Eliminating protein in specific brain cells blocks nicotine reward

ScienceDaily (July 27, 2011) — Removing a protein from cells located in the brain's reward center blocks the anxiety-reducing and rewarding effects of nicotine, according to a new animal study in the July 27 issue of The Journal of Neuroscience. The findings may help researchers better understand how nicotine affects the brain.

Nicotine works by binding to proteins called nicotinic receptors on the surface of brain cells. In the new study, researchers led by Tresa McGranahan, Stephen Heinemann, PhD, and T. K. Booker, PhD, of the Salk Institute for Biological Studies, found that removing a specific type of nicotinic receptor from brain cells that produce dopamine -- a chemical released in response to reward -- makes mice less likely to seek out nicotine. The mice also did not show reductions in anxiety-like behaviors normally seen after nicotine treatment. Smokers commonly report anxiety relief as a key factor in continued smoking or relapse.

"These findings show that the rewarding and anxiety-reducing properties of nicotine, thought to play a key role in the development of tobacco addiction, are related to actions at a single set of brain cells," said Paul Kenny, PhD, an expert on drug addiction at Scripps Research Institute, who was unaffiliated with the study.

Previous studies showed blocking the alpha4 nicotinic receptor within the ventral tegmental area (VTA) -- a brain region important in motivation, emotion, and addiction -- decreases the rewarding properties of nicotine. Because alpha4 receptors are present on several cell types in the VTA, it was unclear how nicotine produced pleasurable feelings.

To zero in on the circuit important in the brain's response to nicotine, researchers developed mice with a mutation that left them unable to produce the alpha4 receptor, but only on dopamine brain cells. Mice lacking alpha4 receptors in these cells spent less time looking to obtain nicotine compared with normal mice, suggesting the alpha4 receptors are required for the rewarding effects of nicotine. Nicotine also failed to reduce anxiety-like behaviors in the mutant mice, as it normally does in healthy mice.

"Identification of the type of nicotinic receptors necessary for two key features of nicotine addiction -- reward and anxiety -- may help us better understand the pathway that leads to nicotine dependence, and potential treatment for the one billion cigarette smokers worldwide," McGranahan said. Diseases from tobacco use remain a major killer throughout the world, causing more than 5 million deaths per year.

The findings could guide researchers to a better understanding of the mechanisms of tobacco addiction and assist in the development of new drugs to treat tobacco addiction and provide relief from anxiety disorders, Kenny added.

The research was supported by the National Institute of Neurological Disorders and Stroke, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute on Drug Abuse.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Society for Neuroscience, via EurekAlert!, a service of AAAS.

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Signal explains why site of origin affects fate of postnatal neural stem cells

ScienceDaily (July 27, 2011) — New research may help to explain why the location of postnatal neural stem cells in the brain determines the type of new neurons that are generated. The research, published by Cell Press in the July 28 issue of the journal Neuron, demonstrates that a signaling pathway which plays a key role in development also actively regulates the fate of neural stem cells in the adult brain. Manipulation of this signaling pathway redirected the fate of adult stem cells, a finding that may impact the design of future strategies for creating stem cell therapies.

Recent research has led to a shift in the long-standing theory that neurons of the central nervous system are produced only during embryonic development. It is now clear that several types of neurons continue to be produced in the adult brain. These new neurons arise from special locations that contain neural stem cells and continue to generate neurons throughout adulthood. "Research has shown that the subventricular zone, the largest germinal zone in the adult brain, is arranged as a mosaic, with stem cells in different locations producing different kinds of neurons," says senior study author Dr. Arturo Alvarez-Buylla from the University of California, San Francisco. "However, the molecular mechanisms responsible for this positional specification in the adult subventricular zone remain unknown."

Using a mouse model system, Dr. Alvarez-Buylla and colleagues discovered that sonic hedgehog (Shh) signaling occurs in the ventral portion of the subventricular zone and is associated with the production of specific types of neurons. Shh belongs to the hedgehog family of signaling molecules that play a key role in patterning the developing nervous system. Neurons residing close to the ventral portion of the subventricular zone were identified as a potential source of Shh signaling molecules. The researchers went on to show that in the absence of Shh, production of ventrally derived neuron types decreased while activation of the Shh pathway in dorsal neural stem cells in the adult mouse brain was sufficient to redirect their fate.

"Our results are the first to identify a signaling pathway that is sufficient to determine neuronal cell fate in adult subventricular zone neural stem cells," explains Dr. Rebecca Ihrie, the lead author of the study. "Importantly, our findings demonstrate that adult neural stem cells may be reprogrammed if the relevant specification signals are identified and suggest that reprogramming of neural stem cells for therapeutic purposes may depend, at least in part, on the identification of signaling pathways involved in the generation of desired cell types."

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Cell Press, via EurekAlert!, a service of AAAS.

Journal Reference:

Rebecca A. Ihrie, Jugal K. Shah, Corey C. Harwell, Jacob H. Levine, Cristina D. Guinto, Melissa Lezameta, Arnold R. Kriegstein, Arturo Alvarez-Buylla. Persistent Sonic Hedgehog Signaling in Adult Brain Determines Neural Stem Cell Positional Identity. Neuron, 2011; 71 (2): 250-262 DOI: 10.1016/j.neuron.2011.05.018

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Multiple sclerosis research: Myelin influences how brain cells send signals

ScienceDaily (July 22, 2011) — The development of a new cell-culture system that mimics how specific nerve cell fibers in the brain become coated with protective myelin opens up new avenues of research about multiple sclerosis. Initial findings suggest that myelin regulates a key protein involved in sending long-distance signals.

Multiple sclerosis (MS) is an autoimmune disease characterized by damage to the myelin sheath surrounding nerve fibers. The cause remains unknown, and it is a chronic illness affecting the central nervous system that has no cure.

MS has long been considered a disease of white matter, a reference to the white-colored bundles of myelin-coated axons that project from the main body of a brain cell. But researchers have discovered that the condition also affects myelinated axons scattered in gray matter that contains main bodies of brain cells, and specifically the hippocampus region, which is important for learning and memory.

Up to half of MS patients suffer cognitive deficits in addition to physical symptoms. Researchers suspect that cognitive problems are caused by abnormal electrical activities of the demyelinated axons extending from hippocampal cells, but until now have not been able to test myelin's role in this part of the brain.

Ohio State University researchers have created a system in which two types of cells interact in a dish as they do in nature: neurons from the hippocampus and other brain cells, called oligodendrocytes, whose role is to wrap myelin around the axons.

Now that the researchers can study how myelination is switched on and off for hippocampal neurons, they also can see how myelin does more than provide insulation -- it also has a role in controlling nerve impulses traveling between distant parts of the nervous system. Identifying this mechanism when myelin is present will help improve understanding of what happens when axons in this critical area of the brain lose myelin as a result of MS, researchers say.

So far, the scientists have used the system to show that myelin regulates the placement and activity of a key protein, called a Kv1.2 voltage-gated potassium channel, that is needed to maintain ideal conditions for the effective transmission of electrical signals along these hippocampal axons.

"This channel is important because it is what leads to electrical activity and how neurons communicate with each other downstream," said Chen Gu, assistant professor of neuroscience at Ohio State and lead author of the study. "If that process is disrupted by demyelination, disease symptoms may occur."

The study appears in the current (July 22, 2011) issue of the Journal of Biological Chemistry.

To create the cell culture system, the researchers began with hippocampus neurons from a rodent brain -- a cell type that Gu has worked with for years. In culture, these cells can grow and develop dendrites -- other branch-like projections off of neurons -- and axons as well as generate electrical activity and synaptic connections, the same events that occur in the brain.

The researchers then added oligodendrocytes, along with some of their precursor cells, to the same dish as the neurons. And eventually, after maturing, these oligodendrocytes began to wrap myelin around the axons of the hippocampal neurons.

This system takes about five weeks to create, but the trickiest part, Gu said, was developing the proper solution for this culture so that both kinds of cells would behave as nature intended.

"In the end, the composition of the culture medium is basically half from a solution that supports the neurons and half from a medium in which the oligodendrocytes function well. We know that all the cells were happy because we got myelin," said Gu, also an investigator in Ohio State's Center for Molecular Neurobiology.

With the system established, they then turned to experimentation to test the effects of the myelin's presence on these specific brain cells.

Nerve cells send their signals encoded in electrical impulses over long distances. Concerted actions of various ion channels are required for properly generating these nerve impulses. Potassium channels are involved at the late phase in an impulse, and its role is to return a nerve cell to a resting state after the impulse has passed through it and gear up for the next one. The Kv1.2 ion channel helps ensure that this process works smoothly.

By experimentally manipulating signal conditions with the new co-culture system, Gu and his colleague were able to establish part of the sequence of events required for myelinated hippocampal neurons to effectively get their signals to their targets. Starting with a protein known to be produced by myelin and axons, called TAG-1, a cell adhesion molecule, they traced a series of chemical reactions indicating that myelin on the hippocampal axons was controlling the placement and activity of the Kv1.2 ion channel.

"The analysis allowed us to see the signaling pathways involving myelin's regulation of the Kv1.2 channel's placement along the axon as well as fine-tuning of the channel's activity," Gu said.

When MS demyelinates these axons, the affected nerve cells don't get the message to rest, and subsequently can't prepare adequately to receive and transmit the next signal that comes along.

"This means a nerve impulse will have a hard time traveling through the demyelinated region," Gu said. "This shows that the ion channel is probably involved in the downstream disease progression of MS."

Gu envisions many additional uses for the new co-culture system, including additional studies of how myelin affects the behavior of other channels, proteins and molecules that function within axons, as well as to screen the effects of experimental drugs on these myelinated cells.

This work was supported by a Career Transition Fellowship Award from the National Multiple Sclerosis Society and a grant from the National Institute for Neurological Disorders and Stroke.

Gu conducted this study with Yuanzheng Gu, a research associate in the Department of Neuroscience at Ohio State.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Ohio State University. The original article was written by Emily Caldwell.

Journal Reference:

C. Gu, Y. Gu. Clustering and Activity Tuning of Kv1 Channels in Myelinated Hippocampal Axons. Journal of Biological Chemistry, 2011; 286 (29): 25835 DOI: 10.1074/jbc.M111.219113

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Fear boosts activation of immature brain cells: Adult neural stem cells play role in creating emotional context of memory

ScienceDaily (June 15, 2011) — Fear burns memories into our brain, and new research by University of California, Berkeley, neuroscientists explains how.

Scientists have long known that fear and other highly emotional experiences lead to incredibly strong memories. In a study appearing online in advance of publication in the journal Molecular Psychiatry, UC Berkeley's Daniela Kaufer and colleagues report a new way for emotions to affect memory: The brain's emotional center, the amygdala, induces the hippocampus, a relay hub for memory, to generate new neurons.

In a fearful situation, these newborn neurons get activated by the amygdala and may provide a "blank slate" to strongly imprint the new fearful memory, she said. In evolutionary terms, it means new neurons are likely helping you to remember the lion that nearly killed you.

"We remember emotional events much more strongly than daily experiences, and for a long time we have known that connections between the amygdala and hippocampus help to encode this emotional information," said Kaufer, an assistant professor of integrative biology and a member of UC Berkeley's Wills Neuroscience Institute. "Our research shows that amygdala input actually pushes the hippocampus to make new neurons from a unique population of neural stem cells. This provides completely new cells that get activated in response to emotional input."

The finding has implications for post traumatic stress disorder (PTSD) and other problems caused by faulty regulation of emotional memory.

"Many affective disorders involve disordered emotional memories like PTSD, depression and anxiety. We think that newborn neurons may play a role in creating these emotional memories," she said.

The finding comes a year after brain researcher Fred Gage at the Salk Institute for Biological Studies in La Jolla, Calif., showed that the formation of new memories is associated with increased activation of two-week-old newborn nerve cells in the hippocampus that are derived from adult neural stem cells. Adult stem cells appear to differentiate continually into new nerve cells -- nearly 100 each day -- yet half of those newborn neurons are slated for death within four weeks after their birth. If they are highly activated, however -- such as in learning new complex information -- many more of them will survive and presumably help in establishing new memories in the brain.

Kaufer, who conducts research on the effects of stress on the brain, knew that many types of positive and negative experiences, such as exercise and stress, affect the rate of neurogenesis in the hippocampus. Along with graduate students Elizabeth Kirby, the lead author of the study, and Aaron Friedman, she was intrigued by the idea that emotions might affect neurogenesis in the hippocampus, since the brain's clearinghouse for emotions, the amygdala, is connected to the hippocampus via multiple neural circuits. To test this, Kirby focused on the basolateral amygdala, the region of the almond-shaped structure that handles negative emotions, including stress, anxiety and fear.

Using rats, Kirby surgically destroyed the basolateral amygdala and discovered that the production of new nerve cells in the hippocampus decreased. To make sure that the cell damage created when the amygdala was surgically destroyed was not affecting the experiment, the researchers borrowed a gene therapy technique from Robert Sapolsky's lab at Stanford University to genetically introduce potassium channels into the amygdala, which shut down the activity of the nerve cells without causing injury. This also decreased neurogenesis in the hippocampus.

They next tested Gage's theory that new neurons are especially sensitive to input two weeks after they form. Kirby and Kaufer labeled hippocampal cells created over a three-day period in a group of rats, and then conditioned a fear response in these rats two weeks later. They then confronted the rats with the same fearful situation or a neutral yet novel context the next day. When they examined the brains, they found that the newborn neurons had been specifically activated by the fearful situation. However, when they destroyed the basolateral amygdala, new neurons were no longer activated in response to the fearful memory.

"The research suggests that newborn neurons play a role not only in the formation of memory, but also in helping to create the emotional context of memory," Kirby said. It also suggests that the basolateral amygdala drives the ability of new neurons to be part of an emotional memory.

The team now plans to see whether other negative stimuli, such as stress and anxiety, similarly cooperate with amygdala activity to alter neurogenesis in the hippocampus.

The coauthors of the paper with Kaufer, Kirby and Friedman are UC Berkeley graduate student David Covarrubias and undergraduates Carl Ying and Wayne G. Sun; Ki Ann Goosens, an assistant professor of brain and cognitive sciences in the McGovern Institute for Brain Research at the Massachusetts Institute of Technology; and Stanford's Sapolsky.

Kaufer's work is funded by a 2010 BRAINS (Biobehavioral Research Awards for Innovative New Scientists) award from the National Institute of Mental Health of the National Institutes of Health and a young investigator award from The Brain and Behavior Research Foundation, formerly the National Alliance for Research on Schizophrenia and Depression (NARSAD). Kirby is supported by a California Institute for Regenerative Medicine pre-doctoral fellowship and a National Defense Science and Engineering Graduate Research fellowship from the U. S. Department of Defense.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of California - Berkeley. The original article was written by Robert Sanders, Media Relations.

Journal Reference:

E D Kirby, A R Friedman, D Covarrubias, C Ying, W G Sun, K A Goosens, R M Sapolsky, D Kaufer. Basolateral amygdala regulation of adult hippocampal neurogenesis and fear-related activation of newborn neurons. Molecular Psychiatry, 2011; DOI: 10.1038/mp.2011.71

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Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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