Performance of Adult Rats Exposed to Elevated Levels of Kynurenic Acid during Gestation in a Rodent Target Detection Task: A Translational Model for Studying the Effects of Cognitive Training Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By David Anthony Phenis Neuroscience Graduate Program The Ohio State University 2018 Dissertation Committee John P. Bruno, Advisor Julie D. Golomb Kathryn M. Lenz Derick H. Lindquist Copyrighted by David Anthony Phenis 2018 2 Abstract Cognitive deficits in executive functions such as attention and cognitive control form a core symptom cluster in schizophrenia that is most predicative of functional outcomes for patients, such as the ability to return to work. Unfortunately this class of symptoms is poorly treated with currently available neuroleptics and so far adjunctive treatment with potential pro- cognitive compounds has not yielded improvements in global cognition. Not only are alternative treatment strategies necessary, but there is a need for better validated preclinical tasks and animal models. The current work seeks to validate the rodent Target Detection Task (rTDT) and the embryonic kynurenine (EKYN) model as a platform for assessing the efficacy of cognitive training via prior experience in a cognitively demanding task. The central hypothesis guiding the experiments in this dissertation is that gestational elevations of kynurenine will induce a profile of translationally relevant attentional deficits in the rTDT and these deficits can be reversed with cognitive training. The first aim consisted of a validation of the rTDT. It was found that rTDT acquisition follows a stable and repeatable pattern. Additionally, rTDT performance is sensitive to manipulations of stimulus parameters including the reduction of stimulus duration and contrast. These manipulations result in predictable impairments in sensitivity, or the ability to discriminate between target and non-target stimuli. The rTDT was also shown to be sensitive to pharmacological challenges with agents that impair glutamatergic and cholinergic neurotransmission. These neurotransmitter systems are known to be essential for intact ii attentional processing. The second aim consisted of a validation of the EKYN model. EKYN animals, compared to control animals, showed disruptions of attentional processing and cognitive control. These deficits did not present during task acquisition but emerged upon challenge with task parameters that enhanced cognitive load in either the rTDT or the Maze Set Shifting task. EKYN animals were vulnerable to reductions in stimulus duration in the rTDT and vulnerable to extradimensional set shifts in the Maze Set Shifting task. The third aim consisted of a proof-of-concept for modeling cognitive training with prior experience in cognitively demanding tasks. To assess the generalization of the effect of cognitive training a fully crossed design was used with task order counterbalanced. EKYN rTDT training rescued deficits in cognitive flexibility in the EKYN animals. Interestingly this protective effect was specific to EKYN animals who were trained in the full rTDT compared to EKYN animals who were exposed to a simple reward-stimulus pairing. In contrast both EKYN maze trained and maze exposed animals showed a protective effect against the attentional deficits shown by EKYN animals in the rTDT. In conclusion the current work (1) further validates the rTDT as a translationally relevant task that challenges animals in the cognitive domains of attention, cognitive control and perception, (2) further validates the EKYN animal model as a naturalistic neurodevelopmental model that induces deficits in attentional processing and cognitive flexibility similar to the cognitive deficits present in patients with schizophrenia, (3) is the first to show, in a strongly validated animal model of schizophrenia, the efficacy of cognitive training in adulthood to reverse cognitive deficits. iii KEYWORDS: rodent target detection task, schizophrenia, embryonic kynurenine, kynurenic acid, cognitive deficits, attentional processes, cognitive control, cognitive remediation therapy, cognitive training, maze set shifting task iv Acknowledgments I would first like to thank my advisor Dr. John Bruno for his fostering of my critical thinking skills and independence. His advice and knowledge were invaluable and constantly challenged me to not only be a better scientist, but a better person. Thank you also to my committee members Julie Golomb, Kathryn Lenz, and Derick Lindquist, whose unique insight helped focus the current work and greatly improved the experimental design. I am grateful for my advisor and committee’s patience and support through this trying experience. I would next like to thank all members of the Bruno lab past and present all of which who helped my development as a scientist. I would like to highlight the contribution of Dr. Valentina Valentini, her unparalleled mastery of techniques was matched only by her teaching ability and always welcoming demeanor. Thank you also to undergraduates Jared Boss and Jackson Schumacher whose contributions always made life a little easier in the lab. Thank you to Dr. Robert Schwarcz and his lab who donated their time and expertise for the measurement of Kynurenic Acid. Thank you to the Lenz lab for the use of their elevated plus maze. Thank you to all members of the Behavioral Neuroscience department for access to lab resources and feedback throughout this process. I would like to acknowledge the members of ULAR who always played an important role in animal care. I would also like express my gratitude to my parents who have always been supportive. Finally thank you to my wife MJ who has endlessly endured all of the highs and lows of this undertaking, I would have never been able to finish without her. v Vita May 2011…………………………B.S. Biochemistry, Case Western Reserve University Publications Ghosal, K., Stathopoulos, A., Thomas, D., Phenis, D., Vitek, M. P., & Pimplikar, S. W. (2013). The Apolipoprotein-E-Mimetic COG112 Protects Amyloid Precursor Protein Intracellular Domain-Overexpressing Animals from Alzheimer’s Disease-Like Pathological Features. Neurodegenerative Diseases, 12(1), 51–58. http://doi.org/10.1159/000341299 Pershing, M. L., Phenis, D., Valentini, V., Pocivavsek, A., Lindquist, D. H., Schwarcz, R., & Bruno, J. P. (2016). Prenatal kynurenine exposure in rats: age-dependent changes in NMDA receptor expression and conditioned fear responding. Psychopharmacology, 233(21–22), 3725–3735. http://doi.org/10.1007/s00213-016-4404-9 Fields of Study Major Field: Neuroscience Graduate Program vi Table of Contents Abstract ........................................................................................................................................... ii Vita ................................................................................................................................................. vi List of Tables ................................................................................................................................. xi List of Figures ............................................................................................................................... xii Chapter 1. Introduction ....................................................................................................................1 1.1 Task Selection ....................................................................................................................... 2 1.2 Animal Model Selection ....................................................................................................... 4 1.3 Treatment selection ............................................................................................................... 7 Chapter 2. Methods ..........................................................................................................................9 2.1 Animals ................................................................................................................................. 9 2.2 Breeding and Kynurenine Supplementation ......................................................................... 9 2.3 Weaning and Distribution of Littermates across Experimental Conditions ....................... 10 2.4 Kynurenic acid (KYNA) in PFC tissue .............................................................................. 10 2.5 Water deprivation................................................................................................................ 11 vii 2.6 Rodent Target Detection Task (rTDT) ............................................................................... 11 2.7 Maze Set Shifting Task ....................................................................................................... 13 Chapter 3: Parmetric and Pharmcological Validation of the rTDT ...............................................16 3.1 Introduction ......................................................................................................................... 16 3.1.1 Attentional Processes ................................................................................................... 16 3.1.2 Preclinical Tasks of Attention ...................................................................................... 17 3.1.3 Rationale .....................................................................................................................