A Healthy Brain: Nerve Cells and their Neighbors

by Lindsay Borthwick

Research highlights from Kavli Neuroscience Institutes

Astrocytes (blue) from three different genetic syndromes (bottom) all secrete more IGFBP2 protein (pink) than do wildtype cells (top). Credit: Salk Institute

The Author

Lindsay Borthwick

Our monthly roundup of neuroscience news from Kavli Institutes brings into focus the diversity of cell types in the brain. Most of us think of nerve cells, but they are vastly outnumbered by star-shaped astrocytes. There are also microglia, a type of immune cell that helps prune neural connections during development and maintain the brain once it reaches maturity. Yet, non-neuronal cell types have historically been overlooked by researchers, especially those studying brain disorders and the evolution of the human brain. That is changing. Researchers are delving into the world of astrocytes, microglia, and other non-neuronal cells, and looking at diverse model systems to explore the idea that neurons are part of a community of cells that influence how the brain works.

Evolutionary Advantage

Humans and non-human primates share most of their DNA. They also share most cell types, the building blocks of life. The tremendous overlap raises the question, what is the biological basis of the cognitive differences that separate humans and our closest peers in the animal kingdom? The answer may lie in which genes are turned on and off, in which cells, and when. A new study in Science, led by Yale neuroscientist Nenad Sestan, moves us closer to the answer. “Today, we view the dorsolateral prefrontal cortex as the core component of human identity, but still we don’t know what makes this unique in humans and distinguishes us from other primate species,” he says in an interview with Yale News. “Now we have more clues.” The clues Sestan is referring to are gene expression changes in single cells of the dorsolateral prefrontal cortex (dlPFC), a part of the brain that is only found in primates. The dlPFC is involved in executive functions like abstract reasoning, so it is the focus of intense interest among researchers who are trying to figure out what makes the human brain unique. Sestan and his collaborators, including Stephen Strittmatter, analyzed single cells in the dlPFC from humans, marmosets, macaque monkeys and chimpanzees, and compared their gene expression patterns. They identified five cell types that are not shared across species, including a human-specific immune cell, or microglia, that may be involved in the brain’s upkeep. They also found gene expression changes in neurons and non-neuronal cells across species, including levels of FOXP2, a gene linked to speech and language as well as some neuropsychiatric disorders. The study opens up new avenues of investigation related to language and disease, according to the authors. Sestan is a member of the Kavli Institute for Neuroscience at Yale and Strittmatter is the Institute’s director.

Beyond Neurons

Astrocytes, named for their star-like shape, are the most common cell type in the brain, far outnumbering neurons. Yet, researchers are only just beginning to examine the role of astrocytes in neurodevelopmental disorders, a group of conditions that affect how the brain functions. Research has shown, for example, that when healthy neurons are mixed with astrocytes affected by disease, the healthy neurons are soon affected, too. Similarly, mixing healthy astrocytes with neurons affected by disease improves neuronal function. In a recent study led by Nicola Allen, a member of the Kavli Institute for Brain and Mind at the Salk Institute, researchers isolated astrocytes from mouse models of Rett, fragile X, and Down syndromes — three neurodevelopmental disorders — and studied the signaling molecules they produce. They found changes in astrocyte protein secretion for all three disorders, but one protein stood out: a protein that blocks insulin-like growth factor (IGF), a signaling molecule produced by neurons that is important for brain development. Allen and her team went on to show that the astrocyte protein interferes with IGF, so it can’t do its job. The study shows how astrocytes may contribute to neurodevelopmental disorders and points toward therapies that target the crosstalk between astrocytes and neurons. Dig a little deeper into the study and its implications in a Q&A with Allen.

Sophisticated Sensing

A new paper from the Vosshall Lab at Rockefeller University overthrows the dogma of “one receptor per smell and one receptor per neuron” in the olfactory system. In an extensive series of experiments, Leslie Vosshall’s research team showed that mosquito neurons have different chemical sensors on the same cell. For example, a cell may express sensors for multiple types of body odor and carbon dioxide. The discovery reveals the complexity and sophistication of the mosquito’s olfactory system and why it’s so hard to thwart the bloodthirsty insects. “Mosquitoes have Plan B after Plan B after Plan B. To me, the system is unbreakable,” says Vosshall in a news article by the Howard Hughes Medical Institute, where she is now vice president and chief scientific officer. Vosshall is the former director of the Kavli Neural Systems Institute at Rockefeller.

Probing the depths

Dr. Gül Dölen’s office reflects “where her mind is these days: deep in the ocean, with its weird and wild creatures, and focused on the healing power of psychedelics,” according to a profile of the neuroscientist recently published in Spectrum News. Dölen is an associate professor of neuroscience at Johns Hopkins University, where she is a member of the Kavli Neuroscience Discovery Institute. The profile chronicles her career from her early research on the brain chemicals that influence our social behavior, to the challenges of leading a laboratory, to a radical experiment that rekindled her love of science. The project? What happens when octopuses take ecstasy, and what can their behavior teach us about theory of mind — the ability to understand other peoples’ thoughts and emotions?

Mental Maneuver

Michael Shadlen is tackling the central question in neuroscience: how we think. He is doing it by focusing on smaller pieces of the puzzle, like what happens in the brain when animals make decisions. In a recent study, Shadlen and co-author NaYoung So, looked at how the brain handles disruptions and manages to keep the decision-making process on track. The study revealed that when faced with interruptions, the brain transfers neural information from one circuit to another within the parietal cortex. (The parietal cortex plays a role in perceptual decision making, linking what an animal sees to how it moves.) This transfer maintains cognitive function and may also ensure that we perceive the world as stable even as we turn our heads and move around. The research contributes to the fundamental understanding of brain function, and may also be relevant to mental illnesses in which decision-making is impaired, such as schizophrenia and severe depression. Shadlen is a Howard Hughes Medical Investigator and a member of the Kavli Institute for Brain Science at Columbia University.

Written by Lindsay Borthwick
Neuroscience

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