Learning and memory changes with aging, but little is known about what causes these changes. Studies in our laboratory demonstrated that just as humans and other animals, mice show age-related deficits in a variety of learning tests designed to test young mice. Interestingly, cells in the brain become progressively less excitable with age, and previous studies suggested that this decrease in excitability could cause deficits in learning and memory. We have also recently discovered that there are pronounced changes in memory linking with aging. What is the reason for these changes?

Recently, our laboratory showed that memory linking mechanisms are disrupted in the aging brain, and that increasing excitability in a subset of cells reverses these memory linking deficits. Two memories are said to be linked, when the recall of one triggers the recall of the other. Recently, our laboratory showed that one memory triggers CREB activation and subsequent increases in excitability in a subset of neurons of a network, so that another memory, even many hours later, can be allocated to some of the same neurons. Recall of the first memory triggers the activation of those neurons, and therefore the reactivation and recall of the other memory.

Deficits in CREB and neuronal excitability associated with aging may contribute to these impairments in memory linking. Indeed, we have also discovered a age-related loss of memory linking that is due to increases in the expression of CCR5 in middle-aged mice. CCR5 inhibits CREB and decreases neuronal excitability. Remarkably, a FDA approved CCR5 inhibitor reverses deficits in memory linking in middle-aged mice. It is possible that the same treatment may also be effective in patients. These results represent the first molecular, cellular and circuit mechanism underlying the age related deficits in linking of memories across time, the first demonstration that memory linking is affected in the aging brain, and the first possible treatment for these deficits. Problems with memory linking may underly well-known source memory problems associated with aging.

Key Publications:

Yang Shen, Miou Zhou1, Denise Cai Daniel Almeida Filho, Giselle Fernandes, Ying Cai, Nury Kim, Deanna Necula, Chengbin Zhou, Andy Liu, Xiaoman Kang, Masakazu Kamata, Ayal Lavi, Shan Huang, Tawnie Silva, Won Do Heo, Alcino J. Silva. CCR5 closes the temporal window for memory linking. Nature (2022). https://doi.org/10.1038/s41586-022-04783-1 (link)

Denise J. Cai, Daniel Aharoni, Tristan Shuman, Justin Shobe, Jeremy Biane, Weilin Song, Brandon Wei, Michael Veshkini, Mimi La-Vu, Jerry Lou, Sergio Flores, Isaac Kim, Yoshitake Sano, Miou Zhou, Karsten Baumgaertel, Ayal Lavi, Masakazu Kamata, Mark Tuszynski, Mark Mayford, Peyman Golshani and Alcino J. Silva. A shared neural ensemble links distinct contextual memories encoded close in time. Nature 534, 115–118 (02 June 2016) (PDF)

Murphy, G., Shah, V.,. Hell, J.W., Silva, A.J. Investigation of age-related cognitive decline using mice as a model system: neurophysiological correlates. Am J Geriatr Psychiatry. 2006 Dec;14(12):1012-21. (PDF).

Murphy, G., Shah, V.,. Hell, J.W., Silva, A.J. Investigation of age-related cognitive decline using mice as a model system: behavioral correlates. Am J Geriatr Psychiatry. 2006 Dec;14(12):1004-11.(PDF).

Murphy GG, Fedorov NB, Giese KP, Ohno M, Friedman E, Chen R, Silva AJ. Increased neuronal excitability, synaptic plasticity, and learning in aged Kvbeta1.1 knockout mice. Curr Biol. 2004 Nov 9;14(21):1907-15.(PDF).

Giese, K.P., J.F. Storm, D. Reuter, N.B. Fedorov, L.-R. Shao, T. Leicher, O. Pongs, and A.J. Silva, Reduced K+ channel inactivation, spike broadening, and after-hyperpolarization in Kvß1.1-deficient mice with impaired learning. Learning and Memory, 1998. 5: p. 257-273 (link)

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