EducationMD, Ohio State University (1979)
Dr. Lewis is the UPMC Professor in Translational Neuroscience
Dr. Lewis' research activities focus on the neural circuitry of the prefrontal cortex and related brain regions, and the alterations of this circuitry in psychiatric disorders such as schizophrenia. The research strategy underlying these investigations involves five components. First, the normal functional architecture of the prefrontal cortex, including its connections with other cortical and subcortical regions, is examined using the macaque monkey as a model system for the human brain. Within these circuits, the expression and cellular localization of specific gene products, and how these change in an activity-dependent fashion, are investigated. In collaboration with Dr. Guillermo Gonzalez-Burgos, the electrophysiological properties of intrinsic prefrontal cortical circuits are studied using an in vitro slice preparation.
The second component of this research strategy involves characterizing the postnatal development of prefrontal cortical circuitry. Special emphasis is placed on maturational events, such as synaptogenesis and synaptic pruning, which occur during early postnatal life and adolescence. The timing and specificity of these processes are examined for their possible contribution to the emergence and refinement of the types of cognitive abilities that are disturbed in schizophrenia. The effects on prefrontal cortical circuitry of chronic exposure to cannabis during adolescence, a risk factor for schizophrenia, are examined at the molecular, circuitry and behavioral levels.
Based on the results of these two lines of investigation, hypotheses are generated regarding the elements of neural circuitry that may be dysfunctional in schizophrenia. These hypotheses are then tested in postmortem human brain specimens from subjects with schizophrenia. These studies utilize a variety of molecular and anatomical approaches. In addition, the primate model system is used to assess the influence of psychotropic medications on the neural circuits of interest.
In the fourth type of study, mouse genetic models are used as "proof of concept" tests of cause-effect relationship. The goal of these studies is to define the pathogenetic and pathophysiological processes that give rise to the cognitive deficits of schizophrenia and to identify potential targets for therapeutic interventions.
Based on these findings, phase II clinical trials are conducted with novel compounds predicted to improve cognitive dysfunction in schizophrenia.