Neuroscience

Articles and news from the latest research reports.

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Imaging Technique Shows Brain Anatomy Change in Women with Multiple Sclerosis, Depression

A multicenter research team led by Cedars-Sinai neurologist Nancy Sicotte, MD, an expert in multiple sclerosis and state-of-the-art imaging techniques, used a new, automated technique to identify shrinkage of a mood-regulating brain structure in a large sample of women with MS who also have a certain type of depression.

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In the study, women with MS and symptoms of “depressive affect” – such as depressed mood and loss of interest – were found to have reduced size of the right hippocampus. The left hippocampus remained unchanged, and other types of depression – such as vegetative depression, which can bring about extreme fatigue – did not correlate with hippocampal size reduction, according to an article featured on the cover of the January 2014 issue of Human Brain Mapping.

The research supports earlier studies suggesting that the hippocampus may contribute to the high frequency of depression in multiple sclerosis. It also shows that a computerized imaging technique called automated surface mesh modeling can readily detect thickness changes in subregions of the hippocampus. This previously required a labor-intensive manual analysis of MRI images.

Sicotte, the article’s senior author, and others have previously found evidence of tissue loss in the hippocampus, but the changes could only be documented in manual tracings of a series of special high-resolution MRI images. The new approach can use more easily obtainable MRI scans and it automates the brain mapping process.

“Patients with medical disorders – and especially those with inflammatory diseases such as MS – often suffer from depression, which can cause fatigue. But not all fatigue is caused by depression. We believe that while fatigue and depression often co-occur in patients with MS, they may be brought about by different biological mechanisms. Our studies are designed to help us better understand how MS-related depression differs from other types, improve diagnostic imaging systems to make them more widely available and efficient, and create better, more individualized treatments for our patients,” said Sicotte, director of Cedars-Sinai’s Multiple Sclerosis Program and the Neurology Residency Program. She received a $506,000 grant from the National Multiple Sclerosis Society last year to continue this research.

(Source: newswise.com)

Filed under brain imaging MS depression hippocampus neuroimaging neuroscience science

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Scientists Discover New Genetic Forms of Neurodegeneration

ucsdhealthsciences:

In a study published in the January 31, 2014 issue of Science, an international team led by scientists at the University of California, San Diego School of Medicine report doubling the number of known causes for the neurodegenerative disorder known as hereditary spastic paraplegia. HSP is characterized by progressive stiffness and contraction of the lower limbs and is associated with epilepsy, cognitive impairment, blindness and other neurological features.

Over several years, working with scientific colleagues in parts of the world with relatively high rates of consanguinity or common ancestry, UC San Diego researchers recruited a cohort of more than 50 families displaying autosomal recessive HSP – the  largest such cohort assembled to date. The scientists analyzed roughly 100 patients from this cohort using a technique called whole exome sequencing, which focuses on mapping key portions of the genome. They identified a genetic mutation in almost 75 percent of the cases, half of which were in genes never before linked with human disease.

“After uncovering so many novel genetic bases of HSP, we were in the unique position to investigate how these causes link together. We were able to generate an ‘HSP-ome,’ a map that included all of the new and previously described causes,” said senior author Joseph G. Gleeson, MD, Howard Hughes Medical Institute investigator, professor in the UC San Diego departments of Neurosciences and Pediatrics and at Rady Children’s Hospital-San Diego, a research affiliate of UC San Diego.

The HSP-ome helped researchers locate and validate even more genetic mutations in their patients, and indicated key biological pathways underlying HSP. The researchers were also interested in understanding how HSP relates to other groups of disorders. They found that the HSP-ome links HSP to other more common neurodegenerative disorders, such as Alzheimer’s disease and amyotrophic lateral sclerosis.

“Knowing the biological processes underlying neurodegenerative disorders is seminal to driving future scientific studies that aim to uncover the exact mechanisms implicated in common neurodegenerative diseases, and to indicate the path toward development of effective treatments,” said Gleeson.

“I believe this study is important for the neurodegenerative research community,” said co-lead author Gaia Novarino, PhD, a post-doctoral scholar in Gleeson’s lab.  “But more broadly, it offers an illustrative example of how, by utilizing genomics in specific patient populations, and then building an ‘interactome,’ we greatly expand knowledge around unknown causes of disease.”

“This is very exciting since identifying the biological processes in neurological disorders is the first step toward the development of new treatments,” agreed co-lead author Ali G. Fenstermaker. “We identified several promising targets for development of new treatments.”

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A shock to the system: Electroconvulsive Therapy shows mood disorder-specific therapeutic benefits The oldest well-established procedure for somatic treatment of unipolar and bipolar disorders, electroconvulsive therapy (ECT) has, at best, a variegated reputation – and not just in its reputation for being a “barbaric” treatment modality (which, as it turns out, it is not). The scientific, clinical, and ethical controversy extends to unanswered questions about its precise mechanism of action – that is, how major electrical discharge over half the brain shows efficacy in recovery from a range of sometimes quite distinct psychological and psychiatric disorders. Recently, however, scientists at Université de Lausanne, Lausanne, Switzerland and Charité University Medicine, Berlin, Germany found local but not general anatomical brain changes following electroconvulsive therapy that are differently distributed in each disease, and are actually the areas believed to be abnormal in each disorder. Since interaction between ECT and specific pathology appears to be therapeutically causal, the researchers state that their results have implications for deep brain stimulation, transcranial magnetic stimulation and other electrically-based brain treatments. Prof. Bogdan Draganski discussed the paper that he, Dr. Juergen Dukart and their co-authors published in Proceedings of the National Academy of Sciences. Read more

A shock to the system: Electroconvulsive Therapy shows mood disorder-specific therapeutic benefits

The oldest well-established procedure for somatic treatment of unipolar and bipolar disorders, electroconvulsive therapy (ECT) has, at best, a variegated reputation – and not just in its reputation for being a “barbaric” treatment modality (which, as it turns out, it is not). The scientific, clinical, and ethical controversy extends to unanswered questions about its precise mechanism of action – that is, how major electrical discharge over half the brain shows efficacy in recovery from a range of sometimes quite distinct psychological and psychiatric disorders. Recently, however, scientists at Université de Lausanne, Lausanne, Switzerland and Charité University Medicine, Berlin, Germany found local but not general anatomical brain changes following electroconvulsive therapy that are differently distributed in each disease, and are actually the areas believed to be abnormal in each disorder. Since interaction between ECT and specific pathology appears to be therapeutically causal, the researchers state that their results have implications for deep brain stimulation, transcranial magnetic stimulation and other electrically-based brain treatments.

Prof. Bogdan Draganski discussed the paper that he, Dr. Juergen Dukart and their co-authors published in Proceedings of the National Academy of Sciences.

Read more

Filed under electroconvulsive therapy mood disorders deep brain stimulation depression neuroscience psychology science

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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."

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."

Filed under anxiety disorders anxiety septohippocampal axis optogenetics neural activity hypothalamus neuroscience science

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UCSF Team Reveals How the Brain Recognizes Speech Sounds UC San Francisco researchers are reporting a detailed account of how speech sounds are identified by the human brain, offering an unprecedented insight into the basis of human language. The finding, they said, may add to our understanding of language disorders, including dyslexia. Scientists have known for some time the location in the brain where speech sounds are interpreted, but little has been discovered about how this process works. Now, in the Jan. 30 edition of Science Express, the fast-tracked online version of the journal Science, the UCSF team reports that the brain does not respond to the individual sound segments known as phonemes – such as the b sound in “boy” – but is instead exquisitely tuned to detect simpler elements, which are known to linguists as “features.” This organization may give listeners an important advantage in interpreting speech, the researchers said, since the articulation of phonemes varies considerably across speakers, and even in individual speakers over time. Read more

UCSF Team Reveals How the Brain Recognizes Speech Sounds

UC San Francisco researchers are reporting a detailed account of how speech sounds are identified by the human brain, offering an unprecedented insight into the basis of human language.

The finding, they said, may add to our understanding of language disorders, including dyslexia.

Scientists have known for some time the location in the brain where speech sounds are interpreted, but little has been discovered about how this process works.

Now, in the Jan. 30 edition of Science Express, the fast-tracked online version of the journal Science, the UCSF team reports that the brain does not respond to the individual sound segments known as phonemes – such as the b sound in “boy” – but is instead exquisitely tuned to detect simpler elements, which are known to linguists as “features.”

This organization may give listeners an important advantage in interpreting speech, the researchers said, since the articulation of phonemes varies considerably across speakers, and even in individual speakers over time.

Read more

Filed under language disorders dyslexia speech sounds phonemes psychology neuroscience science

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Aging brains need ‘chaperone’ proteins

The word “chaperone” refers to an adult who keeps teenagers from acting up at a dance or overnight trip. It also describes a type of protein that can guard the brain against its own troublemakers: misfolded proteins that are involved in several neurodegenerative diseases.

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Researchers at Emory University School of Medicine have demonstrated that as animals age, their brains are more vulnerable to misfolded proteins, partly because of a decline in chaperone activity.

The researchers were studying a model of spinocerebellar ataxia, but the findings have implications for understanding other diseases, such as Alzheimer’s, Parkinson’s and Huntington’s. They also identified targets for potential therapies: bolstering levels of either a particular chaperone or a growth factor in brain cells can protect against the toxic effects of misfolded proteins.

The results were published this week in the journal Neuron.

Scientists led by Shihua Li, MD, and Xiao-Jiang Li, MD, PhD devised a system in which production of a misfolding-prone protein that causes a form of spinocerebellar ataxia can be triggered artificially in mice at various ages. Both Li’s are professors of human genetics at Emory University School of Medicine. The first author of the paper is BCDB graduate student Su Yang.

Spinocerebellar ataxia is an inherited neurodegenerative disease in which patients develop gait problems and a loss of coordination in mid-life, because of atrophy of the cerebellum. There are several types, each caused by a mutation in a different gene.

Most of the mutations that cause spinocerebellar ataxia involve an expansion of a “polyglutamine repeat" in a protein. Having the same protein building block (the amino acid glutamine) repeated dozens of times alters the protein’s function and makes it more likely to misfold and clump together. The misfolded proteins are toxic and interfere with the normal forms of the same protein.

Huntington’s disease is caused by a similar polyglutamine repeat. Misfolded proteins also play roles in Alzheimer’s and Parkinson’s, although their production is not driven by an inherited polyglutamine repeat in those diseases.

Li’s team was trying to distinguish between two possibilities. One was that the duration of mutant protein accumulation is important for disease severity; aging might allow more misfolded proteins to accumulate and become toxic over time.

Instead, the scientists observed that older animals develop disease more quickly after mutant protein production is triggered. The mutant protein accumulates more quickly in 9- and 14-month old mice than in 3-month old mice, suggesting that aged neurons are more vulnerable to the effects of the misfolded protein.

Chaperones are proteins whose job is to “prevent improper liaisons" between other proteins; they prevent the sticky regions of proteins from grabbing something they’re not supposed to. Li’s team identified a particular chaperone called Hsc70 whose activity declines with age in the brain, while others’ activity does not.

To confirm Hsc70’s importance, the researchers showed that boosting cells’ levels of Hsc70 can bolster their ability to cope with misfolded proteins. Injecting mice in the cerebellum with a virus that forces cells to make more Hsc70 can slow degeneration. The researchers found that the mutant protein interferes with production of a growth factor called MANF (mesenchephalic astrocyte-derived neurotrophic factor) in the cerebellum and that Hsc70 can prevent this interference. Injection of a virus that forces cells to make more MANF can also slow degeneration.

Potentially, small molecules that increase Hsc70 or MANF levels could be used for treating spinocerebellar ataxia, says Xiao-Jiang Li.

(Source: news.emory.edu)

Filed under aging chaperone neurodegenerative diseases spinocerebellar ataxia cerebellum neuroscience science

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CC to the brain: How neurons control fine motor behavior of the arm Motor commands issued by the brain to activate arm muscles take two different routes. As the research group led by Professor Silvia Arber at the Basel University Biozentrum and the Friedrich Miescher Institute for Biomedical Research has now discovered, many neurons in the spinal cord send their instructions not only towards the musculature, but at the same time also back to the brain via an exquisitely organized network. This dual information stream provides the neural basis for accurate control of arm and hand movements. These findings have now been published in “Cell”. Movement is a fundamental capability of humans and animals, involving the highly complex interplay of brain, nerves and muscles. Movements of our arms and hands, in particular, call for extremely precise coordination. The brain sends a constant stream of commands via the spinal cord to our muscles to execute a wide variety of movements. This stream of information from the brain reaches interneurons in the spinal cord, which then transmit the commands via further circuits to motor neurons innervating muscles. The research group led by Silvia Arber at the Biozentrum of the University of Basel and the Friedrich Miescher Institute for Biomedical Research has now elucidated the organization of a second information pathway taken by these commands. cc to the brain: one command – two directions The scientists showed that many interneurons in the mouse spinal cord not only transmit their signals via motor neurons to the target muscle, but also simultaneously send a copy of this information back to the brain. Chiara Pivetta, first author of the publication, explains: “The motor command to the muscle is sent in two different directions – in one direction, to trigger the desired muscular contraction and in the other, to inform the brain that the command has actually been passed on to the musculature.” In analogy to e‑mail transmission, the information is thus not only sent to the recipient but also to the original requester. Information to brainstem nucleus segregated by function What happens to the information sent by spinal interneurons to the brain? As Arber’s group discovered, this input is segregated by function and spatially organized within a brainstem nucleus. Information from different types of interneurons thus flows to different areas of the nucleus. For example, spinal information that will influence left-right coordination of a movement is collected at a different site than information affecting the speed of a movement. Fine motor skills supported by dual information stream Arber comments: “From one millisecond to the next, this extremely precise feedback ensures that commands are correctly transmitted and that – via the signals sent back to the brain from the spinal cord – the resulting movement is immediately coordinated with the brain and adjusted.” Interestingly, the scientists only observed this kind of information flow to the brain for arm, but not for leg control. “What this shows,” says Arber, “is that this information pathway is most likely important for fine motor skills. Compared to the leg, movements of our arm and especially our hands have to be far more precise. Evidently, our body can only ensure this level of accuracy in motor control with constant feedback of information.” In further studies, Silvia Arber’s group now plans to investigate what happens if the flow of information back to the brain is disrupted in specific ways. Since some interneurons facilitate and others inhibit movement, such studies could provide additional insights into the functionality of circuits controlling movement.

CC to the brain: How neurons control fine motor behavior of the arm

Motor commands issued by the brain to activate arm muscles take two different routes. As the research group led by Professor Silvia Arber at the Basel University Biozentrum and the Friedrich Miescher Institute for Biomedical Research has now discovered, many neurons in the spinal cord send their instructions not only towards the musculature, but at the same time also back to the brain via an exquisitely organized network. This dual information stream provides the neural basis for accurate control of arm and hand movements. These findings have now been published in “Cell”.

Movement is a fundamental capability of humans and animals, involving the highly complex interplay of brain, nerves and muscles. Movements of our arms and hands, in particular, call for extremely precise coordination. The brain sends a constant stream of commands via the spinal cord to our muscles to execute a wide variety of movements. This stream of information from the brain reaches interneurons in the spinal cord, which then transmit the commands via further circuits to motor neurons innervating muscles. The research group led by Silvia Arber at the Biozentrum of the University of Basel and the Friedrich Miescher Institute for Biomedical Research has now elucidated the organization of a second information pathway taken by these commands.

cc to the brain: one command – two directions

The scientists showed that many interneurons in the mouse spinal cord not only transmit their signals via motor neurons to the target muscle, but also simultaneously send a copy of this information back to the brain. Chiara Pivetta, first author of the publication, explains: “The motor command to the muscle is sent in two different directions – in one direction, to trigger the desired muscular contraction and in the other, to inform the brain that the command has actually been passed on to the musculature.” In analogy to e‑mail transmission, the information is thus not only sent to the recipient but also to the original requester.

Information to brainstem nucleus segregated by function

What happens to the information sent by spinal interneurons to the brain? As Arber’s group discovered, this input is segregated by function and spatially organized within a brainstem nucleus. Information from different types of interneurons thus flows to different areas of the nucleus. For example, spinal information that will influence left-right coordination of a movement is collected at a different site than information affecting the speed of a movement.

Fine motor skills supported by dual information stream

Arber comments: “From one millisecond to the next, this extremely precise feedback ensures that commands are correctly transmitted and that – via the signals sent back to the brain from the spinal cord – the resulting movement is immediately coordinated with the brain and adjusted.” Interestingly, the scientists only observed this kind of information flow to the brain for arm, but not for leg control. “What this shows,” says Arber, “is that this information pathway is most likely important for fine motor skills. Compared to the leg, movements of our arm and especially our hands have to be far more precise. Evidently, our body can only ensure this level of accuracy in motor control with constant feedback of information.”

In further studies, Silvia Arber’s group now plans to investigate what happens if the flow of information back to the brain is disrupted in specific ways. Since some interneurons facilitate and others inhibit movement, such studies could provide additional insights into the functionality of circuits controlling movement.

Filed under arm movement motor movements spinal cord interneurons motor neurons neuroscience science

115 notes

Identified a subgroup of schizophrenia patients with motor disorders

Researchers led by Marta Barrachina, Institute of Neuropathology of the Bellvitge Biomedical Research Institute (IDIBELL) have identified a new subgroup of patients suffering from schizophrenia characterized by motor disorders.

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The study, which was conducted in collaboration with the research team Mairena Martin at the University of Castilla La Mancha at Ciudad Real and clinical researchers of the Health Park Sant Joan de Deu at Sant Boi de Llobregat, has been published in the online edition of the Journal of Psychiatric Research and was funded by the TV3 Marathon in its 2008 edition.

Schizophrenia is a serious mental illness. From a clinical point of view is considered grouping several diseases that are not well defined or characterized by biomarkers.

Barrachina team studies the A2A adenosine receptor, which is highly expressed in the basal ganglia at the central nervous system and is involved in the control of movement. Furthermore this protein inhibits the activity of dopamine D2 receptor, hyperactivated in schizophrenia patients and typical antipsychotics target.

"We studied the post- mortem brains of patients," explains Barrachina "and we found that 50% had very low levels of adenosine A2A receptor. Interestingly, when comparing these data with clinical information provided by the clinical investigators of the study, we note that these patients had motor disorders." "In addition, we identified an epigenetic mechanism associated with the decreased receptor expression."

According to the researcher, this finding allows to “identify a new subset of schizophrenia patients with motor disorders.”

Proposal for combined therapy

This study opens the door to a clinical trial, based on radioimage, which would detect the levels of this protein and identify these patients and also to confirm the results obtained in the postmortem brains of patients. Barrachina team proposes to apply a specific combination therapy of antipsychotics and agonists of A2A adenosine. “Thus, the activity of adenosine A2A receptor will be favoured, reducing the dose of antipsychotics.”

(Source: idibell.cat)

Filed under motor disorders schizophrenia putamen dopamine receptors neuroscience science

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Resetting the Metabolic Clock We’ve all heard about circadian rhythm, the roughly 24-hour oscillations of biological processes that occur in many living organisms. Yet for all its influence in many aspects of our lives — from sleep to immunity and, particularly, metabolism — relatively little is understood about the mammalian circadian rhythm and the interlocking processes that comprise this complex biological clock. Through intensive analysis and computer modeling, researchers at UC Santa Barbara have gained insight into factors that affect these oscillations, with results that could lend themselves to circadian regulation and pharmacological control. Their work appears in the early edition of the Proceedings of the National Academy of Sciences. “Our group has been fascinated with circadian rhythms for over 10 years now, as they represent a marvelous example of robust control at the molecular scale in nature,” said Frank Doyle, chair of UCSB’s Department of Chemical Engineering and the principal investigator for the UCSB team. “We are constantly amazed by the mechanisms that nature uses to control these clocks, and we seek to unravel their principles for engineering applications as well as shed light on the underlying cellular mechanisms for medical purposes.” “Focus is often given to metabolism, cell division and other generic cell processes, but circadian oscillations are just as central to how life is organized,” said Peter St. John, a researcher in the Department of Chemical Engineering and lead author of the study. Blood pressure, he noted, varies with time of day, as do visual acuity, smell and taste. Certain hormones are released at certain times to do their tasks. We get sleepy or become more alert at different hours. All these various highs and lows, rises and falls are the result of our circadian rhythm. “There are genes and proteins that are expressed in a cell and their activity, or expression level, changes with time of day,” explained St. John. “These oscillations are caused by genetic circuits. So you’ll have a gene that’s produced, and when it’s in its finished form, it will turn itself off.” The proteins and genes get cleared away, after which production starts all over again, in a cycle that takes roughly 24 hours to complete. While genetics plays a role in these rhythms — for instance if your parents were night owls, it’s likely you will be one too — environment, habits and lifestyles also affect the clock. “It’s not just this free-running oscillator,” said St. John. “It gets these inputs from light. For instance if you get light early in the morning, it’ll speed up something so your phase is adjusted to the time of day.” Other influences include food (not so much what you eat but when), drugs, shift work and frequent travel across time zones. The healthiest circadian rhythms are the ones that are considered to be “high-amplitude” — where different and complementary processes occur in the body during distinct and regular daytime and nighttime phases. “We’re very different animals during the night and the day,” said St. John. “If you’re fasting at night and you’re asleep, the demands on your cells will be very different than if you’re awake and running around. There’s this temporal separation between the genes that you need during the day and those you need at night.” Problems occur when the amplitude gets repressed, often because of modern-day schedules and lifestyles. Too much light at night, insufficient or irregular sleep hours, and eating or exercising too late in the evening are all habits that don’t allow for the necessary nighttime-phase cellular activity. This in turn can lead to disorders such as diabetes, heart disease and obesity. In very preliminary studies, Alzheimer’s disease and certain liver conditions are also associated with low-amplitude rhythms. Establishing high-amplitude circadian rhythms could be as simple as modifying our schedules, but for some people — those with sleep disorders, for example, or those whose work requires long and irregular hours — it can be difficult, if not impossible. By studying the regulation of the clock proteins called Period (PER) and Cryptochrome (CRY) — proteins that are thought to be involved with metabolism — St. John and Doyle were able to model the mechanisms of two small-molecule drugs — Longdaysin and KL0001 — that regulate the expression of the clock proteins. The insight they gained could lead to therapies that can help those with repressed circadian rhythms. “Everybody thought that these were very similar proteins,” said St. John. “They bind to each other. They enter the nucleus together.” The assumption was that perturbations to those proteins would produce similar results. “But when we analyzed the data,” St. John continued, “it turned out that when you stabilize PER you get these higher-amplitude rhythms, but when you stabilize CRY you get these lower-amplitude rhythms.” These results — obtained by studying cultured human cells that glow depending on their circadian phase, as well as through computer modeling — shed light on the mechanisms behind the metabolic aspect of circadian rhythms and pave the way for drug therapies that could decrease the risk of disease for those with disrupted rhythms. The UCSB researchers worked in collaboration with experimental scientists Tsuyoshi Hirota and Steve Kay from UC San Diego and USC, respectively. “These collaborative partnerships with life scientists are crucial to the success of a project like this,” said Doyle, “and this kind of collaborative research team can implement the paradigm of systems biology with combined mathematical modeling and high-throughput experimental biology.” Future modeling studies will try to determine if there is an optimal phase for taking one drug or the other to improve the amplitude of circadian rhythms. Experimental work will focus on improving specificity and bioavailability — the amount of drug that actually reaches the target tissues before being discharged by the body.

Resetting the Metabolic Clock

We’ve all heard about circadian rhythm, the roughly 24-hour oscillations of biological processes that occur in many living organisms. Yet for all its influence in many aspects of our lives — from sleep to immunity and, particularly, metabolism — relatively little is understood about the mammalian circadian rhythm and the interlocking processes that comprise this complex biological clock.

Through intensive analysis and computer modeling, researchers at UC Santa Barbara have gained insight into factors that affect these oscillations, with results that could lend themselves to circadian regulation and pharmacological control. Their work appears in the early edition of the Proceedings of the National Academy of Sciences.

“Our group has been fascinated with circadian rhythms for over 10 years now, as they represent a marvelous example of robust control at the molecular scale in nature,” said Frank Doyle, chair of UCSB’s Department of Chemical Engineering and the principal investigator for the UCSB team. “We are constantly amazed by the mechanisms that nature uses to control these clocks, and we seek to unravel their principles for engineering applications as well as shed light on the underlying cellular mechanisms for medical purposes.”

“Focus is often given to metabolism, cell division and other generic cell processes, but circadian oscillations are just as central to how life is organized,” said Peter St. John, a researcher in the Department of Chemical Engineering and lead author of the study.

Blood pressure, he noted, varies with time of day, as do visual acuity, smell and taste. Certain hormones are released at certain times to do their tasks. We get sleepy or become more alert at different hours. All these various highs and lows, rises and falls are the result of our circadian rhythm.

“There are genes and proteins that are expressed in a cell and their activity, or expression level, changes with time of day,” explained St. John. “These oscillations are caused by genetic circuits. So you’ll have a gene that’s produced, and when it’s in its finished form, it will turn itself off.” The proteins and genes get cleared away, after which production starts all over again, in a cycle that takes roughly 24 hours to complete.

While genetics plays a role in these rhythms — for instance if your parents were night owls, it’s likely you will be one too — environment, habits and lifestyles also affect the clock.

“It’s not just this free-running oscillator,” said St. John. “It gets these inputs from light. For instance if you get light early in the morning, it’ll speed up something so your phase is adjusted to the time of day.” Other influences include food (not so much what you eat but when), drugs, shift work and frequent travel across time zones.

The healthiest circadian rhythms are the ones that are considered to be “high-amplitude” — where different and complementary processes occur in the body during distinct and regular daytime and nighttime phases.

“We’re very different animals during the night and the day,” said St. John. “If you’re fasting at night and you’re asleep, the demands on your cells will be very different than if you’re awake and running around. There’s this temporal separation between the genes that you need during the day and those you need at night.”

Problems occur when the amplitude gets repressed, often because of modern-day schedules and lifestyles. Too much light at night, insufficient or irregular sleep hours, and eating or exercising too late in the evening are all habits that don’t allow for the necessary nighttime-phase cellular activity. This in turn can lead to disorders such as diabetes, heart disease and obesity. In very preliminary studies, Alzheimer’s disease and certain liver conditions are also associated with low-amplitude rhythms.

Establishing high-amplitude circadian rhythms could be as simple as modifying our schedules, but for some people — those with sleep disorders, for example, or those whose work requires long and irregular hours — it can be difficult, if not impossible.

By studying the regulation of the clock proteins called Period (PER) and Cryptochrome (CRY) — proteins that are thought to be involved with metabolism — St. John and Doyle were able to model the mechanisms of two small-molecule drugs — Longdaysin and KL0001 — that regulate the expression of the clock proteins. The insight they gained could lead to therapies that can help those with repressed circadian rhythms.

“Everybody thought that these were very similar proteins,” said St. John. “They bind to each other. They enter the nucleus together.” The assumption was that perturbations to those proteins would produce similar results. “But when we analyzed the data,” St. John continued, “it turned out that when you stabilize PER you get these higher-amplitude rhythms, but when you stabilize CRY you get these lower-amplitude rhythms.”

These results — obtained by studying cultured human cells that glow depending on their circadian phase, as well as through computer modeling — shed light on the mechanisms behind the metabolic aspect of circadian rhythms and pave the way for drug therapies that could decrease the risk of disease for those with disrupted rhythms. The UCSB researchers worked in collaboration with experimental scientists Tsuyoshi Hirota and Steve Kay from UC San Diego and USC, respectively.

“These collaborative partnerships with life scientists are crucial to the success of a project like this,” said Doyle, “and this kind of collaborative research team can implement the paradigm of systems biology with combined mathematical modeling and high-throughput experimental biology.”

Future modeling studies will try to determine if there is an optimal phase for taking one drug or the other to improve the amplitude of circadian rhythms. Experimental work will focus on improving specificity and bioavailability — the amount of drug that actually reaches the target tissues before being discharged by the body.

Filed under circadian rhythms metabolic disorders clock proteins oscillations medicine neuroscience science

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Parkinson gene: Nerve growth factor halts mitochondrial degeneration Neurodegenerative diseases like Parkinson’s disease involve the death of thousands of neurons in the brain. Nerve growth factors produced by the body, such as GDNF, promote the survival of the neurons; however, clinical tests with GDNF have not yielded in any clear improvements. Scientists from the Max Planck Institute of Neurobiology in Martinsried and their colleagues have now succeeded in demonstrating that GDNF and its receptor Ret also promote the survival of mitochondria, the power plants of the cell. By activating the Ret receptor, the scientists were able to prevent in flies and human cell cultures the degeneration of mitochondria, which is caused by a gene defect related to Parkinson’s disease. This important new link could lead to the development of more refined GDNF therapies in the future. In his “Essay on the Shaking Palsy” of 1817, James Parkinson provided the first description of a disease that today affects almost 280,000 people in Germany. The most conspicuous symptom of Parkinson’s disease is a slow tremor, which is usually accompanied by an increasing lack of mobility and movement in the entire body. These symptoms are visible manifestations of a dramatic change that takes place in the brain: the death of large numbers of neurons in the Substantia nigra of the midbrain. Despite almost 200 years of research into Parkinson’s, its causes have not yet been fully explained. It appears to be certain that, in addition to environmental factors, genetic mutations also play a role in the emergence of the disease. A series of genes is now associated with Parkinson’s disease. One of these is PINK1, whose mutation causes mitochondrial dysfunction. Mitochondria are a cell’s power plants and without them, a cell cannot function properly or regenerate. Scientists from the Max Planck Institute of Neurobiology and their colleagues from Munich and Martinsried have now discovered a hitherto unknown link that counteracts mitochondrial dysfunction in the case of a PINK1 mutation. The PINK1 gene emerged at a very early stage in evolutionary history and exists in a similar form for example in humans, mice and flies. In the fruit fly Drosophila, a mitochondrial defect triggered by a PINK1 mutation manifests in the fraying of the muscles. Less visible, the flies’ neurons also die. The scientists studied the molecular processes involved in these changes and discovered that the activation of the Ret receptor counteracts the muscle degeneration. “This is a really interesting finding which links the mitochondrial degeneration in Parkinson’s disease with nerve growth factors,” reports Rüdiger Klein, the head of the research study. Ret is not an unknown factor for the Martinsried-based neurobiologists: “We already succeeded in demonstrating a few years ago in mice that neurons without the Ret receptor die prematurely and in greater numbers with increasing age,” says Klein. The Ret receptor is the cells’ docking site for the growth factor GDNF, which is produced by the body. Various studies carried out in previous years showed that the binding of GDNF to its Ret receptor can prevent the early death of neurons in the Substantia nigra. However, clinical studies on the influence of GDNF on the progression of Parkinson’s in patients did not lead to any clear improvement in their condition. The new findings from basic research suggest that the mitochondrial metabolism is boosted or re-established through Ret/GNDF. “Based on this finding, existing therapies could be refined or tailored to specific patient groups,” hopes Pontus Klein, who conducted the study within the framework of his doctoral thesis. This hope does not appear to be completely unfounded: The scientists have already discovered a Ret/GDNF effect in human cells with a PINK1 defect similar to that observed in the fruit fly. It may therefore be possible to search for metabolic defects in the mitochondria of Parkinson’s patients in future. A specially tailored GDNF therapy could then provide a new therapeutic approach for patients who test positively.

Parkinson gene: Nerve growth factor halts mitochondrial degeneration

Neurodegenerative diseases like Parkinson’s disease involve the death of thousands of neurons in the brain. Nerve growth factors produced by the body, such as GDNF, promote the survival of the neurons; however, clinical tests with GDNF have not yielded in any clear improvements. Scientists from the Max Planck Institute of Neurobiology in Martinsried and their colleagues have now succeeded in demonstrating that GDNF and its receptor Ret also promote the survival of mitochondria, the power plants of the cell. By activating the Ret receptor, the scientists were able to prevent in flies and human cell cultures the degeneration of mitochondria, which is caused by a gene defect related to Parkinson’s disease. This important new link could lead to the development of more refined GDNF therapies in the future.

In his “Essay on the Shaking Palsy” of 1817, James Parkinson provided the first description of a disease that today affects almost 280,000 people in Germany. The most conspicuous symptom of Parkinson’s disease is a slow tremor, which is usually accompanied by an increasing lack of mobility and movement in the entire body. These symptoms are visible manifestations of a dramatic change that takes place in the brain: the death of large numbers of neurons in the Substantia nigra of the midbrain.

Despite almost 200 years of research into Parkinson’s, its causes have not yet been fully explained. It appears to be certain that, in addition to environmental factors, genetic mutations also play a role in the emergence of the disease. A series of genes is now associated with Parkinson’s disease. One of these is PINK1, whose mutation causes mitochondrial dysfunction. Mitochondria are a cell’s power plants and without them, a cell cannot function properly or regenerate. Scientists from the Max Planck Institute of Neurobiology and their colleagues from Munich and Martinsried have now discovered a hitherto unknown link that counteracts mitochondrial dysfunction in the case of a PINK1 mutation.

The PINK1 gene emerged at a very early stage in evolutionary history and exists in a similar form for example in humans, mice and flies. In the fruit fly Drosophila, a mitochondrial defect triggered by a PINK1 mutation manifests in the fraying of the muscles. Less visible, the flies’ neurons also die. The scientists studied the molecular processes involved in these changes and discovered that the activation of the Ret receptor counteracts the muscle degeneration. “This is a really interesting finding which links the mitochondrial degeneration in Parkinson’s disease with nerve growth factors,” reports Rüdiger Klein, the head of the research study. Ret is not an unknown factor for the Martinsried-based neurobiologists: “We already succeeded in demonstrating a few years ago in mice that neurons without the Ret receptor die prematurely and in greater numbers with increasing age,” says Klein.

The Ret receptor is the cells’ docking site for the growth factor GDNF, which is produced by the body. Various studies carried out in previous years showed that the binding of GDNF to its Ret receptor can prevent the early death of neurons in the Substantia nigra. However, clinical studies on the influence of GDNF on the progression of Parkinson’s in patients did not lead to any clear improvement in their condition.

The new findings from basic research suggest that the mitochondrial metabolism is boosted or re-established through Ret/GNDF. “Based on this finding, existing therapies could be refined or tailored to specific patient groups,” hopes Pontus Klein, who conducted the study within the framework of his doctoral thesis. This hope does not appear to be completely unfounded: The scientists have already discovered a Ret/GDNF effect in human cells with a PINK1 defect similar to that observed in the fruit fly. It may therefore be possible to search for metabolic defects in the mitochondria of Parkinson’s patients in future. A specially tailored GDNF therapy could then provide a new therapeutic approach for patients who test positively.

Filed under parkinson's disease neurodegenerative diseases mitochondria GDNF PINK1 neuroscience science

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