Optogenetics, Oscillations, and Alzheimer’s: Science Non-Fiction

Recent advances in the field of optogenetics have stunned the world of neuroscience and captured imaginations everywhere. The promise of these successes has led many to wonder what the future might look like. The voices of the great science fiction writers of my adolescence grow louder the more I read about what is on the cutting edge. The study I am about to tell you about is not fiction, though at moments you may feel like I am just outlining the plot of my favorite Crichton novel.

In December of 2016, a study was published by Iaccarino et al. in the journal Nature. Their experiment combines a number of state-of-the-art methods in neuroscience to yield striking, almost unbelievable, results. The implications of this study are vast, especially for potential applications in the effort to cure Alzheimer’s disease. Complex and shocking contemporary ideas such as gamma oscillations in the brain and optogenetics make the implications somewhat difficult to access. But that won’t deter us.

Let’s break down the concepts in the article. First of all: Gamma oscillations.

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Gamma oscillations represent the rhythm section of the brain. You may know that neurons communicate signals to each other; they produce action potentials (little electrical pulses), which they pass along to other neurons they are connected to. We never had any particular reason to think that the parts of the brain communicated by means beyond their physical connections between neurons.

It turns out that neurons may oscillate (fire in a regular rhythm) and that they can even synchronize. These so-called gamma oscillations (GOs) are usually measured in Hertz. We have recently begun to see that they might represent a new layer of analysis in the brain. Whereas before, we paid attention to neurons and synapses, how they connected, and if they did or did not fire, now we are attending to these patterns of pulsation.

It doesn’t even seem that a direct connection is required for GOs across separate regions to synchronize. Characteristics like these make it difficult for us to understand these oscillations within our model of neurons and synapses. In the past decade, scientists have set to work trying to fill in the mystery surrounding GOs. We still have a long way to go.

Returning to our study at hand – the researchers started with the observation that GOs seem to be altered in many types of neurological disorders, including Alzheimers Disease. These alterations have been measured in humans and mice. In their mouse model, gamma oscillation deficits (fewer pulsations) seem to occur in mice who are early in the process of developing Alzheimer’s (or the mouse equivalent).

Scientists wanted to know if GOs have something to do with the neurological changes in the cells that happen during the development of Alzheimer’s. Sure, these rhythms exist, but do they have any effect on what’s going on in the cells? They needed a way to affect the oscillations to figure this out. They chose optogenetics.

Optogenetics is a new and popular method for precisely altering the activity of neurons in the brain. Thus, the behavior of the mice can be studied with these alterations. If GOs weren’t science fiction-y enough for you, just wait. In optogenetics the method of affecting cells involves first infecting the mice with a virus that alters only a small subset of cells in the brain. Whereas many previous methods of altering neuron firing in the brain have been fairly diffuse, these viruses are precise.

The virus, like a little organic robot, adds special light Virus-02-june.gifsensitive pumps or channels in the neurons it attaches to. This is a pretty complex genetic process, but the virus basically installs a little switch in the neuron. The cell will turn off or on when a special light activates it – usually this light is inserted in through the skull. This allows scientists to study the function of specific groups of neurons by turning them off to see what happens. This method has been used to do all sorts of unbelievable experiments, like those in which they make mice “remember” past experiences which they had forgotten about or come to ignore.

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Now all the pieces will start to come together. The researchers in our study used mice who were on their way to developing Alzheimer’s. Because the researchers had observed deficits in the gamma oscillations of mice who were in this process they decided to see what happened if they manually reversed that deficit.

They took the mice and prepared them (via optogenetic methods) to have light sensitive neurons. Then they flashed the light at 40Hz (what they think is probably the healthy rhythm for firing in this case). The idea was to bring the mice up to speed, if you will. Instead of deficits in oscillations, they would force the neurons to oscillate at more normal rates.

Incredible things happened next. You see, one of neurological concerns during development of Alzheimer’s is the build up of plaques that gunk up the brain. They wreak all sorts of havoc and they build up because nothing is cleaning them away. In a healthy animal, this is the job of the microglia, but for some reason, in animals with Alzheimer’s, the microglia just aren’t doing their job. The plaques build, and Alzheimer’s sets in.

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When the scientists manually overrode the deficiencies in GOs, microglia, our little caretakers of the brain, got bigger and proliferated! This meant that they were there to clean up those plaques before they became an issue.

It gets even more stunning. The scientists, after their great success wondered whether it could be done more easily. They knew that there was evidence that GOs could be driven by light that enters the brain through visual stimulation. As in, you can see a flickering light and it might effect the gamma oscillations in your brain. Scientists wondered if the fancy opto-genetic methods were even necessary. Maybe the oscillations could be altered by just exposing the mice to a space with flickering lights around them.

It worked! They exposed the mice to an hour of 40Hz flickering lights – no wires in the brain; totally noninvasive. And the same thing happened. Normally difficult to get rid of, insoluble plaque levels were reduced by up to 57.9% with their methods.

Sometimes it seems like we are living on a precipice. So many dazzling new techniques and projects are coming into the spotlight. The positivity and promise of a study like this can always be tempered with the question of where this is leading us. As wonderful as it may be to consider the possibility of being able to just shine a flickering light on someone to help ameliorate their Alzheimer’s, it is equally horrifying to think of being able to potentially affect someone’s essential psychology so easily. Where will this lead us? Huxley, Orwell, Dick, Verne, Bradbury – they can’t tell us. It’s up to us to write the ending to this story…

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