How the Brain Regulates the Body’s Immune Response

Post by Meredith McCarty

The takeaway

The brain can modulate immune responses to prepare the immune system for potential threats or even induce placebo-like effects. This research reveals the functional circuitry underlying the coordination of behavioral and immunological responses in the mouse brain. 

What's the science?

The immune system is responsible for taking protective action to protect the body against perceived external threats. The insular cortex (IC) of the brain is essential for integrating sensory information with bodily states. Prior work has implicated interactions between the insular cortex and the immune system, but the underlying functional dynamics remain unknown. 

This week in Nature Neuroscience, Kayyal and colleagues use behavioral and experimental tools in mouse models to explore the role of IC in regulating immune responses.

How did they do it?

To study the interactions between the body’s immune response and sensory information, the authors utilize a conditioned immune response (CIR) task design. In this design, experimental mice are exposed to a conditioned stimulus (a specific scent) that is paired with an unconditioned stimulus that activates or inhibits the immune system. They learn the association between the scent and the unconditioned stimulus, and the researchers can study what is going on in the brain when this CIR is learned and tested. 

To study brain activity, the researchers utilize retrograde labeling techniques to identify neurons within IC that project from anterior to posterior regions (aIC-to-pIC), or posterior to anterior regions (pIC-to-aIC). They tagged these populations to quantify the degree of connectivity, and changes in connectivity across various task conditions. 

To study changes in the synaptic properties of the neurons, they conducted electrophysiological recordings from tagged neurons to quantify changes in excitability and inhibitory currents. 

To test whether aIC-to-pIC neurons are necessary and sufficient for aspects of the measured CIR, they injected modified receptors into projecting neurons to allow them to experimentally activate or inhibit specific populations of neurons and measure changes in immune and behavioral responses.    

What did they find?

When studying the immune response and behavior after CIR, they found the experimental mice had a strong aversion to the conditioned stimulus and an elevated immune response. This suggests that CIR primes the immune system for potential infection after exposure to harmful bacteria. 

When comparing the neurons that project from aIC-to-pIC and vice versa, they found an increased percentage activation of aIC-to-pIC neurons following CIR, suggesting that these insular projections play a critical role in retrieving memory associated with the conditioned scent stimulus. When quantifying the excitatory to inhibitory ratio of projection neurons, they found reduced excitability and an increased number of active aIC-to-pIC projecting neurons, highlighting a potential mechanism by which information is flexibly retrieved during the retrieval of CIR-related memories.  

Through selectively activating and inhibiting the aIC-to-pIC and pIC-to-aIC projections, they found that inhibiting the aIC-to-pIC pathway reduced learned aversive behavior. Their findings suggest that aIC regions encode taste and its conditioned response (immune system threat) and that the aIC-to-pIC pathway is necessary for the successful retrieval of the CIR. Their results highlight the importance of the aIC-to-pIC projecting neurons in modulating the body’s immune response following exposure to a conditioned aversive sensory stimulus. 

What's the impact?

This study is the first to suggest a novel role for specific regions of the insular cortex in retrieving immune-related information and flexibly tuning behavioral responses. It was previously unknown how the functional connectivity of the insular cortex relates to the body’s immune response and how the brain and body interact to promote immune function. 

Pro Soccer Players Have Unique Cognitive Abilities and Personalities

Post by Anastasia Sares

The takeaway

This study looked at professional soccer players’ cognitive abilities and personalities, finding that they differ significantly from the general population. This shows that it takes more than physical attributes to make it at the highest levels of play.

What's the science?

Professional athletes are often praised for their physical prowess, including their stamina and strength. Yet, in sports such as soccer, there are other important abilities, like keeping track of players’ positions, knowing when and where to pass, and quickly reacting to changes on the field. Not only that but becoming a competitive player involves dedication to hours of practice, as well as confidence and a healthy mentality. Previous studies have begun to quantify these traits, showing that successful soccer players perform better on some cognitive tests than the general population. Still, these studies often have small samples of professional players, or study non-professional athletes, since it’s very hard to get access to top players.

This week in the Proceedings of the National Academy of Sciences, Leonardo Bonetti and colleagues conducted one of the largest studies to date on the cognitive and personality traits of professional soccer players, showing that these traits are distinct from the general population.

How did they do it?

The authors gathered a large group of professional soccer players (over 200) and a matched comparison group from the general population. The comparison group was matched on socio-economic status and age, which are important to consider when it comes to cognitive ability. The authors administered cognitive and personality tests to the participants so that they could compare the two groups. This sample included both men and women players, as well as players from two different countries (Brazil and Sweden), so they could ensure their results were replicated across cultures.

The cognitive tests (taken from the D-KEFS and WAIS IV) were measures of what is sometimes called “fluid intelligence”—cognitive abilities that are less dependent on education. For example, digit span, a simple test of working memory, involves the participant hearing a string of numbers and then reporting back as many as they can remember. Another example is the 5-point test, which evaluates a skill called nonverbal fluency, where participants had to generate as many ways as possible to connect a set of 5 dots in a limited amount of time. A third example is the Tower of Hanoi, where participants must move a series of stacked objects to get from one configuration to another in as few moves as possible. The personality measure used in the study was the Big Five, a science-backed personality system consisting of five traits: Openness, Conscientiousness, Extraversion, Agreeableness, and Neuroticism (often known by the acronym OCEAN or CANOE).

What did they find?

The soccer players performed better than the general population on the cognitive tests: this superior performance included planning, problem-solving, and memory capacities. In the working memory test, the soccer players remembered 6 digits on average, whereas the control group could only remember just above 4 on average. The soccer players also showed higher levels of the personality traits Conscientiousness, Extraversion, and Openness to experience, along with lower levels of Neuroticism and Agreeableness.

The number of goals scored by a player was related to a high score on the 5-point test (nonverbal fluency), high Openness to experience, and low Conscientiousness. On the other hand, attempted and successful dribbles were predicted by a high digit span (working memory), a high Tower of Hanoi score (visuospatial reasoning), and high Openness to experience.

What's the impact?

This study shows that professional soccer players outperform the general population cognitively, not just physically, and that they have a specific pattern of personality traits. The authors think this could be helpful for recruiters looking for the next generation of stars. But it is unclear how these traits come about—are they the result of high-level training, or are they present before any training has begun?

An Atlas of Microglia in Neurodegenerative Disease

Post by Laura Maile

The takeaway

Microglia, the immune cells of the brain, play important roles in both brain homeostasis and disease. Several human datasets have now been compiled to create a human microglia atlas that characterizes microglia across multiple neurodegenerative diseases.

What's the science?

Microglia, the brain's resident immune cells, help maintain homeostasis and normal function of the CNS environment, including modulating synaptic connections between neurons. In cases of injury or infection, microglia convert to an activated state, where they take on an amoeboid shape and work to return the brain to homeostasis. In neurological disease, however, they can become abnormally activated and contribute to disease. Historically, activated microglia were divided into two categories: M1, a pro-inflammatory type, and M2, a neuroprotective type. Since this initial categorization, gene expression analysis led to a distinct class designated “disease-associated microglia” (DAM). DAM gene expression patterns, or signatures, have been commonly used to identify activated microglia in tissue responding to injury or other pathologies. Though the evolution of this field has proposed that these categories are too simplified to describe the range of microglia observed in disease, a comprehensive classification of microglia across different disease states has not yet been achieved. This week in Nature Communications, Martins-Ferreira and colleagues used 19 human datasets to create an atlas describing nine subpopulations of microglia in neurodegenerative disease.

How did they do it?

The authors integrated data from 19 single-cell RNA sequencing datasets from human brain tissue from patients with a variety of neurodegenerative disorders, including autism spectrum disorder (ASD), Alzheimer’s Disease, multiple sclerosis, epilepsy, Lewy Body Disease, and severe COVID-19. The integrated Human Microglia Atlas (HuMicA) accounts for 90,716 cells from 241 patient samples. They completed a cluster analysis to identify natural groupings of the sorted cells based on their gene expression and nine subpopulations were identified. The authors calculated the upregulated gene markers for each subpopulation and compared these markers with other available gene datasets that describe patterns of transcriptomic signatures in microglia populations. They identified specific patterns in each subpopulation and compared the prevalence of each subpopulation across each pathology to understand how microglial changes are associated with specific neurodegenerative diseases. Finally, the authors used the HuMicA to analyze differentially expressed genes (DEGs) in disease and healthy populations, allowing them to detect specific patterns of gene expression associated with individual pathologies.

What did they find?

They identified three homeostatic clusters, representing relatively healthy, inactivated microglia. They noted these clusters shared patterns of upregulated genes that normally identify homeostatic microglia, though each cluster also had its own signature of upregulated genes.

The DAM signature was broken down into four subpopulations, each with its own transcriptional patterns, including pro-inflammatory pathways, phagocytosis, lipid metabolism, or leukocyte activation  In addition, a group of monocyte-derived microglia-like cells previously described in mice are shown here to be prevalent in human brain as well, showed increases in gene expression cytokine production. Though all the clusters were observed across all analyzed human samples and disease profiles, they discovered patterns of expansion or depletion of specific clusters associated with individual neurodegenerative disorders. For example, they found expansion of a subpopulation expressing genes involved in lipid metabolism in AD and MS. After analyzing DEGs, the authors found some general pathology-related patterns of gene expression that were shared across diseases and others that were more specific to an individual disease or group of diseases. 

What's the impact?

This study was the first to create a comprehensive human microglia atlas, which identified subpopulations of microglia associated with neurodegenerative disorders. With this atlas, the authors demonstrated that microglia are complex and exist in many different states in the diseased brain. This data will advance our understanding of microglia in neurodegenerative diseases, and provide a useful tool in the study of microglia and disease.