December 2016 | Issue 27
Hiroshi Makino: unlocking the secrets of sleep’s memory boost

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By Nicole Lim, Assistant Director, Communications & External Relations

From getting a good night’s rest to studying key concepts just before nodding off, top study tips invariably include sleep. These are more than just old wives tales, with countless studies showing a beneficial association between recall or memory and sleep.

Despite this, no one knows exactly what goes on in the sleeping brain. And that’s what keeps LKCMedicine’s latest recruit, Nanyang Assistant Professor Hiroshi Makino, awake at night.

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“I’d like to understand how sleep changes the activity of neurons. With very few system neuroscientists interested in this area, I hope to be able to make a meaningful contribution,” said Asst Prof Makino.

Enchanted as a young child by the asymmetry of the brain’s two halves, Asst Prof Makino pursued his interest in the field more seriously after leaving school, swapping the global metropolis of Tokyo for remote St Andrew’s in Scotland to study neuroscience.

As part of the four-year course, Asst Prof Makino spent a 10-month exchange semester at the Salk Institute for Biological Studies in San Diego. Surrounded by some of the most inspiring minds in neuroscience, the exchange visit set the trajectory of Asst Prof Makino’s career.

Attending a talk, he caught sight of the late Francis Crick, the renowned scientist who didn’t just make his name with the discovery of the structure of DNA (work for which he and James Watson received the Nobel Prize), but also his theories in the area of neuroscience.

“Crick predicted the advent of optogenetics and had many theories about consciousness and sleep, most of which were not and are still not testable with our current knowledge and technology,” said Asst Prof Makino.

Inspired by that chance moment and already set on pursuing his PhD in the US, Asst Prof Makino finally settled on the Watson School of Biological Sciences at Cold Spring Harbour, a centre at the forefront of neuroscience research and whose founder was none other than James Watson.

Working in the lab of neuroscientist Roberto Malinow, Asst Prof Makino focused on synapses, the connections between neurons, and how experience affects the strength of these connections, known as synaptic plasticity. First discovered around 50 years ago, neuroscientists have long known that synapses in the hippocampus (the brain’s centre for memory) change during the learning process. When we memorise something new, they adapt to store this new information. But until recently, it has been nearly impossible to shed more light on exactly what happens and in which synapses.

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GCaMP6-expressing neurons (green) in the mouse primary visual cortex. GCaMP6 is a genetically encoded calcium indicator, which allows measurement of neural activity. Inhibitory neurons are expressing tdTomato (red) (Courtesy of Hiroshi Makino)

“Identifying which synapses are changing during a specific learning experience was like looking for a needle in a haystack. Only a few per cent of synapses are affected and identifying exactly which ones are involved is very hard,” said Asst Prof Makino.

At the time when Asst Prof Makino embarked on his postgraduate studies, a new imaging technology was making waves: two-photon microscopy. This more precise method improved scientists’ ability to study, probe and monitor neuronal activity and anatomy, thereby overcoming one of the limitations of electrophysiology. Electrophysiology lacked spatial resolution, or the ability to pinpoint where exactly the activity takes place.

“The technology was widely shared at Cold Spring Harbour back then and it allowed me to observe the synaptic changes triggered by learning at the level of individual synapses,” said Asst Prof Makino, enabling him to map in detail how these synapses strengthen in response to learning, and how they become incorporated into the main circuits.

From there, he returned to San Diego as a postdoc, this time to the University of California, where he started to focus more on the function of these synapses. Tracking the calcium signals of individual neurons in the visual cortex of a mouse model, Asst Prof Makino studied the behaviour of hundreds of neurons over time.

He found that visual cortex circuits adapt to accommodate experience and identified the tipping point when experience influences activity more than just the information from the sensory environment.

“I found that the activity in the visual cortex does not just reflect the information from the environment. A second mechanism, called top-down control, actually dominates our perception,” he said.

Drawing on experience, the brain learns to allocate energy to the important elements in our environment; something that infants tend to struggle with.

After more than a decade in the US, Asst Prof Makino was keen to be back in Asia. Looking for an environment that supports and nurtures young scientists, he was drawn to Singapore. He also feels he can add to existing expertise. Clinching NTU’s prestigious Nanyang Assistant Professorship, he made LKCMedicine his home, thereby also completing a geographical circle.

In his work, too, he is going back to one of his earliest inspirations – Francis Crick. “One of Crick’s theories was that sleep is important for forgetting things. This is one way of looking at it. What I want to focus on is how sleep changes the activity of neurons,” said Asst Prof Makino.

Using some of the latest imaging technologies including the latest two-photon calcium imaging, he plans to study how neurons are involved during behaviour. Moving from studying hundreds of neurons at a time to tens-of-thousands will give Asst Prof Makino a much more detailed and clearer picture of neural functions and how sleep affects that.

“It is a topic that fascinates me and I could quite happily spend the next 30 years working on it,” said Asst Prof Makino.