Childhood’s end: ADHD, autism and schizophrenia tied to stronger inhibitory interactions in adolescent prefrontal cortex

Key cognitive functions such as working memory (which combines temporary storage and manipulation of information) and executive function (a set of mental processes that helps connect past experience with present action) are associated with the brain’s prefrontal cortex. Unlike other brain regions, the prefrontal cortex does not mature until early adulthood, with the most pronounced changes being seen between its peripubertal (onset of puberty) and postpubertal developmental states. Moreover, this maturation period is correlated with cognitive maturation – but the physical neuronal changes during this transition have remained for the most part unknown. Recently, however, scientists at the Wake Forest School of Medicine in Winston-Salem, NC recorded and compared prefrontal cortical activity peripubertal and adult monkeys.

The researchers found that compared with adults, peripubertal monkeys showed lower connectivity due to stronger inhibitory interactions, suggesting that intrinsic (or resting state) inhibitory connections – that is, inhibitory neural connections that are active in the absence of any particular task – decline with maturation. The scientists then concluded that prefrontal intrinsic connectivity changes are a possible substrate for cognitive maturation.

Prof. Christos Constantinidis discusses the paper that he, Dr. Xin Zhou and their co-authors published in Proceedings of the National Academy of Sciences. When comparing the functional connectivity between pairs of neurons in neuronal activity recorded from the prefrontal cortex of peripubertal and adult monkeys and evaluating the developmental stage of peripubertal rhesus monkeys with a series of morphometric, hormonal, and radiographic measures, Constantinidis tells Medical Xpress that a major challenge was to obtain neural activity from the brain of monkeys around the time of puberty. “We needed to make ourselves experts in the developmental trajectories of monkeys and conduct experiments just at the right time relative to the onset of puberty,” he explains.

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Image caption: An image of the left and right sided habenular nuclei of larval zebrafish showing left/right structural asymmetries in the processes of neurons (pink) and their connections (blue). (Credit: Ana Faro/Tom Hawkins/Steve Wilson/UCL)

Brain asymmetry improves processing of sensory information

Fish that have symmetric brains show defects in processing information about sights and smells, according to the results of a new study into how asymmetry in the brain affects processing of sensory information.

It’s widely believed that the left and right sides of the brain have slightly different roles in cognition and in regulating behaviour. However, scientists don’t know whether these asymmetries actually matter for the efficient functioning of the brain.

Now, a team from UCL and KU Leuven, Belgium has shown that, in zebrafish at least, loss of brain asymmetry can have significant consequences on sensory processing, raising the possibility that defects in the development of brain functions on either the left or right on the brain could cause cognitive dysfunction. The study is published today in Current Biology.

Professor Steve Wilson, senior author of the study from the UCL Department of Cell & Developmental Biology, said: “We don’t know whether asymmetries actually matter for the efficient functioning of the brain. For instance, if your brain was symmetric, would it work any less well than it normally does?

“This is potentially an important issue as brain-imaging studies in various neurological conditions have shown alterations in normally asymmetric patterns of neuronal activity.”

In their study the team used two-photon high resolution microscopy to image the activity of individual neurons in a part of the brain called the habenulae in larval zebrafish. This region of the brain shows asymmetries in many different vertebrates and is involved in mediating addiction, fear and reward pathways and probably influences numerous behaviour patterns.

In zebrafish habenulae most neurons responding to a light stimulus are on the left whereas most responding to odour are on the right. Using this knowledge to their advantage, scientists bred fish in which habenular asymmetry was reversed and fish with double-right and double-left sided habenulae. They then asked how the habenular neurons responded to visual or olfactory stimuli in these different conditions. 

They found that if the direction of brain asymmetry was reversed, the functional properties of the habenular neurons were also reversed, whereas double-left and double-right sided brains almost completely lacked habenular responsiveness to odour or light respectively.

Dr Elena Dreosti, first author of the study, also from UCL Department of Cell & Developmental Biology, said: “These results show that loss of brain asymmetry can have significant consequences upon sensory processing and circuit function”.

The research raises the possibility that defects in the establishment of brain lateralization could indeed be causative of cognitive or other symptoms of brain dysfunction.

Worry on the Brain

According to the National Institute of Mental Health, over 18 percent of American adults suffer from anxiety disorders, characterized as excessive worry or tension that often leads to other physical symptoms. Previous studies of anxiety in the brain have focused on the amygdala, an area known to play a role in fear. But a team of researchers led by biologists at the California Institute of Technology (Caltech) had a hunch that understanding a different brain area, the lateral septum (LS), could provide more clues into how the brain processes anxiety. Their instincts paid off—using mouse models, the team has found a neural circuit that connects the LS with other brain structures in a manner that directly influences anxiety.

"Our study has identified a new neural circuit that plays a causal role in promoting anxiety states," says David Anderson, the Seymour Benzer Professor of Biology at Caltech, and corresponding author of the study. "Part of the reason we lack more effective and specific drugs for anxiety is that we don’t know enough about how the brain processes anxiety. This study opens up a new line of investigation into the brain circuitry that controls anxiety."

The team’s findings are described in the January 30 version of the journal Cell.

Led by Todd Anthony, a senior research fellow at Caltech, the researchers decided to investigate the so-called septohippocampal axis because previous studies had implicated this circuit in anxiety, and had also shown that neurons in a structure located within this axis—the LS—lit up, or were activated, when anxious behavior was induced by stress in mouse models. But does the fact that the LS is active in response to stressors mean that this structure promotes anxiety, or does it mean that this structure acts to limit anxiety responses following stress? The prevailing view in the field was that the nerve pathways that connect the LS with different brain regions function as a brake on anxiety, to dampen a response to stressors. But the team’s experiments showed that the exact opposite was true in their system.

In the new study, the team used optogenetics—a technique that uses light to control neural activity—to artificially activate a set of specific, genetically identified neurons in the LS of mice. During this activation, the mice became more anxious. Moreover, the researchers found that even a brief, transient activation of those neurons could produce a state of anxiety lasting for at least half an hour. This indicates that not only are these cells involved in the initial activation of an anxious state, but also that an anxious state persists even after the neurons are no longer being activated.

"The counterintuitive feature of these neurons is that even though activating them causes more anxiety, the neurons are actually inhibitory neurons, meaning that we would expect them to shut off other neurons in the brain," says Anderson, who is also an investigator with the Howard Hughes Medical Institute (HHMI).

So, if these neurons are shutting off other neurons in the brain, then how can they increase anxiety? The team hypothesized that the process might involve a double-inhibitory mechanism: two negatives make a positive. When they took a closer look at exactly where the LS neurons were making connections in the brain, they saw that they were inhibiting other neurons in a nearby area called the hypothalamus. Importantly, most of those hypothalamic neurons were, themselves, inhibitory neurons. Moreover, those hypothalamic inhibitory neurons, in turn, connected with a third brain structure called the paraventricular nucleus, or PVN. The PVN is well known to control the release of hormones like cortisol in response to stress and has been implicated in anxiety.

This anatomical circuit seemed to provide a potential double-inhibitory pathway through which activation of the inhibitory LS neurons could lead to an increase in stress and anxiety. The team reasoned that if this hypothesis were true, then artificial activation of LS neurons would be expected to cause an increase in stress hormone levels, as if the animal were stressed. Indeed, optogenetic activation of the LS neurons increased the level of circulating stress hormones, consistent with the idea that the PVN was being activated. Moreover, inhibition of LS projections to the hypothalamus actually reduced the rise in cortisol when the animals were exposed to stress. Together these results strongly supported the double-negative hypothesis.

"The most surprising part of these findings is that the outputs from the LS, which were believed primarily to act as a brake on anxiety, actually increase anxiety," says Anderson.

Knowing the sign—positive or negative—of the effect of these cells on anxiety, he says, is a critical first step to understanding what kind of drug one might want to develop to manipulate these cells or their molecular constituents. If the cells had been found to inhibit anxiety, as originally thought, then one would want to find drugs that activate these LS neurons, to reduce anxiety. However, since the group found that these neurons instead promote anxiety, then to reduce anxiety a drug would have to inhibit these neurons.

"We are still probably a decade away from translating this very basic research into any kind of therapy for humans, but we hope that the information that this type of study yields about the brain will put the field and medicine in a much better position to develop new, rational therapies for psychiatric disorders," says Anderson. "There have been very few new psychiatric drugs developed in the last 40 to 50 years, and that’s because we know so little about the brain circuitry that controls the emotions that go wrong in a psychiatric disorder like depression or anxiety."

The team will continue to map out this area of the brain in greater detail to understand more about its role in controlling stress-induced anxiety.

"There is no shortage of new questions that have been raised by these findings," Anderson says. "It may seem like all that we’ve done here is dissect a tiny little piece of brain circuitry, but it’s a foothold onto a very big mountain. You have to start climbing someplace."

Researchers reveal more about how our brains control our arms

Ready, set, go.

Sometimes that’s how our brains work. When we anticipate a physical act, such as reaching for the keys we noticed on the table, the neurons that control the task adopt a state of readiness, like sprinters bent into a crouch.

Other times, however, our neurons must simply react, such as if someone were to toss us the keys without gesturing first, to prepare us to catch.

How do the neurons in the brain control planned versus unplanned arm movements?

Krishna Shenoy, a Stanford professor of electrical engineering, neurobiology (by courtesy) and bioengineering (affiliate), wanted to answer that question as part of his group’s ongoing efforts to develop and improve brain-controlled prosthetic devices.

In a paper published today in the journal Neuron, Shenoy and first author Katherine Cora Ames, a doctoral student in the Neurosciences Graduate Program, present a mathematical analysis of the brain activity of monkeys as they make anticipated and unanticipated reaching motions.

Monitoring the neurons

The experimental data came from recording the electrical activity of neurons in the brain that control motor and premotor functions. The idea was to observe and understand the activity levels of these neurons during experiments in which the monkeys made planned or reactive arm movements. What the researchers found is that when the monkeys knew what arm movement they were supposed to make and were simply waiting for the cue to act, electrical readings showed that the neurons went into what scientists call the prepare-and-hold state – the brain’s equivalent of ready, set, waiting for the cue to go.

But when the monkeys made unplanned or unexpected movements, the neurons did not go through the expected prepare-and-hold state. “This was a surprise,” Ames said.

Before the experiment, the researchers had believed that a prepare-and-hold state had to precede movement. In short, they thought the neurons had to go into a “ready, set” crouch before acting on the “go” command. But they discovered otherwise in three variations of an experiment involving similar arm movements.

Experimental design

In all three cases, the monkeys were trained to touch a target that appeared on a display screen.

During each motion, the researchers measured the electrical activity of the neurons in control of arm movements.

In one set of experiments, the monkeys were shown the target but were trained not to touch it until they got the “go” signal. This is called a delayed reach experiment. It served as the planned action.

In a second set of experiments the monkeys were trained to touch the target as soon as it appeared. This served as the unplanned action.

In a third variant, the position of the target was changed. It briefly appeared in one location on the screen. The target then reappeared in a different location. This required the monkeys to revise their movement plan.

Monkey see, then monkey do

Ames said that, in all three instances, the first information to reach the neurons was awareness of the target.

“Perception always occurred first,” Ames said.

Then, about 50 milliseconds later, some differences appeared in the data. When the monkeys had to wait for the go command, the brain recordings showed that the neurons went into a discernable prepare-and-hold state. But in the other two cases, the neurons did not enter the prepare-and-hold state.

Instead, roughly 50 milliseconds after the electrical readings showed evidence of perception, a change in neuronal activity signaled the command to touch the target; it came with no apparent further preparation between perception and action. “Ready, set” was unnecessary. In these instances, the neurons just said, “Go!”

Applications

“This study changes our view of how movement is controlled,” Ames said. “First you get the information about where to move. Then comes the decision to move. There is no specific prepare-and-hold stage unless you are waiting for the signal to move.”

These nuanced understandings are important to Shenoy. His lab develops and improves electronic systems that can convert neural activity into electronic signals in order to control a prosthetic arm or move the cursor on a computer screen.

One example of such efforts is the BrainGate clinical trial here at Stanford, now being conducted under U.S. Food & Drug Administration supervision, to test the safety of brain-controlled, computer cursor systems – “think-and-click” communication for people who can’t move.

“In addition to advancing basic brain science, these new findings will lead to better brain-controlled prosthetic arms and communication systems for people with paralysis,” Shenoy said.

How the brain makes myelination activity-dependent

A major question regarding how axons acquire a coat of myelin, is the role of spiking activity. It is known that in culture systems oligodendrocytes will at least try to wrap anything that feels like an axon—even dead axons and artificial tubes. As axons acquire additional layers of myelin they conduct signals faster, and presumably become more efficient. It would therefore seem logical that the nervous system should apportion the most myelin to those neurons that are seeing the greatest activity. In that way the brain gets the most bang for its buck, energetically speaking. A new study in PLOS Biology suggests that while myelination is in many cases activity-independent at first, neurons can significantly ramp things up by flipping various molecular switches, one which appears to be Neuregulin (NRG).

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Findings Could Help Explain Origins of Human Limb Control

We might have more in common with a lamprey than we think, according to a new Northwestern University study on locomotion. At its core, the study of transparent zebrafish addresses a fundamental evolution issue: How did we get here?

Neuroscientists Martha W. Bagnall and David L. McLean have found that the spinal cord circuits that produce body bending in swimming fish are more complicated than previously thought.

Vertebrate locomotion has evolved from the simple left-right bending of the body exemplified by lampreys to the appearance of fins in bony fish to the movement of humans, with the complex nerve and muscle coordination necessary to move four limbs.

Bagnall and McLean report that differential control of an animal’s musculature — the basic template for controlling more complex limbs — is already in place in the spinal networks of simple fish. Neural circuits in zebrafish are completely segregated: individual neurons map to specific muscles.

Specifically, the neural circuits that drive muscle movement on the dorsal (or back) side are separate from the neural circuits activating muscles on the ventral (or front) side. This is in addition to the fish being able to separately control the left and right sides of its body [Video]

Ultimately, understanding more about how fish swim will allow scientists to figure out how humans walk.

“Evolution builds on pre-existing patterns, and this is a critical piece of the puzzle,” McLean said. “Our data help clarify how the transition from water to land could have been accomplished by simple changes in the connections of spinal networks.”

The findings will be published Jan. 10 in the journal Science. McLean, an assistant professor of neurobiology in the Weinberg College of Arts and Sciences, and Bagnall, a postdoctoral fellow in his research group who made the discovery, are authors of the paper.

“This knowledge will put us in a better position to devise more effective therapies for when things go wrong with neural circuits in humans, such as spinal cord damage,” McLean said. “If you want to fix something, you have to know how it works in the first place. Given that the fish spinal cord works in a similar fashion to our own, this makes it a fantastic model system for research.”

McLean and Bagnall studied the motor neurons of baby zebrafish because the fish develop quickly and are see-through. They used state-of-art imaging techniques to monitor and manipulate neuronal activity in the fish.

“You can stare right into the nervous system,” McLean said. “It’s quite remarkable.”

The separate circuits for moving the left and right and top and bottom of the fish allow the animal to twist its body upright when it senses that it has rolled too far to one side or the other.

“This arrangement is perfectly suited to provide rapid postural control during swimming,” Bagnall said. “Importantly, this ancestral pattern of spinal cord organization may also represent an early functional template for the origins of limb control.”

Separate control of dorsal and ventral muscles in the fish body is a possible predecessor to separate control of extensors and flexors in human limbs. By tweaking the connections between these circuits as they elaborated during evolution, it is easier to explain how more complicated patterns of motor coordination in the limbs and trunk could have arisen during dramatic evolutionary changes in the vertebrate body plan, the researchers said.

“We are teasing apart basic components of locomotor circuits,” McLean said. “The molecular mechanisms responsible for building spinal circuits are conserved in all animals, so this study provides a nice hypothesis that scientists can test.”

A novel look at how stories may change the brain

Many people can recall reading at least one cherished story that they say changed their life. Now researchers at Emory University have detected what may be biological traces related to this feeling: Actual changes in the brain that linger, at least for a few days, after reading a novel.

Their findings, that reading a novel may cause changes in resting-state connectivity of the brain that persist, were published by the journal Brain Connectivity.

“Stories shape our lives and in some cases help define a person,” says neuroscientist Gregory Berns, lead author of the study and the director of Emory’s Center for Neuropolicy. “We want to understand how stories get into your brain, and what they do to it.”

His co-authors included Kristina Blaine and Brandon Pye from the Center for Neuropolicy, and Michael Prietula, professor of information systems and operations management at Emory’s Goizueta Business School.

Neurobiological research using functional magnetic resonance imaging (fMRI) has begun to identify brain networks associated with reading stories. Most previous studies have focused on the cognitive processes involved in short stories, while subjects are actually reading them as they are in the fMRI scanner.

The Emory study focused on the lingering neural effects of reading a narrative. Twenty-one Emory undergraduates participated in the experiment, which was conducted over 19 consecutive days.

All of the study subjects read the same novel, “Pompeii,” a 2003 thriller by Robert Harris that is based on the real-life eruption of Mount Vesuvius in ancient Italy. “The story follows a protagonist, who is outside the city of Pompeii and notices steam and strange things happening around the volcano,” Berns says. “He tries to get back to Pompeii in time to save the woman he loves. Meanwhile, the volcano continues to bubble and nobody in the city recognizes the signs.”

The researchers chose the book due to its page-turning plot. “It depicts true events in a fictional and dramatic way,” Berns says. “It was important to us that the book had a strong narrative line.”

For the first five days, the participants came in each morning for a base-line fMRI scan of their brains in a resting state. Then they were given nine sections of the novel, about 30 pages each, over a nine-day period. They were asked to read the assigned section in the evening, and come in the following morning. After taking a quiz to ensure they had finished the assigned reading, the participants underwent an fMRI scan of their brain in a non-reading, resting state. After completing all nine sections of the novel, the participants returned for five more mornings to undergo additional scans in a resting state.

The results showed heightened connectivity in the left temporal cortex, an area of the brain associated with receptivity for language, on the mornings following the reading assignments. “Even though the participants were not actually reading the novel while they were in the scanner, they retained this heightened connectivity,” Berns says. “We call that a ‘shadow activity,’ almost like a muscle memory.”

Heightened connectivity was also seen in the central sulcus of the brain, the primary sensory motor region of the brain. Neurons of this region have been associated with making representations of sensation for the body, a phenomenon known as grounded cognition. Just thinking about running, for instance, can activate the neurons associated with the physical act of running.

“The neural changes that we found associated with physical sensation and movement systems suggest that reading a novel can transport you into the body of the protagonist,” Berns says. “We already knew that good stories can put you in someone else’s shoes in a figurative sense. Now we’re seeing that something may also be happening biologically.”

The neural changes were not just immediate reactions, Berns says, since they persisted the morning after the readings, and for the five days after the participants completed the novel.

“It remains an open question how long these neural changes might last,” Berns says. “But the fact that we’re detecting them over a few days for a randomly assigned novel suggests that your favorite novels could certainly have a bigger and longer-lasting effect on the biology of your brain.”

Mapping objects in the brain

The ability to recognize objects in the environment is mediated by the brain’s ability to integrate and process massive amounts of visual information. A research group led by Takayuki Sato and Manabu Tanifuji from the RIKEN Brain Science Institute has now discovered that in macaque monkeys, this remarkable ability is supported by mosaic-like structures in the anterior inferior temporal (IT) cortex, where localized clusters of neurons encode different visual features in an organized hierarchy. 

Two competing models have been proposed to explain the functional organization of brain regions that underlies object recognition in primates. One model states that discrete brain ‘modules’ process stimuli from particular categories, such as faces, with object recognition arising from communication among the modules. The other model postulates that the visual cortex extracts generic features, which are then composited to recognize specific objects. Since both models are based on measurements of functional signals produced by metabolic changes associated with neural activity rather than measurements of the neuronal activity itself, the precise underlying mechanism responsible for object recognition has remained unclear.

To resolve this debate, the researchers undertook dense electrophysiological mapping of neural activity in anesthetized macaque monkeys exposed to a series of color images from different object categories: faces, hands, bodies, food and various other objects. Sato and his colleagues directly recorded neuronal activity from multiple locations within the anterior IT cortex, which allowed them to track the location of neurons that responded to a particular object category.

The team found that some regions responded best to faces and others to monkey bodies. While there were also regions that responded worst to faces, none appeared to respond preferentially to hands, food or manufactured items.

Interestingly, small neuron clusters within a region appeared to be selective to different facial features, responding differently to human and monkey faces and to scrambled and normal faces. This indicates that a region in the anterior IT cortex that is selective for an object category consists of smaller-scale neuron clusters that are selective for particular visual features.

“The cortical mosaics that encode visual information seem to be efficient functional structures where object-category information and information about constituent features are represented within the limited space of the brain,” explains Sato. “This could also be the way that the brain organizes information in other sensory modalities, such as hearing.” If the results are also found to extend to humans, they may offer insight into the visual recognition of objects and the development of language.

Neurons subtract images and use the differences

Efficient reduction of data volumes

Researchers have hitherto assumed that information supplied by the sense of sight was transmitted almost in its entirety from its entry point to higher brain areas, across which visual sensation is generated. “It was therefore a surprise to discover that the data volumes are considerably reduced as early as in the primary visual cortex, the bottleneck leading to the cerebrum,” says PD Dr Dirk Jancke from the Institute for Neural Computation at the Ruhr-Universität. “We intuitively assume that our visual system generates a continuous stream of images, just like a video camera. However, we have now demonstrated that the visual cortex suppresses redundant information and saves energy by frequently forwarding image differences.”

Plus or minus: the brain’s two coding strategies

The researchers recorded the neurons’ responses to natural image sequences, for example vegetation landscapes or buildings. They created two versions of the images: a complete one and one in which they had systematically removed certain elements, specifically vertical or horizontal contours. If the time elapsing between the individual images was short, i.e. 30 milliseconds, the neurons represented complete image information. That changed when the time elapsing in the sequences was longer than 100 milliseconds. Now, the neurons represented only those elements that were new or missing, namely image differences. “When we analyse a scene, the eyes perform very fast miniature movements in order to register the fine details,” explains Nora Nortmann, postgraduate student at the Institute of Cognitive Science at the University of Osnabrück and the RUB work group Optical Imaging. The information regarding those details are forwarded completely and immediately by the primary visual cortex. “If, on the other hand, the time elapsing between the gaze changes is longer, the cortex codes only those aspects in the images that have changed,” continues Nora Nortmann. Thus, certain image sections stand out and interesting spots are easier to detect, as the researchers speculate.

“Our brain is permanently looking into the future”

This study illustrates how activities of visual neurons are influenced by past events. “The neurons build up a short-term memory that incorporates constant input,” explains Dirk Jancke. However, if something changes abruptly in the perceived image, the brain generates a kind of error message on the basis of the past images. Those signals do not reflect the current input, but the way the current input deviates from the expectations. Researchers have hitherto postulated that this so-called predictive coding only takes place in higher brain areas. “We demonstrated that the principle applies for earlier phases of cortical processing, too,” concludes Jancke. “Our brain is permanently looking into the future and comparing current input with the expectations that arose based on past situations.”

Observing brain activities in millisecond range

In order to monitor the dynamics of neuronal activities in the brain in the millisecond range, the scientists used voltage-dependent dyes. Those substances fluoresce when neurons receive electrical impulses and become active. Thanks to a high-resolution camera system and the subsequent computer-aided analysis, the neuronal activity can be measured across a surface of several square millimetres. The result is a temporally and spatially precise film of transmission processes within neuronal networks.

Bibliographic record

N. Nortmann, S. Rekauzke, S. Onat, P. König, D. Jancke (2013): Primary visual cortex represents the difference between past and present, Cerebral Cortex