People have long believed that the placebo effect, in which a doctor gives a patient an inert pill instead of a drug, not only makes him feel better but also affects the immune system. However, the underlying mechanisms are unknown.
Now, Israeli scientists have identified the neuronal circuit in the brain that regulates learned immune response. In addition, a nocebo – said to occur when a patient’s treatment expectations cause it to have a worse effect than it otherwise would have – is also a genuine factor.
The team wondered whether the brain and the immune system share information to improve a person’s health. The connection between the body and the brain has preoccupied scientists and philosophers for thousands of years. Now, they have identified a neural circuit that makes it possible for the brain to regulate the activity of the immune system through learning processes similar to associative learning.
The team wondered whether the brain and the immune system share information to improve a person’s health. The connection between the body and the brain has preoccupied scientists and philosophers for thousands of years. Now, they have identified a neural circuit that makes it possible for the brain to regulate the activity of the immune system through learning processes similar to associative learning.
The innovative study was led by Dr. Haneen Kayyal, Federica Cruciani, and Dr. Sailendrakumar Kolatt Chandran, in collaboration with Prof. Amiram Ariel of the University of Haifa and Prof. Asya Rolls from the Technion-Israel Institute of Technology in Haifa.
It has just been published in the prestigious journal Nature Neuroscience under the title “Retrieval of conditioned immune response in male mice is mediated by an anterior-posterior insula circuit.”
The research was conducted at the University of Haifa’s Laboratory for Research of Molecular and Cellular Mechanisms Underlying Learning and Memory, which is led by Prof. Kobi Rosenblum. The findings show that the brain and the immune system collaborate to prepare for future challenges and reveal how the body “learns” to activate the immune system based solely on sensory information and brain activity.
What does the process involve?
This process involves the “representation” of the immune system in the brain and the integration of this information with sensory inputs such as taste. “We knew that the immune system can sense cells in the body that are behaving abnormally or detect bacteria or viruses that have invaded the body,” Rosenblum noted.
“It can also learn and act decisively and rapidly against invaders it has encountered in the past. Until now, however, researchers believed that the immune system couldn’t connect the information it holds with sensory information stored in the brain – a capability that would provide any animal with a significant evolutionary advantage.”
Through the senses, the brain constantly samples the environment, so the team wanted to know whether the brain and the immune system can share information to improve a person’s health. If so, where does the encounter take place between the memories stored in the brain and the immune system?
The researchers stressed three key existing findings. The first, from a study conducted 70 years ago, showed that it’s possible to create a connection between a particular taste and the activation or suppression of the immune system.
Following this associative learning – similar to other forms of learning – when a person or animal is exposed to the same taste weeks or months later, the immune response mirrors the response of the initial learning even though no direct factor is acting on it.
This phenomenon, known as the conditioned immune response, is considered a primitive explanation for the placebo effect, where an ostensibly inert and inactive substance improves a person’s health condition.
The impact of the brain and learning processes on our health is tied to the broader body-brain connection. The researchers identified a protocol in which a single pairing of a new taste (saccharin) with the injection of a substance derived from the bacterial capsule (LPS, which the immune system recognized as bacteria and mounted a response against) causes a similar immune reaction even days later.
This occurs solely because the mice in the experiment had previously consumed the saccharin.
TO UNDERSTAND how and where in the brain the learning for this conditioned immune response occurs, the researchers relied on previous lab studies. These studies proved that the coding and evaluation of new tastes – whether they are perceived as pleasant, novel, or causing a dislike or disinclination – take place in the inner section of the brain’s cortex known as the insula.
Another study revealed that coding for representing an immune response takes place in the rear section of the insula. Based on these findings, the researchers suggested that the coding or cerebral representation of the conditioned immune response would involve a connection between the front and rear sections of the insula.
To test this hypothesis, the researchers first replicated the conditioned immune response in mice. They showed that a single pairing of consuming a novel taste (saccharin) with an injection of LPS into the abdominal cavity caused the mice to develop an aversion to the taste (retrieval of the memory of altered taste evaluation).
In addition, the presentation of the same taste after learning triggered the retrieval of memory of the immune response.
The researchers next showed that there is a clear neural connection between the peripheral nervous system in the insula (including both the rear and front sections), making possible the passage of information.
To find out whether there is a correlation between the activity of the neural cells that transmit information between the front and rear of the insula (two-way communication), the researchers examined whether these connecting cells were activated following retrieval of the conditioned immune response and whether their electrical properties changed.
They found that there was no change in the majority of nerve cells in the front and rear sections of the insula following the retrieval of the memory of immune conditioning, but clear activation was observed in a specific group of cells that connects the front and rear sections.
The researchers pointed out that this group of connecting cells represents a small and specialized subset of the total nerve cells in the insula. They suppressed the two-way pathways of these nerve cells during the retrieval of the conditioned immune response and found that disrupting these pathways significantly impacted its retrieval.
Thus, it became clear that these neural pathways play an essential role in transmitting information between the brain and the immune system – a key example of functional body-brain communication. The researchers emphasized that this is the first time that science has identified the specific nerve cells and pathways in mammals that make it possible to integrate sensory information with information from the immune system.
This basic understanding opens the possibilities for treating a variety of diseases that arise from problems in the immune system’s ability to respond to threats, leading to either overactive or insufficient responses, as well as autoimmune diseases such as diabetes or irritable bowel syndrome in which the immune system attacks the body.
This study, which has aroused much interest among scientists worldwide, suggests new therapeutic directions in which the regulation of behavior, brain activity, and immune system function are coordinated to optimize disease treatment.