Posts tagged science
Articles and news from the latest research reports.
(Image caption: Researchers at Cold Spring Harbor Laboratory have identified the neurons in the brain that determine if a mouse will learn to cope with stress or become depressed. These neurons, located in a region of the brain known as the medial prefrontal cortex (green, left image), become hyperactive in depressed mice (right panel is close-up of left, yellow indicates activation). The team showed that this enhanced activity in fact causes depression.)
Dealing with stress – to cope or to quit?
We all deal with stress differently. For many of us, stress is a great motivator, spurring a renewed sense of vigor to solve life’s problems. But for others, stress triggers depression. We become overwhelmed, paralyzed by hopelessness and defeat. Up to 20% of us will struggle with depression at some point in life, and researchers are actively working to understand how and why this debilitating mental disease develops.
Today, a team of researchers at Cold Spring Harbor Laboratory (CSHL) led by Associate Professor Bo Li reveals a major insight into the neuronal basis of depression. They have identified the group of neurons in the brain that determines how a mouse responds to stress — whether with resilience or defeat.
For years, scientists have relied on brain imaging to look for neuronal changes during depression. They found that a region of the brain known as the medial prefrontal cortex (mPFC) becomes hyperactive in depressed people. This area of the brain is well known to play a role in the control of emotions and behavior, linking our feelings with our actions. But brain scans aren’t able to determine if increased activity in the mPFC causes depression, or if it is simply a byproduct of other neuronal changes.
Dr. Li set out to identify the neuronal changes that underlie depression. In work published today in The Journal of Neuroscience,Li and his team, including Minghui Wang, Ph.D. and Zinaida Perova, Ph.D., used a mouse model for depression, known as “learned helplessness.” They combined this with a genetic trick to mark specific neurons that respond to stress. They discovered that neurons in the mPFC become highly excited in mice that are depressed. These same neurons are weakened in mice that aren’t deterred by stress – what scientists call resilient mice.
But the team still couldn’t be sure that enhanced signaling in the mPFC actually caused depression. To test this, they engineered mice to mimic the neuronal conditions they found in depressed mice. “We artificially enhanced the activity of these neurons using a powerful method known as chemical genetics,” says Li. “The results were remarkable: once-strong and resilient mice became helpless, showing all of the classic signs of depression.”
These results help explain how one promising new treatment for depression works and may lead to improvements in the treatment.
Doctors have had some success with deep brain stimulation (DBS), which suppresses the activity of neurons in a very specific portion of the brain. “We hope that our work will make DBS even more targeted and powerful,” says Li, “and we are working to develop additional strategies based upon the activity of the mPFC to treat depression.”
Next, Li is looking forward to exploring how the neurons in the mPFC become hyperactive in helpless mice. “These active neurons are surrounded by inhibitory neurons,” says Li. “Are the inhibitory neurons failing? Or are the active neurons somehow able to bypass their controls? These are some of the many open questions we are pursuing to understand the how depression develops.”
Dad’s Brain Becomes More ‘Maternal’ When He’s Primary Caregiver
Fathers who spend more time taking care of their newborn child undergo changes in brain activity that make them more apt to fret about their baby’s safety, a new study shows.
(Image: Shutterstock)
In particular, fathers who are the primary caregiver experience an increase in activity in their amygdala and other emotional-processing systems, causing them to experience parental emotions similar to those typically experienced by mothers, the researchers noted.
The findings suggest there is a neural network in the brain dedicated to parenting, and that the network responds to changes in parental roles, said study senior author Ruth Feldman, a researcher in the department of psychology and the Gonda Brain Sciences Center at Bar-Ilan University in Israel.
"Pregnancy, childbirth and lactation are very powerful primers in women to worry about their child’s survival," said Feldman, who also serves as an adjunct professor at the Yale Child Study Center at Yale University. "Fathers have the capacity to do it as well as mothers, but they need daily caregiving activities to ignite that mothering network."
Did standing up change our brains?
Although lots of animals are smart, humans are even smarter. How and why do we think and act so differently from other species?
A young boy’s efforts while learning to walk have suggested a new explanation, in a new journal paper jointly authored by his father and grandfather, both academics at the University of Sydney.
In the latest issue of the scientific journal, Frontiers in Neuroscience, the son-and-father team Mac and Rick Shine suggest that the big difference between humans and other species may lie in how we use our brains for routine tasks.
They advance the idea that the key to exploiting the awesome processing power of our brain’s most distinctive feature - the cortex - may have been to liberate it from the drudgery of controlling routine activities.
And that’s where young Tyler Shine, now two years old, comes into the story. When Tyler was first learning to walk, his doting father and grandfather noticed that every step took Tyler’s full attention.
But before too long, walking became routine, and Tyler was able to start noticing other things around him. He was better at maintaining his balance, which freed up his attention to focus on more interesting tasks, like trying to get into mischief.
How did Tyler improve? His father and grandfather suggest that he did so by transferring the control of his balance to ‘lower’ parts of the brain, freeing up the powerful cortex to focus on unpredictable challenges, such as a bumpy floor covered in stray toys.
"Any complicated task - like driving a car or playing a musical instrument - starts out consuming all our attention, but eventually becomes routine," Mac Shine says.
"Studies of brain function suggest that we shift the control of these routine tasks down to ‘lower’ areas of the brain, such as the basal ganglia and the cerebellum.
"So, humans are smart because we have automated the routine tasks; and thus, can devote our most potent mental faculties to deal with new, unpredictable challenges.
"What event in the early history of humans made us change the way we use our brains?
Watching Tyler learn to walk suggested that it was the evolutionary shift from walking on all fours, to walking on two legs.
"Suddenly our brains were overwhelmed with the complicated challenge of keeping our balance - and the best kind of brain to have, was one that didn’t waste its most powerful functions on controlling routine tasks."
So, the Shines believe, those first pre-humans who began to stand upright faced a new evolutionary pressure not just on their bodies, but on their brains as well.
"New technologies are allowing us to look inside the brain while it works, and we are learning an enormous amount," Mac Shine says.
"But in order to interpret those results, we need new ideas as well. I’m delighted that my son has played a role in suggesting one of those ideas."
"Hopefully, by the time he is watching his own son learn to walk, we will be much closer to truly understanding the greatest mystery of human existence: how our brains work."
Sex-specific changes in cerebral blood flow begin at puberty
Puberty is the defining process of adolescent development, beginning a cascade of changes throughout the body, including the brain. Penn Medicine researchers have discovered that cerebral blood flow (CBF) levels decreased similarly in males and females before puberty, but saw them diverge sharply in puberty, with levels increasing in females while decreasing further in males, which could give hints as to developing differences in behavior in men and women and sex-specific pre-dispositions to certain psychiatric disorders. Their findings are available in Proceedings of the National Academy of Science (PNAS).
"These findings help us understand normal neurodevelopment and could be a step towards creating normal ‘growth charts’ for brain development in kids. These results also show what every parent knows: boys and girls grow differently. This applies to the brain as well," says Theodore D. Satterthwaite, MD, MA, assistant professor in the Department of Psychiatry in the Perelman School of Medicine at the University of Pennsylvania. "Hopefully, one day such growth charts might allow us to identify abnormal brain development much earlier before it leads to major mental illness."
Studies on structural brain development have shown that puberty is an important source of sex differences. Previous work has shown that CBF declines throughout childhood, but the effects of puberty on properties of brain physiology such as CBF, also known as cerebral perfusion, are not well known. “We know that adult women have higher blood flow than men, but it was not clear when that difference began, so we hypothesized that the gap between women and men would begin in adolescence and coincide with puberty,” Satterthwaite says.
The Penn team imaged the brains of 922 youth ages 8 through 22 using arterial spin labeled (ASL) MRI. The youth were all members of the Philadelphia Neurodevelopmental Cohort, a National Institute of Mental Health-funded collaboration between the University of Pennsylvania Brain Behavior Laboratory and the Center for Applied Genomics at the Children’s Hospital of Philadelphia.
They found support for their hypothesis.
Age related differences were observed in the amount and location of blood flow in males versus females, with blood flow declining at a similar rate before puberty and diverging markedly in mid-puberty. At around age 16, while male CBF values continue to decline with advanced age, females CBF values actually increased. This resulted in females having notably higher CBF than males by the end of adolescence. The difference between males and females was most notable in parts of the brain that are critical for social behaviors and emotion regulation such as the orbitofrontal cortex. The researchers speculate that such differences could be related to females’ well-established superior performance on social cognition tasks. Potentially, these effects could also be related to the higher risk in women for depression and anxiety disorders, and higher risk of flat affect and schizophrenia in men.
(Source: eurekalert.org)
Neurons Can Use Local Stores for Communication Needs
Researchers reveal that neurons can utilize a supremely localized internal store of calcium to initiate the secretion of neuropeptides, one class of signaling molecules through which neurons communicate with each other and with other cells. The study appears in The Journal of General Physiology.
(Image caption: Localization of ryanodine receptors (red) in an isolated nerve terminal from the posterior pituitary gland. Image credit: McNally et al., 2014)
Neuropeptides are released from neurons through a process that—like other secretory events—is triggered primarily by the influx of calcium into the neuron through voltage-gated channels. Although neuropeptides are stored in large dense core vesicles (LDCVs) that also contain large amounts of calcium, it has been unclear whether these locally based calcium supplies can also be used to modulate secretion.
A team of researchers led by José Lemos from the University of Massachusetts Medical School examined the mechanisms at play during secretion of vasopressin from nerve terminals in the posterior pituitary gland, which releases the neuropeptide into the blood so that it can make its way to the kidney and regulate water retention. The researchers found that certain intracellular calcium channels known as ryanodine receptors are likely responsible for mobilizing calcium from LDCVs to facilitate vasopressin release. The findings indicate that neurons have a greater capacity than previously appreciated to fine-tune the release of neuropeptides and thereby their communications with other cells.
(Source: newswise.com)
‘Sticky synapses’ can impair new memories by holding on to old ones
A team of UBC neuroscientists has found that synapses that are too strong or ‘sticky’ can actually hinder our capacity to learn new things.
University of British Columbia researchers have discovered that so-called “sticky synapses” in the brain can impair new learning by excessively hard-wiring old memories and inhibiting our ability to adapt to our changing environment.
Memories are formed by strong synaptic connections between nerve cells. Now a team of UBC neuroscientists has found that synapses that are too strong or “sticky” can actually hinder our capacity to learn new things by affecting cognitive flexibility, the ability to modify our behaviours to adjust to circumstances that are similar, but not identical, to previous experiences.
“We tend to think that strong retention of memories is always a good thing,” says Fergil Mills, UBC PhD candidate and the study’s first author. “But our study shows that cognitive flexibility involves actively weakening old memory traces. In certain situations, you have to be able to ‘forget’ to learn.”
The study, published today in the Proceedings of the National Academy of Sciences, shows that mice with excessive beta-catenin – a protein that is part of the “molecular glue” that holds synapses together – can learn a task just as well as normal mice, but lacked the mental dexterity to adapt if the task was altered.
“Increased levels of beta-catenin have previously been reported in disorders such as Alzheimer’s disease and Huntington’s disease, and, intriguingly, patients with these diseases have been shown to have deficits in cognitive flexibility similar to those we observed in this study,” says Shernaz Bamji, an associate professor in UBC’s Dept. of Cellular and Physiological Sciences.
“Now, we see that changes in beta-catenin levels can dramatically affect learning and memory, and may indeed play a role in the cognitive deficits associated with these diseases,” she adds. “This opens up many exciting new avenues for research into these diseases and potential therapeutic approaches.”
BACKGROUND
To test cognitive flexibility in mice, researchers conducted an experiment where the mice were placed in a pool of water and had to learn to find a submerged hidden platform. The mice with excessive beta-catenin could learn to find the platform just as well as normal mice. However, if the platform was moved to a different location in the pool, these mice kept swimming to the platform’s previous location. Even after many days of training, the ‘sticky synapses’ in their brains made them unable to effectively learn to find the new platform.
Dealing with negative thinking
Is it ‘normal’ to think about pushing someone in front of a train or to fantasise about driving your car into oncoming traffic?
The answer is yes says Victoria University of Wellington researcher Dr Kirsty Fraser who graduated with a PhD in Psychology last week.
“It’s common for people to occasionally have those kind of negative thoughts, but then most of us realise it’s a bit ridiculous and move on,” says Dr Fraser.
For some people, however, those negative thoughts may persist, leading to anxiety and depression.
“It’s how we react to, and process, those negative intrusions that can make the difference between brushing them off and developing obsessive compulsive symptoms, such as severe anxiety and depression.
“For example, some people could be so anxious about those kind of thoughts that they go out of their way to avoid catching a train or driving.”
Dr Fraser’s thesis focused on two ways of processing negative thoughts—inflated responsibility (IR) and thought action fusion (TAF), and the way each relates to mental disorders.
“TAF is when you believe that thinking about an action is equivalent to actually carrying out that action, while IR is one of the driving forces behind obsessive compulsive disorder (OCD), where you believe you can prevent something happening by what you do or don’t do.
“My research demonstrates that both types of beliefs play important roles in the development and maintenance of psychological symptoms related to anxiety, depression and OCD.”
Dr Fraser’s research also looked at how childhood experiences, critical events in one’s life and religious beliefs could impact upon thoughts.
She surveyed more than 1,000 people and divided them into four groups: undergraduate students, so called ‘normal’ citizens, patients from an anxiety clinic and those with religious and atheist beliefs.
“Overall,” she says, “my research provided strong support for existing theories about the role of cognitive processes in the maintenance of symptoms and distress.”
When Kirsty arrived at Victoria in 2002, she began studying human resources. She took a psychology paper out of interest and “never left”.
“The lecturer was John McDowall, who introduced me to how interesting the subject is. He ended up being my supervisor for my PhD.”
For the past three years, Kirsty has combined doctoral study with teaching a second year psychology paper at Victoria, marking for another tertiary institution and being a full-time mother.
“Now I’m starting to think about other challenges, including possible research positions. I’d like to publish my PhD research and continue lecturing.”
Promising approach to slow brain degeneration in a model of Huntington’s disease uncovered
Research presented by Dr. Lynn Raymond, from the University of British Columbia, shows that blocking a specific class of glutamate receptors, called extrasynaptic NMDA receptors, can improve motor learning and coordination, and prevent cell death in animal models of Huntington disease. As Huntington disease is an inherited condition that can be detected decades before any clinical symptoms are seen in humans, a better understanding of the earliest changes in brain cell (neuronal) function, and the molecular pathways underlying those changes, could lead to preventive treatments that delay the onset of symptoms and neurodegeneration. “After more than a decade of research on the pre-symptomatic phase of Huntington disease, markers are being developed to facilitate assessment of interventional therapy in individuals carrying the genetic mutation for Huntington disease, before they become ill. This will make it possible to delay onset of disease,” says Dr. Raymond. These results were presented at the 2014 Canadian Neuroscience Meeting, the 8th annual meeting of the Canadian Association for Neuroscience - Association Canadienne des Neurosciences (CAN-ACN), held in Montreal, May 25-28.
The neurotransmitter glutamate has long been known to promote cell death, and its toxic effects occur through the action of a family of receptors known as the NMDARs (N-methyl-D-Aspartate ionotropic glutamate receptors). Unfortunately, treating disorders of the nervous system by blocking NMDARs has not been successful because such treatments have numerous side effects. A recent hypothesis based on work from many scientists suggests that NMDARs located in different regions at the surface of neurons may have opposite effects, which would explain why blocking all NMDARs is not a good treatment option. A synapse is a structure that allows one neuron to connect to another neuron and pass an electrical or chemical signal between them. Many receptors for neurotransmitters are located in synapses, as these are the main area where these chemical signals are transmitted. However, receptors can also be found outside the synapse, and in this case are called extra-synaptic receptors. Many recent studies have revealed that NMDARs located at synapses act to increase survival signaling and promote learning and memory, whereas extra-synaptic NMDARs shut off survival signaling, interfere with learning mechanisms, and increase cell death pathways.
Dr. Raymond and her team were able, by using a drug that selectively blocks extra-synaptic NMDARs early, before the appearance of any symptoms, to delay the onset of Huntington-like symptoms in a mouse model of the disease. These promising results could lead to new treatment avenues for Huntington patients, and delay the appearance of symptoms. “The drug we used, memantine, is currently being used to treat moderate-stage Alzheimer disease patients. Our results suggest that clinical studies of memantine and similarly-acting drugs in Huntington disease, particularly in the pre-symptomatic stage, are warranted,”says Dr. Raymond.
Extra-synaptic NMDARs have also been shown to be involved in other neurodegenerative diseases, such as Alzheimer disease, and in damage caused by traumatic brain injury and some forms of stroke. These results therefore suggest novel treatment avenues for many conditions in which neurons degenerate and die, a new way to protect neurons before the appearance of symptoms of neurodegeneration.
(Source: eurekalert.org)
Mice with ‘mohawks’ help scientists link autism to 2 biological pathways in brain
"Aha" moments are rare in medical research, scientists say. As rare, they add, as finding mice with Mohawk-like hairstyles.
But both events happened in a lab at NYU Langone Medical Center, months after an international team of neuroscientists bred hundreds of mice with a suspect genetic mutation tied to autism spectrum disorders.
Almost all the grown mice, the NYU Langone team observed, had sideways,”overgroomed” hair with a highly stylized center hairline between their ears and hardly a tuft elsewhere. Mice typically groom each other’s hair.
Researchers say they knew instantly they were on to something, as the telltale overgrooming — a repetitive motor behavior — had been linked in other experiments in mice to the brain condition that prevents children from developing normal social, behavioral, cognitive, and motor skills. People with autism, the researchers point out, exhibit noticeably dysfunctional behaviors, such as withdrawal, and stereotypical, repetitive movements, including constant hand-flapping, or rocking.
Now and for what NYU Langone researchers believe to be the first time, an autistic motor behavior has been traced to specific biological pathways that are genetically determined.
The findings, says senior study investigator Gordon Fishell, PhD, the Julius Raynes Professor of Neuroscience and Physiology at NYU Langone, could with additional testing in humans lead to new treatments for some autism, assuming the pathways’ effects as seen in mice are reversible.
In the study, to be published in the journal Nature online May 25, researchers knocked out production in mice of a protein called Cntnap4. This protein had been found in earlier studies in specialized brain cells, known as interneurons, in people with a history of autism.
Researchers found that knocking out Cntnap4 affected two highly specialized chemical messengers in the brain, GABA and dopamine. Both are so-called neurotransmitters, chemical signals released from one nerve cell to the next to stimulate similar sensations throughout the body. GABA, short for gamma-aminobutyric acid, is the main inhibitory neurotransmitter in the brain. It not only helps control brain impulses, but also helps regulate muscle tone. Dopamine is a well-known hormonal stimulant, highly touted for producing soothing, pleasing sensations.
Among the researchers’ key findings was that in Mohawk-coiffed mice, reduced Cntnap4 production led to depressed GABA signaling and overstimulation with dopamine. Researchers say the lost protein had opposite effects on the neurotransmitters because GABA is fast acting and quickly released, so interfering with its action decreases signaling, while dopamine’s signaling is longer-acting, so impairing its action increases its release.
"Our study tells us that to design better tools for treating a disease like autism, you have to get to the underlying genetic roots of its dysfunctional behaviors, whether it is overgrooming in mice or repetitive motor behaviors in humans," says Dr. Fishell. "There have been many candidate genes implicated in contributing to autism, but animal and human studies to identify their action have so far not led to any therapies. Our research suggests that reversing the disease’s effects in signaling pathways like GABA and dopamine are potential treatment options."
The U.S. Centers for Disease Control and Prevention estimate that one in 68 American children under age 8 has some form of autism, with five times as many boys as girls suffering from the spectrum of disorders.
As part of their study, researchers performed dozens of genetic, behavioral, and neural tests with growing mice to isolate and pinpoint where Cntnap4 acted in their brains, and how it affected chemical signaling among specific interneuron brain cells, which help relay and filter chemical signals between neurons in localized areas of the brain.
They found that Cntnap4 in mature interneurons strengthened GABA signaling, but did not do so in younger interneurons. When researchers traced where Cntnap4 acted in immature brain cells, Dr. Fishell says tests showed that it stimulated “a big bolus of dopamine.”
As part of testing to confirm the hereditary link among Cntnap4, the two pathways, and grooming behaviors, researchers exposed young mice with normal levels of Cntnap4, who did not groom each other, to mature mice with and without Cntnap4. Only mature mice deficient in Cntnap4 preened the hairstyle on other mice. Further tests in young mice without Cntnap4 showed that other, mature mice with normal amounts of Cntnap4 largely let them be, without any particular grooming or hairstyle.
Dr. Fishell and his team plan further analyses of how GABA and dopamine production changes as brain cells mature, and precisely what cellular mechanisms are involved in autism. Their goal is to control and rebalance any biological systems that go awry, as a possible future therapy for the disease.
The control of dendritic branching by mitochondria
A fundamental difference between neurons in real brains and those in artificial neural networks is the way the neurons in each are connected. In artificial nets, the synapses between neurons often have adjustable strengths, but the structure and scale of the input dendritic field generally counts for little. For real neurons, where a “connection” between cells is not just a synapse but rather a whole net unto itself, structure and scale are everything. The architect of this dendritic structure is neither a DNA code nor a spontaneous developmental physics that condenses order from a protein-lipid chaos. This structure is in fact the byproduct of competitive, yet cooperative mitochondria that administer that code to themselves and to their host to control its interaction with other similarly controlled hosts.
Reseachers from Osaku University have found that if mitochondria are depleted from developing dendrites in pyramidal cells, there is increased branching in the proximal region of the dendrites. In their paper last week in the Journal of Neuroscience, they also show that these dendrites grow longer. Since mitochondria distribute not just energy but also metabolites, proteins, and mRNAs throughout the cell, these results may be somewhat surprising. However depending on what manipulations have been done to alter the mitochondria, many things might be expected to happen to dendrites and the cell in general.