“Memory, the biologically encoded information, is the long-lasting and stable change that is caused by learning,” said Tomás J. Ryan, PhD, a neuroscientist who spoke last week at TEDMED in Palm Springs, Calif. Through a series of experiments on targeted memory recall, Dr. Ryan and his colleagues have discovered that memories thought to disappear in those suffering from amnesia—or Alzheimer’s disease—may be retrievable.
“When I was 11 years old, I was involved in a traffic accident—a head-on collision … car versus bicycle,” Dr. Ryan said. “I was on the bicycle. I survived, but I suffered head trauma and a broken collarbone. All of what I am telling you is second-hand information because I don’t remember anything that happened on that day.”
Dr. Ryan is a senior research fellow at the Massachusetts Institute of Technology’s Tonegawa Lab and an incoming assistant professor of neuroscience at Trinity College Dublin.
His own personal experience of memory loss has nothing to do with why he studies memory now, he said. But it serves to illustrate a particular paradox of memory.
“How is it that we can remember a single experience for our lifetime and yet at the same time forget things that are centrally important to us?” he asked. We can recognize a face, a sound or a taste we have not experienced in years but aging and misfortune can result in losing the memories that matter most.
“Why is it that my brain has no ability to remember what happened [the day of the accident], but my collarbone will never forget?” he asked. “Unlike remembering, memory itself is not an activity. It’s not something that we do like learning or remembering.
“Each of us as individuals is the sum total of all of the experiences we have accumulated in our lifetimes. You are your own unique story with some internal life lived in your memories. And when amnesia hits due to trauma or illness, you lose a part of yourself.”
While too many of us will live with dementia, 100 percent of us have experienced infantile amnesia—the global developmental loss of memories formed in the first two years of childhood, Dr. Ryan said. “Memory loss, whether from aging, misadventure, disease or growing up is fundamental to our experiences as humans … What if those memories were not truly lost, but just locked in our brain and not really accessible?”
As a neuroscientist, Dr. Ryan’s research revolves around one question: How are individual memories stored in the brain? The answer: memory engrams.
What memory means
To understand what a memory engram is, we must first grasp the meaning of memory, Dr. Ryan said. “We can broadly define memory as knowledge that is accumulated in your lifetime by a process of learning, and distinct from your genetically encoded instincts.”
Learning involves a particular material change to the brain “that accounts for a specific memory we refer to as a memory engram,” Dr. Ryan said. “Up until recently, we studied memory in the brain by looking at the effect of brain damage and disease in memory function … and we concluded that whatever brain region was damaged or malfunctioning was probably important for the storage and maintenance of our memory engrams in general.”
This approach helped neuroscientists learn a lot about amnesia but not so much about memory itself. “To make progress, we need to differentiate between the act of remembering [and] the memory information content.
“[Memory] can lie dormant for our entire lives, being called upon only when necessary or perhaps just randomly by the taste of a cookie. And just as we can lose access to stored data in our computer hard drives … we must be open to the possibility that our brains may lose access to our memory engrams due to neurological causes that affect our ability to remember but without damaging the memory engrams themselves.”
Finding lost memories
Looking for specific memories in the brain can be difficult, searching among the billions of brain cells connected by trillions of different synaptic connections. “Smoking out” the location of a memory by “hijacking the normal biological processes of memory allocation” can cause the brain to show researchers where the memory is located, Dr. Ryan said.
Because the brain allocated information partly by inducing specific genes to produce specific proteins, “we can make specific brain cells light up when they encode a given memory—the memory engram cells,” Dr. Ryan said. “Activating them should result in targeted memory recall.”
Over the past five years, through experimental studies, Dr. Ryan and his colleagues at the RIKEN Brain Science Institute and the Picower Institute for Learning and Memory at MIT have shown that if they label cells that are activated during learning and stimulate them thereafter in rodents, they get targeted recall of specific memories.
“We can now label and manipulate particular memory engrams in rodent models,” he said. Dr. Ryan trained mice to do a particular task and then induced amnesia by drug treatment. The mice appeared not to remember that task and were amnesiac.
“But when I stimulated the engram cells for that memory directly, the mice showed perfectly normal memory recall,” he said. “The functional engram was still present in the brain.”
The research team found similar results in mice that were genetically engineered to develop Alzheimer’s disease.
“This points to some very exciting prospects. It means that in many cases of amnesia, the physical data of a memory persists beyond the functional experience of amnesia,” Dr. Ryan said. “Amnesia can therefore be attributed, for the first time, to a deficit in memory access, but the information itself survives.”
Researchers now have solid ground to begin developing noninvasive interventions such as drug treatments or cognitive behavioral therapies to help reconnect human amnesia sufferers with some of their memories, he said. But there is still a challenge.
Where is a memory? “Is it in the shape of the brain cells? Is it inside the brain cells?” Dr. Ryan asked. “No. It’s not an arbitrary physical substance. And neither is it mystical or vitalistic. It is information encoded in the specific constellation of brain cells.”
When Dr. Ryan and his colleagues label memory engrams in mice, they see changes in the permanent anatomical connectivity between brain cells and that feature of the engram survives amnesia. “It remains intact even though the mice appear not to remember, and stimulating these neuronal connections results in us getting the memory out,” he said.
The memory engram must have meaning for the organism or else it’s not information, Dr. Ryan said. “A neuroconstellation must carry meaning from the point of view of a host organism struggling to survive and reproduce in its environment.”
“Today, understanding memories as permanent changes that last all the way to [death] provides a novel and optimistic framework for developing therapeutics, prosthetics and external aids for helping to combat memory loss in the old, in the young and the misfortunate,” he said. “Medical interventions can heal lacerations, broken bones and damaged limbs in things that won’t heal on their own.
“What if,” Dr. Ryan wondered, “we could reconnect the brain with its apparently lost memories and forget about amnesia?”
The entirety of Dr. Ryan’s talk will soon be posted to the TEDMED website. In the coming months, all of the talks from TEDMED 2016 will be available to view online.
