The proposed research will examine nicotinic receptor influences on dorsolateral prefrontal cortex (dlPFC) network physiology, with the goal of developing therapeutic agents to treat mental illness and nicotine addiction. Nicotinic agonists have great potential as cognitive enhancers if agents can be found that strengthen PFC without engaging subcortical addictive mechanisms. a4b2 and a7 nicotinic receptor subtypes are localized on presynaptic terminals in PFC, and a7 receptors are also post-synaptic on spines. a7 receptors are of particular interest, as they're genetically altered in some families with schizophrenia, and may not have reinforcing actions in the VTA. The proposed research will characterize the influence of a4b2 and a7 nicotinic receptors on dlPFC network physiology for the very first time. dlPFC networks excite each other via NMDA receptors to maintain persistent firing over the delay period in a working memory task.
Aim 1 will characterize the effects of a4b2 agonists and antagonists on the responses of dlPFC neurons during performance of a spatial working memory task under control and distracting conditions, using iontophoretic application of drug during recording.
Aim 2 will characterize the effects of a7 nicotinic agonists and antagonists, while Aim 3 will examine the interaction of nicotinic influences with NMDA receptor actions. Preliminary data indicate that a7 receptor stimulation enhances the task-related firing of both Delay and Fixation cells, and can rescue loss of firing from NMDA receptor blockade, encouraging the development of a7 agonists as cognitive enhancers.

Public Health Relevance

Disorders such as schizophrenia have devastating effects on patients and their families, and there are currently no treatments for cognitive impairment in this illness. The proposed research may help to develop a new treatment- an alpha7 nicotinic agonist- that can strengthen cognitive function in patients. It is hoped that an alpha7 nicotinic agonist may be able to improve cognition with minimal risk for addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH093354-03
Application #
8578109
Study Section
Cognitive Neuroscience Study Section (COG)
Program Officer
Winsky, Lois M
Project Start
2012-02-10
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
3
Fiscal Year
2014
Total Cost
$299,700
Indirect Cost
$119,700
Name
Yale University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Yang, Yang; Paspalas, Constantinos D; Jin, Lu E et al. (2013) Nicotinic *7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex. Proc Natl Acad Sci U S A 110:12078-83
Wang, Min; Yang, Yang; Wang, Ching-Jung et al. (2013) NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex. Neuron 77:736-49