Researchers at the UNC School of Medicine have used new deep-brain imaging techniques to link the activity of individual, genetically similar neurons to particular behaviours of mice. Specifically, for the first time ever scientists watched as one neuron was activated when a mouse searched for food while a nearly identical neuron next to it remained inactive; instead, the second neuron only became activated when the mouse began eating.
This work suggests that manipulating an entire genetically defined subtype of neurons to treat a condition, such as binge-eating, might be too broad of an approach. Drug developers might have to focus on one type of cell within the subset in order to avoid potentially serious side effects. The opensource study is published in the journal Cell.
This study is one of the first published reports using novel technologies that support the NIH BRAIN Initiative to map how individual neurons and neural circuits interact throughout the brain.
Traditional imaging techniques wouldn’t allow the team to record this kind of activity deep inside the brains of freely moving mice. For the first time, the medical community can view specific, genetically defined neurons in the lateral hypothalamus as they light up while the mice search out food, eat, and drink.
The finding suggests that targeting an entire subpopulation of brain cells to learn about their functions can be somewhat misleading. One type of cell in that subpopulation is somehow predisposed to be involved in one aspect of behaviour, while the adjacent neurons are somehow predisposed to be involved in different aspects of behaviour.
This is important to know because if researchers want to create a drug treatment for obesity, for instance, then they wouldn’t want to affect cells involved in appetite because they might affect cells involved in other aspects of motivated behaviour. But if researchers could target only the cells involved in consumption, then maybe they could modulate only those cells without affecting motivation.
This work, which is part of a larger brain research project in the lab, is a good example of how far brain research has come in recent years.
For more than 50 years, scientists have known that basic motivated behaviours, such as eating, drinking, and sleeping, are controlled within the lateral hypothalamus, whether in a rodent, a shark, a human or any other mammal. This part of the brain is very similar in all mammals.
Later studies showed that electrically stimulating the lateral hypothalamus enhanced motivation, the ‘wanting’ of some kind of basic outcome, such as the motivation to eat. Then, researchers found that this brain region is responsible for eating. That is, if there’s food, animals will eat it if this brain region is electrically stimulated. It doesn’t matter if the animals are hungry or not.
But stimulating an entire brain region can’t tell researchers which cell type is truly responsible for which behaviour. Until recently, scientists were unable to study these different kinds of cells as they relate to certain kinds of behaviour. The team decided to use various techniques, including optogenetics and calcium imaging, to study the roles of GABAergic neurons, a large subset of neurons in the lateral hypothalamus.
By stimulating these cells with light, the team found that they could increase feeding and produce reward-related behaviours in mice. But, frankly, this finding wasn’t much different than what others found decades ago. Therefore, the researchers wanted to see whether individual neurons in this one subset of cells were encoding different aspects of behaviours. And this is really challenging. This is why the team turned to a specific kind of imaging in live animals.
The researchers were able to modify only the GABAergic neurons in the current study to glow fluorescent when calcium entered the neurons, which is what happens during bursts of neuronal activity. Essentially, for the sake of imaging, the fluorescent calcium indicator is a visual proxy for neurons firing.
Because traditional imaging methods do not allow for deep-brain visualization, the team turned to a state-of-the-art endoscope imaging system that few other labs have access to. These microscopes, about one inch long, are attached to the brains of mice, which are then able to move and behave normally without restrictions. The team were able to study 740 GABAergic neurons in live, free-moving mice.
The team then conducted experiments to analyze the neurons that fired during motivated behaviours, such as searching for food, and the neurons that fired during consummatory behaviours, such as eating and drinking. When mice searched for food, approximately 22 percent of GABAergic neurons were activated. When the mice consumed food or drink, about 10 percent of the GABAergic neurons fired.
The key for the researchers was that there was nearly no overlap. There were cells that only fired during motivated behaviours and cells that only fired during consummatory behaviours.
When it comes to how these cells function in the brain, the current study found that there are subpopulations of cells within this larger network of GABAergic neurons. And these individual cells are responsible for these highly intertwined activities.
The team plan to target smaller and smaller subpopulations of neurons. The idea is to find genetic markers to delineate these distinct groups of cells. If so, then the researchers could target these groups and learn a lot more about what they do and how they do it.
Source: UNC School of Medicine