addition to receiving world class training from leaders in neuroscience and brain trauma, I have learned many insightful lessons about integrity, balance, compassion, and grit. I would like to warmly express my gratitude to the members of the community that supported me along the way.
I want to thank the Center for Graduate and Professional Diversity Initiatives (CGPDI) and Black Graduate and Professional Student Association (BGPSA) were instrumental to my success on UK’s campus. A special thank you to Dr. Chassity Holliman-Douglas, Dr. Cleo Price, and members of BGPSA.
The department of Physiology (PGY) and the Spinal Cord and Brain Injury Research Center (SCoBIRC) faculty, administrators, and students of PGY have been so warm and supportive. Thank you. SCoBIRC is truly a family. Zel, thank you for knowing everything and making every last minute need a possibility! Thank you Linda for allowing me to live in the scope room with you! Thank you to all the faculty with open doors who easily give advice and encouragement, with special thanks to Bret, Dr. Hall, John, Adam, and Samir. Special thanks to my committee!
Many thanks to my dear labmates, my work would literally be impossible without all of you! Special thanks to Diana Sama, you and I were in the trenches my dear friend! Amanda Bolton-Hall, you have been such a reliable source of encouragement. Isabel, thank you for being my partner in my previous ephys life! Carrie Boychuk and Kati Halmos, you are everything! My dear Danielle Scott, there is no challenge you don’t rise up to meet. Your presence ensures my daily dose of work-fun and an loving audience for my comedy and complaints! Special thanks to the amazing Anna Juras, Binoy, Jen, Sindhu, Shaun, Anthony. All my nearly 25 labmates that have rotated through Kathy’s lab for different seasons and reasons have been amazing!
I have made amazing lifelong friends in graduate school though PGY and BGPSA that kept me going. Drs. Jenna, Stacy, Katie, and Laura, I love you ladies! Drs. Ese and Courtney, you are my sisters forever. Mike, you are an incredible friend. So many memories with all of you!!
Dr. Lang and Dr. Soltani at the University of Chicago are a major part of the reason I applied to graduate school. I will never forget how much you believed in me and my potential. Dr. Kathy Saatman, my mentor and advisor, I hope that I am a reflection of every one of your strengths and gifts as a woman in science. Thank you so much for pouring into me.
To my extended family from Bethel Harvest Church, I love you. Your support in this journey has been life giving. Donavan Ramon, you are perfect. Thank you for giving so much of yourself all the time. To my friends and blood relatives, thank you for your love and encouragement for the last 20 plus years!
To my family, you are my breath of fresh air. You moved to Kentucky with me and without your support, compassion, and faithfulness I could not be the woman that I am today. Beronica Littlejohn, Quianna Littlejohn and Bridget Reyes, I could write one million love letters to honor what your support has meant to me and it wouldn’t be enough. Thank you for making it ok for me to be me.
To my mommy and granny, my highest honor as a woman is to be the best parts of the both of you. You are the integrity, grit, passion, resilience, intelligence, creativity, curiosity and optimism that marks my character.
To you Jesus. No greater love has any man shown than to lay down his life for his friends. Thank you for being the power and light that sustains me. Thank you for this journey, PhD, and future.
