Neuroscience

Articles and news from the latest research reports.

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(Figure 1: Axons grow and turn in response to guidance cues (arrows), which regulate endocytosis and exocytosis at the tips of growing axons. Credit: © 2014 T. Tojima et al.) Steering the filaments of the developing brain During brain development, nerve fibers grow and extend to form brain circuits. This growth is guided by molecular cues (Fig. 1), but exactly how these cues guide axon extension has been unclear. Takuro Tojima and colleagues from the RIKEN Brain Science Institute have now uncovered the signaling pathways responsible for turning growing nerve fibers, or axons, toward or away from guidance cues. The researchers previously showed that axon-repelling cues act by inducing the removal of cell membrane—a process called endocytosis—from the side of the axon closest to the repulsive cue. The enzyme PIPKIγ90 is known to be involved in endocytosis in axons during certain types of synaptic activity, so the researchers investigated whether PIPKIγ90 also played a role in endocytosis during axon turning. By examining the developing brains of chicken embryos expressing an inactive form of PIPKIγ90, the researchers found that cues normally inducing endocytosis were no longer effective in repelling axon growth. Cues that normally attract axons do so by driving membrane addition—exocytosis—on the side of the axon closest to the cue and also by suppressing endocytosis. Tojima’s team found that axons continued to be attracted to such cues even in the absence of PIPKIγ90, suggesting that PIPKIγ90 signaling is not involved in axon attraction. The activity of PIPKIγ90 is known to be regulated by an enzyme called CDK5, a subunit of which binds to the protein kinase CaMKII. The researchers found that by inhibiting CDK5 or CaMKII, and thereby blocking the regulation of PIPKIγ90 that is needed to suppress endocytosis, endocytosis could occur in response to attractive cues. They also found, however, that blocking CDK5 or CaMKII did not have any effect on endocytosis if the neurons expressed a mutant version of PIPKIγ90 that was unaffected by CDK5 and CaMKII signaling. As inhibitors of CDK5 or CaMKII did not alter endocytosis in response to repulsive cues, the team’s findings indicate that different signaling pathways are responsible for turning axons toward or away from guidance cues. Additionally, Tojima and his colleagues showed that they could induce the attraction of axons toward drugs that inhibit endocytosis, suggesting that being able to control the direction of axon growth has potential therapeutic applications. “We hope our findings will aid in the development of future therapeutic strategies for rewiring neuronal networks after spinal cord injury and neurodegenerative diseases,” explains Tojima.

(Figure 1: Axons grow and turn in response to guidance cues (arrows), which regulate endocytosis and exocytosis at the tips of growing axons. Credit: © 2014 T. Tojima et al.)

Steering the filaments of the developing brain

During brain development, nerve fibers grow and extend to form brain circuits. This growth is guided by molecular cues (Fig. 1), but exactly how these cues guide axon extension has been unclear. Takuro Tojima and colleagues from the RIKEN Brain Science Institute have now uncovered the signaling pathways responsible for turning growing nerve fibers, or axons, toward or away from guidance cues.

The researchers previously showed that axon-repelling cues act by inducing the removal of cell membrane—a process called endocytosis—from the side of the axon closest to the repulsive cue. The enzyme PIPKIγ90 is known to be involved in endocytosis in axons during certain types of synaptic activity, so the researchers investigated whether PIPKIγ90 also played a role in endocytosis during axon turning. By examining the developing brains of chicken embryos expressing an inactive form of PIPKIγ90, the researchers found that cues normally inducing endocytosis were no longer effective in repelling axon growth.

Cues that normally attract axons do so by driving membrane addition—exocytosis—on the side of the axon closest to the cue and also by suppressing endocytosis. Tojima’s team found that axons continued to be attracted to such cues even in the absence of PIPKIγ90, suggesting that PIPKIγ90 signaling is not involved in axon attraction.

The activity of PIPKIγ90 is known to be regulated by an enzyme called CDK5, a subunit of which binds to the protein kinase CaMKII. The researchers found that by inhibiting CDK5 or CaMKII, and thereby blocking the regulation of PIPKIγ90 that is needed to suppress endocytosis, endocytosis could occur in response to attractive cues.

They also found, however, that blocking CDK5 or CaMKII did not have any effect on endocytosis if the neurons expressed a mutant version of PIPKIγ90 that was unaffected by CDK5 and CaMKII signaling. As inhibitors of CDK5 or CaMKII did not alter endocytosis in response to repulsive cues, the team’s findings indicate that different signaling pathways are responsible for turning axons toward or away from guidance cues.

Additionally, Tojima and his colleagues showed that they could induce the attraction of axons toward drugs that inhibit endocytosis, suggesting that being able to control the direction of axon growth has potential therapeutic applications. “We hope our findings will aid in the development of future therapeutic strategies for rewiring neuronal networks after spinal cord injury and neurodegenerative diseases,” explains Tojima.

Filed under brain development endocytosis exocytosis neurons nerve fibers neuroscience science

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Study reveals one reason brain tumors are more common in men

New research at Washington University School of Medicine in St. Louis helps explain why brain tumors occur more often in males and frequently are more harmful than similar tumors in females. For example, glioblastomas, the most common malignant brain tumors, are diagnosed twice as often in males, who suffer greater cognitive impairments than females and do not survive as long.

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The researchers found that retinoblastoma protein (RB), a protein known to reduce cancer risk, is significantly less active in male brain cells than in female brain cells.

The study appears Aug. 1 in The Journal of Clinical Investigation.

“This is the first time anyone ever has identified a sex-linked difference that affects tumor risk and is intrinsic to cells, and that’s very exciting,” said senior author Joshua Rubin, MD, PhD. “These results suggest we need to go back and look at multiple pathways linked to cancer, checking for sex differences. Sex-based distinctions at the level of the cell may not only influence cancer risk but also the effectiveness of treatments.”

Rubin noted that RB is the target of drugs now being evaluated in clinical trials. Trial organizers hope the drugs trigger the protein’s anti-tumor effects and help cancer patients survive longer.

“In clinical trials, we typically examine data from male and female patients together, and that could be masking positive or negative responses that are limited to one sex,” said Rubin, who is an associate professor of pediatrics, neurology and anatomy and neurobiology. “At the very least, we should think about analyzing data for males and females separately in clinical trials.”

Scientists have identified many sex-linked diseases that either occur at different rates in males and females or cause different symptoms based on sex. These distinctions often are linked to sex hormones, which create and maintain many but not all of the biological differences between the sexes.

However, Rubin and his colleagues knew that sex hormones could not account for the differences in brain tumor risk.

“Male brain tumor risk remains higher throughout life despite major age-linked shifts in sex hormone production in males and females,” he said. “If the sex hormones were causing this effect, we’d see major changes in the relative rates of brain tumors in males and females at puberty. But they don’t happen then or later in life when menopause changes female sex hormone production.”

Rubin used a cell model of glioblastoma to prove it is easier to make male brain cells become tumors. After a series of genetic alterations and exposure to a growth factor, male brain cells became cancerous faster and more often than female brain cells.

In experiments designed to identify the reasons for the differences in the male and female cells, the team evaluated three genes to see if they were naturally less active in male brain cells. The genes they studied — neurofibromin, p53 and RB — normally suppress cell division and cell survival. They are mutated and disabled in many cancers.

The scientists found RB was more likely to be inactivated in male brain cells than in female brain cells. When they disabled the RB protein in female brain cells, the cells were equally susceptible to becoming cancers.

“There are other types of tumors that occur at different rates based on sex, such as some liver cancers, which occur more often in males,” Rubin said. “Knowing more about why cancer rates differ between males and females will help us understand basic mechanisms in cancer, seek more effective therapies and perform more informative clinical trials.”

(Source: news.wustl.edu)

Filed under brain tumours retinoblastoma glioblastoma sex differences sex hormones neuroscience science

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Potential basis for the treatment and prevention of Parkinson’s disease

Parkinson’s disease affects neurons in the Substantia nigra brain region – their mitochondrial activity ceases and the cells die. Researchers at the Max Planck Institute of Molecular Cell Biology and Genetics show that supplying D-lactate or glycolate, two products of the gene DJ-1, can stop and even counteract this process: Adding the substances to cultured HeLa cells and to cells of the nematode C. elegans restored the activity of mitochondria and prevented the degeneration of neurons. They also showed that the two substances rescued the toxic effects of the weed killer Paraquat. Cells that had been treated with this herbicide, which is known to cause a Parkinson’s like harm of mitochondria, recovered after the addition of the two substances. Both glycolic and D-lactic acids occur naturally in unripe fruits and certain kinds of yoghurt.

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(Image caption: Inactivation of the DJ-1 gene results in mitochondrial dysfunction (left), which can be restored by glycolate or D-lactate (right). Active mitochondria are shown in red, DNA is shown in blue. Credit: © MPI-CBG)

Teymuras Kurzchalia and Tony Hyman both have labs at the Max Planck Institute of Molecular Cell Biology and Genetics with rather different research programs – but both happened to stumble upon the gene DJ-1 and joined forces. This gene, originally thought of as an oncogene, has been linked to Parkinson’s disease since 2003. Recent studies showed that DJ-1 belongs to a novel glyxolase family. The major function of these genes is assumed to detoxify aggressive aldehyde by-products from mitochondrial metabolism. The Dresden research team now showed that the products of DJ-1, D-lactate and glycolate, are actually required to maintain the high mitochondrial potential and thus can prevent the degeneration of neurons implicated in Parkinson’s disease.

Their experiments proved that both substances are lifesavers for neurons: Adding them to affected cells, in other words cells treated with the environmental poison Paraquat or with a down-regulated DJ-1, decreased the toxic effect of the herbicide, restored the activity of the mitochondria and thus ensured the survival of the neurons.

„We do not yet understand how exactly D-lactate and glycolate achieve this curative and preventive effect, but the next step will be to investigate the molecular mechanism underlying this process”, say Hyman and Kurzchalia. In addition to further molecular investigation, they also have more concrete plans for the future: As Kurzchalia says “we can develop a yoghurt enriched with D-lactate: It could serve as a protection against Parkinson’s and is actually very tasty at the same time!“ This is why the researchers have filed a patent for their finding.

Many diseases are associated with a decline in mitochondrial activity, not only Parkinson’s. Thus, the researchers believe that the DJ1-products could have a general role in protecting cells from decline.

(Source: mpg.de)

Filed under parkinson's disease d-lactate glycolate dopaminergic neurons neuroscience science

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Study reveals brain mechanism behind chronic pain’s sapping of motivation

Chronic pain is among the most abundant of all medical afflictions in the developed world. It differs from a short-term episode of pain not only in its duration, but also in triggering in its sufferers a psychic exhaustion best described by the question, “Why bother?”

A new study in mice, conducted by investigators at the Stanford University School of Medicine, has identified a set of changes in key parts of the brain that may explain chronic pain’s capacity to stifle motivation. The discovery could lead to entirely new classes of treatment for this damaging psychological consequence of chronic pain.

Many tens of millions of people in the United States suffer persistent pain due to diverse problems including migraines, arthritis, lower back pain, sports injuries, irritable bowel syndrome and shingles. For many of these conditions, there are no good treatments, and a crippling loss of mojo can result.

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“With chronic pain, your whole life changes in a way that doesn’t happen with acute pain,” said Robert Malenka, MD, PhD, the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences and the study’s senior author. “Yet this absence of motivation caused by chronic pain, which can continue even when the pain is transiently relieved, has been largely ignored by medical science.”

A series of experiments in mice by Malenka and his colleagues, described in a study published Aug. 1 in Science, showed that persistent pain causes changes in a set of nerve cells in a deep-brain structure known to be important in reward-seeking behavior: the pursuit of goals likely to yield pleasurable results. Malenka’s lab has been studying this brain structure, the nucleus accumbens, for two decades.

“We showed that those brain changes don’t go away when you transiently relieve the mice’s pain,” Malenka said. The experiments also indicated that the mice’s diminished motivation to perform reward-generating tasks didn’t stem from their pain’s rendering them incapable of experiencing pleasure or from any accompanying physical impairment, he said.

How pain and reward interact

“This study is important — to my knowledge, the first to explain how pain and reward interact. It begins to get to an understanding of why it’s such a struggle for people undergoing chronic pain to get through the day,” said Howard Fields, MD, PhD, a professor of neurology at the University of California-San Francisco and founder of that school’s pain management center.

Fields, who did not participate in the Malenka group’s study but wrote an accompanying perspective piece published simultaneously in Science, described the psychological effect of chronic pain as “the clouding of the future. There’s no escape from it. You want it to end, but it doesn’t.” As a result, people become pessimistic and irritable, he said. “People come to expect the next day is going to wind up being painful. It just takes the edge off of life’s little pleasures — and big pleasures, for that matter.”

The experiments were spearheaded by the study’s first author, Neil Schwartz, PhD, a postdoctoral scholar in Malenka’s lab. “You can’t just ask a hungry mouse how motivated it is to pursue its heart’s desire,” Malenka said. “But there are ways of asking that mouse, ‘How hard are you willing to work for food?’”

Schwartz, Malenka and their associates looked at lab mice enduring chronic paw pain due either to persistent inflammation or to nerve damage. The mice also happened to be hungry. The scientists trained the mice to poke their noses into a hole to get a food pellet. At first, a single nose poke earned a pellet. But over time, the number of nose pokes required for a reward was increased. In essence, the researchers were asking these mice: How hard are you willing to work for food? Will you poke your nose into that hole once to satisfy your hunger? Ten times? Even 150 times?

Fading motivation

Within a week after the onset of chronic pain, the animals grew increasingly less likely to work hard for food than pain-free control animals were. The researchers next explored three possible explanations: Were the mice unable to work because their pain was too severe? Did something about being in pain cause them to not value the food reward as much? Or was their failure to seek food due simply to a lack of motivation? Additional tests showed that the mice had no movement problems. “Like other research groups, we found that they can scamper around just fine,” said Malenka. Also, when the mice were given free access to food, they ate just as much as the animals who weren’t in pain — so they still valued the food. But they were less willing to put in an effort to obtain food than mice who’d suffered no pain.

Moreover, the difference didn’t disappear even when the scientists relieved the mice’s pain with analgesics. “They were in demonstrably less pain, but they were still less willing to work,” Malenka said.

The Stanford scientists then focused on the nucleus accumbens, a brain structure known to be involved in computing the behavioral strategies that prompt us to seek or avoid things that can affect our survival. They found that chronic pain permanently changed certain connections to the nucleus accumbens, causing an enduring downshift in the excitation transmitted by them. Importantly, Malenka’s group showed that a particular brain chemical called galanin plays a critical role in this enduring suppression of nucleus accumbens excitability.

Galanin is a short signaling-protein snippet secreted by certain cells in various places in the brain. While its presence in the brain has been known for a good 60 years or so, galanin’s role is not well-defined and probably differs widely in different brain structures. There have been hints, though, that galanin activity might play a role in pain. For example, it’s been previously shown in animal models that galanin levels in the brain increase with the persistence of pain.

Possible therapies?

Schwartz, Malenka and their peers identified receptors for galanin on a set of nerve cells in the nucleus accumbens and demonstrated that disabling galanin’s signaling via this receptor prevented the long-term suppression of motivation seen in mice — and people — with chronic pain. This suggests that therapeutic compounds with similar effects could someday be developed, although they would have to be carefully targeted so as to not disrupt galanin signaling in other important brain circuits.

“There’s no reason to think this finding won’t generalize to people,” said Fields of UCSF. “Our brains have galanin, and a nucleus accumbens, just as mouse brains do. However, before jumping from mice to humans it would be wise to test other animal species. If the same things happen in a non-rodent species that happen in mice, then it’s probable they happen in humans, too.”

(Source: med.stanford.edu)

Filed under pain chronic pain motivation reward nucleus accumbens neuroscience science

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(Image caption: Positron-Emission-Tomography (PET) of a depressive patient without medication (left) with elevated monoamine-oxidase-A-levels (green, yellow, red) and after a six-week-treatment with the monoamine-oxidase-A-inhibitor moclobemid (right). Credit: © Sacher et al., 2011, J Psy Neurosci.) Monoamine oxidase A: biomarker for postpartum depression Many women suffer from baby blues after giving birth. Some even develop full-blown postpartum depression in the weeks that follow. Monoamine oxidase A, an enzyme responsible for the breakdown of neurotransmitters like dopamine and serotonin, plays an important role in this condition. In comparison to healthy women, women who experience postpartum depression present strongly elevated levels of the enzyme in their brains. This was discovered by a Canadian-German research team including Julia Sacher from the Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig. Their findings could help in the prevention of postpartum depression and in the development of new drugs for its treatment. For most women, the birth of their baby is one of the most strenuous but also happiest days in their lives. However, joy and happiness are often followed by fatigue and exhaustion. The vast majority of women experience a temporary drop in mood for a few days after birth. These symptoms of “baby blues” are not an illness; however, in some cases they can represent early signs of an imminent episode of depression: in 13 percent of mothers, the emotional turmoil experienced after childbirth leads to the development of a full-blown postpartum depression. Postpartum depression is harmful not only to the mother, but also to the baby. It is difficult to treat this condition effectively, as its precise neurobiological causes have remained unidentified to date. The new study shows that postpartum depression is accompanied by strongly elevated monoamine oxidase A in the brain, particularly in the prefrontal cortex and in the anterior cingulate cortex. In women with postpartum depression, the values recorded were 21 percent higher than those of women who were not plagued by negative feelings after giving birth. Women who did not develop full-blown depression but found themselves crying more often than usual due to depressed mood also presented moderately elevated values. “Therefore, we should promote strategies that help to reduce monoamine oxidase A levels in the brain, and avoid everything that makes these values rise,” explains Sacher. Such factors include heavy smoking, alcohol consumption and chronic stress, for example when the mother feels neglected and abandoned by her partner and family. “My ultimate goal is to provide women and their families with very concrete lifestyle recommendations that will enable them to prevent postpartum depression,” explains the psychiatrist. A new generation of long-established drugs could also play an important role in the treatment of postpartum depression in future. Up to now, depressed mothers are mainly given drugs that increase the concentration of serotonin in the brain. However, because monoamine oxidase A breaks down not only serotonin but also other monoamines like dopamine and noradrenaline, a treatment that directly targets monoamine oxidase A could have a higher success rate, particularly in very serious cases: this alternative is provided by selective and reversible monoamine-oxidase- A inhibitors. “The first monoamine oxidase inhibitors often had severe side effects, for example hypertensive crises, which necessitated adherence to a strict diet,” explains Sacher. “However, the new selective and reversible drugs are better tolerated,” she adds. In the next stage of this research involving clinical trials, the scientists intend to test the effectiveness of these reversible monoamine oxidase A inhibitors in the treatment of postpartum depression. Because the measurement of this enzyme in the brain requires complex technology, it is not suitable for routine testing. Thus, the researchers are also looking for a peripheral marker of this enzyme that can be detected in saliva or blood. Four years ago, Julia Sacher and her colleagues at the Centre for Addiction and Mental Health CAMH in Toronto already succeeded in showing that, in the first week postpartum, the concentration of the enzyme monoamine oxidase A in the brain is on average 40 percent higher than in women who had not recently given birth. “The monoamine oxidase A values behave in the opposite way to oestrogen levels. When oestrogen levels drop acutely after childbirth, the concentration of monoamine oxidase A rises. This drastic change also influences serotonin levels, known as the happiness hormone,” explains Dr. Sacher. In most women, the values quickly return to normal. In others, they remain raised – and thereby promote the development of depression.

(Image caption: Positron-Emission-Tomography (PET) of a depressive patient without medication (left) with elevated monoamine-oxidase-A-levels (green, yellow, red) and after a six-week-treatment with the monoamine-oxidase-A-inhibitor moclobemid (right). Credit: © Sacher et al., 2011, J Psy Neurosci.)

Monoamine oxidase A: biomarker for postpartum depression

Many women suffer from baby blues after giving birth. Some even develop full-blown postpartum depression in the weeks that follow. Monoamine oxidase A, an enzyme responsible for the breakdown of neurotransmitters like dopamine and serotonin, plays an important role in this condition. In comparison to healthy women, women who experience postpartum depression present strongly elevated levels of the enzyme in their brains. This was discovered by a Canadian-German research team including Julia Sacher from the Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig. Their findings could help in the prevention of postpartum depression and in the development of new drugs for its treatment.

For most women, the birth of their baby is one of the most strenuous but also happiest days in their lives. However, joy and happiness are often followed by fatigue and exhaustion. The vast majority of women experience a temporary drop in mood for a few days after birth. These symptoms of “baby blues” are not an illness; however, in some cases they can represent early signs of an imminent episode of depression: in 13 percent of mothers, the emotional turmoil experienced after childbirth leads to the development of a full-blown postpartum depression. Postpartum depression is harmful not only to the mother, but also to the baby. It is difficult to treat this condition effectively, as its precise neurobiological causes have remained unidentified to date.

The new study shows that postpartum depression is accompanied by strongly elevated monoamine oxidase A in the brain, particularly in the prefrontal cortex and in the anterior cingulate cortex. In women with postpartum depression, the values recorded were 21 percent higher than those of women who were not plagued by negative feelings after giving birth. Women who did not develop full-blown depression but found themselves crying more often than usual due to depressed mood also presented moderately elevated values.

“Therefore, we should promote strategies that help to reduce monoamine oxidase A levels in the brain, and avoid everything that makes these values rise,” explains Sacher. Such factors include heavy smoking, alcohol consumption and chronic stress, for example when the mother feels neglected and abandoned by her partner and family. “My ultimate goal is to provide women and their families with very concrete lifestyle recommendations that will enable them to prevent postpartum depression,” explains the psychiatrist.

A new generation of long-established drugs could also play an important role in the treatment of postpartum depression in future. Up to now, depressed mothers are mainly given drugs that increase the concentration of serotonin in the brain. However, because monoamine oxidase A breaks down not only serotonin but also other monoamines like dopamine and noradrenaline, a treatment that directly targets monoamine oxidase A could have a higher success rate, particularly in very serious cases: this alternative is provided by selective and reversible monoamine-oxidase- A inhibitors. “The first monoamine oxidase inhibitors often had severe side effects, for example hypertensive crises, which necessitated adherence to a strict diet,” explains Sacher. “However, the new selective and reversible drugs are better tolerated,” she adds. In the next stage of this research involving clinical trials, the scientists intend to test the effectiveness of these reversible monoamine oxidase A inhibitors in the treatment of postpartum depression.

Because the measurement of this enzyme in the brain requires complex technology, it is not suitable for routine testing. Thus, the researchers are also looking for a peripheral marker of this enzyme that can be detected in saliva or blood.

Four years ago, Julia Sacher and her colleagues at the Centre for Addiction and Mental Health CAMH in Toronto already succeeded in showing that, in the first week postpartum, the concentration of the enzyme monoamine oxidase A in the brain is on average 40 percent higher than in women who had not recently given birth. “The monoamine oxidase A values behave in the opposite way to oestrogen levels. When oestrogen levels drop acutely after childbirth, the concentration of monoamine oxidase A rises. This drastic change also influences serotonin levels, known as the happiness hormone,” explains Dr. Sacher. In most women, the values quickly return to normal. In others, they remain raised – and thereby promote the development of depression.

Filed under monoamine oxidase A postpartum depression neurotransmitters prefrontal cortex neuroscience science

106 notes

(Image credit: The insular cortex of an autism mouse model is already so strongly activated by a single sensory modality (here a sound), that it is unable to perform its role in integrating information from multiple sources. Credit: © MPI of Neurobiology / Gogolla) Insular cortex alterations in mouse models of autism The insular cortex is an integral “hub”, combining sensory, emotional and cognitive content. Not surprisingly, alterations in insular structure and function have been reported in many psychiatric disorders, such as anxiety disorders, depression, addiction and autism spectrum disorders (ASD). Scientists from Harvard University and the Max-Planck Institute of Neurobiology in Martinsried now describe consistent alterations in integrative processing of the insular cortex across autism mouse models of diverse etiologies. In particular, the delicate balance between excitation and inhibition in the autistic brains was disturbed, but could be pharmacologically re-adjusted. The results could help the development of novel diagnostic and therapeutic strategies. Autism is a neurodevelopmental disorder characterized by impaired social interaction, verbal and non-verbal communication, and by restricted and repetitive behaviors. Diagnosis is solely based on behavioral analysis as biological markers and neurological underpinnings remain unknown. This makes the development of novel therapeutic strategies extremely difficult.  As the cellular basis of autism spectrum disorders cannot be addressed in human patients, scientists have developed a number of mouse models for the disease. Similar to humans, mice are social animals and communicate through species-specific vocalizations. The mouse models harbor all diagnostic hallmark criteria of autism, such as repetitive, stereotypic behaviors and deficits in social interactions and communication. Nadine Gogolla and her colleagues in the laboratory of Takao Hensch at Harvard University have now searched for common neural circuit alterations in mouse models of autism. They concentrated on the insular cortex, a brain structure that contributes to social, emotional and cognitive functions. ‘We wanted to know whether we can detect differences in the way the insular cortex processes information in healthy or autism-like mice’, says Nadine Gogolla, who was recently appointed Leader of a Research Group at the Max Planck Institute of Neurobiology. As the researchers now report, the insular cortex of healthy mice integrates stimuli from different sensory modalities and reacts more strongly when two different stimuli are presented concomitantly (e.g. a sound and a touch). ‘We recognize a rose more easily when we smell and see it rather than when we just see or smell it’ says Nadine Gogolla. This capacity of combining sensory stimuli was consistently affected in all autism models the researchers looked at. Interestingly, often one sense alone elicited such a strong response that adding a second modality did not add further information. This is very reminiscent of the sensory hyper-responsiveness experienced by many autistic patients. The scientist further discovered that the insular cortex of adult autism-model mice resembled the activation patterns observed in very young control mice. ‘It seemed as if the insular cortex of the autism-models did not mature properly after birth’, says Gogolla. For proper brain function, excitation and inhibition have to be in equilibrium. In the now identified part of the insular cortex, the scientists found that this equilibrium was disturbed. In one of the mouse models, inhibitory contacts between nerve cells were strongly reduced. To test the influence of this reduction on sensory processing, the researchers gave mice the drug Diazepam, which is also known under the trade name Valium, to boost inhibitory transmission in the brain. Indeed, this treatment transiently rescued the capacity of the insular cortex to combine stimuli of different sensory modalities. The balance between excitation and inhibition in the brain is established after birth. The scientists thus treated young animals over several days with Diazepam. This treatment was efficient in reestablishing the insular cortex capacity for sensory integration permanently, even in adult mice that did not received any further treatment. Interestingly, also the stereotypic grooming of the animals was significantly reduced. All autism models investigated showed alterations in inhibitory molecules. However, the alterations were very diverse. While in some models certain molecules were reduced, the opposite was true in another model. These results suggest that the disequilibrium between excitation and inhibition may be an important factor in the neuropathology of autism. However, future therapies will need to be carefully tailored to each particular subgroup of autism. For instance, an artificial boost of inhibition through a drug like Diazepam in healthy mice can throw the delicate equilibrium off and create changes in the insular cortex similar to those seen in the autism models. Whether a therapeutic strategy aimed on keeping the brain’s equilibrium between excitation and inhibition could be useful and if so, how to test the individuals’ status of the excitation/inhibition balance and how to implement individually tailored treatments, would need to be established through further studies and pre-clinical tests.

(Image credit: The insular cortex of an autism mouse model is already so strongly activated by a single sensory modality (here a sound), that it is unable to perform its role in integrating information from multiple sources. Credit: © MPI of Neurobiology / Gogolla)

Insular cortex alterations in mouse models of autism

The insular cortex is an integral “hub”, combining sensory, emotional and cognitive content. Not surprisingly, alterations in insular structure and function have been reported in many psychiatric disorders, such as anxiety disorders, depression, addiction and autism spectrum disorders (ASD). Scientists from Harvard University and the Max-Planck Institute of Neurobiology in Martinsried now describe consistent alterations in integrative processing of the insular cortex across autism mouse models of diverse etiologies. In particular, the delicate balance between excitation and inhibition in the autistic brains was disturbed, but could be pharmacologically re-adjusted. The results could help the development of novel diagnostic and therapeutic strategies.

Autism is a neurodevelopmental disorder characterized by impaired social interaction, verbal and non-verbal communication, and by restricted and repetitive behaviors. Diagnosis is solely based on behavioral analysis as biological markers and neurological underpinnings remain unknown. This makes the development of novel therapeutic strategies extremely difficult. 

As the cellular basis of autism spectrum disorders cannot be addressed in human patients, scientists have developed a number of mouse models for the disease. Similar to humans, mice are social animals and communicate through species-specific vocalizations. The mouse models harbor all diagnostic hallmark criteria of autism, such as repetitive, stereotypic behaviors and deficits in social interactions and communication.

Nadine Gogolla and her colleagues in the laboratory of Takao Hensch at Harvard University have now searched for common neural circuit alterations in mouse models of autism. They concentrated on the insular cortex, a brain structure that contributes to social, emotional and cognitive functions. ‘We wanted to know whether we can detect differences in the way the insular cortex processes information in healthy or autism-like mice’, says Nadine Gogolla, who was recently appointed Leader of a Research Group at the Max Planck Institute of Neurobiology.

As the researchers now report, the insular cortex of healthy mice integrates stimuli from different sensory modalities and reacts more strongly when two different stimuli are presented concomitantly (e.g. a sound and a touch). ‘We recognize a rose more easily when we smell and see it rather than when we just see or smell it’ says Nadine Gogolla. This capacity of combining sensory stimuli was consistently affected in all autism models the researchers looked at. Interestingly, often one sense alone elicited such a strong response that adding a second modality did not add further information. This is very reminiscent of the sensory hyper-responsiveness experienced by many autistic patients. The scientist further discovered that the insular cortex of adult autism-model mice resembled the activation patterns observed in very young control mice. ‘It seemed as if the insular cortex of the autism-models did not mature properly after birth’, says Gogolla.

For proper brain function, excitation and inhibition have to be in equilibrium. In the now identified part of the insular cortex, the scientists found that this equilibrium was disturbed. In one of the mouse models, inhibitory contacts between nerve cells were strongly reduced.

To test the influence of this reduction on sensory processing, the researchers gave mice the drug Diazepam, which is also known under the trade name Valium, to boost inhibitory transmission in the brain. Indeed, this treatment transiently rescued the capacity of the insular cortex to combine stimuli of different sensory modalities. The balance between excitation and inhibition in the brain is established after birth. The scientists thus treated young animals over several days with Diazepam. This treatment was efficient in reestablishing the insular cortex capacity for sensory integration permanently, even in adult mice that did not received any further treatment. Interestingly, also the stereotypic grooming of the animals was significantly reduced.

All autism models investigated showed alterations in inhibitory molecules. However, the alterations were very diverse. While in some models certain molecules were reduced, the opposite was true in another model. These results suggest that the disequilibrium between excitation and inhibition may be an important factor in the neuropathology of autism. However, future therapies will need to be carefully tailored to each particular subgroup of autism. For instance, an artificial boost of inhibition through a drug like Diazepam in healthy mice can throw the delicate equilibrium off and create changes in the insular cortex similar to those seen in the autism models. Whether a therapeutic strategy aimed on keeping the brain’s equilibrium between excitation and inhibition could be useful and if so, how to test the individuals’ status of the excitation/inhibition balance and how to implement individually tailored treatments, would need to be established through further studies and pre-clinical tests.

Filed under insular cortex autism brain function diazepam animal model neuroscience science

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New Mapping Approach Lets Scientists Zoom In And Out As The Brain Processes Sound Researchers at Johns Hopkins have mapped the sound-processing part of the mouse brain in a way that keeps both the proverbial forest and the trees in view. Their imaging technique allows zooming in and out on views of brain activity within mice, and it enabled the team to watch brain cells light up as mice “called” to each other. The results, which represent a step toward better understanding how our own brains process language, appear online July 31 the journal Neuron. In the past, researchers often studied sound processing in various animal brains by poking tiny electrodes into the auditory cortex, the part of the brain that processes sound. They then played tones and observed the response of nearby neurons, laboriously repeating the process over a gridlike pattern to figure out where the active neurons were. The neurons seemed to be laid out in neatly organized bands, each responding to a different tone. More recently, a technique called two-photon microscopy has allowed researchers to focus in on minute slices of the live mouse brain, observing activity in unprecedented detail. This newer approach has suggested that the well-manicured arrangement of bands might be an illusion. But, says David Yue, M.D., Ph.D., a professor of biomedical engineering and neuroscience at the Johns Hopkins University School of Medicine, “You could lose your way within the zoomed-in views afforded by two-photon microscopy and not know exactly where you are in the brain.” Yue led the study along with Eric Young, Ph.D., also a professor of biomedical engineering and a researcher in Johns Hopkins’ Institute for Basic Biomedical Sciences. To get the bigger picture, John Issa, a graduate student in Yue’s lab, used a mouse genetically engineered to produce a molecule that glows green in the presence of calcium. Since calcium levels rise in neurons when they become active, neurons in the mouse’s auditory cortex glow green when activated by various sounds. Issa used a two-photon microscope to peer into the brains of live mice as they listened to sounds and saw which neurons lit up in response, piecing together a global map of a given mouse’s auditory cortex. “With these mice, we were able to both monitor the activity of individual populations of neurons and zoom out to see how those populations fit into a larger organizational picture,” he says. With these advances, Issa and the rest of the research team were able see the tidy tone bands identified in earlier electrode studies. In addition, the new imaging platform quickly revealed more sophisticated properties of the auditory cortex, particularly as mice listened to the chirps they use to communicate with each other. “Understanding how sound representation is organized in the brain is ultimately very important for better treating hearing deficits,” Yue says. “We hope that mouse experiments like this can provide a basis for figuring out how our own brains process language and, eventually, how to help people with cochlear implants and similar interventions hear better.” Yue notes that the same approach could also be used to understand other parts of the brain as they react to outside stimuli, such as the visual cortex and the parts of the brain responsible for processing stimuli from limbs.

New Mapping Approach Lets Scientists Zoom In And Out As The Brain Processes Sound

Researchers at Johns Hopkins have mapped the sound-processing part of the mouse brain in a way that keeps both the proverbial forest and the trees in view. Their imaging technique allows zooming in and out on views of brain activity within mice, and it enabled the team to watch brain cells light up as mice “called” to each other. The results, which represent a step toward better understanding how our own brains process language, appear online July 31 the journal Neuron.

In the past, researchers often studied sound processing in various animal brains by poking tiny electrodes into the auditory cortex, the part of the brain that processes sound. They then played tones and observed the response of nearby neurons, laboriously repeating the process over a gridlike pattern to figure out where the active neurons were. The neurons seemed to be laid out in neatly organized bands, each responding to a different tone. More recently, a technique called two-photon microscopy has allowed researchers to focus in on minute slices of the live mouse brain, observing activity in unprecedented detail. This newer approach has suggested that the well-manicured arrangement of bands might be an illusion. But, says David Yue, M.D., Ph.D., a professor of biomedical engineering and neuroscience at the Johns Hopkins University School of Medicine, “You could lose your way within the zoomed-in views afforded by two-photon microscopy and not know exactly where you are in the brain.” Yue led the study along with Eric Young, Ph.D., also a professor of biomedical engineering and a researcher in Johns Hopkins’ Institute for Basic Biomedical Sciences.

To get the bigger picture, John Issa, a graduate student in Yue’s lab, used a mouse genetically engineered to produce a molecule that glows green in the presence of calcium. Since calcium levels rise in neurons when they become active, neurons in the mouse’s auditory cortex glow green when activated by various sounds. Issa used a two-photon microscope to peer into the brains of live mice as they listened to sounds and saw which neurons lit up in response, piecing together a global map of a given mouse’s auditory cortex. “With these mice, we were able to both monitor the activity of individual populations of neurons and zoom out to see how those populations fit into a larger organizational picture,” he says.

With these advances, Issa and the rest of the research team were able see the tidy tone bands identified in earlier electrode studies. In addition, the new imaging platform quickly revealed more sophisticated properties of the auditory cortex, particularly as mice listened to the chirps they use to communicate with each other. “Understanding how sound representation is organized in the brain is ultimately very important for better treating hearing deficits,” Yue says. “We hope that mouse experiments like this can provide a basis for figuring out how our own brains process language and, eventually, how to help people with cochlear implants and similar interventions hear better.”

Yue notes that the same approach could also be used to understand other parts of the brain as they react to outside stimuli, such as the visual cortex and the parts of the brain responsible for processing stimuli from limbs.

Filed under sound processing brain activity auditory cortex hearing neuroscience science

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Noise-Induced Hearing Loss Alters Brain Responses to Speech Prolonged exposure to loud noise alters how the brain processes speech, potentially increasing the difficulty in distinguishing speech sounds, according to neuroscientists at The University of Texas at Dallas. In a paper published this week in Ear and Hearing, researchers demonstrated for the first time how noise-induced hearing loss affects the brain’s recognition of speech sounds. Noise-induced hearing loss (NIHL) reaches all corners of the population, affecting an estimated 15 percent of Americans between the ages of 20 and 69, according to the National Institute of Deafness and Other Communication Disorders (NIDCD). Exposure to intensely loud sounds leads to permanent damage of the hair cells, which act as sound receivers in the ear. Once damaged, the hair cells do not grow back, leading to NIHL. “As we have made machines and electronic devices more powerful, the potential to cause permanent damage has grown tremendously,” said Dr. Michael Kilgard, co-author and Margaret Fonde Jonsson Professor in the School of Behavioral and Brain Sciences. “Even the smaller MP3 players can reach volume levels that are highly damaging to the ear in a matter of minutes.” Before the study, scientists had not clearly understood the direct effects of NIHL on how the brain responds to speech. To simulate two types of noise trauma that clinical populations face, UT Dallas scientists exposed rats to moderate or intense levels of noise for an hour. One group heard a high-frequency noise at 115 decibels inducing moderate hearing loss, and a second group heard a low-frequency noise at 124 decibels causing severe hearing loss. For comparison, the American Speech-Language-Hearing Association lists the maximum output of an MP3 player or the sound of a chain saw at about 110 decibels and the siren on an emergency vehicle at 120 decibels. Regular exposure to sounds greater than 100 decibels for more than a minute at a time may lead to permanent hearing loss, according to the NIDCD. Researchers observed how the two types of hearing loss affected speech sound processing in the rats by recording the neuronal response in the auditory cortex a month after the noise exposure. The auditory cortex, one of the main areas that processes sounds in the brain, is organized on a scale, like a piano. Neurons at one end of the cortex respond to low-frequency sounds, while other neurons at the opposite end react to higher frequencies. In the group with severe hearing loss, less than one-third of the tested auditory cortex sites that normally respond to sound reacted to stimulation. In the sites that did respond, there were unusual patterns of activity. The neurons reacted slower, the sounds had to be louder and the neurons responded to frequency ranges narrower than normal. Additionally, the rats could not tell the speech sounds apart in a behavioral task they could successfully complete before the hearing loss. In the group with moderate hearing loss, the area of the cortex responding to sounds didn’t change, but the neurons’ reaction did. A larger area of the auditory cortex responded to low-frequency sounds. Neurons reacting to high frequencies needed more intense sound stimulation and responded slower than those in normal hearing animals. Despite these changes, the rats were still able to discriminate the speech sounds in a behavioral task. “Although the ear is critical to hearing, it is just the first step of many processing stages needed to hold a conversation,” Kilgard said. “We are beginning to understand how hearing damage alters the brain and makes it hard to process speech, especially in noisy environments.”

Noise-Induced Hearing Loss Alters Brain Responses to Speech

Prolonged exposure to loud noise alters how the brain processes speech, potentially increasing the difficulty in distinguishing speech sounds, according to neuroscientists at The University of Texas at Dallas.

In a paper published this week in Ear and Hearing, researchers demonstrated for the first time how noise-induced hearing loss affects the brain’s recognition of speech sounds.

Noise-induced hearing loss (NIHL) reaches all corners of the population, affecting an estimated 15 percent of Americans between the ages of 20 and 69, according to the National Institute of Deafness and Other Communication Disorders (NIDCD).

Exposure to intensely loud sounds leads to permanent damage of the hair cells, which act as sound receivers in the ear. Once damaged, the hair cells do not grow back, leading to NIHL.

“As we have made machines and electronic devices more powerful, the potential to cause permanent damage has grown tremendously,” said Dr. Michael Kilgard, co-author and Margaret Fonde Jonsson Professor in the School of Behavioral and Brain Sciences. “Even the smaller MP3 players can reach volume levels that are highly damaging to the ear in a matter of minutes.”

Before the study, scientists had not clearly understood the direct effects of NIHL on how the brain responds to speech.

To simulate two types of noise trauma that clinical populations face, UT Dallas scientists exposed rats to moderate or intense levels of noise for an hour. One group heard a high-frequency noise at 115 decibels inducing moderate hearing loss, and a second group heard a low-frequency noise at 124 decibels causing severe hearing loss.

For comparison, the American Speech-Language-Hearing Association lists the maximum output of an MP3 player or the sound of a chain saw at about 110 decibels and the siren on an emergency vehicle at 120 decibels. Regular exposure to sounds greater than 100 decibels for more than a minute at a time may lead to permanent hearing loss, according to the NIDCD.

Researchers observed how the two types of hearing loss affected speech sound processing in the rats by recording the neuronal response in the auditory cortex a month after the noise exposure. The auditory cortex, one of the main areas that processes sounds in the brain, is organized on a scale, like a piano. Neurons at one end of the cortex respond to low-frequency sounds, while other neurons at the opposite end react to higher frequencies.

In the group with severe hearing loss, less than one-third of the tested auditory cortex sites that normally respond to sound reacted to stimulation. In the sites that did respond, there were unusual patterns of activity. The neurons reacted slower, the sounds had to be louder and the neurons responded to frequency ranges narrower than normal. Additionally, the rats could not tell the speech sounds apart in a behavioral task they could successfully complete before the hearing loss.

In the group with moderate hearing loss, the area of the cortex responding to sounds didn’t change, but the neurons’ reaction did. A larger area of the auditory cortex responded to low-frequency sounds. Neurons reacting to high frequencies needed more intense sound stimulation and responded slower than those in normal hearing animals. Despite these changes, the rats were still able to discriminate the speech sounds in a behavioral task.

“Although the ear is critical to hearing, it is just the first step of many processing stages needed to hold a conversation,” Kilgard said. “We are beginning to understand how hearing damage alters the brain and makes it hard to process speech, especially in noisy environments.”

Filed under hearing loss auditory cortex hair cells speech sounds neuroscience science

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New research links anxiety to epilepsy-like seizures

New research by clinical psychologists from Arizona State University and the United Kingdom has revealed seizures that could be mistaken for epilepsy are linked to feelings of anxiety.

The team of researchers devised a new set of tests to determine whether there was a link between how people interpret and respond to anxiety, and incidences of psychogenic nonepileptic seizures (PNES).

Nicole Roberts, an associate professor in ASU’s New College of Interdisciplinary Arts and Sciences, collaborated with colleagues from the University of Lincoln, University of Nottingham and University of Sheffield in the United Kingdom. The team’s findings were published in the journal Epilepsy and Behavior.

The researchers used a series of questionnaires and computer tests to determine if a patient regularly avoids situations which might bring on anxiety.

These tests correctly predicted whether a patient had epilepsy or PNES – seizures that can be brought on by threatening situations, sensations, emotions, thoughts or memories – in 83 percent of study participants. Such seizures appear on the surface to be similar to epileptic fits, which are caused by abnormal brain activity.

“This research underscores the fact that PNES is a ‘real’ and disabling disorder with a potentially identifiable pathophysiology,” said Roberts, who directs New College’s Emotion, Culture, and Psychophysiology Laboratory, located on ASU’s West campus. “We need to continue to search for answers, not just in epilepsy clinics, but also in the realm of affective science and complex brain-behavior relationships.”

“PNES can be a very disabling condition, and it is important that we understand the triggers so that we provide the correct care and treatment,” said Lian Dimaro, a clinical psychologist based at Nottinghamshire Healthcare NHS Trust, who served as lead researcher for the study.

“This study was one of the first to bring modern psychological tools of investigation to this problem,” Dimaro said. “The findings support the idea that increasing a person’s tolerance of unpleasant emotions and reducing avoidant behavior may help with treatment, suggesting that patients could benefit from a range of therapies, including acceptance and commitment therapy to help reduce the frequency of seizures, although more research is needed in this area.”

Participants completed questionnaires to determine the level to which they suffered from anxiety, their awareness of their experiences and if they would avoid situations which would make them feel anxious.

They then completed a computer task which required rapid responses to true or false statements. This test was designed to gather data on immediate, or implicit, beliefs about anxiety. Participants also answered questions about common physical complaints that may have no medical explanation, also called somatic symptoms. These can include things like gastrointestinal problems, tiredness and back pain.

Results showed that those with PNES reported significantly more somatic symptoms than others in the study, as well as avoidance of situations which might make them anxious. The group with PNES also scored significantly higher on a measure of how aware they were of their anxiety compared with the control group.

The test subjects were 30 adults with PNES, 25 with epilepsy and 31 with no reported history of seizures who served as a nonclinical control group.

The researchers suggest that including tests to determine levels of anxiety and avoidance behavior may enable health professionals to make earlier diagnosis, and develop more effective intervention plans.

“Epileptic seizures are caused by abnormal electrical activity in the brain, while most PNES are thought to be a consequence of complex psychological processes that manifest in physical attacks,” said David Dawson, a research clinical psychologist from the University of Lincoln.

“It is believed that people suffering with PNES may have difficulty actively engaging with anxiety – a coping style known as experiential avoidance,” Dawson said. “We wanted to examine whether it was possible to make a clear link between seizure frequency and how people experience and manage anxiety. Our study is another step in understanding PNES, which could ultimately lead to better treatment and, therefore, patient outcomes in the future.”

Roberts, who received her doctorate in clinical psychology from the University of California, Berkeley, focuses her research on the study of emotion and on the cultural and biological forces that shape emotional responses. Examples include investigating how ethnicity and culture influence emotional displays and experiences; how the daily hassles of life, such as job stress and sleep deprivation, impact emotion regulation among individuals and couples; and how the emotion system breaks down in patients with psychopathology (such as PNES and post-traumatic stress disorder) or neurological dysfunction (such as epilepsy).

(Source: asunews.asu.edu)

Filed under anxiety psychogenic nonepileptic seizures seizures brain activity epilepsy neuroscience science

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ucsdhealthsciences: Birthday Matters for Wiring-Up the Brain’s Vision Centers Researchers at the University of California, San Diego School of Medicine have evidence suggesting that neurons in the developing brains of mice are guided by a simple but elegant birth order rule that allows them to find and form their proper connections. The study is published online July 31 in Cell Reports. “Nothing about brain wiring is haphazard,” said senior author Andrew Huberman, PhD, assistant professor in the Department of Neurosciences, Division of Biological Sciences and Department of Ophthalmology, UC San Diego. A mature, healthy brain has billions of precisely interconnected neurons. Yet the brain starts with just one neuron that divides and divides – up to 250,000 new neurons per minute at times during early development. The question for biologists has been how do these neurons decide which other neurons to connect to, a process neuroscientists call target selection. The answer has both fundamental scientific value and clinical relevance. Some researchers believe that autism and other disorders linked to brain development may be caused, in part, by a failure of neurons to properly reposition their axons as needed when mistakes in target selection occur. To better understand how a young brain gets wired, researchers focused on the development of retinal ganglion cells (RGCs) in mice. These cells connect the eyes and brain. Specifically, the main cell bodies of RGCs reside in the retina but their axons – slender projections along which electrical impulses travel – extend into the centers of the brain that process visual information and give rise to what we commonly think of as “sight,” as well as other light-influenced physiological processes, such as the effect of light on mood. For the study, scientists tagged RGCs and watched where they directed their axons during development. The experiments revealed that specific types of RGCs target specific areas of the brain, allowing mice to do things such as sense direction of motion, move their eyes and detect changes in daily light cycles. It was also observed that some types of RGCs (such as those that detect brightness and control pupil constriction) are created early in development while others (such as those controlling eye movements) are created later. The study’s main finding is that early RGCs (those created early in the sequence of brain division) make a lot of connections to other neurons and a lot of mistakes, which they then correct by repositioning or removing their axons. By contrast, later RGCs were observed to be highly accurate in their target selection skills and made almost no errors. “The neurons are paying attention to when they were born and reading out which choices they should make based on their birthdate,” said Jessica Osterhout, a doctoral student in biology and the study’s lead author. “It seems to all boil down to birthdate.” The idea that timing is important for cell differentiation is a classic principle of developmental biology, but this study is among the first to show that the timing of neuronal generation is linked to how neurons achieve specific brain wiring. In addition to clarifying normal brain development, researchers plan to examine the role of time-dependent wiring mishaps in models of human disorders, such as autism and schizophrenia, as well as diseases specific to the visual system, such as congenital blindness. “We want to know if in diseases such as autism neurons are made out of order and as a result get confused about which connections to make,” Huberman said.

ucsdhealthsciences:

Birthday Matters for Wiring-Up the Brain’s Vision Centers

Researchers at the University of California, San Diego School of Medicine have evidence suggesting that neurons in the developing brains of mice are guided by a simple but elegant birth order rule that allows them to find and form their proper connections.

The study is published online July 31 in Cell Reports.

“Nothing about brain wiring is haphazard,” said senior author Andrew Huberman, PhD, assistant professor in the Department of Neurosciences, Division of Biological Sciences and Department of Ophthalmology, UC San Diego.

A mature, healthy brain has billions of precisely interconnected neurons. Yet the brain starts with just one neuron that divides and divides – up to 250,000 new neurons per minute at times during early development. The question for biologists has been how do these neurons decide which other neurons to connect to, a process neuroscientists call target selection.

The answer has both fundamental scientific value and clinical relevance. Some researchers believe that autism and other disorders linked to brain development may be caused, in part, by a failure of neurons to properly reposition their axons as needed when mistakes in target selection occur.

To better understand how a young brain gets wired, researchers focused on the development of retinal ganglion cells (RGCs) in mice. These cells connect the eyes and brain. Specifically, the main cell bodies of RGCs reside in the retina but their axons – slender projections along which electrical impulses travel – extend into the centers of the brain that process visual information and give rise to what we commonly think of as “sight,” as well as other light-influenced physiological processes, such as the effect of light on mood.

For the study, scientists tagged RGCs and watched where they directed their axons during development. The experiments revealed that specific types of RGCs target specific areas of the brain, allowing mice to do things such as sense direction of motion, move their eyes and detect changes in daily light cycles. It was also observed that some types of RGCs (such as those that detect brightness and control pupil constriction) are created early in development while others (such as those controlling eye movements) are created later.

The study’s main finding is that early RGCs (those created early in the sequence of brain division) make a lot of connections to other neurons and a lot of mistakes, which they then correct by repositioning or removing their axons. By contrast, later RGCs were observed to be highly accurate in their target selection skills and made almost no errors.

“The neurons are paying attention to when they were born and reading out which choices they should make based on their birthdate,” said Jessica Osterhout, a doctoral student in biology and the study’s lead author. “It seems to all boil down to birthdate.”

The idea that timing is important for cell differentiation is a classic principle of developmental biology, but this study is among the first to show that the timing of neuronal generation is linked to how neurons achieve specific brain wiring.

In addition to clarifying normal brain development, researchers plan to examine the role of time-dependent wiring mishaps in models of human disorders, such as autism and schizophrenia, as well as diseases specific to the visual system, such as congenital blindness.

“We want to know if in diseases such as autism neurons are made out of order and as a result get confused about which connections to make,” Huberman said.

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