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

Public Health Relevance

The proposed research will determine why the brain regions afflicted in cognitive disorders such as Alzheimer?s Disease and schizophrenia are so vulnerable to disease, and why other brain regions are resistant to degeneration. We hypothesize that recently evolved, molecular adaptations in our association cortex provide mental flexibility for high order cognitive operations, but may also render these brain circuits especially vulnerable to genetic and environmental insults. Understanding these fundamental differences may provide a new strategy for disease prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1AG047744-05
Application #
9280865
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wagster, Molly V
Project Start
2013-09-30
Project End
2018-05-31
Budget Start
2017-07-01
Budget End
2018-05-31
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Yale University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Galvin, Veronica C; Arnsten, Amy F T; Wang, Min (2018) Evolution in Neuromodulation-The Differential Roles of Acetylcholine in Higher Order Association vs. Primary Visual Cortices. Front Neural Circuits 12:67
Constantinidis, Christos; Funahashi, Shintaro; Lee, Daeyeol et al. (2018) Persistent Spiking Activity Underlies Working Memory. J Neurosci 38:7020-7028
Datta, Dibyadeep; Arnsten, Amy F T (2018) Unique Molecular Regulation of Higher-Order Prefrontal Cortical Circuits: Insights into the Neurobiology of Schizophrenia. ACS Chem Neurosci 9:2127-2145
Yang, Sheng-Tao; Wang, Min; Paspalas, Constantinos D et al. (2018) Core Differences in Synaptic Signaling Between Primary Visual and Dorsolateral Prefrontal Cortex. Cereb Cortex 28:1458-1471
Paspalas, Constantinos D; Carlyle, Becky C; Leslie, Shannon et al. (2018) The aged rhesus macaque manifests Braak stage III/IV Alzheimer's-like pathology. Alzheimers Dement 14:680-691
Morozov, Yury M; Datta, Dibyadeep; Paspalas, Constantinos D et al. (2017) Ultrastructural evidence for impaired mitochondrial fission in the aged rhesus monkey dorsolateral prefrontal cortex. Neurobiol Aging 51:9-18
Arnsten, Amy F T; Girgis, Ragy R; Gray, David L et al. (2017) Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia. Biol Psychiatry 81:67-77
Arnsten, Amy F T; Murray, John D; Seo, Hyojung et al. (2016) Ketamine's Antidepressant Actions: Potential Mechanisms in the Primate Medial Prefrontal Circuits That Represent Aversive Experience. Biol Psychiatry 79:713-5
Opler, Lewis A; Opler, Mark G A; Arnsten, Amy F T (2016) Ameliorating treatment-refractory depression with intranasal ketamine: potential NMDA receptor actions in the pain circuitry representing mental anguish. CNS Spectr 21:12-22
Arnsten, Amy F T; Wang, Min (2016) Targeting Prefrontal Cortical Systems for Drug Development: Potential Therapies for Cognitive Disorders. Annu Rev Pharmacol Toxicol 56:339-60

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