Summary: From researching the microbiome and immune system to nociception, scientists are looking beyond the nervous system to gain a better understanding of neurological and mental health disorders.
It turns out that understanding the brain, with its hundreds of billions of cells and trillions of circuit connections, also requires looking at the heart, and following the winding path of the intestine. In fact, as Picower Institute research is helping to show, neuroscience not only has to go beyond the nervous system, but also to cells that aren’t even part of the same organism that the nervous system belongs to. The colonies of bacteria that we host — our “microbiome” — appear to exert a mysterious and multifaceted influence on our mental function and health.
In other words, the rest of the body has a lot to teach us about the brain and a important influence over our mental health. That’s why three Picower Institute professors – Emery N. Brown, Gloria Choi and Steve Flavell – are looking below the neck to get a better view inside the head.
Going with the gut
Flavell is investigating communication between the brain and body using the nematode worm C. elegans. But what he has found in that simple creature’s alimentary canal may help explain a great deal about how our mood changes with our sense of satiety, and one of the main ways that the bacterial microbiome communicates with the brain.
In a paper in Cell earlier this year, Flavell’s lab discovered the function of two genes – also expressed in the intestines of humans – at the nexus of how the worm senses that it has happened up on a yummy lunch of bacteria and should slow its movement to slurp up the meal. The finding represents a significant leap in connecting bacterial sensing in the gut with behavior, providing clues about how the gut and brain might communicate in people, too.
In 2013 Flavell had identified an important role in behavioral regulation for a C. elegans neuron named “NSM,” which extends dendrites into the alimentary canal. He showed that when a worm is eating, the neuron emits the neurotransmitter serotonin to signal to other neurons. In the new paper, he showed that this all depends on the neuron deploying two acid sensing ion channels (ASICs) called DEL-3 and DEL-7, encoded by those newly characterized genes. These ASICs appear to be critical for NSM’s detection of bacteria in the alimentary canal. There is still much more he wants to learn, including exactly what chemicals the bacteria emit to trigger the neuron, whether there are other DELs that sense other bacterial substances, and whether other neurons express as yet uncharacterized channels, too. Moreover, there is still plenty to know about how neurotransmitters emanating from the gut, like serotonin, influence the brain to affect behavior, in both the worm and in people.
The answers have wide-ranging implications. Earlier this year, a broad epidemiological study found widespread, specific associations between differences in gut microbiome bacterial populations and the likelihood that individuals suffer from mental health concerns such as autism and depression.
“There appear to be specific types of gut bacteria that are overrepresented and underrepresented in humans that suffer from these disorders,” Flavell said. “These types of data make the case that there is at least a correlation between the bacteria that live in our gut and our complex behaviors.”
Flavell’s work could help explain exactly how those associations arise.
Choi is also minding the mechanisms linking the microbiome to the brain, but in a different way. Her research investigates the surprising proposition that the immune system directly impacts on the nervous system. Immune system cells communicate by secreting proteins called cytokines. These, she has found, can also affect neurons in the brain.
It makes sense that this could be the case. Immune system cells are sentinels of health. Perhaps the immune system is an efficient messenger for the brain about aspects of the body’s status.
Suggestive links are everywhere. Our mood and behavior change when we are sick, and there are often mood-related side effects to medications that affect the immune system. Like Flavell, Choi is on the forefront of showing detailed, tangible cause-and-effect evidence, which the field has rightly demanded.
“The primary goal of my research program is to elucidate the mechanisms through which the immune system modulates neural circuit function, ultimately shaping animal behavior,” Choi said.
She did exactly that in three papers linking infection in pregnant mice with neurodevelopmental symptoms in their offspring. In a 2016 paper in Science, she and collaborators showed that a particular type of immune cell and its secretion of the cytokine interleukin-17a (IL-17a), mediated the mother mouse’s immune system activation and the development of autism-like behavioral abnormalities in offspring. The next year, the collaboration followed with a tandem of papers in Nature. One showed the phenomenon was further mediated by the presence of maternal intestinal bacteria that promote differentiation of the implicated immune cells. The other showed that the effect of IL-17a in the brain was focused in the S1DZ region of the cortex where they observed dysregulated neural activity. The team showed that by intervening to reduce excess neural activity, they could mitigate behavioral abnormalities associated with maternal infection.
Choi continues to study instances of immune system influence on the nervous system and modulation of this interaction by constituents of the gut microbiome. Understanding fundamentals of this tripartite relationship, she said, might lead to ways to prevent or mitigate mental health problems possibly by means involving the immune system or the gut microbiome. To her the potential contributions she can make to fundamental science and the ability to inform treatment of disease are each intensely motivating.
It might seem intuitive that Brown studies heart rate and blood pressure. He is, after all, not only an MIT neuroscientist, but also a Massachusetts General Hospital anesthesiologist, and for decades anesthesiologists have used such apparently non-neural bellwethers to assess consciousness in patients. But that’s where the surprise comes in. Brown is actually changing the way anesthesia is administered by investigating the connection of those responses back to the brain.
Brown studies the circuits that sense damage to the body, or “nociception,” and relay that information to the brain. When you are conscious, the body’s nociception system’s warnings are experienced as pain, but even when you are unconscious it is still working. Via one particular circuit, the brain then directs the “sympathetic” responses detected in the circulatory system and the skin. Brown calls that circuit the medullary nociceptive autonomic circuit.
“This should be anesthesiology 101,” Brown said. “This is the sacred circuit.”
Brown is interested in nociception because his research shows that it should be the central focus of dosing and administering anesthetic drugs. Managing nociception means properly suppressing pain. His careful study of the diversity of circuits involved in processing nociception has led to the crucial insight, published last year in Anesthesia and Analgesia, that by targeting them with low doses of different antinociceptive drugs – a custom cocktail he conceives for each patient – he can provide better nociception and pain management, limiting the use of opioids. Meanwhile, because many of these drugs also reduce consciousness, he can radically scale back the amount of drug needed for that. Patients wake up more quickly and less groggy, a significant benefit for old and young patients who are subject to post-operative delirium.
On day in May, still in the operating room right after a bladder surgery at MGH, a patient woke up and said, “We’re good,” Brown said. His rapid return to lucidity was the product of using much less drug for unconsciousness.
“Up until three years ago, this wasn’t how I practiced, but we’ve come to a deeper appreciation of nociception,” he said.
In the OR, Brown carefully monitors consciousness in the brain by reading out EEGs (another innovative practice), and he also still uses those traditional methods of reading out heart rate and blood pressure. By studying the medullary nociceptive autonomic circuit he’s also hoping to have a refined method for monitoring nociception. There is currently no model for doing so.
To change that, graduate student Sandya Subramanian is dedicating her thesis research to studying the circuit and measuring these circulatory systems and other responses during surgery, and in normal awake and low-stress states as a baseline. Deriving an objective biomarker of nociceptive response will help refine anesthesia dosing strategy even further.
Ultimately, anesthesia acts on the brain, but understanding that fully requires looking to the body. Like Flavell and Choi, Brown is studying the brain by looking beyond it.
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