Cognitive disorders such as Alzheimer's Disease (AD), Fronto-Temporal Dementia and schizophrenia are a tremendous burden on our society, as patients are often unable to care for themselves, and require extensive resources for many years. These disorders will be an even greater burden as our society grows older in the next decades. Current treatments are inadequate, and research in this arena continues to focus on mouse models. However, AD, schizophrenia, and related cognitive disorders primarily afflict the highly evolved association cortices which are poorly developed in mice, while the primary sensory cortices are little affected in these disorders. What makes the association cortices so vulnerable? And why are more basic cortical areas, such as the sensory cortices, more resistant to disease? These are fascinating evolutionary questions with immediate medical relevance. The proposed research will test the hypothesis that the highly evolved primate association cortices are more vulnerable to disease because they are regulated by Ca2+-cAMP signaling pathways in a fundamentally different manner than the evolutionarily older, sensory cortices, and that dysregulation of Ca2+-cAMP signaling following genetic or environmental insults predisposes these higher circuits to dysfunction and degeneration, e.g. through hyper-phosphorylation of tau. Our data have revealed that primate prefrontal association circuits contain high levels of cAMP-regulated K+ channels near their network connections that normally serve to gate inputs and provide mental flexibility. However, this process requires precise regulation, and even small insults to regulatory processes impair cognition and may increase risk for degeneration. A striking number of these proteins are genetically linked to schizophrenia, and show changes with advancing age. We hypothesize that primate cortical circuits will have differing sensitivities to Ca2+-cAMP signaling based on their evolutionary st

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
1DP1AG047744-01
Application #
8558580
Study Section
Special Emphasis Panel (ZRG1-BCMB-N (50))
Program Officer
Wagster, Molly V
Project Start
2013-09-30
Project End
2018-06-30
Budget Start
2013-09-30
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$832,500
Indirect Cost
$332,500
Name
Yale University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Carlyle, Becky C; Nairn, Angus C; Wang, Min et al. (2014) cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex. Proc Natl Acad Sci U S A 111:5036-41