Posts tagged neuroscience

If the violins were taken away from the musicians performing Beethoven’s 9th symphony, the resulting composition would sound very different. If the violins were left on stage but the violinists were removed, the same mutant version of the symphony would be heard.

But what if it ended up sounding like “Hey Jude” instead?

This sort of surprise is what scientists from the Virginia Tech Carilion Research Institute had during what they assumed to be a routine experiment in neurodevelopment. Previous studies had shown that the glycoprotein Reelin is crucial to developing healthy neural networks. Logically, taking away the two receptors that Reelin is known to act on early in the brain’s development should create the same malformations as taking away Reelin itself.

It didn’t.

“We conducted the experiment thinking we’d see the same defects for both cases – Reelin deficiency and its receptors’ deletion – but we didn’t,” said Michael Fox, an associate professor at the research institute and the lead author of the study. “If you take away the receptors instead of the targeting molecule, you get an entirely separate set of abnormalities. The results raise the question of the identity of other molecules with which Reelin and the two receptors are interacting.”

The study, first published online in June in Neural Development, could prove useful for the development of therapies and diagnostics to combat brain disease.

In the early stages of neural development, neurons grow from the retina to a small portion of the brain called the thalamus. All sensory information coming into the brain gets routed through this region, before being transmitted to the cerebral cortex for further processing. Because these retinal neurons carry specific types of information, they must connect to specific places in the thalamus, which Reelin helps them find.

In the experiment, the scientists bred mice lacking both Reelin receptors known to be critical for neurons to navigate their targets during development. The scientists expected the neurons in the mutants to become lost and unable to find their targets, which is what happens in Reelin-deficient mice. Instead, the neurons were able to locate their targets, but those targets had wandered off.

While these results were surprising, they weren’t the most interesting of the experiment. Although most neurons look the same to people without advanced training in neuroscience, many different types are intermixed in distinct regions with strict borders. How these borders are formed, however, is still an open question.

“Many of us have questioned how you can have such a crisp boundary between two regions of the brain,” said Jianmin Su, a research assistant professor at the research institute and first author of the study. “I always thought it was a large number of cells creating some kind of cue or environment, but that isn’t what this experiment indicates.”

In the mice without the Reelin receptors, neurons from one part of the thalamus migrated to an area where they weren’t supposed to be. Even though only a handful of neurons were misplaced, they did not mingle with their new neighbors. They stayed separate.

“The result is a baffling curiosity that nobody in the lab expected – just how distinct these little regions can be,” Fox said. “How do just a few cells create such a barrier? How many cells does it take? Maybe these little islands can teach us something about how you create boundaries between larger regions of functionally similar cells.”

This experiment isn’t the only example Fox has had recently of neurons invading regions in which they weren’t supposed to be. In a second experiment, researchers examined how neurons from the cortex connect to the thalamus during the initial stages of development.

And neurons seem to be polite.

The results showed that neurons from the cortex grow to the edge of the part of the thalamus dedicated to visual signals, called the dorsal lateral geniculate nucleus, but then stop. In fact, they stay on standby for nearly two weeks before making their way into the region. It seems as though they’re waiting for the retinal neurons to make their connections before beginning to make their own. If researchers surgically removed the eyes or genetically removed the retinal cells connecting the eyes to the thalamus, neurons from the cortex invaded more than a week earlier than they were supposed to.

“It turns out that the cortical neurons are waiting for the retinal axons to mature and find the most appropriate spots to connect before they’re allowed to come in,” said Fox. “There’s some form of instructional role that retinal axons play in the timing of the cortical axons entering.”

(Source: newswise.com)

Alzheimer’s disease is thought to be caused by the buildup of abnormal, thread-like protein deposits in the brain, but little is known about the molecular structures of these so-called beta-amyloid fibrils. A study published by Cell Press September 12th in the journal Cell has revealed that distinct molecular structures of beta-amyloid fibrils may predominate in the brains of Alzheimer’s patients with different clinical histories and degrees of brain damage. The findings pave the way for new patient-specific strategies to improve diagnosis and treatment of this common and debilitating disease.

"This work represents the first detailed characterization of the molecular structures of beta-amyloid fibrils that develop in the brains of patients with Alzheimer’s disease," says senior study author Robert Tycko of the National Institutes of Health. "This detailed structural model may be used to guide the development of chemical compounds that bind to these fibrils with high specificity for purposes of diagnostic imaging, as well as compounds that inhibit fibril formation for purposes of prevention or therapy."

Tycko and his team had previously noticed that beta-amyloid fibrils grown in a dish have different molecular structures, depending on the specific growth conditions. Based on this observation, they suspected that fibrils found in the brains of patients with Alzheimer’s disease are also variable and that these structural variations might relate to each patient’s clinical history. But it has not been possible to directly study the structures of fibrils found in patients because of their low abundance in the brain.

To overcome this hurdle, Tycko and his collaborators developed a new experimental protocol. They extracted beta-amyloid fibril fragments from the brain tissue of two patients with different clinical histories and degrees of brain damage and then used these fragments to grow a large quantity of fibrils in a dish. They found that a single fibril structure prevailed in the brain tissue of each patient, but the molecular structures were different between the two patients.

"This may mean that fibrils in a given patient appear first at a single site in the brain, then spread to other locations while retaining the identical molecular structure," Tycko says. "Our study also shows that certain fibril structures may be more likely than others to cause Alzheimer’s disease, highlighting the importance of developing imaging agents that target specific fibril structures to improve the reliability and specificity of diagnosis."

(Source: eurekalert.org)

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have found a group of proteins essential to the formation of long-term memories.

The study, published online ahead of print on September 12, 2013 by the journal Cell Reports, focuses on a family of proteins called Wnts. These proteins send signals from the outside to the inside of a cell, inducing a cellular response crucial for many aspects of embryonic development, including stem cell differentiation, as well as for normal functioning of the adult brain.

“By removing the function of three proteins in the Wnt signaling pathway, we produced a deficit in long-term but not short-term memory,” said Ron Davis, chair of the TSRI Department of Neuroscience. “The pathway is clearly part of the conversion of short-term memory to the long-term stable form, which occurs through changes in gene expression.”

The findings stem from experiments probing the role of Wnt signaling components in olfactory memory formation in Drosophila, the common fruit fly—a widely used doppelgänger for human memory studies. In the new study, the scientists inactivated the expression of several Wnt signaling proteins in the mushroom bodies of adult flies—part of the fly brain that plays a role in learning and memory.

The resulting memory disruption, Davis said, suggests that Wnt signaling participates actively in the formation of long-term memory, rather than having some general, non-specific effect on behavior.

“What is interesting is that the molecular mechanisms of adult memory use the same processes that guide the early development of the organism, except that they are repurposed for memory formation,” he said. “One difference, however, is that during early development the signals are intrinsic, while in adults they require an outside stimulus to create a memory.”

(Source: scripps.edu)

Isabelle Arnulf and colleagues from the Sleep Disorders Unit at the Université Pierre et Marie Curie (UPMC) have outlined case studies of patients with Auto-Activation Deficit who reported dreams when awakened from REM sleep – even when they demonstrated a mental blank during the daytime. This paper proves that even patients with Auto-Activation Disorder have the ability to dream and that it is the “bottom-up” process that causes the dream state.

In a new paper for the neurology journal Brain, Arnulf et al compare the dream states of patients with Auto-Activation Deficit (AAD) with those of healthy, control patients. AAD is caused by bilateral damage to the basal ganglia and it is a neuro-physical syndrome characterized by a striking apathy, a lack of spontaneous activation of thought, and a loss of self-driven behaviour. AAD patients must be stimulated by their care-givers in order to take part in everyday tasks like standing up, eating, or drinking. If you were to ask an AAD patient: “what are you thinking?” they would report that they have no thoughts.

During sleep, the brain is operating on an exclusively internal basis. In REM sleep, the higher cortex areas are internally stimulated by the brainstem. When awakened, most normal subjects will remember some dreams that were associated with their previous sleep state, especially in REM sleep. Would the self-stimulation of the cortex by the brainstem be sufficient to stimulate spontaneous dreams during sleep in AAD patients?

Discovering the answer to this question would go some way to proving either the top-down or bottom-up theories of dreaming. The top-down theory stipulates that dreaming begins in higher cortex memory structures and then proceeds backwards as imagination develops during wakefulness. The bottom-up theory posits that the brainstem structures which elicit rapid eye movements and cortex activation during REM sleep result in the emotional, visual, sensory, and auditory elements of dreaming.

Thirteen patients with AAD agreed to participate in the study and record their dreams in dream diaries during the week leading up to the evaluation. These patients were compared with thirteen non-medicated, healthy control subjects. Video and sleep monitoring were performed on all twenty six participants for two consecutive nights. The first night evaluated the patient’s sleep duration, structure, and architecture of their dreams. During the second night of sleep evaluation, the researchers woke the subjects up as they entered the second non-REM sleep cycle, and again after 10 min of established REM sleep during the following sleep cycle, and asked them what they were dreaming before being woken up. The dream reports were then independently analysed and scored according to; complexity of dream, bizarreness, and elaboration.

Four of the thirteen patients with AAD reported dreaming when awakened from REM sleep, even though they demonstrated a mental blank during the daytime. This is compared to 12 out of 13 of the control patients. However, the four AAD patients’ dreams were devoid of any complex, bizarre, or emotional elements. The presence of simple yet spontaneous dreams in REM sleep, despite the absence of thoughts during wakefulness in AAD patients, supports the notion that simple dream imagery is generated by brainstem stimulation and sent to the sensory cortex. The lack of complexity in the dreams of the four AAD patients, as opposed to the complexity of the control patients’ dreams, demonstrates that the full dreaming process require these sensations to be interpreted by a higher-order cortical area.

Therefore, this study shows for the first time that it is the bottom-up process that causes the dream state.

Yet, despite the simplicity of the dreams, Isabelle Arnulf commented that the banal tasks that the AAD patients dreamt about were fascinating. For instance, Patient 10 dreamt of shaving – an activity he never initiated during the daytime without motivation from his caregivers, and an activity he could not do by himself due to severe hand dystonia. Similarly, Patient 5 dreamt about writing even though he would never write in the daytime without being invited by his caregivers to do so.

Interestingly, there were no real differences in the sleep measures between the AAD patients and the control patients apart from 46% of the AAD patients had a complete absence of sleep spindles (a burst of oscillatory brain activity visible on an EEG that occurs during stage 2 sleep). The striking absence of sleep spindles in localized lesions in the basal ganglia of these 6 AAD patients highlights the role of the pallidum and striatum in spindling activity during non-REM sleep. This is a key distinction between the AAD patients and the control patients; all thirteen control subjects displayed signs of sleep spindles.

(Source: alphagalileo.org)

Researchers at the Stanford University School of Medicine have shown that oxytocin — often referred to as “the love hormone” because of its importance in the formation and maintenance of strong mother-child and sexual attachments — is involved in a broader range of social interactions than previously understood.

The discovery may have implications for neurological disorders such as autism, as well as for scientific conceptions of our evolutionary heritage.

Scientists estimate that the advent of social living preceded the emergence of pair living by 35 million years. The new study suggests that oxytocin’s role in one-on-one bonding probably evolved from an existing, broader affinity for group living.

Oxytocin is the focus of intense scrutiny for its apparent roles in establishing trust between people, and has been administered to children with autism spectrum disorders in clinical trials. The new study, published Sept. 12 in Nature, pinpoints a unique way in which oxytocin alters activity in a part of the brain that is crucial to experiencing the pleasant sensation neuroscientists call “reward.” The findings not only provide validity for ongoing trials of oxytocin in autistic patients, but also suggest possible new treatments for neuropsychiatric conditions in which social activity is impaired.

"People with autism-spectrum disorders may not experience the normal reward the rest of us all get from being with our friends," said Robert Malenka, MD, PhD, the study’s senior author. "For them, social interactions can be downright painful. So we asked, what in the brain makes you enjoy hanging out with your buddies?"

Some genetic evidence suggests the awkward social interaction that is a hallmark of autism-spectrum disorders may be at least in part oxytocin-related. Certain variations in the gene that encodes the oxytocin receptor — a cell-surface protein that senses the substance’s presence — are associated with increased autism risk.

Malenka, the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences, has spent the better part of two decades studying the reward system — a network of interconnected brain regions responsible for our sensation of pleasure in response to a variety of activities such as finding or eating food when we’re hungry, sleeping when we’re tired, having sex or acquiring a mate, or, in a pathological twist, taking addictive drugs. The reward system has evolved to reinforce behaviors that promote our survival, he said.

For this study, Malenka and lead author Gül Dölen, MD, PhD, a postdoctoral scholar in his group with over 10 years of autism-research expertise, teamed up to untangle the complicated neurophysiological underpinnings of oxytocin’s role in social interactions. They focused on biochemical events taking place in a brain region called the nucleus accumbens, known for its centrality to the reward system.

In the 1970s, biologists learned that in prairie voles, which mate for life, the nucleus accumbens is replete with oxytocin receptors. Disrupting the binding of oxytocin to these receptors impaired prairie voles’ monogamous behavior. In many other species that are not monogamous by nature, such as mountain voles and common mice, the nucleus accumbens appeared to lack those receptors.

"From this observation sprang a dogma that pair bonding is a special type of social behavior tied to the presence of oxytocin receptors in the nucleus accumbens. But what’s driving the more common group behaviors that all mammals engage in — cooperation, altruism or just playing around — remained mysterious, since these oxytocin receptors were supposedly absent in the nucleus accumbens of most social animals," said Dölen.

The new discovery shows that mice do indeed have oxytocin receptors at a key location in the nucleus accumbens and, importantly, that blocking oxytocin’s activity there significantly diminishes these animals’ appetite for socializing. Dölen, Malenka and their Stanford colleagues also identified, for the first time, the nerve tract that secretes oxytocin in the region, and they pinpointed the effects of oxytocin release on other nerve tracts projecting to this area.

Mice can squeak, but they can’t talk, Malenka noted. “You can’t ask a mouse, ‘Hey, did hanging out with your buddies a while ago make you happier?’” So, to explore the social-interaction effects of oxytocin activity in the nucleus accumbens, the investigators used a standard measure called the conditioned place preference test.

"It’s very simple," Malenka said. "You like to hang out in places where you had fun, and avoid places where you didn’t. We give the mice a ‘house’ made of two rooms separated by a door they can walk through at any time. But first, we let them spend 24 hours in one room with their littermates, followed by 24 hours in the other room all by themselves. On the third day we put the two rooms together to make the house, give them complete freedom to go back and forth through the door and log the amount of time they spend in each room."

Mice normally prefer to spend time in the room that reminds them of the good times they enjoyed in the company of their buddies. But that preference vanished when oxytocin activity in their nucleus accumbens was blocked. Interestingly, only social activity appeared to be affected. There was no difference, for example, in the mice’s general propensity to move around. And when the researchers trained the mice to prefer one room over the other by giving them cocaine (which mice love) only when they went into one room, blocking oxytocin activity didn’t stop the mice from picking the cocaine den.

In an extensive series of sophisticated, highly technical experiments, Dölen, Malenka and their teammates located the oxytocin receptors in the murine nucleus accumbens. These receptors lie not on nucleus accumbens nerve cells that carry signals forward to numerous other reward-system nodes but, instead, at the tips of nerve cells forming a tract from a brain region called the dorsal Raphe, which projects to the nucleus accumbens. The dorsal Raphe secretes another important substance, serotonin, triggering changes in nucleus accumbens activity. In fact, popular antidepressants such as Prozac, Paxil and Zoloft belong to a class of drugs called serotonin-reuptake inhibitors that increase available amounts of serotonin in brain regions, including the nucleus accumbens.

As the Stanford team found, oxytocin acting at the nucleus accumbens wasn’t simply squirted into general circulation, as hormones typically are, but was secreted at this spot by another nerve tract originating in the hypothalamus, a multifunction midbrain structure. Oxytocin released by this tract binds to receptors on the dorsal Raphe projections to the nucleus accumbens, in turn liberating serotonin in this key node of the brain’s reward circuitry. The serotonin causes changes in the activity of yet other nerve tracts terminating at the nucleus accumbens, ultimately resulting in altered nucleus accumbens activity — and a happy feeling.

"There are at least 14 different subtypes of serotonin receptor," said Dölen. "We’ve identified one in particular as being important for social reward. Drugs that selectively act on this receptor aren’t clinically available yet, but our study may encourage researchers to start looking at drugs that target it for the treatment of diseases such as autism, where social interactions are impaired."

Malenka and Dölen said they think their findings in mice are highly likely to generalize to humans because the brain’s reward circuitry has been so carefully conserved over the course of hundreds of millions of years of evolution. This extensive cross-species similarity probably stems from pleasure’s absolutely essential role in reinforcing behavior likely to boost an individual’s chance of survival and procreation.

(Source: med.stanford.edu)

UI study documents the illness’s effect on brain tissue

It’s hard to fully understand a mental disease like schizophrenia without peering into the human brain. Now, a study by University of Iowa psychiatry professor Nancy Andreasen uses brain scans to document how schizophrenia impacts brain tissue as well as the effects of anti-psychotic drugs on those who have relapses.

Andreasen’s study, published in the American Journal of Psychiatry, documented brain changes seen in MRI scans from more than 200 patients beginning with their first episode and continuing with scans at regular intervals for up to 15 years. The study is considered the largest longitudinal, brain-scan data set ever compiled, Andreasen says.

Schizophrenia affects roughly 3.5 million people, or about one percent of the U.S. population, according to the National Institutes of Health. Globally, some 24 million are affected, according to the World Health Organization.

The scans showed that people at their first episode had less brain tissue than healthy individuals. The findings suggest that those who have schizophrenia are being affected by something before they show outward signs of the disease.

“There are several studies, mine included, that show people with schizophrenia have smaller-than-average cranial size,” explains Andreasen, whose appointment is in the Carver College of Medicine. “Since cranial development is completed within the first few years of life, there may be some aspect of earliest development—perhaps things such as pregnancy complications or exposure to viruses—that on average, affected people with schizophrenia.”

Andreasen’s team learned from the brain scans that those affected with schizophrenia suffered the most brain tissue loss in the two years after the first episode, but then the damage curiously plateaued—to the group’s surprise. The finding may help doctors identify the most effective time periods to prevent tissue loss and other negative effects of the illness, Andreasen says.

The researchers also analyzed the effect of medication on the brain tissue. Although results were not the same for every patient, the group found that in general, the higher the anti-psychotic medication doses, the greater the loss of brain tissue.

“This was a very upsetting finding,” Andreasen says. “We spent a couple of years analyzing the data more or less hoping we had made a mistake. But in the end, it was a solid finding that wasn’t going to go away, so we decided to go ahead and publish it. The impact is painful because psychiatrists, patients, and family members don’t know how to interpret this finding. ‘Should we stop using antipsychotic medication? Should we be using less?’”

The group also examined how relapses could affect brain tissue, including whether long periods of psychosis could be toxic to the brain. The results suggest that longer relapses were associated with brain tissue loss.

The insight could change how physicians use anti-psychotic drugs to treat schizophrenia, with the view that those with the disorder can lead productive lives with the right balance of care.

“We used to have hundreds of thousands of people chronically hospitalized. Now, most are living in the community, and this is thanks to the medications we have,” Andreasen notes. “But antipsychotic treatment has a negative impact on the brain, so … we must get the word out that they should be used with great care, because even though they have fewer side effects than some of the other medications we use, they are certainly not trouble free and can have lifelong consequences for the health and happiness of the people and families we serve.”

(Source: now.uiowa.edu)