aging and cognition


Deficits in learning and memory can occur with aging, but little is known about what causes them. Studies in our laboratory demonstrated that just as humans and other animals, mice show age-related deficits in a variety of learning tests. 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.

Remarkably, our laboratory has shown that a change in a gene that increases the excitability of brain cells (the Kvb1.1 gene) improves long term potentiation as well as learning and memory specifically in aged mice.

We are engaged in a number of memory studies that will impact on how we understand and treat age-related cognitive decline, including studies of how the prefrontal cortex modulates the storage and retrieval of remote memory, and how memories are allocated in neuronetworks.

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 underlie these impairments in memory linking. These results represent the first molecular, cellular and circuit mechanism underlying the linking of memories across time, and the first demonstration that memory linking is affected in the aging brain. It is possible that problems with memory linking may underly well-known source memory problems associated with aging.

Key Publications:

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.