Summary: Study reveals how the insular cortex helps assess and predict physiological states of the body. The findings shed light on the neural basis for interoception.
Interoception is the awareness of our physiological states; it’s how animals and humans know they’re hungry or thirsty, and how they know when they’ve had enough to eat or drink. But precisely how the brain estimates the state of the body and reacts to it remains unclear. In a paper published in the journal Neuron, neuroscientists at Beth Israel Deaconess Medical Center (BIDMC) shed new light on the process, demonstrating that a region of the brain called the insular cortex orchestrates how signals from the body are interpreted and acted upon. The work represents the first steps toward understanding the neural basis of interoception, which could in turn allow researchers to address key questions in eating disorders, obesity, drug addiction, and a host of other diseases.
Using a mouse model his lab developed at BIDMC, Mark Andermann, PhD, principal investigator in the Division of Endocrinology, Diabetes and Metabolism at BIDMC and Associate Professor of Medicine at Harvard Medical School, and colleagues recorded the activity of hundreds of individual brain cells in the insular cortex to determine exactly what is happening as hungry animals ate.
The team observed that when mice hadn’t eaten for many hours, the activity pattern of insular cortex neurons reflected current levels of hunger. As the mice ate, this pattern gradually shifted over hours to a new pattern reflecting satiety. When mice were shown a visual cue predicting impending availability of food – akin to a person seeing a food commercial or a restaurant logo – the insular cortex appeared to simulate the future sated state for a few seconds, and then returned to an activity pattern related to hunger. These findings provided direct support for studies in humans that hypothesized that the insular cortex is involved in imagining or predicting how we will feel after eating or drinking.
“It is as if the insular cortex is briefly estimating, or simulating, the physiological consequences of eating a meal,” said first author Yoav Livneh, PhD, a postdoctoral research fellow in Andermann’s lab. “When hungry, this would be a simulation of satiety. But when considering whether to eat in the absence of hunger, for example when eating dessert after a big meal, this would be a simulation of the consequences of overeating. We hypothesized in this paper that when insular cortex activity shifts from a pattern reflecting current bodily state to a pattern reflecting a future satiety state, the size of this shift actually predicts how rewarding it will be to eat the food.”
A second experiment in which thirsty mice were presented with water yielded nearly identical results – with an important difference. The patterns of activity related to hunger and thirst were quite different, allowing the insular cortex to monitor multiple body states simultaneously.
“Another surprising finding was that insular cortex activity that reflects bodily state was independent of the hypothalamus, which is normally thought to be a master regulator of physiological need states in the brain,” Andermann said. “In contrast, we found that even when we artificially activate hypothalamus in a way that compels sated mice to eat, insular cortex activity isn’t fooled, and still reflects the body’s current physiological state of satiety.”
Next, Andermann and colleagues plan to directly manipulate specific patterns of activity in the insular cortex with the goal of changing the prediction the brain makes when presented with food or water, thereby making eating and drinking more or less rewarding.
“If successful, this approach might provide an intervention that could reduce seeking of unhealthy rewards (such as unhealthy foods or drugs of abuse) without affecting the seeking of other, healthier rewards,” said Andermann. “Such an intervention could potentially have a lot of value in both medicine and psychiatry.”
In addition to Andermann and Livneh, authors included Arthur U. Sugden, Joseph C. Madera, Rachel A Essner, Vanessa I Flores, Jon M. Resch and Bradford B. Lowell, all of BIDMC; and Lauren A. Sugden of Duquesne University.
Funding: This work was supported by The Charles A. King Trust Postdoctoral Fellowship; Boston Nutrition Obesity Research Center P&F 2P30DK046200-26; grants from the National Institutes of Health (K99 HL144923; T32 5T32DK007516; DP2 DK105570; R01 DK109930; DP1 AT010971; R01 DK075632; R01 DK096010; R01 DK089044; R01 DK111401; P03 DK046200; and P03 DK057521); grants from the National Science Foundation (DGE1745303); Klarman Family Foundation; McKnight Foundations; Smith Family Foundation; and Pew Scholars Program.
Estimation of Current and Future Physiological States in Insular Cortex
Highlights • InsCtx ongoing activity patterns reflect current bodily state, not behavioral state • Hypothalamic hunger/thirst neurons gate InsCtx responses to food/water cues • Hypothalamic hunger/thirst neurons do not gate InsCtx ongoing activity • Food/water cues drive transient “simulations” of future bodily states in InsCtx
Summary Interoception, the sense of internal bodily signals, is essential for physiological homeostasis, cognition, and emotions. While human insular cortex (InsCtx) is implicated in interoception, the cellular and circuit mechanisms remain unclear. We imaged mouse InsCtx neurons during two physiological deficiency states: hunger and thirst. InsCtx ongoing activity patterns reliably tracked the gradual return to homeostasis but not changes in behavior. Accordingly, while artificial induction of hunger or thirst in sated mice via activation of specific hypothalamic neurons (AgRP or SFO GLUT) restored cue-evoked food- or water-seeking, InsCtx ongoing activity continued to reflect physiological satiety. During natural hunger or thirst, food or water cues rapidly and transiently shifted InsCtx population activity to the future satiety-related pattern. During artificial hunger or thirst, food or water cues further shifted activity beyond the current satiety-related pattern. Together with circuit-mapping experiments, these findings suggest that InsCtx integrates visceral-sensory signals of current physiological state with hypothalamus-gated amygdala inputs that signal upcoming ingestion of food or water to compute a prediction of future physiological state.