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Unlocking the Brain’s Memory Retrieval System

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Memory Trace in Mouse Hippocampus

Credit:Sahay Lab, Massachusetts General Hospital, Boston

Play the first few bars of any widely known piece of music, be it The Star-Spangled Banner, Beethoven’s Fifth, or The Rolling Stones’ (I Can’t Get No) Satisfaction, and you’ll find that many folks can’t resist filling in the rest of the melody. That’s because the human brain thrives on completing familiar patterns. But, as we grow older, our pattern completion skills often become more error prone.

This image shows some of the neural wiring that controls pattern completion in the mammalian brain. Specifically, you’re looking at a cross-section of a mouse hippocampus that’s packed with dentate granule neurons and their signal-transmitting arms, called axons, (light green). Note how the axons’ short, finger-like projections, called filopodia (bright green), are interacting with a neuron (red) to form a “memory trace” network. Functioning much like an online search engine, memory traces use bits of incoming information, like the first few notes of a song, to locate and pull up more detailed information, like the complete song, from the brain’s repository of memories in the cerebral cortex.

The image comes from the NIH-supported lab of Amar Sahay at Massachusetts General Hospital, Boston. In mouse work recently published in the journal Nature Medicine, Sahay’s team discovered a molecular switch, controlled by a protein called abLIM3, that appears to play a critical role in the formation of filopodia [1].

The researchers also found that older mice have fewer filopodia than younger mice. And, by experimentally manipulating levels of abLIM3 in the dentate granule cells of older mice, they were able to restore many of those lost connections. In subsequent experiments that used an imaging technique called optogenetics to watch the hippocampus in action, the researchers found that the improved connectivity translated into better pattern completion skills for the older mice.

Sahay’s work provides experimental support for a theory of episodic memory retrieval first proposed in the mid-1980s, called the Hippocampal Memory Indexing Theory [2]. Timothy Teyler and Pascal DiScenna, then scientists at Northeastern Ohio Universities College of Medicine, Rootstown, proposed that the hippocampus maintains the neural equivalent of a library index card to retrieve the full memory back in the stacks of cerebral cortex. According to their theory, if an “index card” happens to disappear due to aging or injury, so too does access to the associated memory.

Clearly, more research is needed to see if the latest findings in mice apply to humans. But Sahay notes that the structure and function of the hippocampus are fairly well conserved among mammals. In addition to continuing its work on age-related memory loss, Sahay’s team plans to investigate the possible role of abLIM3 in the storage and retrieval of memories associated with post-traumatic stress disorder.

References:

[1] Dentate granule cell recruitment of feedforward inhibition governs engram maintenance and remote memory generalization. Guo N, Soden ME, Herber C, Kim MT, Besnard A, Lin P, Ma X, Cepko CL, Zweifel LS, Sahay A. Nat Med. 2018 May;24(4):438-449.

[2] The hippocampal memory indexing theory. Teyler TJ, DiScenna P. Behav Neurosci. 1986 Apr;100(2):147-154.

Links:

Brain Basics: Know Your Brain (National Institute of Neurological Disorders and Stroke/NIH)

Sahay Lab (Massachusetts General Hospital, Boston)

NIH Support: National Institute of Mental Health; National Institute on Aging