Abstract

Project 3 - Chronically implanted, movable, multielectrode arrays will be used to study medial prefrontal cortex (PFC) in young adult and aged rats during a delayed alternation task. The overall hypothesis is that aged PFC is impaired at encoding information that is critical for guiding future behavioral decisions. Neural coding of task events (e.g., correct and incorrect responding) will be quantified using statistical classifiers. Classifiers will also be used to quantify the extent of redundancy in the ensembles, a measure of functional interactions. These studies will provide the first data, to our knowledge, on the effects of aging on neuronal activity in rat PFC during a behavioral task that depends on PFC function.
Aim 1 will examine how aging alters neuronal correlates of working memory. We hypothesize that, due to weakened connectivity between PFC neurons with advancing age, there will be a loss of functional interactions within PFC. We will also examine effects of distracting stimuli on persistent activity during delay periods.
Aim 2 will examine effects of the alpha-2A agonist guanfacine, a potential cognitive enhancer, on PFC neural ensembles. We hypothesize that inhibition of cAMP/HCN signaling through chronic treatment with guanfacine will strengthen PFC connectivity and improve working memory in aged rats. Specifically, guanfacine will improve the signal-tonoise ratios of delay-related neuronal firing and will increase correlations between neurons with delay-related activity. This study will provide a unique opportunity to observe evolving changes in circuit strength during chronic drug treatment.
Aim 3 will examine effects of altered expression of PDE4 or HCN channels in PFC on on PFC neural ensembles. Adeno-viral technology, developed in Project 2, will be used to manipulate cAMP/HCN signaling in the aging PFC by either overexpressing PDE4 or knocking down levels of HCN channels. We hypothesize that these manipulations will have effects similar to guanfacine: improving the signai-to-noise ratios of delay-related neuronal firing and increasing correlations between neurons with delay-related activity. LAY SUMMARY: Project 3 will determine if aging alters how neurons in the prefrontal cortex work together and will investigate effects of potential cognitive enhancing drugs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG030004-03
Application #
8039102
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2010-03-15
Budget End
2011-02-28
Support Year
3
Fiscal Year
2010
Total Cost
$138,916
Indirect Cost

  Institution

Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520

  Publications

Laubach, Mark; Caetano, Marcelo S; Narayanan, Nandakumar S (2015) Mistakes were made: neural mechanisms for the adaptive control of action initiation by the medial prefrontal cortex. J Physiol Paris 109:104-17
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
Arnsten, Amy F T; Jin, Lu E (2014) Molecular influences on working memory circuits in dorsolateral prefrontal cortex. Prog Mol Biol Transl Sci 122:211-31
Narayanan, Nandakumar S; Cavanagh, James F; Frank, Michael J et al. (2013) Common medial frontal mechanisms of adaptive control in humans and rodents. Nat Neurosci 16:1888-1895
Paspalas, Constantinos D; Wang, Min; Arnsten, Amy F T (2013) Constellation of HCN channels and cAMP regulating proteins in dendritic spines of the primate prefrontal cortex: potential substrate for working memory deficits in schizophrenia. Cereb Cortex 23:1643-54
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
Gamo, N J; Duque, A; Paspalas, C D et al. (2013) Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction. Transl Psychiatry 3:e328
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
Arnsten, Amy F T; Wang, Min J; Paspalas, Constantinos D (2012) Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses. Neuron 76:223-39
Wei, Lan; Simen, Arthur; Mane, Shrikant et al. (2012) Early life stress inhibits expression of a novel innate immune pathway in the developing hippocampus. Neuropsychopharmacology 37:567-80

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