Executive functions controlled by the prefrontal cortex (PFC) grant us flexibility in our behavior and allow us to behave adaptively in the current context. The functional interaction between the PFC and the mediodorsal thalamus (MD), a higher-order thalamic nucleus, has been shown to be important for a variety of cognitive tasks requiring executive control. Disrupted functional and anatomical connectivity of these two reciprocally connected brain regions has been observed in clinical populations such as schizophrenia patients. While a topographic organization of MDPFC projections has been identified across species, little is known about how changes in specific components of the broader MD-PFC circuitry lead to certain cognitive deficits. The availability of powerful molecular and genetic tools in mice has now made it possible to study the functional influence of defined projection populations on cortical processing. In particular, the functional role of distinct MD projections onto the lateral orbitofrontal cortex (lOFC) has yet to be investigated in depth. The lOFC is thought to maintain a cognitive map -- a representation of different task states -- in order to ensure adaptive decision-making in different contexts determined by external and internal variables. To better understand how the MD may be contributing to this cortical function, real-time activity patterns of the MDlOFC projection population and the lOFC population will be measured using fiber photometry in freely behaving mice, during an incentive learning task that depends on the lOFC. This technique will allow us to study the functional relationship between the MD and lOFC when a motivationally-induced task state change occurs, and when this task state change informs the control of instrumental behavior. Ex vivo electrophysiology will be used to investigate how MDlOFC synaptic transmission may change following the encoding of a new task state in incentive learning. Together, the proposed experiments will help determine the manner in which the MD influences lOFC activity during state-dependent decision-making, and more generally, they will add to our understanding of how higher-order thalamic nuclei contribute to cortical computations.

Public Health Relevance

The proposed research will investigate the functional influence of the mediodorsal thalamus (MD) on the activity of the lateral orbitofrontal cortex (lOFC), a prefrontal brain region implicated in value-based decision-making and, more recently, representing task state. Results of this work will elucidate the functional interactions between the MD and lOFC during state-dependent decision-making, and how synaptic transmission between the two regions may be altered following the encoding of a new task state (state-dependent outcome value updating). Given the evidence that MD-prefrontal cortex circuit dysfunction contributes to the emergence of neuropsychiatric disorders such as schizophrenia, identifying the functional role of this distinct MD projection onto the lOFC will contribute to our broader understanding of how this higher-order thalamic nucleus is affecting cortical processing and the particular cognitive deficits that may result from its disruption.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Pinard, Courtney
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University of California, San Diego
Schools of Arts and Sciences
La Jolla
United States
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