On a day in late August 1953, a young man later known to medical history as patient H.M. underwent an experimental procedure. The operation, an effort to control the debilitating seizures he suffered, meant the removal of parts of his brain, among them was part of a mechanism known as the hippocampus. The surgery was successful, and H.M. no longer suffered from seizures.
Unfortunately, it wasn’t the only effect that patient H.M. experienced. H.M. awoke in the recovery room and realized he was unable to create new long-term memories, even though his other cognitive abilities remained normal, and his brain could still process language as well as short-term working memory. Patient H.M.’s condition revealed to scientists that our brain’s ability to form long-term memories is its own distinct process from short term memory and relies on the brain’s hippocampus.
Scientists learned where the brain makes memories — but for nearly 70 years, the exact process behind making them remained a mystery. Recently, neuroscientists at Harvard Medical School (HMS) have made a pivotal step in uncovering the mystery, uncovering a major piece of the puzzle as they sought to find the cause of memory loss due to disease and advanced age.
In a study published by the journal Nature, they describe their findings: Working with adult lab mice, they isolated a mechanism in the hippocampus that neurons used to compute signals they receive from other neurons — one of the signature processes for the consolidation of memory and recollection. The study was led by researchers Lynn Yap, an HMS graduate student of neurobiology, and the neurobiology chair Dr. Michael Greenberg of the Blavatnik Institute at HMS. “Memory is essential to all aspects of human existence. The question of how we encode memories that last a lifetime is a fundamental one, and our study gets to the very heart of this phenomenon,” says Greenberg, who served as the study’s corresponding author.
The researchers observed that new experiences activate sparse populations of neurons in the hippocampus that express two genes, Fos and Scg2. These genes then enable the neurons to fine-tune input from what the researchers call inhibitory interneurons: cells that serve as a dimmer switch on neuronal excitation. “This mechanism likely allows neurons to better talk to each other so that the next time a memory needs to be recalled, the neurons fire more synchronously,” Yap said. “We think coincident activation of this Fos-mediated circuit is potentially a necessary feature for memory consolidation, for example, during sleep, and also memory recall in the brain.”
Staying In Sync
To create new episodic memories, your brain needs to encode a particular experience into its neurons. Once those neurons are reactivated, the experience is recalled, and the individual relives what happened in their past. For the study, Greenberg, Yap, and fellow researchers examined the gene Fos for the role that it plays in its relationship to memory.
Greenberg and his colleagues were in fact among the first to describe the presence of Fos in memory cells back in 1986, a gene that is expressed just minutes after you activate one of your neurons. Researchers began looking for the role Fos plays in both learning and memory, but for decades, its function remained elusive.
In this new experiment, researchers placed their mice in new environments and then analyzed the pyramidal neurons in their brains — the primary cells of the hippocampus. It became clear that after the mice began to familiarize themselves with the new location, small populations of neurons began to express Fos. Afterward, the researchers suppressed Fos, using a virus-based precision tool targeting a specific region of the hippocampus, which did not affect the neighboring cells.
Mice whose Fos had been blocked were unable to recall key portions of the maze, suggesting that the gene is critical for memory formation. The researchers then looked at the differences between the neuron populations that expressed Fos and their counterparts that did not. With the aid of optogenetics to switch inputs from separate nearby neurons on or off, they realized that activity within the Fos-expressing neurons was impacted the most by two kinds of interneurons — the central nodes of neural circuits.
Neurons expressive of Fos showed an increase of activity-dampening, or inhibitory, signals from one kind of interneuron and a drop of inhibitory signals from the other type. These signaling patterns were absent in neurons that blocked Fos expression. “What’s critical about these interneurons is that they can regulate when and how much individual Fos-activated neurons fire, and also when they fire relative to other neurons in the circuit,” says Yap. “We think that at long last we have a handle on how Fos may in fact support memory processes, specifically by orchestrating this type of circuit plasticity in the hippocampus.”
Saving The Day
The researchers probed deeper into the function of Fos, a common coding protein involved in the regulation of other genes. With the use of single cell sequencing alongside additional genomic screens to recognize the genes switched on by Fos, they discovered that one exemplary gene, the Scg2, had a key role in the interpretation of inhibitory signals.
In mice whose Scg2 gene had been switched off, the Fos-activated neurons in their hippocampus showed a failure in signaling from two different kinds of interneurons. The mice also displayed defects in their theta and gamma rhythms — two brain functions thought to play a role in learning and memory formation. Studies in the past have demonstrated that Scg2 codes for a neuropeptide protein capable of division into four distinct types, that are then secreted by the hippocampus. For this new study, Yap and his team found that the neurons evidently use these neuropeptides as a sort of receptor to fine tune input signals they receive from the interneurons.
Looked at in full, the researcher’s efforts indicate that after an individual experiences something new, a small group of neurons begin to express Fos in unison, activating Scg2 along with the derived neuropeptides, building up a massive, corresponding neural network whose activity is then regulated by the interneurons. “When neurons are activated in the hippocampus after a new experience, they aren’t necessarily linked together in any particular way in advance,” Greenberg said. “But interneurons have very broad axonal arbors, meaning they can connect with and signal to many cells at once. This may be how a sparse group of neurons can be linked together to ultimately encode a memory.”
The study’s findings could lead the way to a potential molecular- and even circuit-level mechanism for the creation of long-term memory. Although the results are an important step in our understanding of the inner workings of memory, numerous unanswered questions about the newly identified mechanisms remain. The answer isn’t apparent just yet, but Greenberg feels that he’s on the right track: “If we can better understand this process, we will have new handles on memory and how to intervene when things go wrong, whether in age-related memory loss or neurodegenerative disorders such as Alzheimer’s disease.”
Like all good research, the conclusions made here are the product of decades’ worth of research, yet they raise a number of new questions for the field of neuroscience to consider, new avenues of inquiry that could take decades to fully investigate. “I arrived at Harvard in 1986, just as my paper describing the discovery that neuronal activity can turn on genes was published,” he said, reminiscing on the connection between their latest efforts and his life’s work. “Since that time, I’ve been imagining the day when we would figure out how genes like Fos might contribute to long-term memory.”
More From Brain World
- The Art of Remembering Everything: A Q&A with Memory Champion Joshua Foer
- Beyond The Books: 6 Tips For Improving Learning and Memory
- Imagine That — Imagination Is Lot Like the Real Thing (To Your Brain)
- Know Your Brain: The Hippocampus — Your Brain’s GPS
- The Mystery of Memory: In Search of the Past
- Not-So-Total Recall: The Elusive Story Behind What We Remember and Forget
