Dogs who hear a bell every day at chowtime become classically trained to drool at its mere sound, as Ivan Pavlov, a physiologist in the 1890s demonstrated: Their brains associate the bell with food and instruct their salivary glands accordingly.
Asya Rolls, a neuroimmunologist, has demonstrated that similar conditioning can be extended to immune responses more than 100 years later in a paper published in Cell today. Her team at Technion, Haifa, Israel used state-of the-art genetic tools to identify brain neurons that were activated by experimentally inducing inflammation in the abdomen. The researchers later discovered that the same type of inflammation could be triggered by restimulating these neurons.
Kevin Tracey (a neurosurgeon who is also president of the Feinstein Institutes for Medical Research, Manhasset, New York) said that "this is an outstanding body work." He said it "establishes the classic concept of immune memory can be represented by neurons." While others have suggested that the brain could retrieve and remember immune responses, Tracey stated that she proved it.
Ruslan Medzhitov is an immunologist at Yale School of Medicine in New Haven. He considers this new research "very provocative." However, unlike other groundbreaking studies that challenge established concepts and push boundaries, he says that this one also elicits the "Oh, it makes sense" type of reaction.
Research over decades and daily experience have provided striking examples of how mind and body interact. John Mackenzie, an American physician, observed Pavlov's experiments with drooling dogs. One of his patients developed an itchy throat and difficulty breathing after seeing artificial roses. This indicated that her body was sensitized to pollen. Scientists discovered similar symptoms while performing taste-aversion experiments with rats in the 1970s. They gave the animals both an immunosuppressive drug and the artificial sweetener saccharin repeatedly until they were able to quell their immune activity using saccharin alone. Many of us recall instances when the smell of food could cause nausea again.
However, the mechanism behind these psychosomatic reactions is still a mystery. Rolls stated that such experiences "cannot possibly be guided by immunological memories as we know them." She said that it appears that immune responses begin in the brain. These thoughts can initiate physiological processes.
Rolls' lab began to understand how emotions and thoughts could impact physical health in recent years. She and her coworkers discovered that stimulating neurons in the brain's pleasure centres in mice disengaged a subset immune cells that suppress the body’s defenses. Tumor growth was slowed in these animals. Her team discovered that activating certain nerves in the colon blocked immune cells from entering tissue, in a study published in May. This could be used to control local inflammation.
Rolls couldn’t believe that these neurons controlled immune activity with such precision that the brain could control an entire system without knowing its state. She said, "So we wanted the brain to represent the state of our immune system."
Her research focused on the insular cortex, which is a deep-seated structure of the brain that processes emotions, pain and body's inner sensations. Rolls stated that it would make perfect sense for the immune system to be part of interoceptive data.
Researchers added a chemical to the water of laboratory mice to induce colitis for a week. The chemical caused damage to the colon's inner lining and activated immune cells. This led to a dangerous spiral of inflammation. Rolls and her colleagues were able to use a genetic modification in mice to enable them to fluorescently label neurons that were active at the peak of inflammation, which lit up the cells in the insulation. The team then applied a second genetic tool: they placed a molecular switch on the activated cells of the insula.
Rolls, her coworkers and she waited. After the colitis had subsided, and the mice were fully recovered, Rolls and her co-workers waited. The researchers then used their on/off switch in order to reactivate neurons. This triggered an identical inflammatory response within the colon. Similar results were observed in mice infected with peritonitis in the abdominal lining.
Rolls stated that the immune responses to neural stimulation were "reminiscent of the original" condition. Rolls said that the similarities reached the molecular level. In mice with induced peritanism, white blood cells containing a particular receptor protein increased in abundance in the abdominal lining of mice during both the initial inflammation and the subsequent inflammation.
Researchers also found the opposite effect. Animals' symptoms didn't get as severe when they were unable to activate the first set of neurons. This suggests that the brain could be determining its severity even when chemically inducing inflammation is occurring.
Rolls stated that nerve-mapping experiments revealed that the insula neurones that triggered during inflammation actually "have a way of delivering a message all through the colon."
Tracey believes that the new research proves "you can't distinguish the state of neuron activity and the state of immune system activity." It's a two-way street.
Tracey and his coworkers made a breakthrough in this area when they discovered that the brain could send anti-inflammatory messages to other parts of our bodies through the vagus nerve. Bioelectronic devices have been developed to combat inflammation in rheumatoid and pulmonary hypertension, as well as other diseases.
Medzhitov explained that the insula neuron in Rolls' mechanism senses inflammation and can activate it. This is different from the vagal nerve system. Tracey sees it as a brake line for a car. He said that Rolls' study showed "there is a driving force." "There's someone who decides whether the gas pedal should be pressed or the brake."
Rolls and her coworkers noted in their paper that they are unable to say if the "memory of inflammation" in the insula neuron is a description of the immune response or if it is a record the sensations of inflamed tissues. In other words, it is a memory of what it was like to feel sick from inflammation. It is possible that other brain parts could also be involved in the memory of the immune response. Medzhitov said that the study shows that this information is encoded, even though it might not be conscious.
This research could have profound implications. Medzhitov described an anatomical pathway linking "your emotional state all of the way to the inflammation within the colon," and said that "that is probably the most effective demonstration available for psychosomatic controls."
These new findings also challenge the traditional top-down view on the brain. Tracey stated that most people believe they are so smart that they decide what to do and then make their body do it. "But that's not the way the nervous system works." Instead the brain processes information from the body, such as a fever or infection, and then delivers a response.
Tracey said that Rolls' research shows that the brain and immune system are inseparable. "I believe both neuroscientists and immunologists will be thrilled and surprised," said Tracey.
