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Hippocampal M1 receptor function associated with spatial learning and memory in aged female rhesus macaques

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Abstract

Of the acetylcholine muscarinic receptors, the type 1 (M1) and type 2 (M2) receptors are expressed at the highest levels in the prefrontal cortex (PFC) and hippocampus, brain regions important for cognition. As equivocal findings of age-related changes of M1 and M2 in the nonhuman primate brain have been reported, we first assessed age-related changes in M1 and M2 in the PFC and hippocampus using saturation binding assays. Maximum M1 receptor binding, but not affinity of M1 receptor binding, decreased with age. In contrast, the affinity of M2 receptor binding, but not maximum M2 receptor binding, increased with age. To determine if in the elderly cognitive performance is associated with M1 or M2 function, we assessed muscarinic function in elderly female rhesus macaques in vivo using a scopolamine challenge pharmacological magnetic resonance imaging and in vitro using saturation binding assays. Based on their performance in a spatial maze, the animals were classified as good spatial performers (GSP) or poor spatial performers (PSP). In the hippocampus, but not PFC, the GSP group showed a greater change in T2*-weighted signal intensity after scopolamine challenge than the PSP group. The maximum M1 receptor binding and receptor binding affinity was greater in the GSP than the PSP group, but no group difference was found in M2 receptor binding. Parameters of circadian activity positively correlated with the difference in T2*-weighted signal intensity before and after the challenge, the maximum M1 receptor binding, and the M1 receptor binding affinity. Thus, while in rhesus macaques, there are age-related decreases in M1 and M2 receptor binding, in aged females, hippocampal M1, but not M2, receptor function is associated with spatial learning and memory and circadian activity.

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Acknowledgments

The authors would like to thank Dominique Eghlidi, Sharon Kryger, Laurie Renner, Alison Weiss, and Vince Warren for their technical assistance. This work was supported by NIH grants RR-000163, AG-023477, and AG-029612 and an OHSU Tartar Fellowship.

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Authors and Affiliations

  1. Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, 97006, USA

    Gwendolen E. Haley, Chris Kroenke, Steven G. Kohama, Henryk F. Urbanski & Jacob Raber

  2. Portland Veterans Administration Medical Center, Division of Psychiatry, Oregon Health and Science University, Portland, OR, 97239, USA

    Daniel Schwartz

  3. Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR, 97239, USA

    Henryk F. Urbanski

  4. Department of Neurology, Oregon Health and Science University, Portland, OR, 97239, USA

    Jacob Raber

  5. Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, 97239, USA

    Gwendolen E. Haley, Chris Kroenke, Henryk F. Urbanski & Jacob Raber

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  1. Gwendolen E. Haley
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  2. Chris Kroenke
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Correspondence to Jacob Raber.

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Haley, G.E., Kroenke, C., Schwartz, D. et al. Hippocampal M1 receptor function associated with spatial learning and memory in aged female rhesus macaques. AGE 33, 309–320 (2011). https://doi.org/10.1007/s11357-010-9184-2

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