Researchers boost insect aggression by altering brain metabolism

Scientists report they can crank up insect aggression simply by interfering with a basic metabolic pathway in the insect brain. Their study, of fruit flies and honey bees, shows a direct, causal link between brain metabolism (how the brain generates the energy it needs to function) and aggression.

The team reports its findings in the Proceedings of the National Academy of Sciences.

The new research follows up on previous work from the laboratory of University of Illinois entomology professor and Institute for Genomic Biology director Gene Robinson, who also led the new analysis. When he and his colleagues looked at brain gene activity in honey bees after they had faced down an intruder, the team found that some metabolic genes were suppressed. These genes play a key role in the most efficient type of energy generation in cells, a process called oxidative phosphorylation.

“It was a counterintuitive finding because these genes were down-regulated,” Robinson said. “You tend to think of aggression as requiring more energy, not less.”

In the new study, postdoctoral researcher Clare Rittschof used drugs to suppress key steps in oxidative phosphorylation in the bee brains. She saw that aggression increased in the drugged bees in a dose-responsive manner, Robinson said. But the drugs had no effect on chronically stressed bees – they were not able to increase their aggression in response to an intruder.

“Something about chronic stress changed their response to the drug, which is a fascinating finding in and of itself,” Robinson said. “We want to know just how this experience gets under their skin to affect their brain.”

In separate experiments, postdoctoral researcher Hongmei Li-Byarlay and undergraduate student Jonathan Massey found that reduced oxidative phosphorylation in fruit flies also increased aggression. Using advanced fly genetics, the team found this effect only when oxidative phosphorylation was reduced in neurons, but not in neighboring cells known as glia. This finding, too, was surprising, since “glia are metabolically very active, and are the energy storehouses of the brain,” Robinson said.

The findings offer insight into the immediate and longer-term changes that occur in response to threats, Robinson said.

“When an animal faces a threat, it has an immediate aggressive response, within seconds,” Robinson said. But changes in brain metabolism take much longer and cannot account for this immediate response, he said. Such changes likely make individuals more vigilant to subsequent threats.

“This makes good sense in an ecological sense,” Robinson said, “because threats often come in bunches.”

The fact that the researchers observed these effects in two species that diverged 300 million years ago makes the findings even more compelling, Robinson said.

“Because fruit flies and honey bees are separated by 300 million years of evolution, this is a very robust and well-conserved mechanism.”

Copper on the Brain

The value of copper has risen dramatically in the 21^st century as many a thief can tell you, but in addition to the thermal and electrical properties that make it such a hot commodity metal, copper has chemical properties that make it essential to a healthy brain. Working at the interface of chemistry and neuroscience, Berkeley Lab chemist Christopher Chang and his research group at UC Berkeley have developed a series of fluorescent probes for molecular imaging of copper in the brain. Speaking at the recent national meeting of the American Chemical Society in New Orleans, he described the challenges of creating and applying live-cell and live-animal copper imaging probes and explained the importance of meeting these challenges.

“The human brain is a unique biological system, possessing unparalleled biological complexity in a compact space,” Chang said. “Although it accounts for only two-percent of total body mass, it consumes 20-percent of the oxygen taken in through respiration. As a consequence of its high demand for oxygen and oxidative metabolism, the brain has among the highest levels of copper, as well as iron and zinc in the body.”

Neuron and glia cells in the brain both require copper for the basic respiratory and antioxidant enzymes cytochrome c oxidase and superoxide dismutase. Copper is also necessary for brain-specific enzymes that control neurotransmitters, such as dopamine, as well as neuropeptides and dietary amines. Disruption of copper oxidation in the brain has been linked to several neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Menkes’ and Wilson’s.

“The complex relationships between copper status and various stages of health and disease have been difficult to determine in part because of a lack of methods for monitoring dynamic changes in copper pools in whole living organisms,” Chang said. “We’ve been designing fluorescent probes that can map the movement of copper in live cells, tissue or even model organisms, such as mice and zebrafish.”

Their first success was Coppersensor-3 (CS3), a small-molecule fluorescent probe that can be used to image labile copper pools in living cells at endogenous, basal levels. They used CS3 in conjunction with synchrotron-based X-ray fluorescence microscopy (XRFM) to discover that neuronal cells move significant pools of copper upon activation and that these copper movements are dependent on calcium signaling.

“This was the first established link between mobile copper and major cell signaling pathways,” Chang said. “Being able to map transient copper movements after neuronal depolarization revealed how neural activity triggers copper mobility, and enabled us to create a model for calcium/copper crosstalk in neurons.”

The CS3 probe was followed by Mitochondrial Coppersensor-1 (Mito-CS1), a fluorescent sensor that can selectively target mitochondria and detect basal and labile copper pools in living cells. Mitochondria, the organelles that generate most of the chemical energy used by cells, are important reservoirs for copper. By allowing direct, real-time visualization of exchangeable mitochondrial copper pools, the Mito-CS1 probe enabled Chang and his colleagues to discover that cells maintain copper homeostasis in mitochondria even in situations of copper deficiency and metabolic malfunctions.

“This work illustrated the importance of regulating copper stores in mitochondria,” Chang said.

The latest copper probe from Chang’s group is Coppersensor 790 (CS790), a fluorescent sensor that features near-infrared excitation and emission capabilities, ideal for penetrating thicker biological specimens. CS790 can be used to monitor fluctuations in exchangeable copper stores under basal conditions, as well as under copper overload or deficiency conditions. Chang and his group are using CS790 to study a mouse model of Wilson’s disease, a genetic disorder characterized by an accumulation of excess copper.

“The in vivo fluorescence detection of copper provided by CS790 and our other fluorescent probes is opening up unique opportunities to explore the roles that copper plays in the healthy physiology of the brain, as well as in the development and progression copper-related diseases,” Chang said.