The O'Donnell lab
at the Department
of Anatomy & Neurobiology and Program in Neuroscience
Our research:
Schizophrenia is a devastating disorder in which the nature of changes occurring in the brain remains unclear. Extensive research has shown that a number of brain regions and systems are involved in schizophrenia or in its treatment; these include the prefrontal cortex, temporal lobe (hippocampus), ventral striatum and dopamine systems. Our research is directed to understanding the neurobiology of schizophrenia and related neuropsychiatric disorders focusing on the interactions among these systems. The primary approach involves the use of electrophysiological techniques, looking particularly at the modulation of information flow through the neural circuits linking these brain regions. Both in vivo and in vitro intracellular recordings from neurons in the prefrontal cortex and nucleus accumbens are employed to study these interactions, as well as juxtacellular recordings in anesthetized animals and single unit/field potential recordings in awake, behaving rats. We focus on the role of dopamine on the control of such information flow through the ventral basal ganglia circuit with experiments involving stimulation of the source (the ventral tegmental area, or VTA) and application of agonists/antagonists. We have shown that neurons in the prefrontal cortex and ventral striatum alternate between active and inactive states, as defined by changes in their membrane potential. The hippocampus and other limbic inputs may gate prefrontal cortical throughput in the ventral striatum by enabling active states; this phenomenon is also controlled by dopamine, a transmitter implicated in schizophrenia, and can be overriden by strong prefrontal cortical activation, perhaps allowing the nucleus accumbens a role in switching behaviors. Our goal is to understand the function and interactions among systems involved in higher cognitive functions, that are known to be disturbed in a number of neuropsychiatric disorders.
We are also studying these interactions in developmental, pharmacological and genetic animal models of schizophrenia. A neonatal hippocampal lesion produces behavioral alteration that resemble phenomena observed in schizophrenia, which emerge after puberty. A number of electrophysiological changes, primarily in the response of the ventral basal ganglia circuit to activation of the mesolimbic projections, have been observed. We are also collaborating with colleagues that provide us with genetic models of the disease, such as DISC1 or variations in COMT. The emerging data identify prefrontal cortical GABA interneurons as a critical population that is affected across animal models, a finding that is consistent with human postmortem findings.
We are exploring the changes in these circuits and the functions they subserve during adolescence. We have recently shown that inhibitory GABA interneurons in the prefrontal cortex change dramatically their response to dopamine during adolescence, a finding that highlights the complex maturation of these circuits, so important for decision making, during that late developmental stage. We are exploring the mechanisms behind such maturation, and whether and how they become affected in schizophrenia models.
Another set of experiments are aimed at elucidating whether the increase liability for drug taking is indeed a self-medicating attempt. Rats with a neonatal ventral hippocampal lesion self-administer stimulants more readily than their control littermates. We are exploring whether this is due to altered synaptic activity and dopamine responses within the prefrontal cortex, and whether this is another symptom of the condition.