Learning about anxiety and depression

Animal models can also be used to investigate anxiety or depression-like behaviors. That is possible because the animals present those behaviors innately and the behavior task is just designed to isolate that behavior for investigation purposes. One example of an anxiety-like behavior is the open field task. Now, before getting into the details of the task, let’s imagine you are going to a dance party, but you don’t know many people there. Once you arrive, is your first instinct to go to the middle of the room? Or stay close to a wall? This behavior is innate in humans and mice, and is related to anxiety. Both humans and animals get anxious in the center of an open space and tend to prefer the borders. The open field task is designed to investigate that behavior. So how does the testing work?

The animals are placed inside an open box (Figure 3A). Because mice are curious animals they will start to investigate the place by sniffing around. Now, since the box is an open space the animals will prefer to stick to the walls of the box and avoid the center. That doesn’t mean the mouse will not walk through the center of the box, just that it will spend most of its time closer to the walls than in the center. At the end of the experiment, the mice with higher anxiety-like behavior will have spent a significantly less amount of time at the center of the box (Figure 3B).

All three examples given have one thing in common: a specific task is designed to investigate in animals a symptom of a disease in humans. This article focused on how mice are used to study behavior but other model organisms can be used, too. Researchers study behavior in rats, zebrafish, flies, and worms to name a few!

How is this related to the SLC13A5 patient community?

Behavioral investigations are key to understanding diseases: they can give insight into the brain regions to be investigated, targeted drug approaches, long-term consequences of a disease, among many others. The SLC13A5 patient community has benefited from the use of behavioral investigations in mice.

SLC13A5 Epilepsy is characterized by the presence of seizures very early in life. Within hours or days after birth, kids are already having seizures. As they grow older, kids affected have a developmental delay, tooth issues and intellectual disability. Most kids only say a few words but can understand a lot more than what they can communicate themselves. Thus far, there are no cures. This is where animal models can be useful.

Since the disease is caused by mutations in the SLC13A5 gene, animal models for the disease are obtained by deleting the same gene in mice. The SLC13A5 gene encodes for a sodium-dependent citrate transporter (NaCT), a protein responsible for the movement of citrate into cells. Citrate is important for metabolism, and without a proper functioning NaCT citrate levels build up outside the cell. Indeed, patients have elevated levels of citrate in the blood and the cerebrospinal fluid.

Using behavioral assessments in a model of SLC13A5 Epilepsy

Similarly, mice with a deleted copy of SLC13A5 gene show elevated citrate in the blood and cerebrospinal fluid, and behavioral investigations show the animals have learning disabilities. When we use animal models to study human diseases, we sometimes use behavioral tests to confirm that the animal models are presenting with symptoms that match the human disease-associated symptoms. For example, since cognitive delay and disability is a symptom in the human version of SLC13A5 Epilepsy, memory deficits would also be expected in a mice model during the object recognition test. If the memory deficits appear to be present in a mice model during these tests, then the scientists have shown that the mouse model can be used to study and test treatments.

Mice and humans share a lot of similarities in the genes they express, this is why mice are such great models to investigate human disease. But, even with all similarities, some genes are different between humans and mice, and so is their regulation. Therefore, expressing human genes in mice allows for a more accurate representation of the disease in an animal model. TESS Research Foundation received a grant from the Orphan Disease Center to create a humanized mouse model. This is important because the mouse SLC13A5 gene functions slightly differently than the human SLC13A5 gene. Scientists will be replacing the SLC13A5 gene normally expressed in a mouse with the human copy of SLC13A5. Behavioral tasks can then be used to assess and validate this model.

This article was written by Paula da Silva Frost. Paula is a neuroscience graduate student at the University of California, Riverside. She studies lung allergy and how the brain contributes to respiratory symptoms. She has hosted multiple podcasts, one from Brazil called Neuropod and the other developed in California called Welcome to Grad School. You can follow her on Twitter: @ps_frost.

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