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 Research & Giving News Article  of Depression in Rats A hippocampal circuit is involved in both depression and depression treatment Karl Deisseroth, M.D., Ph.D., assistant professor of bioengineering and of psychiatry and behavioral sciences at Stanford and a 2005 NARSAD Young Investigator, employed high-speed imaging technology to study depression in rats. Reasoning that the brain is essentially a complex electrical circuit, Dr. Deisseroth’s team set out to test the theory of whether a malfunction in brain circuitry could be at the root of depression.  To explore the idea in a precise, quantitative way, they needed to develop a visualization technology that was faster and sharper than brain-imaging systems currently available, such as MRI or CT scans. Raag Airan, an M.D.-Ph.D. student in the Deisseroth lab, led the development of a technique called voltage-sensitive dye imaging for this work. The technique allows intact brain circuits to be viewed in real time, enabling researchers to watch living neurons in action, across entire brain networks.The system uses a fluorescent dye, sensitive to alterations in the voltage of currents flowing through brain circuits. The dye is introduced into brain tissue, and as dyed circuits light up and darken again in response to the brain’s electrical activity, very fast high-resolution cameras capture the action. The researchers can observe how different stimuli received by the brain, such as a dose of an antidepressant drug, affects circuit operation. Dr. Deisseroth and colleagues used slices of rat brain, somewhat in the manner of computer technicians removing individual circuit boards from a machine to test their functional properties. The brain slices used in the experiments, which remained active for many hours, came from parts of the hippocampus, a brain region long thought to be implicated in depression. The researchers also tested slices from depressed rats that were treated with the antidepressant medications fluoxetine (Prozac) and imipramine. The team carried out the study using a standard rat model of depression. In these rats, the research team found an alteration in electrical activity that could be corrected by antidepressants. Specifically, they found that the “percolation” or spatial spread of electrical activity in the dentate gyrus of depressed rats was smaller than in that of normal rats, and that this electrical anomaly was corrected after antidepressant administration. (The dentate gyrus is a region within the brain’s hippocampal formation.) Observations of rapidly changing electrical activity in the hippocampus would likely not be possible without whole-circuit imaging methods, according to Dr. Deisseroth. His team needed to be able to image a whole circuit simultaneously—and very rapidly—to see the effect. Leslie Meltzer, a member of the research team, was involved in the search for a biological basis of the observed changes in circuitry. An obvious place to start, she said, was to look at the formation of new neurons in the hippocampus, a process some neuroscientists believe is at the root of how antidepressants work. Meltzer found that the growth of new hippocampal neurons could account for the behavioral improvements; yet she did not find the converse to be true: fewer new neurons in the hippocampus did not, by itself, signal depression. In the team’s model system, the two states--depression behavior and its treatment--appeared to manifest themselves through the same pathway in the dentate gyrus, despite very different cellular mechanisms. Dr. Deisseroth commented that the findings may help to “make sense of how there can be so many different causes and treatments of depression, and also help us understand conceptually how something that seems as hard to get traction on as depression can have a really quantitative, concrete basis.” “The holy grail of psychiatry,” Dr. Deisseroth said, is to try to find common pathways that can make sense of the enormous complexity of both disease states and the ways in which treatments exert their beneficial effects. “You can use that common pathway as the most efficient, most direct” way to identify specific treatment targets, he said. Matching up depressed behavior with activity in the hippocampus is “pretty amazing,” said Helen Mayberg, professor of psychiatry and neurology at Emory University in Atlanta and a NARSAD Distinguished Investigator and Scientific Council member. “It tells us the hippocampus is very involved” in depression, she said, “but it doesn't tell us it’s the origin of the problem.” The hippocampus sends and receives information to and from many other brain regions, and mapping those connections in depressed animals is the next step, in Dr. Mayberg’s view. Dr. Deisseroth agrees: “It is important to note as we do in our paper that this is only the first step in probing depression circuitry with high-speed imaging technology, and there is much more work to be done to probe the possible convergence of other life experiences, treatments and genes on this and other brain circuits.” |
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