CCR5 closes the temporal window for memory linking

Yang Shen, Miou Zhou (), Denise Cai, Daniel Almeida Filho, Giselle Fernandes, Ying Cai, André F. Sousa, Min Tian, Nury Kim, Jinsu Lee, Deanna Necula, Chengbin Zhou, Shuoyi Li, Shelbi Salinas, Andy Liu, Xiaoman Kang, Masakazu Kamata, Ayal Lavi, Shan Huang, Tawnie Silva, Won Do Heo and Alcino J. Silva ()
Additional contact information
Yang Shen: University of California Los Angeles
Miou Zhou: University of California Los Angeles
Denise Cai: University of California Los Angeles
Daniel Almeida Filho: University of California Los Angeles
Giselle Fernandes: University of California Los Angeles
Ying Cai: University of California Los Angeles
André F. Sousa: University of California Los Angeles
Min Tian: University of California Los Angeles
Nury Kim: Institute for Basic Science
Jinsu Lee: Korea Advanced Institute of Science and Technology
Deanna Necula: University of California Los Angeles
Chengbin Zhou: University of California Los Angeles
Shuoyi Li: University of California Los Angeles
Shelbi Salinas: Western University of Health Sciences
Andy Liu: University of California Los Angeles
Xiaoman Kang: University of California Los Angeles
Masakazu Kamata: University of California Los Angeles
Ayal Lavi: University of California Los Angeles
Shan Huang: University of California Los Angeles
Tawnie Silva: University of California Los Angeles
Won Do Heo: Korea Advanced Institute of Science and Technology
Alcino J. Silva: University of California Los Angeles

Nature, 2022, vol. 606, issue 7912, 146-152

Abstract: Abstract Real-world memories are formed in a particular context and are often not acquired or recalled in isolation1–5. Time is a key variable in the organization of memories, as events that are experienced close in time are more likely to be meaningfully associated, whereas those that are experienced with a longer interval are not1–4. How the brain segregates events that are temporally distinct is unclear. Here we show that a delayed (12–24 h) increase in the expression of C-C chemokine receptor type 5 (CCR5)—an immune receptor that is well known as a co-receptor for HIV infection6,7—after the formation of a contextual memory determines the duration of the temporal window for associating or linking that memory with subsequent memories. This delayed expression of CCR5 in mouse dorsal CA1 neurons results in a decrease in neuronal excitability, which in turn negatively regulates neuronal memory allocation, thus reducing the overlap between dorsal CA1 memory ensembles. Lowering this overlap affects the ability of one memory to trigger the recall of the other, and therefore closes the temporal window for memory linking. Our findings also show that an age-related increase in the neuronal expression of CCR5 and its ligand CCL5 leads to impairments in memory linking in aged mice, which could be reversed with a Ccr5 knockout and a drug approved by the US Food and Drug Administration (FDA) that inhibits this receptor, a result with clinical implications. Altogether, the findings reported here provide insights into the molecular and cellular mechanisms that shape the temporal window for memory linking.

Date: 2022
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DOI: 10.1038/s41586-022-04783-1

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