Before your most recent meal, you might have felt some hunger pangs, signaling it was time to eat. Maybe you developed a sudden craving for Italian or another cuisine. These cues did not come out of thin air—they are the work of an almond-sized region in the brain called the hypothalamus. This area of the brain, despite its tiny size, has an enormous job in keeping us alive.
Nicknamed the master switchboard, the hypothalamus works in the background making sure our bodies are in the best condition possible. And, like the way many background actors are kept on the edges of a frame, its role has been taken for granted in the science community. “The hypothalamus is a very underappreciated region,” says Dayu Lin, a professor in the department of neuroscience and physiology at the NYU Grossman School of Medicine. She’s seen research interest in the brain region wane, with some even considering it to be less interesting compared to areas involved in higher and complex cognition.
But there’s still much more we have yet to uncover about the hypothalamus, as four review papers show in a series published by the journal Science today. Advanced technology has opened up new ways of examining the small brain region, redefining its old roles and identifying previously unknown ones.
The body’s regulator
The hypothalamus controls a variety of vital processes. Working with the pituitary gland, it’s in charge of all hormone production. It is also involved in controlling temperature, blood pressure, heart rate, appetite, and other parts of our physiology.
“The hypothalamus is regarded as an integral element in central nervous system control of both bodily hormonal activity, as well as a number of cognitive, emotional, and behavioral states,” says James Giordano, a Pellegrino Center professor of neurology at Georgetown University Medical Center, who was not involved in the current studies.
Complex structures and circuits give the hypothalamus a wide range of influence over multiple bodily processes, the first new paper shows. The hypothalamus is divided into a cluster of cell bodies, called nuclei, with intersecting pathways that help it communicate and coordinate activity within itself and with other outside brain regions. “Hypothalamic function is critical to the integrative activity of the brain, and in this way can be seen as important to defining the integrity of body to brain, and brain to body activity,” Giordano adds.
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Until now, a lack of scientific resources prevented researchers from understanding the function of these cells. Lin, who co-authored another paper on the brain region’s role in social behavior, said it was difficult to study what was going on in this area without disrupting the communication between cells. Past research relied on animals with lesions in specific areas of the hypothalamus, but this does not give a full picture of how the removed cells interact with the rest of the region.
The 2009 invention of single-cell RNA sequencing, a laboratory technique that allows scientists to analyze the genetic information of individual cells, has helped in better dissecting the circuitry that give hypothalamic clusters their diverse functions. In the recent work, researchers have mapped the cell subtypes in the hypothalamus based on. The next challenges will be to figure out why certain cell types group together and how the clumps govern different behaviors.
This isn’t the only new tool that these scientists employed. Another new research technique, optogenetics, allows neuroscientists to use light to monitor brain cell activity. A third, retrograde tracing, uses a virus to track neural connections starting from synapses all the way to their cell bodies, which helped identify never-before-seen circuits. In the future, these could reveal the hypothalamus’s other roles in regulating behaviors that include pain responses and anxiety. At the same time, the study authors speculate that the hypothalamus directly connects to the gut microbiome, with the implication that this brain area would be in charge of gut bacterial effects as well as serotonin and other hormones involved in the regulation of food.
Sleep, socialization, and goals
The other three papers focus on some of this brain controller’s major functions. Sleep, for example, is governed by specific neurons that act as a “switch” for transition from rest to wakefulness. But that’s not their only purpose. Sleep-wake cells are equally involved with other hypothalamic activities such as the control of energy metabolism and core body temperature.
“Our manuscript highlights the fact that most neuronal circuits in the hypothalamus serve more than one function, and that they are all interconnected,” says Luis de Lecea, a professor of psychiatry and behavioral sciences at Stanford University who served as author of the new review article. “Sleep is [also] intertwined with pretty much all brain function and loss of sleep affects many aspects of our health including aging and neurodegeneration.”
Another review article focused on how the hypothalamus can promote motivation towards necessities for us to survive such as food and water. To aim us toward such goals, the hypothalamus organizes its neural circuits to work with the ventral tegmental area, a part of the brain involved with reward processes. Optogenetic stimulation has revealed the hypothalamus sends messages to the ventral tegmental area that reinforce or inhibit motivation, and could explain food-seeking behavior.
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It also influences how we interact with others in a range of social behaviors. These can involve friendly and parental interactions, or aggressive or sexual actions. “These behaviors are critical for the animals to survive in the community and reproduce. The hypothalamus is essential for mediating these daily interactions,” says Lin, a co-author of this paper.
In that research, Lin proposes a dual-control system between the hypothalamus and brainstem-spinal cord. When someone spots a person they want to interact with, the hypothalamus engages with the dopamine system—dopamine is important for movements and reward—to maintain social interest and reinforce other socially acceptable actions. The brainstem-spinal cord circuit then takes this information and uses it to guide socially favorable responses and actions.
From lab animals to human health
Much of the work in investigating the ins and outs of the hypothalamus are in animals. Transgenic mice—genetically manipulated animals used to study biological processes and human diseases—make it easier for scientists to examine a specific section of the hypothalamus, Lin says, without putting any creatures under anesthesia. This is especially helpful to study communal behaviors, because animals need to be freely moving for their social brain circuits to activate.
Although these studies originated in animals, the new information about the hypothalamus is already being used to form treatments for humans. Efforts are underway to use deep-brain stimulation to target the posterior end of the hypothalamus to prevent or reduce aggression, for example. There is also potential in targeting specific circuits in the hypothalamus to stop other problems such as insomnia and addiction. In the next 10 years, Lin predicts, we’ll be hearing more news of clinical trials that target the hypothalamus to treat troubling behaviors.
