Precise control of brain circuit alters mood

By combining super-fine electrodes and tiny amounts of a very specific drug, researchers have singled out a circuit in mouse brains and taken control of it to dial an animal's mood up and down. (© mgkuijpers / Fotolia)

By combining super-fine electrodes and tiny amounts of a very specific drug, Duke University researchers have singled out a circuit in mouse brains and taken control of it to dial an animal's mood up and down.

Stress-susceptible animals that behaved as if they were depressed or anxious were restored to relatively normal behavior by tweaking the system, according to a study appearing in the July 20 issue of Neuron.

"If you 'turn the volume up' on animals that hadn't experienced stress, they start normal and then they have a problem," said lead researcher Kafui Dzirasa, an assistant professor of psychiatry and behavioral sciences, and neurobiology. "But in the animals that had experienced stress and didn't do well with it, you had to turn their volume up to get them back to normal. It looked like stress had turned the volume down."

The circuit the team identified and altered is a connection the prefrontal cortex uses to keep time for the limbic system, which governs emotions and basic drives. To regulate mood, the prefrontal cortex acts as a pacemaker to coordinate the actions of the amygdala, which governs stress responses, and the ventral tegmental area, which plays a role in the brain's reward circuitry.

"These subcortical circuits are the key regulators of our emotional life," said Helen Mayberg, a professor of psychiatry, neurology and radiology at Emory University who was not involved in this research. "What's great about this paper is that they use different approaches to see a circuit that's relevant to a lot of disorders," said Mayberg, who has been pioneering deep-brain stimulation of very specific sites in the human prefrontal cortex to treat mood disorders.

The emerging picture from this study and others is of a brain built of multi-part circuits that respond in concert and regulate one another. Specificity in understanding these circuits is going to be key to resolving different disorders, Dzirasa said.

"The prefrontal cortex is not just a blob of cells," Mayberg said. "These findings give insight into which cells go to which area and allow researchers to kind of choreograph their actions."

Dzirasa is an M.D. just finishing his residency in psychiatry and a Ph.D. neuroscientist with an engineering background. Postdoctoral researcher and first author Rainbo Hultman is a biochemist.

In addition to overcoming the challenges of understanding each other, they asked, "Could we go from a protein, to a signaling activity, to a cell, to a circuit, to this big activity that happens across the whole brain, to actual behavior?" Hultman said.

"Illness can happen at any one of these levels," said Dzirasa, who is also a member of the Duke Institute for Brain Sciences.

The team started by precisely placing arrays of 32 electrodes in four brain areas of the mice. Then they recorded brain activity as these mice were subjected to a stressful situation called chronic social defeat. This allowed them to see activity between the prefrontal cortex and three areas of the limbic system that are implicated in major depression.

To interpret the complicated data coming from the electrodes, the neuroscientists then turned to Duke colleagues David Dunson of statistical science and Lawrence Carin of electrical engineering, who specialize in statistical analysis of noisy data to find important patterns. Using machine learning algorithms, they identified which parts of the data seemed to be the timing control signal between the prefrontal cortex and the amygdala and zeroed in on the individual neurons involved in that circuit.

"They came back with, 'It's this clock signature here that is responsible for which mice become susceptible to stress and which become resilient,'" Dzirasa said.

Hultman then turned to engineered molecules called DREADD developed by University of North Carolina at Chapel Hill pharmacologist Bryan Roth. These Designer Receptors Exclusively Activated by Designer Drug are very specific signal receptors that can be incorporated into the neural circuit's control spots in very tiny amounts (0.5 microliter). A drug that attaches only to that DREADD is then administered to give the researchers control over the circuit.

This new combination of electronics and drugs to intervene in an individual brain circuit might be used to create mouse models of other mood disorders for other studies, Dzirasa said. But Emory's Mayberg cautions that a mouse brain is not a human brain and to assess anything like "mood" in a mouse, one can only infer from its behaviors. "It's hard to do, even in a human," she said.

Story Source:

The above story is based on materials provided by Duke University. Note: Materials may be edited for content and length.

Journal Reference:

Rainbo Hultman, Stephen D. Mague, Qiang Li, Brittany M. Katz, Nadine Michel, Lizhen Lin, Joyce Wang, Lisa K. David, Cameron Blount, Rithi Chandy, David Carlson, Kyle Ulrich, Lawrence Carin, David Dunson, Sunil Kumar, Karl Deisseroth, Scott D. Moore, and Kafui Dzirasa. Dysregulation of Prefrontal Cortex-Mediated Slow-Evolving Limbic Dynamics Drives Stress-Induced Emotional Pathology. Neuron, June 2016 DOI: 10.1016/j.neuron.2016.05.038

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Cells in standby mode

Normally, yeast cells are rod-shaped (above). After having their cell wall removed, however, they become spherical (below left). During dormancy (above right) the loss of the cell wall the cells retain their stability and keep their rod-shaped appearance (below right). (MPI f. Molecular Cell Biology and Genetics)

Normally, cells are highly active and dynamic: in their liquid interior, called the cytoplasm, countless metabolic processes occur in parallel, proteins and particles jiggle around wildly. If, however, those cells do not get enough nutrients, their energy level drops. This leads to a marked decrease of the cytoplasmic pH -- the cells acidify. In response, cells enter into a kind of standby mode, which enables them to survive. A team of researchers from Dresden, Germany, have found out that the cytoplasm of these seemingly dead cells changes its consistency from liquid to solid. Thereby, they protect the sensitive structures in the cellular interior.

Cells can enter into a kind of standby mode -- called dormancy -- when confronted with unfavorable conditions such as nutrient deprivation. In this state, cells drastically reduce their metabolism and shut down growth and cell division. In extreme cases, such cells are hardly or not at all distinguishable from dead cells -- and yet they can re-emerge from this state unharmed and continue to grow and divide when conditions in their environment improve.

Munder and colleagues from Dresden (Germany) under supervision of Simon Alberti wanted to understand how cells switch on and off the standby mode. They focused their efforts on yeast cells, which they observed during starvation. Their observation: The cytoplasm loses its dynamics, cell organelles and particles slow down and many proteins form large, microscopically visible structures. It seems as if the cytoplasm changes its consistency in response to nutrient deprivation. And indeed: a closer look with highly sensitive biophysical methods shows that the material state of the cytoplasm changes from liquid to solid -- the cell enters into a kind of rigor mortis. As it turns out, the cytoplasmic pH, which decreases markedly under starvation conditions, plays a crucial role in this process.

Remarkably, the sleeping cells -- in contrast to dead cells -- can also reverse this process. When nutrients are added back, the pH rises again, the cytoplasm fluidizes and cells continue to grow and divide. The studies of Munder and colleagues show that the state of the cytoplasm is crucial for switching on and off the standby mode: ''Cells seem to have a control mechanism in place, which they use for the regulation of their material properties in response to certain environmental cues, thereby ensuring their survival''. Thus, it seems to be possible to trick death by shutting down all processes of life in a controlled manner. Whether this trick can be taught to human cells will become clear in the next couple of years.

Story Source:

The above story is based on materials provided by Max-Planck-Gesellschaft. Note: Materials may be edited for content and length.

Journal Reference:

Matthias Christoph Munder, Daniel Midtvedt, Titus Franzmann, Elisabeth Nüske, Oliver Otto, Maik Herbig, Elke Ulbricht, Paul Müller, Anna Taubenberger, Shovamayee Maharana, Liliana Malinovska, Doris Richter, Jochen Guck, Vasily Zaburdaev, Simon Alberti. A pH-driven transition of the cytoplasm from a fluid- to a solid-like state promotes entry into dormancy.eLife, 2016; 5 DOI: 10.7554/eLife.09347

Source : ScienceDaily

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Our closest wormy cousins

About 70% of our genes trace their ancestry back to the acorn worm

This is a juvenile of Saccoglossus kowalevskii with one of the transcription factors expressed in the pharyngeal region (highlighted in blue).

Credit: Andrew Gillis

A team from the Okinawa Institute of Science and Technology Graduate University (OIST) and its collaborators has sequenced the genomes of two species of small water creatures called acorn worms and showed that we share more genes with them than we do with many other animals, establishing them as our distant cousins.

The study found that 8,600 families of genes are shared across deuterostomes, a large animal grouping that includes a variety of organisms, ranging from acorn worms to star fishes, from frogs to dogs, to humans. This means that approximately 70% of our genes trace their ancestry back to the original deuterostome. By comparing the genomes of acorn worms to other animals, OIST scientists inferred the presence of these genes in the common ancestor of all deuterostomes, an extinct animal that lived half a billion years ago. This research shows that the pharyngeal gene cluster is unique to the deuterostomes and it could be linked to the development of the pharynx, the region that links the mouth and nose to the esophagus in humans. These findings were published in Nature, summarizing an international collaboration between OIST researchers and teams from the US, UK, Japan, Taiwan and Canada.

Around 550 million years ago, a great variety of animals burst onto the world in an event known as the Cambrian explosion. This evolutionary radiation revealed several new animal body plans, and changed life on Earth forever, as complex animals with specialized guts and behavioural features emerged. Thanks to the genome sequencing of multiple contemporary animals of the deuterostome group, we can go back in time to unveil aspects of the long-lost ancestor of this diverse group of animals.

Acorn worms are marine creatures that live on the ocean floor and feed by filtering a steady flow of sea water through slits in the region of their gut between mouth and esophagus. These slits are distantly related to the gills of fish, and represent a critical innovation in evolution not shared with animals like flies or earthworms. Since acorn worms occupy such a critical evolutionary position relative to humans the researchers sequenced two distantly related acorn worm species, Ptychodera flava, collected in Hawaii, and Saccoglossus kowalevskii, from the Atlantic Ocean. "Their genomes are necessary to fill the gap in our understanding of the genes shared by the common ancestor of all deuterostomes," explains Dr Oleg Simakov, lead author of this study.

Indeed, beyond sequencing these two organisms, the team was also interested in identifying ancient gene families that were already present in the deuterostome ancestor. The team compared the genomes of the two acorn worms with the genomes of 32 diverse animals and found that about 8,600 families of genes are homologous, that is, evolutionarily-related, across all deuterostomes and so are confidently inferred to have been present also in the genome of their deuterostome ancestor. Human arms, birds' wings, cats' paws and the whales' flippers are classical examples of homology, because they all derive from the limbs of a common ancestor. As with anatomical structures, genes homology is defined in terms of shared ancestry. Because of later gene duplications and other processes, these 8,600 homologous genes correspond to at least 14,000 genes, or approximately 70%, of the current human genome.

The study also identified clusters of genes that are close together in acorn worm genomes and in the genomes of humans and other vertebrates. The ancient proximity of these gene clusters, preserved over half a billion years, suggests that the genes may function as a unit. One gene cluster connected with the development of the pharynx in vertebrates and acorn worms is particularly interesting. It is shared by all deuterostomes, but not present in non-deuterostome animals such as insects, octopuses, earthworms and flatworms. The pharynx of acorn worms and other animals functions to filter food and to guide it to the digestive system. In humans, this cluster is active in the formation of the thyroid glands and the pharynx. Scientists suggest there is a connection between the function of the modern thyroid and the filter feeding mechanism of acorn worms. This pharyngeal gene cluster contains six genes ordered in a common pattern in all deuterostomes and includes the genes for four proteins that are critical transcriptional regulators that control activation of numerous other genes. Genes ordered in the same way and located next to each other in the chromosomal DNA are linked and transferred together from one generation to the next. Interestingly, not only the DNA that codes for these transcription factor genes is shared among the deuterostomes, but also some of the DNA pieces that are used as binding sites for the transcription factors are conserved among these animals.

"Our analysis of the acorn worm genomes provides a glimpse into our Cambrian ancestors' complexity and supplies support for the ancient link between the pharyngeal development and the filter feeding life style that ultimately contributed to our evolution," explains Dr Simakov.

Recently, the OIST team also sequenced the genomes of the octopus and the coral Porites australiensis.

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Story Source:

The above post is reprinted from materials provided by Okinawa Institute of Science and Technology (OIST) Graduate University. Note: Materials may be edited for content and length.

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Important notice for Mphil Research Students

Mphil Students who have Completed their Research work in Spring 2015 have to submit their thesis for external evaluation before 21st sept 2015. In case of Failing to meet the Deadline , shall have to Register for Fall 2015 semester, on payment of dues as described by the Treasurer Office.

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