Manipulating motivation in mice

In humans, the medial orbitofrontal cortex (mOFC) is thought to be important for determining the value of a perceived reward. Through manipulation of a growth factor in the mOFC, Emory scientists were able to modulate a mouse’s tendency to persist in reward seeking. Image from O’Doherty et al, PLOS Biology (2006).

Emory researchers have identified molecular mechanisms that regulate motivation and persistence in mice. Their findings could have implications for intervention in conditions characterized by behavioral inflexibility, such as drug abuse and depression.

Scientists showed that by manipulating a particular growth factor in one region of the brain, they could tune up or down a mouse’s tendency to persist in seeking a reward. In humans, this region of the brain is located just behind the eyes and is called the medial orbitofrontal cortex or mOFC.

“When we make decisions, we often need to gauge the value of a reward before we can see it — for example, will lunch at a certain restaurant be better than lunch at another, or worth the cost,” says Shannon Gourley, PhD, assistant professor of pediatrics and psychiatry at Emory University School of Medicine. “We think the mOFC is important for calculating value, particularly when we have to imagine the reward, as opposed to having it right in front of us.”

The results were published Wednesday in Journal of Neuroscience.

Shannon Gourley, PhD

Being able to appropriately determine the value of a perceived reward is critical in goal-directed decision making, a component of drug-seeking and addiction-related behaviors. While scientists already suspected that the medial orbitofrontal cortex was important for this type of learning and decision-making, the specific genes and growth factors were not as well-understood.

The researchers focused on brain-derived neurotrophic factor (BDNF), a protein that supports the survival and growth of neurons in the brain. BDNF is known to play key roles in long-term potentiation and neuronal remodeling, both important in learning and memory tasks. Variations in the human gene that encodes BDNF have been linked with several psychiatric disorders.

Continue reading “Manipulating motivation in mice”

Starvation signals control intestinal inflammation in mice

Intestinal inflammation in mice can be dampened by giving them a diet restricted in amino acids. Critical role for the amino acid sensor GCN2. Nature paper from Bali Pulendran and colleagues.

Intestinal inflammation in mice can be dampened by giving them a diet restricted in amino acids, the building blocks of proteins, researchers have found. The results were published online by Nature on Wednesday, March 16.

The findings highlight an ancient connection between nutrient availability and control of inflammation. They also suggest that a low protein diet — or drugs that mimic its effects on immune cells — could be tools for the treatment of inflammatory bowel diseases, such as Crohn’s disease or ulcerative colitis.

The research team, led by Emory Vaccine Center immunologist Bali Pulendran, discovered that mice lacking the amino acid sensor GCN2 are more sensitive to the chemical irritant DSS (dextran sodium sulfate), often used to model colitis in animals. This line of research grew out of the discovery by Pulendran and colleagues that GCN2 is pivotal for induction of immunity to the yellow fever vaccine.

“It is well known that the immune system can detect and respond to pathogens, but these results highlight its capacity to sense and adapt to environmental changes, such as nutritional starvation, which cause cellular stress,” he says.

Continue reading “Starvation signals control intestinal inflammation in mice”

‘Mountain of data’ on flu vaccine responses

Bali Pulendran’s lab at Emory Vaccine Center teamed up with UCSD researchers to analyze a ‘mountain of data’ on flu vaccine responses. Points to remember: hints on why anti-flu antibodies last longer in some people, factors that inhibit good vaccine responses in the elderly, and sharing of big data sets.

Bali Pulendran’s lab at Emory Vaccine Center teamed up with UCSD researchers and recently published a huge analysis of immune responses after seasonal flu vaccination (Immunity is making it available free this week, no subscription needed). Hundreds of volunteers at the Vaccine Center’s Hope Clinic took part in this study.

Note — this study looked at antibody responses to flu vaccines, but didn’t assess protection: whether study participants actually became sick with flu or not.

Our write-up is here. Immunity’s preview, from the Karolinska Institute’s Petter Brodin, is here, Cell Press’s press release is here.

Three points we wanted to call attention to:

*Long-lasting antibodies A surprising finding was how the “molecular signatures” that predict the strength of the immune response a few weeks after vaccination did not predict how long anti-flu antibodies stayed around. Instead, a separate set of signatures predicted the durability of antibody levels.

These distinct signatures may be connected with how plasma cells, responsible for antibody production, need to find homes in the bone marrow. That sounds like the process highlighted by Eun-Hyung Lee and colleagues in an Immunity paper published in July. In bone marrow samples from middle-aged volunteers, her team had found antibody-secreting cells that survive from childhood infections.

*Interfering (?) activation of NK cells/monocytes in elderly While the researchers found people older than 65 tended to have weaker antibody responses to vaccination, there were common elements of molecular signatures that predicted strong antibody responses in younger and older volunteers. However, elderly volunteers tended to have stronger signatures from immune cells that are not directly involved in producing antibodies (monocytes and ‘natural killer’ cells), both at baseline and after vaccination.

From the discussion: “This indicates a potential connection between the baseline state of the immune system in the elderly and reduced responsiveness to vaccination.” Additional comments on this from Shane Crotty in Brad Fikes’ article for the Union Tribune.

*The mountain of data from this and similar studies is available for use by other researchers on the web site ImmPort.

Graft vs host? Target the aurora

A recent Science Translational Medicine paper draws a bright red circle around aurora kinase A as a likely drug target in graft-vs-host disease. Aurora kinase inhibitors are already in cancer clinical trials.

 

Graft-vs-host disease is a common and potentially deadly complication following bone marrow transplants, in which immune cells from the donated bone marrow attack the recipient’s body.

Winship Cancer Institute’s Ned Waller and researchers from Children’s Healthcare of Atlanta and Yerkes National Primate Research Center were part of a recent Science Translational Medicine paper that draws a bright red circle around aurora kinase A as a likely drug target in graft-vs-host disease.

Aurora kinases are enzymes that control mitosis, the process of cell division, and were first discovered in the 1990s in yeast, flies and frogs. Now drugs that inhibit aurora kinase A are in clinical trials for several types of cancer, and clinicans are planning to examine whether the same type of drugs could help with graft-vs-host disease.

Leslie Kean, a pediatric cancer specialist at Seattle Children’s who was at Emory until 2013, is the senior author of the STM paper. Seattle Childrens’ press release says that Kean wears a bracelet around her badge from a pediatric patient cured of leukemia one year ago, but who is still in the hospital due to complications from graft-vs-host. Continue reading “Graft vs host? Target the aurora”

Everything in moderation, especially TH17 cells

Reflections on how too many and too few of a particular type of T cells, Th17 cells, are both problematic. Th17 cells are very popular these days.
Image: human blood, with T cells in orange, courtesy of the NIGMS Life Magnified/Dennis Kunkel Microscopy.

I was struck by one part of Mirko Paiardini’s paper that was published this week in Journal of Clinical Investigation. It describes a treatment aimed at repairing immune function in SIV-infected monkeys, with an eye toward helping people with HIV one day. One of the goals of their IL-21 treatment is to restore intestinal Th17 cells, which are depleted by viral infection. In this context, IL-21’s effect is anti-inflammatory.

However, Th17 cells are also involved in autoimmune disease. A recent Cell Metabolism paper from endocrinologist Roberto Pacifici and colleagues examines Th17 cells, with the goal of treating bone loss coming from an overactive parathyroid. In that situation, too many Th17 cells are bad and they need to be beaten back. Fortunately, both an inexpensive blood pressure medication and a drug under development for psoriasis seem to do just that.

Note for microbiome fans: connections between Th17 cells and intestinal microbes (segmented filamentous bacteria) are strengthening. It gets complicated because gut microbiota, together with Th17 cells, may influence metabolic disease and Th17-like cells are also in the skin — location matters.

Epigenetic inheritance via sperm RNA

A possible explanation for a surprising result, on how smell sensitivity can be inherited

In 2013, Brian Dias (at Yerkes) and Kerry Ressler (now at Harvard) described a surprising example of epigenetic inheritance.

They found that a mouse, exposed to a smell in combination with stress, could transmit the resulting sensitivity to that smell to its offspring. At the time, there wasn’t a lot of information about mechanism.

Now other scientists have substantiated a proposal that micro RNA in playing a role in sperm. See this story (“Sperm RNAs transmit stress”) from Kate Yandell in The Scientist or this one from Rachel Zamzow at Spectrum, the Simons Foundation’s autism news site, for more. An added wrinkle is that this research shows that descendants of stress-exposed mice show a muted response to stress.

Note for Emory readers: Dias is scheduled to give a Frontiers in Neuroscience talk on Friday.

HIV vaccine news: a glass half full

A HIV vaccine research paper that contains good or bad news, depending on how you look at it. Vaccinated monkeys make effective neutralizing antibodies against SIV, but the antibodies don’t always stop the virus.

This week, researchers from Yerkes and Emory Vaccine Center led by Cindy Derdeyn published a paper that I first thought was disturbing. It describes how monkeys vaccinated against HIV’s relative SIV (simian immunodeficiency virus) still become infected when challenged with the virus. Moreover, it’s not clear whether the vaccine-induced antibodies are exerting any selective pressure on the virus that gets through.

But then I realized that this might be an example of “burying the lead,” since we haven’t made a big hoopla about the underlying vaccine studies, conducted by Rama Amara. Some of these studies showed that a majority of monkeys can be protected from repeated viral challenge. The more effective vaccine regimens include adjuvants such as the immune-stimulating molecules GM-CSF or CD40L (links are the papers on the protective effects). Continue reading “HIV vaccine news: a glass half full”

Do Alzheimer’s proteins share properties with prions?

Some “strains” of amyloid-beta may resemble spooky prions in their ability to spread within the brain, even if they can’t infect other people.

If you’ve come anywhere near Alzheimer’s research, you’ve come across the “amyloid hypothesis” or “amyloid cascade hypothesis.”

This is the proposal that deposition of amyloid-beta, a major protein ingredient of the plaques that accumulate in the brains of Alzheimer’s patients, is a central event in the pathology of the disease. Lots of supporting evidence exists, but several therapies that target beta-amyloid, such as antibodies, have failed in large clinical trials.

Jucker_Walker_May_2014
Lary Walker and Matthias Jucker in Tübingen, 2014

In a recent Nature News article, Boer Deng highlights an emerging idea in the Alzheimer’s field that may partly explain why: not all forms of aggregated amyloid-beta are the same. Moreover, some “strains” of amyloid-beta may resemble spooky prions in their ability to spread within the brain, even if they can’t infect other people (important!).

Prions are the “infectious proteins” behind diseases such as bovine spongiform encephalopathy. They fold into a particular structure, aggregate and then propagate by attracting more proteins into that structure.

Lary Walker at Yerkes National Primate Research Center has been a key proponent of this provocative idea as it applies to Alzheimer’s. To conduct key experiments supporting the prion-like properties of amyloid-beta, Walker has been collaborating with Matthias Jucker in Tübingen, Germany and spent four months there on a sabbatical last year. Their paper, describing how aggregated amyloid-beta is “seeded” and spreads through the brain in mice, was recently published in Brain Pathology.
Continue reading “Do Alzheimer’s proteins share properties with prions?”

Effects of cocaine exposure in adolescent rodents

The effects on neurons are like losing entire branches from a tree, neuroscientists are finding

Much of neuroscientist Shannon Gourley’s work focuses on the idea that adolescence is a vulnerable time for the developing brain. She and graduate student Lauren DePoy recently published a paper in Frontiers in Pharmacology showing that in adolescent rodents, cocaine exposure can cause the loss of dendritic arbors in part of the brain important for decision-making.

The researchers examined neurons in the orbitofrontal cortex, a region of the brain thought to be important for “linking reward to hedonic experience.” It was known that stimulants such as cocaine can cause the loss of dendritic spines: small protrusions that are critical for communication and interaction between neurons.

“To make an analogy, it’s like a tree losing some of its leaves,” Gourley writes. “Lauren’s work shows for the first time that if cocaine is given in adolescence, it can cause the loss of dendrite arbors – as if entire branches are being cut from the tree.”

The mice are exposed to cocaine over the course of five days in early adolescence, and then their behavior is studied in adulthood. This level of cocaine exposure leads to impairments in instrumental task reversal, a test where mice need to change their habits (which chamber they poke their noses into) to continue receiving food pellets.

The findings suggest a partial explanation for the increased risk of dependence in people who start using cocaine during adolescence.

Nobel Prize for place cells + grid cells

Connection to neuroscience research performed at Yerkes

Congratulations to John O’Keefe, May-Britt Moser and Edvard Moser for receiving the 2014 Nobel Prize in Medicine. The prize is for discovering “the brain’s navigation system”: place cells, cells in the hippocampus which are active whenever a rat is in a particular place, and grid cells, cells in the entorhinal cortex which are active when the animal is at multiple locations in a grid pattern.

Former Yerkes researcher Beth Buffalo and her graduate student Nathan Killian were the first to directly detect, via electrode recordings, grid cells in the brains of non-human primates. Buffalo is now at the University of Washington and Killian is at Harvard Medical School.

A significant difference about their experiments was that they could identify grid cells when monkeys were moving their eyes, suggesting that primates don’t have to actually visit a place to construct the same kind of mental map. Another aspect of grid cells in non-human primates not previously seen with rodents is that the cells’ responses change when monkeys are seeing an image for the second time.

Following that report, grid cells were also directly detected in human epilepsy patients. The Mosers themselves noted in a 2014 review, “It will be interesting to see whether the same cells that respond to visual movement in monkeys also respond to locomotion, or whether there is a separate system of grid cells that is responsive to locomotion.”