Scientists use zebrafish to understand how the brain makes decisions!

Dr. Hannah Shoenhard was the lead author on this study. Hannah hopes to one day run a lab that connects the “small picture“ (molecules, genes, and proteins) to the “big picture“ (circuits and behaviors) in neuroscience. After earning her PhD in the Granato lab using zebrafish as a model system to study decision making, she moved to do a postdoc in the Sehgal lab studying sleep and memory in fruit flies.

or technically,

The calcium-sensing receptor (CaSR) regulates zebrafish sensorimotor decision making via a genetically defined cluster of hindbrain neurons

[See Original Abstract on Pubmed]

Authors of the study: Hannah Shoenhard, Roshan A. Jain, Michael Granato

How we make decisions is a question that scientists and philosophers have considered for ages. But did you know that there are different types of decision making? The type that we are most familiar with involves decisions that we make in our everyday lives: Should I walk to school or take the bus? Should I have pasta or salad for dinner? But the brain is actually responsible for lots of different kinds of decisions - some of which we don’t even think about! One type of decision making that is commonly studied in the field of neuroscience is called sensorimotor decision making. In this form of decision making, the brain takes in sensory information from the world, processes the information while considering past experiences, and then produces a behavioral response. 

Figure 1:

Image of a zebrafish used in scientific research. 

Source: https://news.mit.edu/2022/smarter-zebrafish-study-1118

To understand more about this type of decision making, Dr. Hannah Shoenhard, a recent Penn Neuroscience PhD graduate, and her lab used zebrafish, a common animal model that is used in neuroscience research. Her lab had previously found that when fish are presented with a sudden quiet sound, they respond with a “reorientation” response - the fish slowly turn their bodies. But if the fish are presented with a sudden loud sound, they respond with an “escape” response - the fish rapidly turn their bodies. Having learned about this fascinating behavioral phenomenon, Hannah was interested in how different proteins may be involved in this sensorimotor decision making process. Through whole-genome sequencing (a fancy way of scanning for important genes) in the zebrafish, the lab identified a protein named CaSR that is essential for sensorimotor decision. When the lab removed CaSR from the zebrafish, they found that they would produce the wrong response to a loud sound by reorienting instead of trying to escape.

Given that CaSR is important for normal sensorimotor decision making, Hannah next wanted to know which part of the zebrafish brain uses CaSR to perform this behavior. She first looked at the neurons that drive the escape response. When she reintroduced CaSR into these escape neurons, she found that it did not restore the correct escaping response. This meant that CaSR had to be acting elsewhere.

To find the location where CaSR is acting, Hannah developed a novel experimental strategy. This approach combined behavior and brain imaging. Hannah expressed CaSR in random sets of neurons in zebrafish that didn’t have any CaSR of their own. Some of these fish displayed normal decision-making, meaning CaSR had been expressed in the “correct” neurons, and some displayed impaired decision-making, meaning the “correct” neurons had been missed. Hannah then compared which neurons had CaSR in zebrafish that displayed normal decision-making or abnormal decision-making. Using this novel strategy, Hannah found a brain region in the zebrafish called DCR6, which is located in the hindbrain, near both the escape and reorientation neurons. The hindbrain controls many reflexive behaviors in both fish and humans. To validate her findings and test if this region is actually involved in sensorimotor decision making, she drove extra CaSR expression in the DCR6 and found that this was sufficient to drive escape responses in zebrafish exposed to quiet noises – in other words, the opposite of what happens when CaSR is missing.  Additionally, she used the original zebrafish strain that lacked CaSR and specifically restored CaSR only in DCR6 neurons. Hannah found that these fish performed reorientations in response to quiet sounds and escapes in response to loud sounds - just as we expect healthy zebrafish to do! 

Thus far, Hannah’s experiments have pointed to two major findings: 1) CaSR is important for normal sensorimotor decision making and 2) CaSR acts locally in DCR6 neurons, but not reorientation or escape neurons, to enable normal sensorimotor decision making. Given these findings, Hannah asked an important follow-up question - are there connections between DCR6 and reorientation or escape neurons? To answer this, she used a unique zebrafish strain that labels DCR6 neurons and escape neurons. Hannah found that DCR6 neurons do connect to escape neurons but found no connections with reorientation neurons. Nevertheless, Hannah and her colleagues were excited to find this result. 

Hannah’s amazing work in the zebrafish underscores that it is important to examine the brain both at a large scale (i.e., behavior and decision making) as well as a small scale (i.e., individual neurons and proteins, like CaSR) in order to more fully understand how it works. Secondly, her work tells us that decisions are the result of distinct parts of the brain working together to perform a behavior. When you decide to have a salad for dinner, there is one part of your brain that controls your muscles and allows you to eat the salad. There is a different part of your brain that helps in deciding to eat the salad in the first place! In the example of the zebrafish, reorientation/escape neurons allow the fish to perform the actions, but the decision making site is elsewhere - namely, in a brain region known as DCR6. On a final note, Hannah’s research reminds us of the incredible value and insight that animal models, like the zebrafish, bring to us. They allow us to study behaviors that are very seemingly very human (like decision making) in very deliberate and precise ways!

About the brief writer: Jafar Bhatti

Jafar is a PhD Candidate in Maria Geffen’s lab. He is broadly interested in brain networks involved in auditory processing and decision-making.

Want to learn more about how these researchers study decision making in zebrafish? You can find Hannah’s paper here!