June 4, 2014
A team of researchers from the University of California, San Diego, has determined the cellular mechanism of memory formation, putting an end to decades of speculation about the matter.
Most neuroscientists agree that memory formation involves the strengthening of synapses in the brain, and have assumed that this strengthening occurs by a form of synaptic plasticity called long-term potentiation (LTP), even though there was no hard evidence that this is the case.
The new research uses state-of-the-art neurotechnology to show not only that that the strengthening of synapses by LTP is required for the formation of fearful memories, but also that weakening of the same synapses by a similar, opposing mechanism can erase the memories.
LTP was discovered in the 1960s by a Norwegian scientist named Terje Lømo, who was using pairs of electrodes to examine the activity of nerve cells in the rabbit hippocampus. Lømo used one electrode to stimulate cells in one region, and the other to simultaneously measure changes in the activity of connected cells in a neighbouring area.
Lømo noticed that electrically stimulating pairs of cells at the same time strengthened the connection between them. In particular, when repetitive high-frequency stimulation of one cell coincided with regular stimulation of another, the signalling between them seemed to become more efficient, so that a small burst of activity in one would subsequently produce a prolonged response in the other.
The importance of the hippocampus for memory was by then well established, and so when LTP was discovered, it was widely assumed to be the cellular basis of memory formation, and its mechanism has been studied intensively, generating more papers than any other area of brain research. Much of this work shows that LTP is involved in various kinds of memories, and that drugs or genetic mutations that block the mechanism produce memory deficits of some kind, but none directly shows that it is the cellular basis of memory formation.
Roberto Malinow and his colleagues approached this problem using a technique called optogenetics. This involves inserting the gene encoding a light-sensitive protein called Channelrhodopsin into specific groups of neurons, so that the cells can be switched on or off with remarkable precision, with pulses of laser light delivered via an optical fibre into the brain.
The researchers created a genetically engineered virus carrying the Channelrhodopsin gene and injected it into the brains of rats, targeting part of the amygdala (commonly known as the brain’s “fear centre“) containing cells that process sound information. They then taught the animals to fear a sound, using the famous classical conditioning method, with a twist.
Normally, repeated pairings of a sound or some other stimulus with a mild electric shock leads to a fear response. The rats quickly learn to associate the stimulus with the shock, and react with fear when presented with the stimulus later on.
Malinow and his colleagues induced fear conditioning by giving the rats small electric shocks while using high frequency pulses of laser light to activate the amygdala neurons. They thus learned to associate the shock with the pulses of light, so that they would respond with fear to the light pulses alone, and when the researchers examined their brains, they found that the light pulses had successfully induced LTP in the amygdala.
Crucially, the researchers also found that a different pattern of light pulses delivered to the same cells could abolish LTP by inducing an opposing mechanism called long-term depression in the same synapses. This made the animals “forget” the association between the light pulses and electric shocks, so that they were no longer scared of the pulses, but this “erasure” was reversible – if the first pattern of pulses was delivered a second time, it induced LTP once again and reactivated the memory.
“We were playing with memory like a yo-yo,” Malinow told Nature news reporter Ewen Callaway, adding that it was “a bit of relief” that such challenging experiments worked, and that he and his colleagues can now “celebrate a little”. And now that LTP has once and for all been established as the cellular basis of memory, thousands of memory researchers around the world will no doubt feel like celebrating, too.
Reference: Nabavi, S., et al. (2014). Engineering a memory with LTD and LTP. Nature, doi: 10.1038/nature13294