QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, March 21, 2007, 27(12):3098-3110; doi:10.1523/JNEUROSCI.4163-06.2007

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Rowe, W. B. Articles by Landfield, P. W. Search for Related Content PubMed PubMed Citation Articles by Rowe, W. B. Articles by Landfield, P. W. Pubmed/NCBI databases GEO DataSet GEO Profiles

 Previous Article  |  Next Article 

Behavioral/Systems/Cognitive
Hippocampal Expression Analyses Reveal Selective Association of Immediate-Early, Neuroenergetic, and Myelinogenic Pathways with Cognitive Impairment in Aged Rats

Wayne B. Rowe,^1 * Eric M. Blalock,^2 * Kuey-Chu Chen,² Inga Kadish,³ Daguang Wang,¹ James E. Barrett,⁴ Olivier Thibault,² Nada M. Porter,² Gregory M. Rose,¹ and Philip W. Landfield²

¹Department of Functional Neuroscience, Memory Pharmaceuticals Corporation, Montvale, New Jersey 07645, ²Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, Kentucky 40536, ³Department of Cell Biology, University of Alabama, Birmingham, Alabama 35294, and ⁴Adolor Corporation, Exton, Pennsylvania 19341

Correspondence should be addressed to Philip W. Landfield, Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, MS-310, Lexington, KY 40536. Email: pwland{at}uky.edu

Although expression of some genes is known to change during neuronal activity or plasticity, the overall relationship of gene expression changes to memory or memory disorders is not well understood. Here, we combined extensive statistical microarray analyses with behavioral testing to comprehensively identify genes and pathways associated with aging and cognitive dysfunction. Aged rats were separated into cognitively unimpaired (AU) or impaired (AI) groups based on their Morris water maze performance relative to young-adult (Y) animals. Hippocampal gene expression was assessed in Y, AU, and AI on the fifth (last) day of maze training (5T) or 21 d posttraining (21PT) and in nontrained animals (eight groups total, one array per animal; n = 78 arrays). ANOVA and linear contrasts identified genes that differed from Y generally with aging (differed in both AU and AI) or selectively, with cognitive status (differed only in AI or AU). Altered pathways/processes were identified by overrepresentation analyses of changed genes. With general aging, there was downregulation of axonal growth, cytoskeletal assembly/transport, signaling, and lipogenic/uptake pathways, concomitant with upregulation in immune/inflammatory, lysosomal, lipid/protein degradation, cholesterol transport, transforming growth factor, and cAMP signaling pathways, primarily independent of training condition. Selectively, in AI, there was downregulation at 5T of immediate-early gene, Wnt (wingless integration site), insulin, and G-protein signaling, lipogenesis, and glucose utilization pathways, whereas Notch2 (oligodendrocyte development) and myelination pathways were upregulated, particularly at 21PT. In AU, receptor/signal transduction genes were upregulated, perhaps as compensatory responses. Immunohistochemistry confirmed and extended selected microarray results. Together, the findings suggest a new model, in which deficient neuroenergetics leads to downregulated neuronal signaling and increased glial activation, resulting in aging-related cognitive dysfunction.

Key words: microarray; immediate-early genes; insulin; glycogen; cholesterol; myelination; astrocyte; inflammation; Alzheimer's; aging brain

---

Received Sept. 22, 2006; revised Feb. 12, 2007; accepted Feb. 13, 2007.

Correspondence should be addressed to Philip W. Landfield, Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, MS-310, Lexington, KY 40536. Email: pwland{at}uky.edu

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help