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!

Does the size of your social network predict how big certain parts of your brain are?

Camille was the lead author on this study. She is a 5th year graduate student at the University of Pennsylvania with Dr. Michael Platt. She wants to understand the evolution and neurobiological mechanisms of social relationships in primates using approaches from behavioral ecology of primates in the wild to single cell electrophysiology in the lab!

or technically,

Social Connections predict brain structure in a multidimensional free-ranging primate society

[See original abstract on PubMed]

Authors of the study: Camille Testard, Lauren J. N. Brent, Jesper Andersson, Kenneth L. Chiou, Josue E. Negron-Del Valle, Alex R. DeCasien, Arianna Acevedo-Ithier, Michala K. Stock, Susan C. Antón, Olga Gonzalez, Christopher S. Walker, Sean Foxley, Nicole R. Compo, Samuel Bauman, Angelina V. Ruiz-Lambides, Melween I. Martinez, J. H. Pate Skene, Julie E. Horvath, Cayo Biobank Research Unit, James P. Higham, Karla L. Miller, Noah Snyder-Mackler, Michael J. Montague, Michael L. Platt, Jérôme Sallet

When I think of neuroscience, I think of scientists in white lab coats examining brains under a microscope. While it’s true that neuroscience these days typically takes place in a laboratory environment, some would argue that this isn’t the best way to study the brain. If we want to study how the brain works naturally, why would we study it in an artificial environment, such as a lab?

While of course there are some topics that are better suited to be studied in labs like how individual neurons in the brain function and work together, topics like social behavior, which is what Camille and her colleagues were interested in, may benefit from more naturalistic experimental conditions. In particular, Camille and her colleagues wanted to know how the size of an individual’s social network can affect their brain structure and function. To do this they studied the behavior and brains of rhesus macaque monkeys living in a semi-free range colony on Cayo Santiago Island in Puerto Rico. 

In their paper, the researchers examined the behavior of a single social group composed of 103 individual monkeys of which 39 were male and 64 were female. For each monkey in the colony, the researchers looked at two measures of social behavior. The first measure was the monkey’s social network, which was based on the number of grooming interactions a given monkey had with other monkeys. The more grooming partners a monkey had, the larger its network was. The second measure they looked at was the monkey’s social status, which was based on aggressive interactions given and received that a given monkey encountered with others (threats, chases, submissions, etc.). 

Camille and her team observed each monkey’s behavior for 3 months prior to  measuring their brain structure using a technique known as MRI, or magnetic resonance imaging. With this technique, they were able to determine the size of different brain areas in each monkey. Then, they wanted to see if there was a relationship between a given monkey’s social behavior and any part of the monkey’s brain. 

Interestingly, the researchers found that there was a positive correlation between the social network size (i.e, number of grooming partners) of a monkey and the size of two specific brain regions (see Figure 1). The first brain region is called the mid superior temporal sulcus (mid-STS, for short). In previous studies, the mid-STS has been found to be involved in responding to social scenes. This region is also thought to be involved in deciding whether to cooperate versus compete with a partner. The second brain region is called the ventral dysgranular insula (vd-insula, for short). In previous studies, this region has been found to be involved in grooming behavior in macaques and empathy in humans!

Because social interactions between monkeys are multi-faceted, just as in humans, Camille also looked at several other nuances of the monkeys’ social network to see if they predicted the size of these brain regions. For example, they looked at “betweenness” (was a given monkey able to bridge connections between distant members of the colony?) and “closeness” (how close was a given monkey to every other monkey in the colony?). These other measures did not correlate with any brain region in these monkeys. Because of this, the researchers took a closer look at social network size, which did show a correlation with brain size. Since this measure was determined by grooming interactions, they were curious if the direction of the grooming mattered: whether the monkey actively groomed other individuals or was being groomed. When they looked at the data this way, they found that how many individuals in the colony that groomed a given monkey more closely predicted its brain size. 

Finally, the researchers wondered if the relationship that they found between social network size and brain size in adult monkeys was also true for infant monkeys. These monkeys are too young to form complex social networks so the researchers instead used the social network of the mothers of these infants. They reasoned that they might still see a relationship because previous studies showed that an infant macaque’s social network mimick the social network of his/her mother. However they found no clear relationship between a mother’s social network and her infant’s brain size. The authors suggested that the infants were perhaps too young for their brains to have fully developed and any size differences to be observable. These results led the researchers to believe that the brain-size differences that they see in adult macaques are due to the increased sociability that occurs during development. 

In summary, Camille’s research offers incredible insight into how the size of specific brain regions is related to the ability of mammals to form large social networks in their natural environment. Her team determined the social network size of each monkey in the colony and found a significant correlation with two socialization-related brain regions, the mid-STS and the vd-Insula. Furthermore, this relationship could not be found in infant monkeys, leading them to believe that increased sociability during development leads to the observed differences in brain structure seen in adult monkeys. Camille’s work is important because her discoveries in wild, free-ranging monkeys emphasize that complex social forces, for instance in human societies, can powerfully drive the physical expansion of socially related areas in the brain.

About the brief writer: Jafar Bhatti

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

Want to learn more about how these researchers study the social behavior and brains of free ranging monkeys? You can find Camille’s full paper here!