Is An Ancient Virus The Physical Substrate For Memory Formation?

royalsocietyofbiology |  Understanding how memories are formed and stored is one of the great enigmas in neuroscience. After more than a century of research, detailed knowledge of the mechanisms of memory formation remain elusive.

In the past decade, memory research has been advanced by the study of neuronal engrams, or networks of neurons that are incorporated into a memory. In particular brain regions associated with memory, a neuronal engram is theorised to consist of a subset of neurons within that brain region that is uniquely activated by a behaviour that leads to memory formation.

For example, when mice are trained on a simple, initial behavioural task, a certain subset of neurons within a specific brain region will become activated. Genetic techniques can be used to ‘tag’ this network of neurons.

If the mouse is then placed in a different behavioural or environmental context, and the network of neurons from the initial behavioural task is artificially activated, the mouse will display behaviour that it learned in the initial task[1]. The initial behavioural task triggered the incorporation of a subset of neurons into an engram, which encoded the memory for that task.

Given the vast number of neurons in the brain, the potential combination of neurons that could make up separate memory engrams is virtually limitless. So the question that is key to our understanding of the mechanisms of memory formation is: what causes the incorporation of one neuron, but not another, into memory engrams?

Research has demonstrated that certain proteins can ‘prime’ neurons for incorporation into an engram[2]. Neurons that naturally express more of these proteins are frequently found in memory engrams for a behaviour. Artificially inducing more of these substances to be expressed can encourage neurons to become part of an engram.

One substance in particular that was found to be important for priming neurons for engram incorporation is known as Arc[3]. This protein is induced rapidly by neuronal activity and regulates levels of receptors at synapses that are critical for synaptic function and neuronal communication.

Mice that genetically lack Arc protein are unable to form memories that last longer than the course of a behavioural training session (known as long-term memories), although they can learn normally at short-term time scales. Although these experimental findings suggest that Arc is an important piece of the memory puzzle, the mechanisms that regulate Arc at the cellular and molecular level remain unclear.

Recently, research I conducted in the laboratory of Dr Jason Shepherd at the University of Utah[4] revealed something very surprising: Arc structurally and functionally resembles a retrovirus such as HIV. This is the first time a neuronal protein, much less one underlying a process as crucial as memory formation, has been shown to have a viral structure. Evolutionary analysis from our laboratory showed that Arc protein is distantly related to a class of retrotransposons that also gave rise to retroviruses such as HIV.