Schizophrenia is characterized by cognitive impairments that are not adequately treated by currently available medications and may contribute to the poor outcomes of afflicted individuals. Evidence from post-mortem analyses suggests that inhibitory ?-aminobutyric acid (GABA) neurons are dysfunctional within the prefrontal cortex of people with schizophrenia. The prefrontal cortex is critical for optimal cognitive functioning, thus neuropathology within this brain area may contribute to cognitive deficits observed in schizophrenia. Using rat models of attention and decision-making this proposal aims to determine the extent to which dysregulation of cortical GABA transmission impairs cognitive function. We have previously reported that blockade of GABAA receptors in the prefrontal cortex impairs attention. Because this manipulation can increase dopamine release, the first aim of this of this proposal is to reverse the observed attentional deficit by systemically administering dopamine receptor antagonists.
The second aim of the proposal will investigate whether reducing GABA synthesis, which more closely models the neuropathology observed in schizophrenia, is sufficient to impair attention. Finally, the effects of reducing GABA transmission (both by GABAA receptor blockade and by inhibiting GABA synthesis) on decision-making will be assessed. In addition to the scientific goals of this proposal, these studies will b conducted as a means to teach undergraduate researchers about the scientific process. Engaging students in research will enhance their educational experience and enrich the research environment at Oberlin College.
Schizophrenia is a debilitating mental illness characterized, in part, by cognitive deficits, which may contribute to the poor outcome of afflicted individuals. Neuropathological evidence suggests that cortical GABA transmission is reduced in schizophrenia. The goals of this project are to more fully characterize the role of decreased GABA transmission in schizophrenia by 1) assessing whether attentional deficits caused by GABAA receptor blockade are attenuated by dopamine receptor antagonists, 2) assessing whether blocking GABA synthesis, which mimics the neuropathology in schizophrenia, impairs attention and, 3) assessing whether reduced GABA transmission impairs decision-making. Gaining a better understanding of the role of cortical GABA dysfunction in the cognitive deficits in schizophrenia may lead to improved treatment strategies.
|Paine, T A; O'Hara, A; Plaut, B et al. (2015) Effects of disrupting medial prefrontal cortex GABA transmission on decision-making in a rodent gambling task. Psychopharmacology (Berl) 232:1755-65|
|Asinof, Samuel K; Paine, Tracie A (2014) The 5-choice serial reaction time task: a task of attention and impulse control for rodents. J Vis Exp :e51574|
|Asinof, Samuel K; Paine, Tracie A (2013) Inhibition of GABA synthesis in the prefrontal cortex increases locomotor activity but does not affect attention in the 5-choice serial reaction time task. Neuropharmacology 65:39-47|
|Paine, Tracie A; Asinof, Samuel K; Diehl, Geoffrey W et al. (2013) Medial prefrontal cortex lesions impair decision-making on a rodent gambling task: reversal by D1 receptor antagonist administration. Behav Brain Res 243:247-54|