Study finds most teens avoid rash, impulsive behaviors

New UO-led research could reduce the worry for parents of teenagers. Most teens do have the behavioral brakes to keep their risk-taking experiments in check.

Only a subset of teens – those with weak cognitive control – engage in excessive levels of impulsiveness, such as acting without thinking, and end up struggling with addictions or other behavioral problem as young adults, said Atika Khurana, associate professor and director of graduate programs in the UO’s prevention science program.

Cognitive control is the ability to exert top-down control over behavior, thoughts and emotions. This ability, tied to executive functions, rests in the brain’s prefrontal cortex.

The findings, published in the Journal of Youth and Adolescence, challenge traditional thinking that adolescence is a time of universal imbalance, with kids lacking cognitive control and taking risks to reap instant rewards.

“People have heard so much about the teenage brain being all gas and no brakes, stemming from an imbalance between the reward and control regions of the brain,” Khurana said. “This study shows that this is not true. There is an imbalance for some youth, but it is not universal.”

Khurana and colleagues analyzed six waves of data collected from 387 adolescents, ages 11 to 18, in the Philadelphia area. They looked at changes in sensation-seeking and impulsivity during in the teenage years in relation to cognitive control and as predictors of substance use disorders in late adolescence.

Only those teens with weakness in cognitive control were at risk for impulsive behaviors, putting them at higher risk for substance abuse. While sensation-seeking did increase during teenage years, it was not associated with weakness in cognitive control or later substance abuse.

“Previous studies modeling changes in impulsivity and sensation seeking during adolescence drew conclusions based on age differences without looking at the same adolescents over time as they developed,” she said. “This study looked at individual trajectories and captured distinct patterns of change that were not otherwise observable when looking at youth at different ages.”

The study, funded by the National Institutes of Health, supported predictions of the Lifespan Wisdom Model developed by study co-author Daniel Romer of the University of Pennsylvania’s Annenberg Public Policy Center.

It also was in line with a series of published findings that have emerged from Khurana’s work with the same data, which began while she was a postdoctoral fellow at the Annenberg Public Policy Center.

In 2012, her group reported a positive association of working memory with sensation-seeking and a negative association with impulsivity. While children with sensation seeking engaged in exploratory forms of risk-taking, they were not getting stuck in unhealthy patterns of risk-taking.

Subsequently, the group has shown that weak working memory in combination with impulsivity can be used to predict trajectories of early alcohol use and risky sexual behavior in adolescents, and that adolescents with strong working memory are better equipped to escape early progression in drug use and avoid substance abuse issues.

The research, Khurana said, speaks to the need for greater emphasis on early interventions that can strengthen cognitive control.

Targeting a brain mechanism could treat aggression

A number of psychiatric disorders present with aggression and violence, which, needless to say, are destructive to both individuals and societies worldwide: death, disease, disability, and numerous socioeconomic problems can often be traced back to aggressive behavior.

But despite being common, aggression has proven very difficult to treat. Some pharmacological regimens can be of some help, but treatments repeatedly fail, while psychiatrists still consider certain types of aggression intractable. And a glance at daily news reveals that violence persists despite the best policies and sociocultural factors to address it.

On the level of biology, studies of the genomes of aggressive individuals have tried to identify molecules that might underlie aggression. The idea behind this is that if we were to identify molecular targets, we could potentially develop more effective treatments.

In a new study, scientists from EPFL’s Brain Mind Institute, led by Professor Carmen Sandi, have identified some of the key neurobiological mechanisms that control aggression. The scientists chose to study a special breed of mice that show symptoms of psychiatric disorders such as schizophrenia, autism, and bipolar disorder – all of which can involve aggressive behavior.

The main characteristic of these mice is that they lack the gene that produces an enzyme called ST8SIA2 (“knockout” mice). This enzyme produces polysialic acid, a sugar molecule that forms a complex with a group of sticky proteins on the surface of neurons and helps them migrate and connect, particularly during prenatal and early postnatal development – not only in mice, but humans as well.

Based on this, the researchers aimed to find out if the absence of ST8SIA2 – and therefore, polysialic acid during early development– affects aggressive and violent behavior in the mice. Unless provoked, mice are normally not aggressive, so it is easy to observe and measure deviations in behavior. Among other things in this study, the researchers measured the time it took the knockout mice to attack harmless opponents such as juvenile mice or females (if they did), and whether the attacks were directed to vulnerable body parts. They found that the knockout mice showed signs of abnormal aggressive behavior compared to healthy mice.

In addition, the team looked as well at two behavioral traits that are increased in certain types of aggression in humans and can be measured reliably in mice: Reduced fear processing and reduced anxiety. Both of these traits are known to be important in the emergence of abnormal aggression, especially in psychopathy and schizophrenia.

“Deficits in fear learning are typically found in individuals with psychopathy and aggressive individuals showing different psychopathologies,” Carmen Sandi points out. “These deficits have been hypothesized to promote antisocial behaviors, as they preclude individuals from learning from punishment and from following a normative socialization.”

Further examination of mice’s brains showed that these behavioral alterations are due to problems with the neurons of the amygdala, the brain’s center of emotional processing and emotional behavior. Specifically, the scientists found that the neurons of the amygdala in the knockout mice were largely unable to form new connections and showed impairments with glutamate neurotransmission, which transmits signals related to the processing of fear.

With further molecular studies, the team was able to identify a deficiency of a neuron receptor in the amygdala as a key element for developing aggression. The receptor is called NMDA (this particular one is called GluN2B-containing NMDA) and is involved in the connectivity of neurons as well as the proper formation of fear memories.

Armed with this discovery, the researchers proceeded to activate the NMDA receptor of the aggressive mice with a drug (D-cycloserine). The treatment was found to effectively reduce aggressive behavior as well as the associated low fear of the animals. Though a proof-of-concept at this stage, the finding opens up a potentially effective pharmaceutical target and treatment of aggression backed up by solid biological evidence.

“Our study underscores a key neurobiological mechanism that can explain the link between fear memory disturbances and the development of pathological aggression,” says Carmen Sandi. “A next logical step will be to investigate if our findings can help ameliorate aggressive dysfunctions in humans.”

Neuroscientists get at the roots of pessimism

Many patients with neuropsychiatric disorders such as anxiety or depression experience negative moods that lead them to focus on the possible downside of a given situation more than the potential benefit.

MIT neuroscientists have now pinpointed a brain region that can generate this type of pessimistic mood. In tests in animals, they showed that stimulating this region, known as the caudate nucleus, induced animals to make more negative decisions: They gave far more weight to the anticipated drawback of a situation than its benefit, compared to when the region was not stimulated. This pessimistic decision-making could continue through the day after the original stimulation.

The findings could help scientists better understand how some of the crippling effects of depression and anxiety arise, and guide them in developing new treatments.

“We feel we were seeing a proxy for anxiety, or depression, or some mix of the two,” says Ann Graybiel, an MIT Institute Professor, a member of MIT’s McGovern Institute for Brain Research, and the senior author of the study, which appears in the Aug. 9 issue of Neuron. “These psychiatric problems are still so very difficult to treat for many individuals suffering from them.”

The paper’s lead authors are McGovern Institute research affiliates Ken-ichi Amemori and Satoko Amemori, who perfected the tasks and have been studying emotion and how it is controlled by the brain. McGovern Institute researcher Daniel Gibson, an expert in data analysis, is also an author of the paper.

Emotional decisions

Graybiel’s laboratory has previously identified a neural circuit that underlies a specific kind of decision-making known as approach-avoidance conflict. These types of decisions, which require weighing options with both positive and negative elements, tend to provoke a great deal of anxiety. Her lab has also shown that chronic stress dramatically affects this kind of decision-making: More stress usually leads animals to choose high-risk, high-payoff options.

In the new study, the researchers wanted to see if they could reproduce an effect that is often seen in people with depression, anxiety, or obsessive-compulsive disorder. These patients tend to engage in ritualistic behaviors designed to combat negative thoughts, and to place more weight on the potential negative outcome of a given situation. This kind of negative thinking, the researchers suspected, could influence approach-avoidance decision-making.

To test this hypothesis, the researchers stimulated the caudate nucleus, a brain region linked to emotional decision-making, with a small electrical current as animals were offered a reward (juice) paired with an unpleasant stimulus (a puff of air to the face). In each trial, the ratio of reward to aversive stimuli was different, and the animals could choose whether to accept or not.

This kind of decision-making requires cost-benefit analysis. If the reward is high enough to balance out the puff of air, the animals will choose to accept it, but when that ratio is too low, they reject it. When the researchers stimulated the caudate nucleus, the cost-benefit calculation became skewed, and the animals began to avoid combinations that they previously would have accepted. This continued even after the stimulation ended, and could also be seen the following day, after which point it gradually disappeared.

This result suggests that the animals began to devalue the reward that they previously wanted, and focused more on the cost of the aversive stimulus. “This state we’ve mimicked has an overestimation of cost relative to benefit,” Graybiel says.

The study provides valuable insight into the role of the basal ganglia (a region that includes the caudate nucleus) in this type of decision-making, says Scott Grafton, a professor of neuroscience at the University of California at Santa Barbara, who was not involved in the research.

“We know that the frontal cortex and the basal ganglia are involved, but the relative contributions of the basal ganglia have not been well understood,” Grafton says. “This is a nice paper because it puts some of the decision-making process in the basal ganglia as well.”

A delicate balance

The researchers also found that brainwave activity in the caudate nucleus was altered when decision-making patterns changed. This change, discovered by Amemori, is in the beta frequency and might serve as a biomarker to monitor whether animals or patients respond to drug treatment, Graybiel says.

Graybiel is now working with psychiatrists at McLean Hospital to study patients who suffer from depression and anxiety, to see if their brains show abnormal activity in the neocortex and caudate nucleus during approach-avoidance decision-making. Magnetic resonance imaging (MRI) studies have shown abnormal activity in two regions of the medial prefrontal cortex that connect with the caudate nucleus.

The caudate nucleus has within it regions that are connected with the limbic system, which regulates mood, and it sends input to motor areas of the brain as well as dopamine-producing regions. Graybiel and Amemori believe that the abnormal activity seen in the caudate nucleus in this study could be somehow disrupting dopamine activity.

“There must be many circuits involved,” she says. “But apparently we are so delicately balanced that just throwing the system off a little bit can rapidly change behavior.”

(Image caption: Researchers believe that large cells called nucleus gigantocellularis neurons, pictured here, modulate blood flow by releasing nitric oxide)

Giant neurons in the brain may play similarly giant role in awareness and cognition

There is no shortage of wonders that our central nervous system produces—from thought and language to movement to the five senses. All of those dazzling traits, however, depend on an underappreciated deep brain mechanism that Donald Pfaff, head of the Laboratory of Neurobiology and Behavior at The Rockefeller University, calls generalized arousal, or GA for short. GA is what wakes us up in the morning and keeps us aware and in touch with ourselves and our environment throughout our conscious hours.

“It’s so fundamental that we don’t pay attention to it,” says Pfaff, “and yet it’s so important that we should.”

Pfaff and his team of researchers certainly do. Now, in a series of experiments involving a particular type of brain cell, they have advanced our understanding of the roots of consciousness. Their work may potentially prove relevant in the study of some psychiatric diseases.

The big cells in the black box

The findings, published in Proceedings of the National Academy of Sciences, shed light on an area of the brainstem that is so little understood the first author of the paper, Inna Tabansky, a research associate in Pfaff’s lab, calls it “the black box.” That term is certainly simpler than its actual name—the nucleus gigantocellularis (NGC), which is part of a structure called the medullary reticular formation.

In her work, using mice, Tabansky focused on a subtype of extremely large neurons in the NGC with links to virtually the entire nervous system, including the thalamus, where neurons can activate the entire cerebral cortex. “If you just look at the morphology of NGC neurons, you know they’re important,” Pfaff says. “It’s just a question of what they’re important for. I think they’re essential for the initiation of any behavior.”

To discover what role the NGC neurons might play in GA, Tabansky and her colleagues, including Joel Stern, a visiting professor in the Pfaff lab, began by identifying the genes that these neurons express. They used a technique known as “retro-TRAP,” developed in the lab of Rockefeller scientist Jeffrey Friedman.

To Tabansky’s surprise, the NGC neurons were found to express the gene for an enzyme, endothelial nitric oxide synthase (eNOS), which produces nitric oxide, which in turn relaxes blood vessels, increasing the flow of oxygenated blood to tissue. (No other neurons in the brain are known to produce eNOS.) They also discovered that the eNOS-expressing NGC neurons are located close to blood vessels.

In Pfaff’s view, the neurons are so critical for the normal functions of the central nervous system that they have evolved the ability to control their own blood supply directly. ‘“We’re pretty sure that if these neurons need more oxygen and glucose, they will release nitric oxide into these nearby blood vessels in order to get it,” he says.

The circumstances that would prompt such a response were the subject of further experiments. The scientists found evidence that changes in the environment, such as the introduction of novel scents, activated eNOS in the NGC neurons and produced increased amounts of nitric oxide in mice.

“There is some low level of production when the animal is in a familiar setting,” says Tabansky, “which is what you expect as they maintain arousal. But it is vastly increased when the animal is adapting to a new environment.” This activation of the NGC neurons supports the case for their central role in arousal, Tabansky says.

From cells to psychiatry

Going forward, Tabansky says she’s interested in exploring if their findings might help fill a gap in the understanding of certain disorders, such as bipolar disorder, suicidality, and ADHD. Some genetic research has implicated a role for the neurons she studied in these diseases, but the mechanism behind this link is not known.

“By showing that this gene and its associated pathways have a particular role, at least in the rodent brain, that relates to a fundamental function of the nervous system, is a hint about how this gene can cause psychiatric disease,” she says. “It’s very preliminary, and there is a lot more work to be done, but it potentially opens a new way to study how this gene can alter an individual’s psychology.”

How to Trigger Innate Fear Response?

When animals encounter danger, they usually respond to the situation in one of two ways: to freeze or to flee. How do they make this quick decision in a life or death moment?

According to KAIST neuroscientists, there are two types of fear: learned versus innate. The latter is known to be induced without any prior experience and is thus naturally encoded in the brain. A research team under Professor Jin-Hee Han in the Department of Biological Sciences identified the brain circuit responsible for regulating the innate fear response.

The study, which appeared in the July 24 issue of Nature Communications represents a significant step toward understanding how the neural circuits in the prefrontal cortex create behavioral responses to external threats. This also represents a new paradigm in therapeutic development for fear-related mental disorders.

Responses of freezing or fleeing when facing external threats reflect behavioral and physiological changes in an instinctive move to adapt to the new environment for survival. These responses are controlled by the emotional circuit systems of the brain and the malfunction of this circuit leads to fear-related disorders.

The anterior cingulate cortex (ACC) is a sub-region within the prefrontal cortex, comprising a part of the brain circuitry that regulates behavioral and physiological fear responses. This area is capable of high-order processing of the perceived sensory information and conveys ‘top-down’ information toward the amygdala and brainstem areas, known as the response outlet.

Many studies have already demonstrated that the brain regions in the prefrontal cortex regulate the response against learned threats. However, it has been unknown how innate responses against fear are encoded in the neural circuits in the prefrontal cortex.

Dr. Jinho Jhang, the lead author of the study explains how the team achieved their key idea. “Many overseas studies have already proved that the prefrontal cortex circuit works to regulate the fear response. However, researchers have paid little attention to the innate response against predators. Professor Han suggested we do research on the instinctive fear response instead of the learned response. We particularly focused on the anterior cingulate region, which has been connected with memory, pain, and sympathy, but not the fear response itself. Since we turned in this new direction, we have accumulated some significant data,” said Dr. Jhang.

For this study, Professor Han’s team investigated how mice react when exposed to the olfactory stimuli of predators. Based on the results of optogenetic manipulation, neural circuit tracing, and ex vivo slice electrophysiology experiments, the team demonstrated that the anterior cingulate cortex and its projection input to the basolateral amygdala play a role in the inhibitory regulation of innate fear responses to predators’ odors in mice.

Professor Han believes these results will extend the understanding of how instinctive fear responses can be encoded in our brain circuits. “Our findings will help to develop therapeutic treatments for mental disorders aroused from fear such as panic disorders and post-traumatic stress disorder,” said Professor Han.

(Image caption: A slight concentration gradient (0.4 percent) in netrin-1 (blue) induces a 71 percent difference in shootin1a phosphorylation (green) within growth cones. Credit: Naoyuki Inagaki)

How axons change chemical cues to mechanical force

While today’s technology is growing increasingly wireless, nature’s greatest technology, the human brain, still depends on neurons being directly connected to one another. Two neurons are connected when one extends its axon to the other. This extension is activated by chemical cues that causes the axon to exert a directional force towards the proper direction. While scientists have long known of different molecules that can act as cues, the molecules that initiate the force have remained a mystery. In a new study published in eLIFE, a team of Japanese and American scientists report that shootin1 is one such molecule and is essential for guiding the axon to its final destination.

Naoyuki Inagaki, Professor at the Nara Institute of Science and Technology (NAIST) and leader of the study, explains that there are two molecules that have vital roles in axon guidance.

“Nectin-1 is a well characterized axon guidance molecule. Shootin1 is a brain-specific protein involved in axon outgrowth.”

Concentration changes in nectin-1 cause an axon to change its direction of growth with such abruptness that under a microscope it almost seems like someone is controlling the axon with a steering wheel. However, just how big an effect shocked even the scientists.

“We found that a slight concentration gradient in netrin-1 of only 0.4% induces a 71% difference in shootin1a phosphorylation within growth cones,” says Dr. Kentarou Baba, who first-authored the study. “That is remarkable sensitivity.”

That means even if the difference between the amount of nectin-1 on the two sides of the growth cone was less than 1%, more than two-thirds of phosphorylated shootin1 would accumulate on the side with more nectin-1, and thus steer the axon to its proper direction.

Further, the phosphorylation significantly enhanced the binding of shootin1 to L1-CAM, a molecule which Inagaki says “are the wheels of the axon.”  The axons could still grow if the interaction between shootin1 and L1-CAM was disrupted, albeit at a slower velocity, but not in the direction signaled by the nectin-1 gradient.

“The direct interaction between shootin1 and L1-CAM generated the traction force for growth cone motility,” says Baba.

The findings suggest that shootin1 is a natural chemo-mechanical transducer, converting chemical information into mechanical output.

“Our findings suggest that the polarized phosphorylation of shootin1 within growth cones is required for the directional axon guidance induced by netrin-1 gradients,” says Inagaki.