Posts tagged psychology

The hippocampus represents an important brain structure for learning. Scientists at the Max Planck Institute of Psychiatry in Munich discovered how it filters electrical neuronal signals through an input and output control, thus regulating learning and memory processes. Accordingly, effective signal transmission needs so-called theta-frequency impulses of the cerebral cortex. With a frequency of three to eight hertz, these impulses generate waves of electrical activity that propagate through the hippocampus. Impulses of a different frequency evoke no transmission, or only a much weaker one. Moreover, signal transmission in other areas of the brain through long-term potentiation (LTP), which is essential for learning, occurs only when the activity waves take place for a certain while. The scientists even have an explanation for why we are mentally more productive after drinking a cup of coffee or in an acute stress situation: in their experiments, caffeine and the stress hormone corticosterone boosted the activity flow.

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Researchers in the Taub Institute at Columbia University Medical Center (CUMC) have identified a mechanism that appears to underlie the common sporadic (non-familial) form of Parkinson’s disease, the progressive movement disorder. The discovery highlights potential new therapeutic targets for Parkinson’s and could lead to a blood test for the disease. The study, based mainly on analysis of human brain tissue, was published in the online edition of Nature Communications.

Studies of rare, familial (heritable) forms of Parkinson’s show that a protein called alpha-synuclein plays a role in the development of the disease.  People who have extra copies of the alpha-synuclein gene produce excess alpha-synuclein protein, which can damage neurons. The effect is most pronounced in dopamine neurons, a population of brain cells in the substantia nigra that plays a key role in controlling normal movement and is lost in Parkinson’s.  Another key feature of Parkinson’s is the presence of excess alpha-synuclein aggregates in the brain.

As the vast majority of patients with Parkinson’s do not carry rare familial mutations, a key question has been why these individuals with common sporadic Parkinson’s nonetheless acquire excess alpha-synuclein protein and lose critical dopamine neurons, leading to the disease.

Using a variety of techniques, including gene-expression analysis and gene-network mapping, the CUMC researchers discovered how common forms of alpha-synuclein contribute to sporadic Parkinson’s. “It turns out multiple different alpha-synuclein transcript forms are generated during the initial step in making the disease protein; our study implicates the longer transcript forms as the major culprits,” said study leader Asa Abeliovich, MD, PhD, associate professor of pathology and cell biology and neurology at CUMC. “Some very common genetic variants in the alpha-synuclein gene, present in many people, are known to impact the likelihood that an individual will suffer from sporadic Parkinson’s. In our study, we show that people with ‘bad’ variants of the gene make more of the elongated alpha-synuclein transcript forms. This ultimately means that more of the disease protein is made and may accumulate in the brain.”

“An unusual aspect of our study is that it is based largely on detailed analysis of actual patient tissue, rather than solely on animal models,” said Dr. Abeliovich. “In fact, the longer forms of alpha-synuclein are human-specific, as are the disease-associated genetic variants. Animal models don’t really get Parkinson’s, which underscores the importance of including the analysis of human brain tissue.”

“Furthermore, we found that exposure to toxins associated with Parkinson’s can increase the abundance of this longer transcript form of alpha-synuclein. Thus, this mechanism may represent a common pathway by which environmental and genetic factors impact the disease,” said Dr. Abeliovich.

The findings suggest that drugs that reduce the accumulation of elongated alpha-synuclein transcripts in the brain might have therapeutic value in the treatment of Parkinson’s. The CUMC team is currently searching for drug candidates and has identified several possibilities.

The study also found elevated levels of the alpha-synuclein elongated transcripts in the blood of a group of patients with sporadic Parkinson’s, compared with unaffected controls. This would suggest that a test for alpha-synuclein may serve as a biomarker for the disease. “There is a tremendous need for a biomarker for Parkinson’s, which now can be diagnosed only on the basis of clinical symptoms. The finding is particularly intriguing, but needs to be validated in additional patient groups,” said Dr. Abeliovich. A biomarker could also speed clinical trials by giving researchers a more timely measure of a drug’s effectiveness.

(Source: cumc.columbia.edu)

Most people equate “gray matter” with the brain and its higher functions, such as sensation and perception, but this is only one part of the anatomical puzzle inside our heads. Another cerebral component is the white matter, which makes up about half the brain by volume and serves as the communications network.

The gray matter, with its densely packed nerve cell bodies, does the thinking, the computing, the decision-making. But projecting from these cell bodies are the axons—the network cables. They constitute the white matter. Its color derives from myelin—a fat that wraps around the axons, acting like insulation.

Alex Schelgel, first author on a paper in the August 2012 Journal of Cognitive Neuroscience, has been using the white matter as a landscape on which to study brain function. An important result of the research is showing that you can indeed “teach old dogs new tricks.” The brain you have as an adult is not necessarily the brain you are always going to have. It can still change, even for the better.

"This work is contributing to a new understanding that the brain stays this plastic organ throughout your life, capable of change," Schlegel says. "Knowing what actually happens in the organization of the brain when you are learning has implications for the development of new models of learning as well as potential interventions in cases of stroke and brain damage."

Schlegel is a graduate student working under Peter Tse, an associate professor of psychological and brain sciences and a coauthor on the paper. “This study was Peter’s idea,” Schlegel says. “He wanted to know if we could see white matter change as a result of a long-term learning process. Chinese seemed to him like the most intensive learning experience he could think of.”

Twenty-seven Dartmouth students were enrolled in a nine-month Chinese language course between 2007 and 2009, enabling Schlegel to study their white matter in action. While many neuroscientists use magnetic resonance imaging (MRI) in brain studies, Schlegel turned to a new MRI technology, called diffusion tensor imaging (DTI). He used DTI to measure the diffusion of water in axons, tracking the communication pathways in the brain. Restrictions in this diffusion can indicate that more myelin has wrapped around an axon.

"An increase in myelination tells us that axons are being used more, transmitting messages between processing areas," Schlegel says. "It means there is an active process under way."

Their data suggest that white matter myelination is precisely what was seen among the language students. There is a structural change that goes along with this learning process. While some studies have shown that changes in white matter occurred with learning, these observations were made in simple skill learning and strictly on a “before and after” basis.

"This was the first study looking at a really complex, long-term learning process over time, actually looking at changes in individuals as they learn a task," says Schlegel. "You have a much stronger causal argument when you can do that."

The work demonstrates that significant changes are occurring in adults who are learning. The structure of their brains undergoes change.

"This flies in the face of all these traditional views that all structural development happens in infancy, early in childhood," Schlegel says. "Now that we actually do have tools to watch a brain change, we are discovering that in many cases the brain can be just as malleable as an adult as it is when you are a child or an adolescent."

(Source: eurekalert.org)

By Sabrina Richards | September 20, 2012

Researchers find that photoreceptors expressed in zebrafish hypothalamus contribute to light-dependent behavior.

Juvenile zebrafish.

Zebrafish larvae without eyes or pineal glands can still respond to light using photopigments located deep within their brains.  Published in Current Biology, the findings are the first to link opsins, photoreceptors located in the hypothalamus and other brain areas, to increased swimming in response to darkness, a behavior researchers hypothesize may help the fish move toward better-lit environments.

“[It’s a] strong demonstration that opsin-dependent photoreceptors in deep brain areas affect behaviors,” said Samer Hattar, who studies light reception in mammals at Johns Hopkins University but did not participate in the research.

Photoreceptors in eyes enable vision, and photoreceptors in the pineal gland, a small endocrine gland located in the center of the vertebrate brain, regulate circadian rhythms. But photoreceptors are also found in other brain areas of both invertebrates and vertebrate lineages. The function of these extraocular photoreceptors has been best studied in birds, where they regulate seasonal reproduction, explained Harold Burgess, a behavioral neurogeneticist at the Eunice Kennedy Shriver National Institute for Child Health and Human Development.

Many opsins have been reported in the brains of tiny and transparent larval zebrafish, raising the possibility that light could be stimulating the photoreceptors even deep in the brain. To test for behaviors that may be regulated by deep brain photoreceptors, Burgess and his colleagues in Wolfgang Driever’s lab at the University of Freiburg removed the eyes of zebrafish larvae, and compared their behavior to larvae that retained their eyes. Although most light-dependent behavior required eyes, the eyeless larvae did respond when the lights were turned off, increasing their activity for a several minutes, though to a somewhat lesser extent than control larvae. But the fact that they responded at all suggests that non-retinal photoreceptors contributed to the behavior.

To confirm the role of the deep brain photoreceptors, the researchers also tested eyeless larvae that had been genetically modified to block expression of photoreceptors in the pineal gland. This fish still showed this jump in activity for several minutes after entering darkness.

Two different types of opsins—melanopsin and multiple tissue opsin—are expressed in the same type of neuron in zebrafish hypothalamus. Burgess and his colleagues looked at zebrafish missing the transcription factor Orthopedia, which is unique to these neurons, and found that the darkness-induced activity boost is nearly absent in these fish. To further narrow the search for the responsible photoreceptors, the researchers overexpressed melanopsin in hypothalamus neurons that co-express Orthopedia and melanopsin, and found that it increased the sensitivity of eyeless zebrafish to reductions in light. The results point to both melanopsin and Orthopedia as key players in modulating this behavior and pinpoint the location to neurons that coexpress these factors in the zebrafish hypothalamus.

Interestingly, the hypothalamus is one of the oldest parts of the vertebrate brain, said Detlev Arendt, a developmental biologist at the European Molecular Biology Laboratory in Heidelberg. “It’s very possible that this is one of the oldest functions”—one that evolved in “non-visual organisms” that had no eyes but still needed to sense light.

Although not as directed and efficient as eye-dependent behaviors that help fish swim toward light, Burgess speculates that deep brain opsins can still benefit zebrafish larvae. “You could imagine situation where it can’t see light, if a leaf falls on it and it doesn’t know where to swim. I think this behavior puts it in a hyperactive state where it swims wildly for several minutes until it reaches enough light for eyes to take over,” he explained, noting that such behavior is common in invertebrates.

It remains to be seen whether these deep brain opsins regulate other behaviors, perhaps in similar fashion to seasonal hormonal regulation in birds, but Hattar believes it is likely. “It’s beyond reasonable doubt there are many functions for these deep brain photoreceptors.”

(Source: the-scientist.com)

Millions of Americans take antidepressants such as Prozac, Effexor, and Paxil, but the explanations for how they work never satisfied René Hen, a professor of psychiatry, neuroscience and pharmacology.

So the French-born researcher began a series of experiments a decade ago that are now helping to overturn conventional wisdom about the class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs) and providing new insights into the biological mechanisms in the brain that affect mood and cognition.

Adult-born neurons in the hippocampus have been engineered to express channelrhodopsin (red), a protein that allows the activation of these neurons and the study of their impact on pattern separation and mood. (Image credit: Mazen Kheirbek and René Hen)

SSRIs, it has long been thought, work by inhibiting brain cells from reabsorbing serotonin, a signaling agent in the brain associated with positive mood. Yet unlike with psychoactive substances, the effects of the drugs take weeks to be felt—even though the increase in serotonin circulating in the brain begins almost immediately. Something more, Hen concluded, must be happening after that to create such a profound effect in depressed patients.

In 2003, Hen demonstrated an important finding in mice: The change in mood—measured by the amount of time it took the animals to overcome anxiety and feed in new environments—appeared to be due in part to the production of new brain cells in the hippocampus, an area of the brain associated with learning and memory. And those new brain cells, Hen thinks, are the result of growth-stimulating chemicals released in the brain, in response to the increased serotonin.

Last year, Hen published another groundbreaking study, suggesting how these new brain cells might affect mood. The new brain cells are located in the dentate gyrus, an area of the hippocampus involved in pattern separation, a cognitive process that helps us to recognize that something is new and different from similar experiences and stimuli. This information is then sent to other brain regions where the new stimulus is assigned a positive or negative emotional value.

Using genetic manipulations that block or enhance the production of brain cells in the dentate gyrus, Hen demonstrated that the new brain cells led to a marked improvement not just in the cognitive abilities of mice, but also in their mood. “What we think, even though it hasn’t been proven yet, is that some depressed human patients also have a problem with pattern separation,” Hen says. “What we are hoping is, if we can boost production of new neurons in their hippocampus, maybe we can improve pattern separation in patients and decrease general symptoms.”

Hen sees numerous ways that a disruption in pattern separation might lead to negative emotions such as anxiety and depression. The hippocampus is located next to, and is strongly linked with, another brain structure, the almond-shaped amygdala, thought to be the seat of our emotions.

If wrong judgments were assigned to novel stimuli in the amygdala, that could easily trigger the brain’s fight-or-flight instinct or, at the very least, produce fear. That might help explain features of anxiety disorders—why survivors of the 9/11 terrorist attacks suffering from post-traumatic stress disorder, for instance, might be hit with a panic attack whenever they see an airplane fly over a skyscraper, Hen says.

A deficit in pattern separation might also help explain why depressed patients often are unable to experience pleasure, exhibit a lack of interest in novel experiences, and feel profound malaise. Perhaps they are simply unable to register an experience as novel or pleasurable because they are unable to recognize it as sufficiently different from prior experiences.

Hen is quick to point out that new brain cell production in the hippocampus is just one effect of a cascade of neurochemical changes unleashed by SSRIs. Other researchers have demonstrated, among other things, that the drugs also have a strong impact on the prefrontal cortex, the area of the brain associated with executive functions such as decision-making and restraint.

Even so, Hen hopes his findings will have significant implications for some depressed patients—and perhaps even reveal why certain antidepressants work for some people and not others. Over the next several years, he plans to explore his hypotheses further by evaluating the pattern-separation abilities of depressed patients before and after they are treated with SSRIs.

“There is still a long way to go, but we are at least starting to provide a theoretical framework,” Hen says. “With complex disorders such as anxiety and depression, you are dealing with many parts of the brain. We think we have identified the biological basis for one of the symptoms present in a subgroup of patients, and maybe by targeting it, we will be able to help them.”

(Source: news.columbia.edu)