The brain's silent memory archives

How do we remember what we had for dinner last night, or our graduation ceremony? Are these memories physically stored in our brains? When we reach into the depths of our brain to retrieve the name of a long-lost friend, how does the brain retrieve that information? A long-held view in neuroscience is that memories are stored as physical changes in brain cells or neurons.

New experiences cause increased activity in neurons, which strengthens connections between them. This principle is called Hebb’s Law – neurons that fire together wire together. More specifically, there is evidence that collections of brain cells called engrams encode specific memories, sort of like how information is burnt into the grooves of a CD. The theory runs thus — experiences trigger coordinated activity in a set of cells that then represent the memory of that experience.

Imagine you are driving down a mud lane somewhere in rural India, and the smell of cow dung wafts through your open window. This sensory experience triggers activity in a set of ‘cow dung (+) neurons’ in your brain. These ‘cow dung engram’ cells now store the memory of the smell of cow dung and help you identify the smell the next time. Groundbreaking recent studies in mice have shown that engram cells encoding a memory can actually be identified. In this case, it was the memory of an unpleasant event — a shock to the foot. Forcibly triggering these cells even causes the poor mouse to remember the associated event, even when there is no foot shock!

Need for balance

This is all very well, but a lot of questions remain. If memories are indeed stored as engrams, how are they recalled at later times? What is the mechanism behind this retrieval? In a bid to answer these questions, Professor Mani Ramaswami at the National Centre for Biological Sciences (NCBS), Bengaluru, proposes the concept of ‘inhibitory engrams’ in a new perspective article published in the journal Proceedings of the National Academy of Sciences. The article, that Mani has co-authored with Helen Barron, Tim Vogels and Tim Behrens from the University of Oxford, proposes that inhibitory engrams — counterparts to their excitatory brethren — are responsible, among other things, for maintaining memories in a ‘latent’ state, to be recalled upon demand. Mani says, “The concept explains how we store perceptions and memories in a latent form in the brain, and provides a framework to explain how feelings and memories are reactivated and recalled.”

To understand the basis of the inhibitory engram concept, it is important to understand the brain’s need to balance itself. The brain contains two major classes of cells — excitatory and inhibitory. Excitatory cells release neurotransmitters that trigger activity in the cells they are connected to, whereas inhibitory cells release neurotransmitters that reduce the activity of cells they are connected to. The brain maintains a balance of excitation/inhibition — what goes up tends to come down. This balance, Mani says, is important to prevent “runaway excitation”, which would lead to a “broad increase in excitation and very limited storage capacity in the brain.”

Excitatory or inhibitory balance forms the basis of the inhibitory engram concept. When an experience is recorded as an engram of excitatory cells, the brain’s need to balance itself ends up forming an inhibitory replica. Your cow dung experience, for example, results in increased excitation of a group of ‘cow dung (+) neurons’ in the brain. The inhibitory neurons associated with the ‘cow dung (+) neurons’ — let us call them ‘cow dung (-) neurons’, are also strengthened, creating a negative replica of the ‘cow dung (+) neurons’.

What is the function of the inhibitory engram? One possible role is to quench a familiar memory, maintaining it in a latent state to be recalled at a later time. The authors point to studies in songbirds, which show that inhibitory engrams ‘silence’ newly formed memories and removing this inhibition, activates the memory. In the cow dung example, if the cow dung (-) neurons are weakened, say after a period of time when the smell is not around, then reintroducing the smell triggers a recall of the original memory.

In 2014, Mani proposed a different function of inhibitory engrams: habituation, or the ability to ignore familiar stimuli. Again, in the cow dung example, the cow dung (-) cells silence the feeling associated with the smell. Therefore, even if the smell is still around, we don’t ‘smell’ it anymore because we have become habituated.

Explaining neurological disorders

The inhibitory engram theory is particularly useful in coming up with mechanistic explanations for several neurological disorders. Memory disorders like Alzheimer’s disease could be caused by faulty recall mechanisms. Even if physical memory storage through engrams is intact, lack of appropriate disinhibition may cause problems with the recall of the memory. This prediction of the inhibitory engram model has already been demonstrated in mouse models of Alzheimer’s disease.

As Mani points out, inhibitory engrams “keep old memories silent until required, preventing them from corrupting new and independent memories as they form.” It is possible that when this mechanism goes awry, random unconnected memory traces are recalled at inappropriate times — causing the vivid hallucinations and delusions characteristic of schizophrenia.

Mani believes that the insight into neurological diseases could help guide approaches to treat these disorders. “An increased focus would be on a combination of cognitive, environmental and pharmacological approaches that facilitate formation of inhibitory engrams that help the brain cope with distractions and confoundment among various external inputs and diverse stored memories,” he says.

(The author is with Gubbi Labs, a Bengaluru-based research collective)