Researchers Identify Key Factor in Transition from Moderate to Problem Drinking

A team of UC San Francisco researchers has found that a tiny segment of genetic material known as a microRNA plays a central role in the transition from moderate drinking to binge drinking and other alcohol use disorders.

Previous research in the UCSF laboratory of Dorit Ron, PhD, Endowed Chair of Cell Biology of Addiction in Neurology, has demonstrated that the level of a protein known as brain-derived neurotrophic factor, or BDNF, is increased in the brain when alcohol consumed in moderation. In turn, experiments in Ron’s lab have shown, BDNF prevents the development of alcohol use disorders.

In the new study, Ron and first author Emmanuel Darcq, PhD, a former postdoctoral fellow now at McGill University in Canada, found that when mice consumed excessive amounts of alcohol for a prolonged period, there was a marked decrease in the amount of BDNF in the medial prefrontal cortex (mPFC), a brain region important for decision making. As reported in the October 21, 2014 online edition of Molecular Psychiatry, this decline was associated with a corresponding increase in the level of a microRNA called miR-30a-5p.

MicroRNAs lower the levels of proteins such as BDNF by binding to messenger RNA, the molecular middleman that carries instructions from genes to the protein-making machinery of the cell, and tagging it for destruction.

Ron and colleagues then showed that if they increased the levels of miR-30a-5p in the mPFC, BDNF was reduced, and the mice consumed large amounts of alcohol. When mice were treated with an inhibitor of miR-30a-5p, however, the level of BDNF in the mPFC was restored to normal and alcohol consumption was restored to normal, moderate levels.

“Our results suggest BDNF protects against the transition from moderate to uncontrolled drinking and alcohol use disorders,” said Ron, senior author of the study and a professor in UCSF’s Department of Neurology. “When there is a breakdown in this protective pathway, however, uncontrolled excessive drinking develops, and microRNAs are a possible mechanism in this breakdown. This mechanism may be one possible explanation as to why 10 percent of the population develop alcohol use disorders and this study may be helpful for the development of future medications to treat this devastating disease.”

One reason many potential therapies for alcohol abuse have been unsuccessful is because they inhibit the brain’s reward pathways, causing an overall decline in the experience of pleasure. But in the new study, these pathways continued to function in mice in which the actions of miR-30a-5p had been tamped down—the mice retained the preference for a sweetened solution over plain water that is seen in normal mice.

This result has significant implications for future treatments, Ron said. “In searching for potential therapies for alcohol abuse, it is important that we look for future medications that target drinking without affecting the reward system in general. One problem with current alcohol abuse medications is that patients tend to stop taking them because they interfere with the sense of pleasure.”

Selectively Rewiring the Brain’s Circuitry to Treat Depression

On Star Trek, it is easy to take for granted the incredible ability of futuristic doctors to wave small devices over the heads of both humans and aliens, diagnose their problems through evaluating changes in brain activity or chemistry, and then treat behavior problems by selectively stimulating relevant brain circuits.

While that day is a long way off, transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex does treat symptoms of depression in humans by placing a relatively small device on a person’s scalp and stimulating brain circuits. However, relatively little is known about how, exactly, TMS produces these beneficial effects.

Some studies have suggested that TMS may modulate atypical interactions between two large-scale neuronal networks, the frontoparietal central executive network (CEN) and the medial prefrontal-medial parietal default mode network (DMN). These two functional networks play important roles in emotion regulation and cognition.

In order to advance our understanding of the underlying antidepressant mechanisms of TMS, Drs. Conor Liston, Marc Dubin, and their colleagues conducted a longitudinal study to test this hypothesis.

The researchers used functional magnetic resonance imaging in 17 currently depressed patients to measure connectivity in the CEN and DMN networks both before and after a 25-day course of TMS. They also compared the connectivity in the depressed patients with a group of 35 healthy volunteers.

TMS normalized depression-related hyperconnectivity between the subgenual cingulate and medial prefrontal areas of the DMN, but did not alter connectivity in the CEN.

Liston, an Assistant Professor at Weill Cornell Medical College, further details their findings, “We found that connectivity within the DMN and between nodes of the DMN and CEN was elevated in depressed individuals compared to healthy volunteers at baseline and normalized after TMS. Additionally, individuals with greater baseline connectivity with subgenual anterior cingulate cortex – an important target for other antidepressant modalities – were more likely to respond to TMS.”

These findings indicate that TMS may act, in part, by selectively regulating network-level connectivity.

Dr. John Krystal, Editor of Biological Psychiatry, comments, “We are a long way from Star Trek, but even the current ability to link brain stimulation treatments for depression to the activity of particular brain circuits strikes me as incredible progress.”

Dubin, also an Assistant Professor at Weill Cornell Medical College, adds, “Our findings may inform future efforts to develop personalized strategies for treating depression with TMS based on the connectivity of an individual’s default mode network. Further, they may help triage to TMS only those patients most likely to respond.”

(Image caption: In the two brain regions IPF (lateral prefrontal cortex) and V4, a region of the visual system, the brain activity oscillates in a specific frequency range. Credit: © Stefanie Liebe, MPI for biological Cybernetics)

Synchronous oscillations in the short-term memory

School children and university students are often big fans of the short-term memory – not least when they have to cram large volumes of information on the eve of an exam. Although its duration is brief, short term memory is a complex network of neurons in the brain that includes different brain regions. To store the information, these regions must work together. Researchers from the Max Planck Institute for Biological Cybernetics in Tübingen have now discovered that the participating regions must be active at the same time to enable us to form short-term memories of things that happen.

When we see something, signals from the eyes are processed in areas of the cerebral cortex located at the back of the head. For short-term memory, in contrast, regions in the front part of the cerebral cortex must be active. In order for us to remember something we have seen briefly, these far-apart regions of the brain must collate their information.

How this works can only be examined in apes. Scientists from Nikos Logothetis’s Department at the Max Planck Institute for Biological Cybernetics in Tübingen measured the electrical activity in an optic region and in the front area of the brain while the animals had to remember different images.

In the process, the scientists observed electrical vibrations, known as theta-band oscillations, in the two regions of brain. Surprisingly, these oscillations did not arise independently, but were synchronous. The more synchronously active the regions, the better the animals were able to remember an image.

Accordingly, the functioning of short-term memory can be envisaged as two revolving doors: While the memory is at work, the two doors move in time with each other and, in this way, facilitate the more effective exchange of information.

The study shows how important synchronised brain oscillations are for the communication between the different regions of the brain. Almost all higher intellectual capacities result from the complex interplay of specialised neuronal networks in different parts of the brain.

The interactive brain

Neuroscientist explores mechanism that can cause deficit in working memory

Amy Griffin, associate professor of psychological and brain sciences at the University of Delaware, has received a five-year, $1.78 million grant from the National Institute of Mental Health to support her research into the brain mechanisms of working memory.

A neuroscientist, Griffin has been interested for some time in the interaction between the prefrontal cortex, located at the front of the brain, and the hippocampus, a region in the temporal lobe of the brain. When the two areas fail to work together, that failure appears to be correlated with deficits in working memory, a condition that commonly occurs in schizophrenia, general anxiety and other psychiatric disorders.

The hippocampus is the portion of the brain responsible for memory, while the prefrontal cortex controls executive function, a term that includes such cognitive abilities as problem-solving, planning and abstract thinking.

“These are two areas of the brain that are far apart, but their oscillations [rhythmic activities] are synchronized,” Griffin said. “When one area is active, so is the other.”

Working memory, sometimes called short-term memory, is “the kind of memory that fails when you walk into a room and forget why you came there,” she said.

When the oscillations in the hippocampus and prefrontal cortex are out of sync, deficits of working memory occur. In those cases, Griffin said, “both regions are active, but they’re not talking to each other.” The mechanism that causes that lack of communication has not been well explored, and her research will seek to do that.

Griffin and her research team plan to conduct two types of experiments. One will inhibit activity in a brain region called the nucleus reuniens, a region that is hypothesized to synchronize the hippocampus and prefrontal cortex and is expected to cause impairments with working memory. In the other experiment, researchers will activate the nucleus reuniens to increase synchrony, hoping to learn if that improves working memory.

The research will employ a cutting-edge technique called optogenetics, a process that uses proteins to make neurons sensitive to light and then uses light to control them. 

“Optogenetics is becoming a common technique,” Griffin said. “It’s a way to study these processes on a millisecond timescale.” 

A 2013 article in the journal Nature Neuroscience said optogenetics “is transforming the field of neuroscience. For the first time, it is now possible to use light to both trigger and silence activity in genetically defined populations of neurons with millisecond precision.”

Griffin, using a rat model, will inject the light-sensitizing substance — a harmless virus — into the nucleus reuniens and then use a laser to inhibit or activate this brain region. The rats then perform tasks that assess their working memory. Synchronization between the hippocampus and prefrontal cortex will also be recorded, with the prediction that the degree of the working memory impairment will be correlated with reductions in synchrony.

“Our experiments will not be interfering with the activities of the hippocampus or the prefrontal cortex within themselves,” Griffin said. “We want to affect only the ability of the structures to talk to each other.”

Status and the Brain

Social hierarchy is a fact of life for many animals. Navigating social hierarchy requires understanding one’s own status relative to others and behaving accordingly, while achieving higher status may call upon cunning and strategic thinking. The neural mechanisms mediating social status have become increasingly well understood in invertebrates and model organisms like fish and mice but until recently have remained more opaque in humans and other primates. In a new study in this issue, Noonan and colleagues explore the neural correlates of social rank in macaques. Using both structural and functional brain imaging, they found neural changes associated with individual monkeys’ social status, including alterations in the amygdala, hypothalamus, and brainstem—areas previously implicated in dominance-related behavior in other vertebrates. A separate but related network in the temporal and prefrontal cortex appears to mediate more cognitive aspects of strategic social behavior. These findings begin to delineate the neural circuits that enable us to navigate our own social worlds. A major remaining challenge is identifying how these networks contribute functionally to our social lives, which may open new avenues for developing innovative treatments for social disorders.

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Reacting to Personal Setbacks: Do You Bounce Back or Give Up?

Sometimes when people get upsetting news – such as a failing exam grade or a negative job review – they decide instantly to do better the next time. In other situations that are equally disappointing, the same people may feel inclined to just give up.

How can similar setbacks produce such different reactions? It may come down to how much control we feel we have over what happened, according to new research from Rutgers University-Newark. The study, published in the journal Neuron, also finds that when these setbacks occur, the level of control we perceive may even determine which of two distinct parts of the brain will handle the crisis.

“Think of the student who failed an exam,” says Jamil Bhanji, a postdoctoral fellow at Rutgers and one of the study’s co-authors. “They might feel they wouldn’t have failed if they had studied harder, studied differently – something under their control.” That student, Bhanji says, resolves to try new study habits and work hard toward acing the next exam. Functional magnetic resonance imaging (fMRI) used in the study showed activity in a part of the brain called the ventral striatum – which has been shown to guide goals based on prior experiences.

A different student might have failed the same test, but believes it happened because the questions were unfair or the professor was mean, things that he could not control. The negative emotions produced by this uncontrollable setback may cause the student to drop the course.

Overcoming those negative emotions and refocusing on doing well in the class may require a more complicated thought process. In cases like this, fMRI revealed that activity in the ventromedial prefrontal cortex (vmPFC), a part of the brain that regulates emotions in more flexible ways, is necessary to promote persistence.

Mauricio Delgado, an associate professor of psychology at Rutgers’ Newark College of Arts and Sciences and the study’s other co-author, says people whose jobs include delivering bad news should pay attention to these results, because their actions might influence how the news is received.

“You may deliver the news to the student – no sugar coating, here’s your setback,” says Delgado. “But then you make an offer – ‘would you like to review those study habits with me? I’d be happy to do it.’ This puts the student in a situation where they may experience control and be more likely to improve the next time.” This approach, Delgado says, may be far more constructive than curtly delivering a bad grade.

Bhanji says lessons from the study may even guide certain people toward giving up too soon on careers where they could do well. “We wonder why there are fewer women and minorities in the sciences, for example,” he explains. “Maybe in cases like that it’s fair to say there are things we can do to promote reactions to negative feedback that encourage persistence.”

That is not to say everyone should persist. “There are times,” Delgado adds, “when you should not be persistent with your goals. That’s where the striatal system in the brain, which can be a source of more habitual responses, may be a detriment. You keep thinking ‘I can do it, I can do it.’ But maybe you shouldn’t do it. During these times, interpreting the setback more flexibly, via the vmPFC, may be more helpful.”

As research continues, adds Bhanji, important areas to explore will include “figuring out when it’s worth continuing to keep trying and when it’s not.”