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)

People with degenerative neurological conditions could benefit from research that shows why their brain cells stop communicating properly.

Scientists believe that the findings could help to develop treatments that slow the progress of a broad range of brain disorders such as Huntington’s, Alzheimer’s and Parkinson’s diseases.

The team at the University, led by Professor Tom Gillingwater, analysed how connection points between brain cells break down during disease and identified six proteins that control the process.

Sending Signals

When connection points in the brain, known as synapses, stop working - because of injury or disease - the chain of brain signalling breaks down and cannot be repaired.

The research from The Roslin Institute and Centre for Integrative Physiology at the University will help scientists identify drugs that target these proteins.

This could eventually enable clinicians to slow the progress of these disorders.

This study has identified key proteins that may control what goes wrong in a range of brain disorders. We now hope to identify drugs that prevent the breakdown of communication between brain cells and, as a result, halt the progress of these devastating neurodegenerative conditions. — Dr Thomas Wishart Career Track Fellow, The Roslin Institute at the University

(Source: ed.ac.uk)

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)