Project Summary

Evelyn Lambe, Ph.D. (Young Investigator 2004) of Yale University School of Medicine, notes that the prefrontal cortex is the target of the ascending arousal pathway and is critically involved in attention. Patterns of activation within this region are disordered in patients with schizophrenia and depression, particularly during cognitive tasks, when prefrontal cortex typically becomes more active in healthy controls. A large proportion of people with schizophrenia and depression smoke, and the attention enhancing effects of nicotine may be an under-appreciated reason for this comorbidity. The thalamocortical synapse in prefrontal cortex is the final synapse in the ascending arousal pathway and is critical for executive aspects of attention. Dr. Lambe has preliminary evidence suggesting that nicotine and the recently-discovered arousal peptide, hypocretin (orexin), excite this synapse. Interaction between nicotine and hypocretin at thalamocortical synapses would have profound effects on attention. Using a novel 2-photon imaging paradigm she will demonstrate for the first time whether nicotine and hypocretin excite the same thalamocortical synapses or activate parallel pathways. She will also explore the effects of chronic nicotine on the excitability of thalamocortical synapses. as other brain areas have shown long-term exposure to nicotine upregulates the relevant hypocretin receptor. Understanding these mechanisms may help to identify rational pharmacological intervention for attention and cognitive deficits associated with schizophrenia and depression.

Program Area: MULTIPLE FOCUS AREAS\Mood Disorders/Schizophrenia

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