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Dissertation Final 11.13.2018.pdf (2.32 MB)

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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

Phenis, David Anthony
http://orcid.org/0000-0002-8967-3361
http://rave.ohiolink.edu/etdc/view?acc_num=osu154211727456543

Abstract Details

2018, Doctor of Philosophy, Ohio State University, Neuroscience Graduate Studies Program.
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 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.
Bruno John (Advisor)
Golomb Julie (Committee Member)
Lenz Kathryn (Committee Member)
Lindquist Derick (Committee Member)
123 p.
Behavioral Psychology; Neurobiology; Neurosciences
rodent target detection task, schizophrenia, embryonic kynurenine, kynurenic acid, cognitive deficits, attentional processes, cognitive control, cognitive remediation therapy, cognitive training, maze set shifting task

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Citations

  • Phenis, D. A. (2018). 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 [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu154211727456543

    APA Style (7th edition)

  • Phenis, David. 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. 2018. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu154211727456543.

    MLA Style (8th edition)

  • Phenis, David. "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." Doctoral dissertation, Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu154211727456543

    Chicago Manual of Style (17th edition)

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