Abstract

Project 3 - Chronically implanted, movable, multielectrode arrays will be used to study medial prefrontalcortex (PFC) in young adult and aged rats during a delayed alternation task. The overall hypothesis is thataged PFC is impaired at encoding information that is critical for guiding future behavioral decisions. Neuralcoding 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 functionalinteractions. These studies will provide the first data, to our knowledge, on the effects of aging on neuronalactivity in rat PFC during a behavioral task that depends on PFC function.
Aim 1 will examine how agingalters neuronal correlates of working memory. We hypothesize that, due to weakened connectivity betweenPFC neurons with advancing age, there will be a loss of functional interactions within PFC. We will alsoexamine effects of distracting stimuli on persistent activity during delay periods.
Aim 2 will examine effects ofthe alpha-2A agonist guanfacine, a potential cognitive enhancer, on PFC neural ensembles. We hypothesizethat inhibition of cAMP/HCN signaling through chronic treatment with guanfacine will strengthen PFCconnectivity and improve working memory in aged rats. Specifically, guanfacine will improve the signal-tonoiseratios of delay-related neuronal firing and will increase correlations between neurons with delay-relatedactivity. This study will provide a unique opportunity to observe evolving changes in circuit strength duringchronic drug treatment.
Aim 3 will examine effects of altered expression of PDE4 or HCN channels in PFCon on PFC neural ensembles. Adeno-viral technology, developed in Project 2, will be used to manipulatecAMP/HCN signaling in the aging PFC by either overexpressing PDE4 or knocking down levels of HCNchannels. We hypothesize that these manipulations will have effects similar to guanfacine: improving thesignai-to-noise ratios of delay-related neuronal firing and increasing correlations between neurons withdelay-related activity. LAY SUMMARY: Project 3 will determine if aging alters how neurons in the prefrontalcortex 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 #
1P01AG030004-01A1
Application #
7347292
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (O2))
Project Start
Project End
Budget Start
2008-04-01
Budget End
2009-02-28
Support Year
1
Fiscal Year
2008
Total Cost
$193,398
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
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
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
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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