Current Research Description
Our laboratory currently focuses on the development of animal models to study the neurobiological bases of cognitive impairments in schizophrenia. Collectively, these studies are designed to provide insights into possible etiologies of these cognitive symptoms as well as to design valid preclinical screens for the development of novel, more efficacious pharmacotherapies. We are particularly interested in the psychobiology of two cognitive operations (attentional processing and cognitive lexibility/set-shifting) as they are expressed in normal animals and in those animals designed to model various aspects of schizophrenia. Deficits in attention and cognitive flexibility can significantly impair the detection and processing of relevant stimuli as well as the ability to adjust behavior in light of changing events.
The anatomical mediation of attention and cognitive flexibility involves a distributed neural system that includes the hippocampus, nucleus accumbens, basal forebrain, and prefrontal cortex. Research in our laboratory, as well as others, has demonstrated the importance of interactions among cholinergic, glutamatergic, and dopaminergic transmitter systems, throughout these brain regions, in the mediation of attentional processing and set-shifting behavior. Moreover, dysregulations in these transmitter systems have been linked to the cognitive deficits seen in schizophrenia.
We utilize several different animal models (reversible and non-reversible inactivation of hippocampal outflow during sensitive developmental periods; pharmacological disruption of alpha7 nicotine receptors in prefrontal cortex and accumbens using elevations of the endogenous gliotransmitter kynurenic acid; acute and chronic administration of NMDA antagonists) to simulate the neurochemical dysfunctions believed to underlie several of the cognitive deficits seen in schizophrenia. The impact of these manipulations on ACh, glutamate, and dopamine release are determined using state-of-the-art neurochemical methods (high temporal resolution electrochemistry using enzyme-based microelectrodes; in vivo microdialysis) in animals as they perform behavioral tasks designed to assess attentional processing or set-shifting behavior. These experimental protocols then provide a sensitive platform for assessing the efficacy of novel pharmacotherapeutic compounds.