The Biology of Decision-Making and Behaviors

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Have you ever wondered why, on a hot summer day, you would find yourself reaching for a cool glass of freshly-squeezed orange juice rather than a mug of piping hot chocolate? Is it the weather? Is it the nostalgia of that one particular drink from your childhood? Were you influenced by your friend’s drink of choice? Several factors could have influenced your decision-making processes, including environmental stimuli, the body’s innate survival responses, learned behaviors from prior experience, and the social patterns you observe on a daily basis. At UC San Diego, the laboratories of Sreekanth Chalasani and Matthew LovettBarron seek to better understand what drives decision-making processes, and how various factors influence behaviors.

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Food Foragers At Work

At the Chalasani Lab, researchers Jessica Haley and Irene Chen study prey nematode species Caenorhabditis elegans, or roundworms, to understand how organisms pursue food and make survival-related decisions. To observe foraging strategies and mimic environments with varying degrees of food availability, the researchers place groups of C. elegans on separate plates with varying amounts of food. The worms are then left to acclimate to the specific food concentrations for a three hour training period. After this training interval, the C. elegans are transferred to a plate with lower food concentration — a “patchy” environment. Then, the researchers recorded the nematodes’ search pattern as they explored a new environment with less accessibility to food, in comparison to the training plate. According to their observations, C. elegans initially exposed to high food availability during the first training period searched a wider area of the foodless environment, while those with low food availability searched a smaller area. What is going on inside a worm’s nervous system that caused these results? The lab found that the C. elegans’ decision to explore farther for more food rather than settle for the most accessible patch is determined by dopamine, the neurotransmitter responsible for motivation. The dependence of foraging behavior on dopamine signifies that C. elegans internalize their observed patterns of food accessibility which triggers the release of dopamine in new environments and, in turn, influences their search behaviors.

While dopamine drives reward-based decision-making in C. elegans another neurotransmitter may be involved in decisions surrounding survival instinct in more predatory species: octopamine. Pristionchus pacificus a predatory nematode, competes with the C. elegans for bacterial food, following a slightly different decision-making process. To model the strategic value of predation for the P. pacificus nematode, the Chalasani Lab used previously established neuroeconomics and foraging theory. The theory dictates that predatory foraging strategies involve exploration and an offensive strategy with the motivation being food as a reward, whereas territorial foraging strategies involve a more defensive approach. For example, the P. pacificus nematode is motivated by predation when it bites larval C. elegans However, biting an adult C. elegans, which are more difficult to kill, is considered a territorial defense of bacterial food. This difference in motivational approach is mediated by the previously mentioned octopamine (invertebrate version of norepinephrine) acting as both a hormone and neurotransmitter. The multifaceted messenger plays the key role of increasing and maintaining blood pressure and is released when the body enters a “fight-or-flight” response. Therefore, octopamine is significant in guiding the nematodes’ switches between predatory behaviors with prey and territorial behaviors in defense of bacterial food.

Social Influencers In The Wild

The Lovett-Barron Lab examines decision-making from another approach: by focusing on how sharing information through social interaction impacts behavior. To study these connections, the undergraduate researchers, John Jefferson and Shefali Gupta, worked with postdoctoral fellow Lisanne Schulze to monitor changes in brain activity from states of passiveness to alertness, hunger, and stress, using Danionella translucida, or glassfish. Glassfish are ideal subjects for this study because they exhibit social behaviors such as moving in groups, or schools, and are mostly adaptive due to visual cues. Conversely, in humans or mice, the process of sensation and behavioral modification is complicated by additional abilities of touch and smell. To analyze the neural activity of D. translucida the Lovett-Baron Lab utilizes two-photon calcium imaging to record brain activity while the transparent fish experience the illusion of moving and schooling from a virtual reality simulation. In two-photon imaging, a green fluorescent protein extracted from jellyfish is engineered to glow brighter in the presence of calcium, and thus indicate which areas of the glassfish brain are most active in reaction to stimuli. Because neurons are activated by calcium flooding the cell during action potential, the glassfish injected with the green fluorescent protein exhibit the artificial green glow when their neurons are active. By analyzing the GCaMP (a genetically encoded calcium indicator) signals through microscopic imaging, the lab maps out which areas are most active during each glassfish interaction. This information is then used to identify what genes are expressed for each behavior exhibited; live-brain volumes with activity information are compared with fixed brain-volumes using patternmatching algorithms. Because the goal of this lab is to understand how animals make decisions as a cohesive group, this method of gene comparison with simpler organisms is useful to identify how social interactions and visual decision making evolved. Through these experimental methods, the Lovett-Baron Lab monitors the neural activity of individual glassfish after exposure to certain visual cues in order to find recurrently expressed genes. The goal is to ultimately determine possible links between these

.common genes and observed behaviors, such as escaping and eating, carried out by the other glassfish. The lab hopes to find how groups of animals become more social through development, as well as determine how groups of animals are able to escape from predators and hunt prey in a more effective way than individuals alone. Through the experiments conducted thus far, they found that no glassfish took the initiative of engaging in more risky behaviors or venturing out further than the others. Instead, they found that no fish ranks above the others, with the group moving as a cohesive whole and changing direction in direct response to one another. This process is analogous to the broader patterns found in highway traffic: no individual car causes the traffic, yet the interactions between each car impedes overall movement.

SEARCHING, SOCIALIZING, SUMMARIZING

The research conducted by these two labs suggests that decision-making behavior is impacted by a variety of factors, including environmental conditions, learned survival patterns, and social visual cues. Environmental inputs and visual cues are some of the sole influences on decision-making behavior of these nematodes and glassfish. Humans, while subject to the same influences, also have other senses such as sound and smell that complicate decision-making. While more research needs to be done to fully understand complex decision-making, it remains clear that our surroundings directly influence our decisions. So the next time you reach for the orange juice over the hot chocolate, consider reflecting on how your decision was influenced by the environment around you.

Imagine passing through security at an airport — how does security prevent unauthorized passengers or prohibited objects onto the flight? Officers check boarding passes at multiple points, metal detectors screen each person before entry, and upon arrival, customs screens for unwanted goods again. In other words, a multi-tiered security system creates a nearly impenetrable barrier against potential threats. Our body has a similar network of defensive measures: the immune system. One tier of this system consists of T cells, which are cells that screen potentially dangerous entities like viruses or bacteria. But what happens when the body’s security systems make a mistake and detect threats where none are present?

This results in a phenomenon known as autoimmunity (or selfimmunity), where T cells attack the wrong target: our own tissue. However, there is no reason to worry just yet as our body has a second tier of defense. This includes regulatory T cells (Treg cells) that distinguish and filter out malfunctioning T cells from properly functioning ones. By dampening the attacking instincts of T cells, Treg cells prevent an ‘overreaction.’ Unfortunately, this secondary procedure can fail, causing rogue T cells to fall through the cracks.

For the 24 million U.S. citizens affected by autoimmune conditions, this prolonged internal assault has significant health impacts. One of the most common conditions resulting from this is Rheumatoid Arthritis (RA). Treg cells play a particularly essential role in regulating RA, since they control how hyperactive, or T cell-intensive, the body’s response is. This can either be pro-inflammatory (hyperactive) or anti-inflammatory (“nonhyperactive”). In RA, defective Treg cells skew the response towards hyperactivity. As a result, the action of rogue T cells leads to inflammation, causing stiffness, discomfort, pain, and even loss of joint function.

What can be done to remedy the situation? Preventative measures have failed, so it is important to brainstorm ways to minimize harm. This is what drives researchers in the Zheng Lab, at the Salk Institute for Biological Studies, and the Ay Lab, at the La Jolla Institute for Immunology, as they look to pinpoint specific genes and molecules that contribute to the stability of Treg cells. By essential damage control process.

Locating The Source

The first step towards a solution is identifying the cause. The Zheng Lab research focuses on the which is critical for the development and function of Treg cells. The FOXP3 gene appears to act as an “on-off” switch, deciding when T cells or Treg cells are deployed. This introduces fascinating possibilities, as wielding power over this “master remote” would provide unprecedented control over the body’s immune response. The Zheng Lab previously demonstrated the link between FOXP3 and Treg cells. When PhD researcher Tianyun Hua removed FOXP3 from mice Treg cells using gene therapy, they observed a more hyperactive immune response in these mice. This suggested that removing FOXP3 leads to fewer or dysfunctional Treg cells, which established FOXP3’s the optimal Treg cell potency. Furthermore, the study explained how FOXP3 maintains balance within the body’s immune system by encoding proteins that determine when, where, and how many Treg cells are present at a given time.

In order to determine the actual transcription factors or coding regions associated with FOXP3 performed a genome-wide analysis in Treg into mouse

T cells, the lab individually knocked out, or removed, parts of the genome to observe the functional changes in the immune system. They discovered that the absence of a specific proteincoding section called the “ncBAF complex” reduced Treg cell activity, making the ncBAF complex a

With this information, researchers can better treat the Treg cell imbalance in RA. With a precise target to manipulate, researchers will be able to increase Treg cell functionality, which might lead to novel treatments against this widespread autoimmune disease. Overall, by identifying the source of the problem, the Zheng Lab lays the foundation for future research that works and led to increased severity of RA symptoms in the affected mice. Mice without the gene for PTPN2 died earlier than those containing the gene, indicating that loss of function of PTPN2 in Treg cells enhances autoimmunity by causing the FOXP3 proteins to become less stable.

While the Zheng Lab studies the regulation gene, the Ay laboratory at the La Jolla Institute for Immunology focuses on the molecular FOXP3.

The Ay Lab studies the expression of proteins that contribute to the stability of Treg cells. Specifically, PhD researcher Joaquin Reyna studies PTPN2, an enzyme that resides inside of cells and contributes , therefore maintaining

To test the role of PTPN2 in Treg stability, gene in mice and treated them with compounds that induce autoimmunity, which led to destabilization of the PTPN2 protein. This significantly reduced the expression of the PTPN2 enzyme

What would happen if the mice had a non-autoimmune form of arthritis? To test this, researchers in the Ay Lab transferred human serum that lacked PTPN2 into mice with non-autoimmune arthritis, also known as osteoarthritis, which is caused by the mechanical wearing down of joint cartilage. The researchers found that the lack of PTPN2 in mice with a non-autoimmune disease did not change the disease progression! However, when they transferred this PTPN2-negative serum to mice with autoimmune arthritis, they observed a rise of pro-inflammatory T cells that caused a significant increase in the disease progression. Based on these experiments, Reyna and their team established an association between the loss of the PTPN2 intracellular enzyme and increased progression of rheumatoid arthritis. This research propels future research to focus on how PTPN2 is regulated, and how it functions in autoimmune vs. nonautoimmune forms of arthritis.

STEP 3: IMPLEMENTING THE SOLUTION

Studying autoimmune diseases like Rheumatoid Arthritis presents dozens of intricate views on how the body’s vital defenses can malfunction and cause collateral damage, creating a multitude of questions researchers still have yet to answer. However, the incredible work done in the Ay and Zheng Labs have provided hope for patients in the future. While researchers like Hua and Reyna have identified and extensively studied specific mechanisms involved in autoimmune processes, understanding the role of Treg cells in the immune system is only the first essential step towards developing autoimmune therapies that target these specific genes and pathways. For the countless people across the globe who suffer from autoimmune conditions, continued research and progress towards future treatment options hopes to improve the function and balance of the body’s personal security system.