CCR5 expression closes the temporal window for linking memories!
The Silva lab at UCLA published in Nature the first known mechanism of how time organizes memories. Events that happen close in time (e.g. within the same day) are more likely to be recalled together than those that we experience weeks apart. Our memories are almost never stored alone in the brain, but instead they are organized so that the recall of one triggers the recall of related memories.
The Nature paper just published by the Silva lab addresses the mechanisms responsible for how time either connects or separates our memories. They discovered that there is a time dependent expression of a gene for a receptor (CCR5) that is responsible for this. This receptor regulates the overlap between the neuronal ensembles that encode each memory. This overlap between memory ensembles is critical for connecting or linking memories because the greater the overlap the greater the likelihood that two memories will be recalled together. Expression of this gene in one memory ensemble inhibits for a time the ability of neurons in that ensemble to store additional memories, thus inhibiting the memory ensemble overlap so critical for linking memories.
Amazingly, they also found that higher expression levels of this gene in middle-aged mice are responsible for the loss of memory linking in these animals. Middle-age mice can remember contextual memories (e.g., the memory of having visited a novel cage) but they no longer can link or connect these memories. The authors were able to rescue this age-related decline In memory linking by different manipulations that decreased CCR5 levels in middle-aged mice, including a CCR5 inhibitor that is FDA approved (Maraviroc). This is exciting because source and relational memory problems so common in aging are thought to be mediated by the very processes described above. It is possible that Maraviroc could be used to treat these age related memory problems.
Maraviroc has been used for treating HIV, since the CCR5 receptor is used by the HIV virus to enter cells! So the same receptor that the virus uses to invade cells is also used by the brain to separate memories so that we do not connect or link memories that are unrelated!
For a Nature News and Views article on this discovery go to here
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)
Sousa, AF, Chowdhury, A, and Silva, AJ Dimensions and mechanisms of memory organization (2021) Neuron https://doi.org/10.1016/j.neuron.2021.06.014 (link)
Alcino J Silva How the Brain Builds Memory Chains. Scientific American July 2017
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)