Bacteria living on human bodies contain genes that are likely to code for a vast number of drug-like molecules — including a new antibiotic made by bacteria that live in the vagina, researchers report in this week’s issue of Cell1.
The drug, lactocillin, hints at the untapped medical potential of this microbial landscape.
“They have shown that there is a huge diverse potential of the microbiome for producing antimicrobial molecules,” says Marc Ouellette, a microbiologist at the University of Laval’s Hospital Centre (CHUL) in Quebec, Canada, who was not involved in the research.
Cell 158, 1402–1414 (2014)et al.
You are what you eat, the saying goes, and now a study conducted by researchers at UC Santa Barbara and the University of Pittsburgh suggests that the oft-repeated adage applies not just to physical health but to brain power as well.
In a paper published in the early online edition of the journal Prostaglandins, Leukotrienes and Essential Fatty Acids, the researchers compared the fatty acid profiles of breast milk from women in over two dozen countries with how well children from those same countries performed on academic tests.
Their findings show that the amount of omega-3 docosahexaenoic acid (DHA) in a mother’s milk — fats found primarily in certain fish, nuts and seeds — is the strongest predictor of test performance. It outweighs national income and the number of dollars spent per pupil in schools.
DHA alone accounted for about 20 percent of the differences in test scores among countries, the researchers found.
On the other hand, the amount of omega-6 fat in mother’s milk — fats that come from vegetable oils such as corn and soybean — predict lower test scores. When the amount of DHA and linoleic acid (LA) — the most common omega-6 fat — were considered together, they explained nearly half of the differences in test scores. In countries where mother’s diets contain more omega-6, the beneficial effects of DHA seem to be reduced.
More omega-3, less omega-6
“Human intelligence has a physical basis in the huge size of our brains — some seven times larger than would be expected for a mammal with our body size,” said Steven Gaulin, UCSB professor of anthropology and co-author of the paper. “Since there is never a free lunch, those big brains need lots of extra building materials — most importantly, they need omega-3 fatty acids, especially DHA. Omega-6 fats, however, undermine the effects of DHA and seem to be bad for brains.”
Both kinds of omega fat must be obtained through diet. But because diets vary from place to place, for their study Gaulin and his co-author, William D. Lassek, M.D., a professor at the University of Pittsburgh’s Graduate School of Public Health and a retired assistant surgeon general, estimated the DHA and LA content — the good fat and the bad fat — in diets in 50 countries by examining published studies of the fatty acid profiles of women’s breast milk.
The profiles are a useful measure for two reasons, according to Gaulin. First, because various kinds of fats interfere with one another in the body, breast milk DHA shows how much of this brain-essential fat survives competition with omega-6. Second, children receive their brain-building fats from their mothers. Breast milk profiles indicate the amount of DHA children in each region receive in the womb, through breastfeeding, and from the local diet available to their mothers and to them after they are weaned.
The academic test results came from the Programme for International Student Assessment (PISA), which administers standardized tests in 58 nations. Gaulin and Lassek averaged the three PISA tests — math, science and reading ability — as their measure of cognitive performance. There were 28 countries for which the researchers found information about both breast milk and test scores.
DHA content: best predictor of math test performance
“Looking at those 28 countries, the DHA content of breast milk was the single best predictor of math test performance,” Gaulin said. The second best indicator was the amount of omega-6, and its effect is opposite. “Considering the benefits of omega-3 and the detriment of omega-6, we can get pretty darn close to explaining half the difference in scores between countries,” he added. When DHA and LA are considered together, he added, they are twice as effective at predicting test scores as either is alone, Gaulin said.
Gaulin and Lassek considered two economic factors as well: per capita gross domestic product (a measure of average wealth in each nation) and per student expenditures on education. “Each of these factors helps explain some of the differences between nations in test scores, but the fatty acid profile of the average mother’s milk in a given country is a better predictor of the average cognitive performance in that country than is either of the conventional socioeconomic measures people use,” said Gaulin.
From their analysis, the researchers conclude that both economic wellbeing and diet make a difference in cognitive test performance, and children are best off when they have both factors in their favor. “But if you had to choose one, you should choose the better diet rather than the better economy,” Gaulin said.
The current research follows a study published in 2008 that showed that the children of women who had larger amounts of gluteofemoral fat “depots” performed better on academic tests than those of mothers with less. “At that time we weren’t trying to identify the dietary cause,” explained Gaulin. “We found that this depot that has been evolutionarily elaborated in women is important to building a good brain. We were content at that time to show that as a way of understanding why the female body is as evolutionarily distinctive as it is.”
Now the researchers are looking at diet as the key to brain-building fat, since mothers need to acquire these fats in the first place.
Their results are particularly interesting in 21st-century North America, Gaulin noted, because our current agribusiness-based diets provide very low levels of DHA — among the lowest in the world. Thanks to two heavily government-subsidized crops — corn and soybeans — the average U.S. diet is heavy in the bad omega-6 fatty acids and far too light on the good omega-3s, Gaulin said.
Wrong kind of polyunsaturated fat
“Back in the 1960s, in the middle of the cardiovascular disease epidemic, people got the idea that saturated fats were bad and polyunsaturated fats were good,” he explained. “That’s one reason margarine became so popular. But the polyunsaturated fats that were increased were the ones with omega-6, not omega-3. So our message is that not only is it advisable to increase omega 3 intake, it’s highly advisable to decrease omega-6 — the very fats that in the 1960s and ’70s we were told we should be eating more of.”
Gaulin added that mayonnaise is, in general, the most omega-6-laden food in the average person’s refrigerator. “If you have too much of one — omega-6 — and too little of the other — omega 3 — you’re going to end up paying a price cognitively,” he said.
The issue is a huge concern for women, Gaulin noted, because “that’s where kids’ brains come from. But it’s important for men as well because they have to take care of the brains their moms gave them.
“Just like a racecar burns up some of its motor oil with every lap, your brain burns up omega-3 and you need to replenish it every day,” he said.
(Image: Stacy Librandi)
In what may be the largest study of sleep problems among individuals with multiple sclerosis (MS), researchers at UC Davis have found that widely undiagnosed sleep disorders may be at the root of the most common and disabling symptom of the disease: fatigue.
Conducted in over 2,300…
Using human induced pluripotent stem cells (hiPSCs), researchers at Skaggs School of Pharmacy and Pharmaceutical Sciences at University of California, San Diego have discovered that neurons from patients with schizophrenia secrete higher amounts of three neurotransmitters broadly implicated in a range of psychiatric disorders.
The findings, reported online Sept. 11 in Stem Cell Reports, represent an important step toward understanding the chemical basis for schizophrenia, a chronic, severe and disabling brain disorder that affects an estimated one in 100 persons at some point in their lives. Currently, schizophrenia has no known definitive cause or cure and leaves no tell-tale physical marks in brain tissue.
"The study provides new insights into neurotransmitter mechanisms in schizophrenia that can lead to new drug targets and therapeutics,” said senior author Vivian Hook, PhD, a professor with Skaggs School of Pharmacy and UC San Diego School of Medicine.
In the study, UC San Diego researchers with colleagues at The Salk Institute for Biological Studies and the Icahn School of Medicine at Mount Sinai, N.Y., created functioning neurons derived from hiPSCs, themselves reprogrammed from skin cells of schizophrenia patients. The approach allowed scientists to observe and stimulate human neurons in ways impossible in animal models or human subjects.
Researchers activated these neurons so that they would secrete neurotransmitters – chemicals that excite or inhibit the transmission of electrical signals through the brain. The process was replicated on stem cell lines from healthy adults.
A comparison of neurotransmitters produced by the cultured “brain in a dish” neurons showed that the neurons derived from schizophrenia patients secreted significantly greater amounts of the catecholamine neurotransmitters dopamine, norepinephrine and epinephrine.
Catecholamine neurotransmitters are synthesized from the amino acid tyrosine and the regulation of these neurotransmitters is known to be altered in a variety of psychiatric diseases. Several psychotropic drugs selectively target the activity of these neurotransmitters in the brain.
In addition to documenting aberrant neurotransmitter secretion from neurons derived from patients with schizophrenia, researchers also observed that more neurons were dedicated to the production of tyrosine hydroxylase, the first enzyme in the biosynthetic pathway for the synthesis of dopamine, from which both norepinephrine and epinephrine are made.
This discovery is significant because it offers a reason for why schizophrenia patients have altered catecholamine neurotransmitter levels: They are preprogrammed to have more of the neurons that make these neurotransmitters.
“All behavior has a neurochemical basis in the brain,” Hook said. “This study shows that it is possible to look at precise chemical changes in neurons of people with schizophrenia.”
The applications for future treatments include being able to evaluate the severity of an individual’s disease, identify different sub-types of the disease and pre-screen patients for drugs that would be most likely to help them. It also offers a way to test the efficacy of new drugs.
“It is very powerful to be able to see differences in neurons derived from individual patients and a big accomplishment in the field to develop a method that allows this,” Hook said.
Pictured: Enzymes that biosynthesize the neurotransmitters dopamine (left), norepinephrine (center) and epinephrine (right).
When Joanna Mattis started her doctoral project she expected to map how two regions of the brain connect. Instead, she got a surprise. It turns out the wiring diagram shifts depending on how you flip the switch.
"There’s a lot of excitement about being able to make a map of the brain with the idea that if we could figure out how it is all connected we could understand how it works," Mattis said. "It turns out it’s so much more dynamic than that."
Mattis is a co-first author on a paper describing the work published August 27 in the Journal of Neuroscience. Julia Brill, then a postdoctoral scholar, was the other co-first author.
Mattis had been a graduate student in the lab of Karl Deisseroth, professor of bioengineering and of psychiatry and behavioral sciences, where she helped work on a new technique called optogenetics. That technique allows neuroscientists to selectively turn parts of the brain on and off to see what happens. She wanted to use optogenetics to understand the wiring of a part of the brain involved in spatial memory – it’s what makes a mental map of your surroundings as you explore a new city, for example.
Scientists already knew that when an animal explores habitats, two parts of the brain are involved in the initial exploring phase and then in solidifying a map of the environment – the hippocampus and the septum.
When an animal is exploring an environment, the neurons in the hippocampus fire slow signals to the septum, essentially telling the septum that it’s busy acquiring information. Once the animal is done exploring, those same cells fire off intense signals letting the septum know that it’s now locking that information into memory. The scientists call this phase consolidation. The septum uses that information to then turn around and regulate other signals going into the hippocampus.
"I wanted to study the hippocampus because on the one hand so much was already known – there was already this baseline of knowledge to work off of. But then the question of how the hippocampus and septum communicate hadn’t been accessible before optogenetics," Mattis said.
Neurons in the hippocampus were known to fire in a rhythmic pattern, which is a particular expertise of John Huguenard, a professor of neurology. Mattis obtained an interdisciplinary fellowship through Stanford Bio-X, which allowed her to combine the Deisseroth lab’s expertise in optogenetics with the rhythmic brain network expertise of Julia Brill from the Huguenard lab.
Mattis and Brill used optogenetics to prompt neurons of the hippocampus to mimic either the slow firing characteristic of information acquisition or the rapid firing characteristic of consolidation. When they mimicked the slow firing they saw a quick reaction by cells in the septum. When they mimicked the fast consolidation firing, they saw a much slower response by completely different cells in the septum.
Same set of wires – different outcome. That’s like turning on different lights depending on how hard you flip the switch. “This illustrates how complex the brain is,” Mattis said.
Most scientific papers answer a question: What does this protein do? How does this part of the brain work? By contrast, this paper raised a whole new set of questions, Mattis said. They more or less understand the faster reaction, but what is causing the slower reaction? How widespread is this phenomenon in the brain?
"The other big picture thing that we opened up but didn’t answer is: How can you then tie this back to the circuit overall and learning memory?" Mattis said. "Those would be exciting things to follow up on for future projects."
Transcranial magnetic stimulation (TMS) is a painless, non-invasive stimulation method, where an electromagnetic coil held above the head is used to generate a strong magnetic field. This method is deployed to activate or inhibit specific brain regions. Even though the number of its medical applications is constantly on the increase, TMS’ precise neuronal mechanisms of action are not, as yet, very well understood. That is because imaging used for humans, such as fMRI (functional magnetic resonance imaging), do not possess the temporal resolution necessary for recording neural activities in milliseconds. More rapid measurement methods, such as EEG or MEG, on the other hand, are affected by the induced magnetic field, with the results that strong interferences are generated that cover important information regarding immediate TMS-based changes to brain activities.
Observing effect on neurons in real time
High-res images of TMS effects have now for the first time been successfully generated by RUB researchers in animal testing. The work group headed by PD Dr Dirk Jancke, Institut für Neuroinformatik, utilises voltage-sensitive dyes which, anchored in cell membranes, send out fluorescent light signals once neurons get activated or inhibited. By using light, the researchers avoided the problem of measurement of artefacts occurring due to magnetic fields. “We can now demonstrate in real time how one single TMS pulse suppresses brain activity across a considerable region, most likely through mass activation of inhibiting brain cells,” says Dr Jancke. With higher TMS frequencies, each additional TMS pulse generates an incremental increase in brain activity. “This results in a higher cortical activation state, which opens up a time window for plastic changes,” explains Dr Vladislav Kozyrev, the first author of the study.
Chances for patients
The increased neuronal excitability may be utilised to effect specific reorganisation of cell connections by means of targeted learning processes. For example, through visual training after TMS, the ability to identify image contours improves; moreover, a combination of these methods enhances contrast perception in patients with amblyopia - a disorder of sight acquired during child development. For many neurological diseases of the brain, such as epilepsy, depression and stroke, specific models have been developed. “Deployed in animal testing, our technology has delivered high spatiotemporal resolution imaging data of cortical activity changes,” says Dirk Jancke. “We are hoping that these data will enable us to optimise TMS parameters and learning processes in a targeted manner, which are going to be used in future to adapt this technology for medical treatment of humans.”