The Human Brain Has a “Ready-to-Remember” Mode

Spiking activity in the hippocampus triggers a “ready-to-encode” memory mode.

Posted Jun 02, 2020

 Life Science Databases/Wikimedia
Hippocampus in red.
Source: Life Science Databases/Wikimedia

Neuroscientists and psychologists have known for decades that the hippocampus plays a vital role in the encoding of declarative memories. In the 1990s, Larry Squire of the University of California, San Diego, published a landmark paper (Squire, 1992) that synthesized modern era research to date on "memory and the hippocampus." Squire writes:

"The hippocampus (together with anatomically related structures) is essential for a specific kind of memory, here termed 'declarative memory' [i.e., explicit memory]. Declarative [or explicit] memory is contrasted with a heterogeneous collection of non-declarative (implicit memory) abilities that do not require the hippocampus (skills and habits, simple conditioning, and the phenomenon of priming). The hippocampus is needed temporarily to bind together distributed sites in the neocortex that together represent a whole memory."

In another seminal paper published in the Journal of Neuroscience, "Memory and Brain Systems: 1969–2009," Larry Squire provides an empirical (and personal) overview of evidence-based memory research during this era. He writes: "The modern era of memory research can be said to have begun in 1957 when Brenda Milner described the profound effects on memory of bilateral medial temporal lobe resection [of the hippocampus], performed to relieve epilepsy in a patient who became known as H.M." (Scoville and Milner, 1957)

Squire's Memory Research Laboratory at UCSD has been a pioneer and global leader of human and animal hippocampal research for decades.

In his lifetime, my late father, neuroscientist and neurosurgeon Richard Bergland (1932-2007) frequently referred to Larry Squire as the 'world's leading expert on the hippocampus.' Some of my fondest (and most vivid) childhood memories are associated with Polaroids I took during a father-son trip to San Diego for a medical conference where my dad met with Squire and other thought leaders of his generation in the early 1970s. (See "The Split-Brain: An Ever-Changing Hypothesis")

Larry Squire, who was born in 1941, continues to advance our understanding of the hippocampus and how it works. Recently, he co-authored a new study, "Spiking Activity in the Human Hippocampus Prior to Encoding Predicts Subsequent Memory." This paper (Urgolites et al., 2020) was published on June 1 in Proceedings of the National Academy of Sciences.

In a statement of significance, the authors sum up their latest research on the human hippocampus based on neuronal recordings of 34 epilepsy patients as they attempted to encode random words to declarative memory:

"[Our] study found that spiking activity in the hippocampus prior to the onset of the to-be-studied item predicted both [neuronal] activity during encoding and subsequent memory. Thus, when the hippocampus is in a "ready-to-encode" mode before stimulus presentation, the stimulus is likely to be encoded and subsequently remembered. By contrast, if the hippocampus is not in a ready-to-encode mode before the presentation of a stimulus, the stimulus is likely to be poorly encoded and subsequently forgotten. We conclude that prestimulus 'attention to encoding' predicts subsequent memory."

At the onset of this study, participants heard or read a stream of random words that were a "novel stimulus" when the experiment began. The firing rate of neurons in the hippocampus was monitored throughout each person's process of reading or hearing a novel word in the stream. As the study progressed, certain words were repeated. "For each word, the patient's task was to decide whether it was novel or repeated," the authors explain.

Larry Squire and colleagues were able to calculate the average number of times hippocampal neurons fired in response to every word. They also calculated the neuronal firing rates that immediately preceded each word. The firing rate about one second before seeing or hearing a new word turned out to be the strongest predictor of someone remembering or forgetting a word. "We found that pre-onset spiking activity in the hippocampus (when the word was novel) predicted subsequent memory when the word was later repeated," the authors explain.

"If a person's hippocampal neurons were already firing above baseline when they saw or heard a word, their brain was more likely to successfully remember that word later," co-author Stephen Goldinger, professor of psychology at Arizona State University, said in a June 1 news release. "We think new memories are created by sparse collections of active neurons, and these neurons get bundled together into a memory. This work suggests that when a lot of neurons are already firing at high levels, the neuronal selection process during memory formation works better." 

"A key question going forward is how to put our brains into 'encoding mode' when we wish to do so," John Wixted, professor of psychology at UC San Diego and co-author of this paper, said in the news release. "Since we know, based on earlier research, that people can actively suppress memory formation, it might be possible for people to get their hippocampus ready to encode as well. But how one might go about doing that, we just don't know yet."

Short-Term Plasticity of Hippocampal Synapses and Engram Formation

Another "in press" paper (Vandael et al., 2020) on short-term memory storage and the hippocampus by researchers from the Institute of Science and Technology in Austria was published online on June 2 in the journal Neuron. This study investigates how a quick burst of activity in a single synapse of the hippocampus may be key to forming the 'engram' of a memory. 

"Synaptic plasticity, the strengthening of communication between neurons, explains memory formation at the subcellular level. To find the engram, we, therefore, explored structural correlates of synaptic plasticity," Peter Jonas explained in a June 2 news release. Co-author David Vandael added: "Firing patterns induce plasticity through an increase of vesicles in this active zone, which can be stored for a few minutes." 

Before this groundbreaking research, Vandael and Jonas hypothesized that plasticity arises after a burst of neuronal activity because this surge in hippocampal activity makes the release of certain neurotransmitters into the synapse more likely. "Instead, we found that after a granule cell is active, more vesicles containing neurotransmitters are stored at the pre-synaptic terminal," the authors explain. "Short-term memory might be activity stored as vesicles that are released later," Vandael noted.

"It is fascinating to think of memories as numbers of neurotransmitter-containing quanta, and we truly believe it will be inspiring for the neuroscience research community. We hope our work will contribute to solving part of the unresolved mysteries of learning and memory," Jonas concludes.


Zhisen J. Urgolites, John T. Wixted, Stephen D. Goldinger, Megan H. Papesh, David M. Treiman, Larry R. Squire, and Peter N. Steinmetz. "Spiking Activity in the Human Hippocampus Prior to Encoding Predicts Subsequent Memory." PNAS (First published: June 1, 2020) DOI: 10.1073/pnas.2001338117

David Vandael, Carolina Borges-Merjane, Xiaomin Zhang, Peter Jonas. "Short-Term Plasticity at Hippocampal Mossy Fiber Synapses Is Induced by Natural Activity Patterns and Associated with Vesicle Pool Engram Formation." Neuron (In-press version of this article first published online ahead of print: June 2, 2020) DOI: 10.1016/j.neuron.2020.05.013