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Transient Inactivation of the Neonatal Ventral Hippocampus as a Novel Animal Model of Schizophrenia

Brooks, Julie Marie
http://rave.ohiolink.edu/etdc/view?acc_num=osu1303918697

Abstract Details

2011, Doctor of Philosophy, Ohio State University, Psychology.
Cognitive deficits are core symptoms in schizophrenia (SZ). These symptoms reflect developmental dysregulations within a distributed neural system involving the ventral hippocampus (VH), nucleus accumbens (NAC), basal forebrain (BF), and prefrontal cortex (PFC). We have reported that activation of NMDA receptors in NAC results in increased acetylcholine (ACh) release in PFC but not in other cortical regions in intact rats. This NAC-mediated cholinergic activation may facilitate top-down regulation of attentional processing when motivation is heightened following increased demands. Given the importance of VH input to NAC and PFC development, we determined the neurochemical and cognitive effects of transiently inactivating VH projections, during development. The first experiments determined the ability of intra-NAC NMDA administration to increase cortical ACh release in adult rats sustaining VH infusions of tetrodotoxin (TTX) or saline on postnatal day 7 (PD7) or 32 (PD32). In saline control animals, intra-NAC perfusions of NMDA (250 μM) increased ACh in the PFC. This effect was absent in PD7 TTX infusion rats. Conversely, PD32 TTX infusion rats exhibited an NMDA-evoked increase in PFC ACh that did not differ from controls. These data suggest an age-dependent period during which VH inactivation impacts the maturational development of the NAC-BFCS-PFC circuit. Moreover, identical PD7 TTX inactivation of the dorsal hippocampus or basolateral amygdala did not affect NMDA-evoked cortical cholinergic transmission demonstrating the necessity of developmental VH outflow in the development of the NAC-BFCS-PFC circuit. The second set of experiments examined the functional consequences of VH inactivation in an attentional set-shifting task. In this task, rats are required to solve a two-pot discrimination in order to secure a cereal reward. Following acquisition of the discrimination, animals are tested for several reversals, an intra-dimensional shift (IDS) and an extra-dimensional shift (EDS). Previous studies have demonstrated that performance is dependent upon PFC function and patients with SZ exhibit deficits in the reversal and EDS stages of such tasks. TTX infusions did not affect the initial acquisition or IDS. However, TTX rats exhibited significant deficits (greater trials to criterion) during the first reversal and EDS shift stages when compared to control animals. These cognitive deficits were also age-specific as rats sustaining VH infusion of TTX or saline at PD32 exhibited comparable performance at all discrimination stages of the task. Finally, the third set of experiments investigated potential neurochemical correlates underlying the cognitive flexibility impairments seen following VH inactivation during early neonatal development. Prefrontal glutamatergic and cholinergic neurotransmission have previously shown to contribute to different forms of cognitive flexibility. Prefrontal cortical infusion of the NMDA receptor antagonist MK801 in intact rats produced TTX-like deficits in the EDS stage of the task. Conversely, rats receiving intra-PFC infusions of muscarinic (scopolamine) or nicotinic (mecamylamine) ACh receptor antagonists exhibited TTX-like deficits in the first reversal stage. Collectively, these data underscore the critical role of VH activity, during a sensitive period of early development, in the functional maturation of a distributed neural system believed to be central to the symptomatology associated with schizophrenia.
John Bruno, PhD (Advisor)
Susan Travers, PhD (Committee Member)
Gary Wenk, PhD (Committee Member)
163 p.
Behavioral Psychology; Neurosciences
schizophrenia; cognition; animal model

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Citations

  • Brooks, J. M. (2011). Transient Inactivation of the Neonatal Ventral Hippocampus as a Novel Animal Model of Schizophrenia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1303918697

    APA Style (7th edition)

  • Brooks, Julie. Transient Inactivation of the Neonatal Ventral Hippocampus as a Novel Animal Model of Schizophrenia. 2011. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1303918697.

    MLA Style (8th edition)

  • Brooks, Julie. "Transient Inactivation of the Neonatal Ventral Hippocampus as a Novel Animal Model of Schizophrenia." Doctoral dissertation, Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1303918697

    Chicago Manual of Style (17th edition)

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© 2011, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.