Although mechanisms involved in encoding, storing and retrieving memory have attracted a great deal of attention, the processes that allocate individual memories to specific neurons within a network have remained elusive. Similarly, although the processes that connect and link information across time are critical for survival, they have also remained unexplored.

Recent findings from our laboratory, using methods, such as optogenetics and a new generation of head mounted fluorescent microscopes, unraveled the first insights into the mechanisms that modulate memory allocation in neuronetworks, and showed that they are critical to link memories across time.

We have shown that neurons compete to take part in memory traces and that the levels of the transcription factor CREB (cAMP-response element binding protein) determine the probability that a given neuron will be recruited into a given memory representation. Our electrophysiological studies showed that CREB-dependent transcription increases the excitability of neurons, and thus affects the probability that they will be recruited into a given memory.

We first proposed that a key function of memory allocation mechanisms is to link memories across time! 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. Delayed increases in CCR5 following the first memory eventually close the temporal window for both memory ensemble overlap and memory linking. This is accomplished by CCR5's role in decreasing the neuronal excitability of the neurons recruited to encode the first memory, thus ensuring that those neurons do not also encode the second memory. These results represent the first molecular, cellular and circuit mechanism underlying the linking of memories across time! These studies involved state of the art tools such as optogenetic molecular actuators and sensors, as well as state of the art imaging methods.

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. Remarkably, a FDA approved CCR5 inhibitor (Maraviroc) reverses deficits in memory linking in middle-aged mice. It is possible that the same treatment may also be effective in aging subjects.

With the Poirazi lab, we have also published a biological model of memory linking across time in which linked memories are stored in clustered spines in overlapping neurons (PDF)

Our Memory Allocation and Linking discovery was highlighted by Scientific American as one of "13 Discoveries that Could Change Everything"

Key Publications:

Chowdhury A, Luchetti A, Fernandes G, Almeida Filho D, Tzilivaki A, Kastellakis G, Ramirez E, Tran MM, Poirazi P, Silva AJ. A role for the Locus Coeruleus dorsal CA1 dopaminergic projection in the modulation of contextual memory ensembles and contextual memory linking. Neuron 2022, Aug 24;S0896-6273(22)00707-3. doi: 10.1016/j.neuron.2022.08.001 (link) Kaoru Inokuchi' Neuron Preview on this article (link)

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). (link) Priya Rajasethupathy Nature News and Views on this article (link)

Sousa, AF, Chowdhury, A, and Silva, AJ Dimensions and mechanisms of memory organization (2021) Neuron (link)

Frank, A. C., S. Huang, M. Zhou, A. Gdalyahu, G. Kastellakis, T. K. Silva, E. Lu, X. Wen, P. Poirazi, J. T. Trachtenberg and A. J. Silva (2018). "Hotspots of dendritic spine turnover facilitate clustered spine addition and learning and memory." Nat Commun 9(1): 422.(link)

Lisman, John, Cooper, Katie, Segal, Megha, and Silva, Alcino J. Memory formation depends on both synapse specific modifications of synaptic strength and cell-specific increases in excitability.
Nature Neuroscience 2018

Silva, A.J. (2017). Memory's Intricate Web: How One Memory Attaches to Another. Scientific American 317, 30-37. PMID:28632232

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)

Kastellakis, G., Silva, AJ and Poirazi, P,
Linking memories across time via synapse clustering in nonlinear dendrites. Cell Reports, Volume 17, Issue 6, p1491–1504, 1 November 2016 (PDF)

Rogerson, T., B. Jayaprakash, D.J. Cai, Y. Sano, Y.S. Lee, Y. Zhou, P. Bekal, K. Deisseroth, and A.J. Silva,
Molecular and Cellular Mechanisms for Trapping and Activating Emotional Memories. PLoS One, 2016. 11(8): p. e0161655.(PDF)

Sano, Y, Shobe, JL, Zhou, M, Huang, S, Cai, DJ, Roth, BL, Kamata, M, and Silva, AJ. CREB regulates memory allocation in the insular cortex. Current Biology 2014 (PDF). For a Scientist article on this research paper click here

Czajkowski, R, Jayaprakash, B, Wiltgen, B, Rogerson, T, Karlsson, MG, Barth, A, Trachtenberg, J, and Silva, AJ. E
ncoding and storage of spatial information in the retrosplenial cortex, PNAS Proc Natl Acad Sci U S A. 2014 (PDF)

Thomas Rogerson, Denise J. Cai, Adam Frank, Yoshitake Sano, Justin Shobe, Manuel F. Lopez-Aranda & Alcino J. Silva. S
ynaptic tagging during memory allocation. Nature Reviews Neuroscience 15, 157–169 (2014) PMID: 24496410 (PDF)

Silva, A. J., Y. Zhou, et al. (2009).
"Molecular and cellular approaches to memory allocation in neural circuits." Science 326(5951): 391-395.(PDF)

Zhou, Y., J. Won, et al. (2009). "
CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala." Nat Neurosci. (PDF)

Han, J. H., S. A. Kushner, et al. (2007). "
Neuronal competition and selection during memory formation." Science 316(5823): 457-460.(PDF).

Won, J. and A. J. Silva (2008). "
Molecular and cellular mechanisms of memory allocation in neuronetworks." Neurobiology of Learning and Memory 89(3): 285-292.

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