Using a miniscope to observe the brain in action, researchers find evidence that memory loss in Alzheimer’s may partly be a signalling problem
Alzheimer’s is a particularly cruel disease. It erodes people’s memories – loved ones are in many ways ‘lost’ well before they ever pass away.
But we are gradually learning more about how Alzheimer’s Disease happens and why – and treatments are improving. An as yet unanswered question is whether the memory problems in Alzheimer’s Disease are related to the recording of memories, or whether it makes it harder to ‘replay’ memories.
This is important because if Alzheimer’s Disease is primarily a signal problem, it suggests that there may be ways to devise therapies that could ‘rescue’ memory in these patients by ‘sharpening’ the signal.
In a collaboration between medicine and electrical engineering, we used a “camera in the brain” technique to find evidence that when mimicking the effects of Alzheimer’s in mouse models, memory traces were still present but became much less distinct – like a fuzzy video screen.
Signal and noise
Our results, published in the journal Frontiers in Neuroscience, suggest that memories in Alzheimer’s may be left intact, but that the signal for replaying these memories is impaired by interference – or what we call noise.
The effects of Alzheimer’s can be mimicked in animals with a drug called scopolamine that temporarily impairs memory.
Our challenge was working out how to directly monitor the activity of neurons inside the brain to find clues of what is more precisely going on as we put the mice through a simple memory test – navigating a linear track.
This is where the ‘camera in the brain’ comes in.
It involved electronics graduate research student, Dechuan Sun, implanting a light weight and removable miniaturised fluorescent microscope – called a miniscope – on top of a mouse’s head. This enabled us to observe brain cells in action in the mouse hippocampus, a region that encodes new memories and is strongly affected by Alzheimer’s.
Fluorescent microscopes work by detecting signals from Green Fluorescent Protein (GFP) connected to a calcium sensor molecule (known as GCaMP) that has been added to cells to ‘light up’ different cellular operations.
The discovery and development of GFP won the Nobel Prize for chemistry in 2008 and involves inserting a gene derived from a bioluminescent jellyfish into a cell.
To generate observable light signals when neurons activate, GCaMP DNA is inserted into the cells using a benign viral carrier, Adeno-Associated Virus (AAV). The neurons then generate their own GCaMP which changes fluorescence when neurons discharge.
The fluorescence changes because when a neuron activates, calcium flux binds to the protein and alters the intensity of the fluorescence. This activity can then be detected by shining light with the correct spectral properties onto the neurons.
This light comes from the miniscope.