How the brain can distinguish good from bad smells 04-03

How the brain can distinguish good from bad smells

Scientists from Max Planck Institute for Chemical Ecology in Jena, Germany, have found that in fruit flies, the quality and intensity of odors can be mapped in the so-called lateral horn. They have created a spatial map of this part of the olfactory processing system in the fly brain and showed that the lateral horn can be segregated into three activity domains, each of which represents an odor category.

Whether an odor is pleasant or disgusting to an organism is not just a matter of taste. Often, an organism's survival depends on its ability to make just such a discrimination, because odors can provide important information about food sources, oviposition sites or suitable mates. However, odor sources can also be signs of lethal hazards. Scientists from the BMBF Research Group Olfactory Coding at the Max Planck Institute for Chemical Ecology in Jena, Germany, have now found that in fruit flies, the quality and intensity of odors can be mapped in the so-called lateral horn.

They have created a spatial map of this part of the olfactory processing system in the fly brain and showed that the lateral horn can be segregated into three activity domains, each of which represents an odor category. The categories are good versus bad, as well as weak versus strong smells. These categorizations have a direct impact on the behavior of the flies, suggesting that the function of the lateral horn is similar to that of the amygdala in the brains of vertebrates. The amygdala plays a crucial role in the evaluation of sensory impressions and dangers and the lateral horn may also. (eLife, December 2014)

In order to survive, organisms must be able to sense information in their environment and to adapt their behavior accordingly. Animals use their senses, such as vision and olfaction, to perceive visual cues or odors in their surroundings and to process and evaluate the information that is sent via these senses to their brains. They must be able to tell good from bad odors. Good odors are important signals when animals search for food or a mating partner. Female insects also use olfactory signals to select a good oviposition place. Bad smells, on the other hand, can signal danger, for example, rotten and toxic food.

Representations of odors in the fly brain can be studied by using functional imaging techniques. Interestingly, an attractive odor activates a different region in the lateral horn than the region activated by a repulsive odor. These regions are the same in every fly and therefore genetically determined. Credit: Silke Sachse, , Max Planck Institute for Chemical Ecology

Modern functional imaging methods show that these sensory perceptions cause certain response patterns in the brain: Depending on the processed information, specific brain areas are activated. If an odor is rated as pleasant or disgusting, this classification method is called "hedonic valence." Studies of fruit flies revealed that odor features which could be characterized according to the scales of hedonic valence and odor intensity excited activity in a higher region of the brain, namely, the lateral horn. Depending on whether an odor was categorized as good or bad, strong or weak, brain activity could be made visible in spatially segregated regions of the lateral horn.

"We were very surprised to find that the lateral horn, which is a brain region as big as the antennal lobe (i.e. the olfactory bulb of insects), can be segregated into only three activity domains, while the antennal lobe consists of about 50 functional units," Silke Sachse, head of the BMBF Research Group, summarized. "Our results show that the higher brain is representing categories of odors, i.e. good versus bad odors, rather than the identity of an odor, which is represented at a lower processing stage such as the antenna and the antennal lobe."

Like many other sensory networks, the olfactory circuit of the fly contains spatially distinct pathways to the higher brain consisting of excitatory and inhibitory projection neurons. Projection neurons are nerve cells that transmit sensory signals to other regions of the nervous system. Notably, the inhibitory projections, which were examined in this study, convey olfactory information from the antennal lobe, the first processing center, to the lateral horn exclusively and bypass the mushroom body, which is the center for learning and memory. The inhibitory projection neurons can be subdivided into two morphological groups: the first subset processes information about whether an odor is attractive or repulsive, and the second subset processes information about the intensity of an odor. To test the functionality of these neurons, the scientists worked with flies in which these neurons had been silenced.

"Interestingly, we observed that the flies did not show attraction to any odor anymore but suddenly avoided highly attractive odors such as e.g. balsamic vinegar. We therefore concluded that the inhibitory projection neurons mediate attraction to odors and therefore enable a fly to find its food source or oviposition site," Silke Sachse explains. Moreover, the scientists were able to identify higher-order neurons in the lateral horn, that is, neurons that exclusively represent repulsive odors. These neurons communicate with inhibitory projection neurons via synapses.

The researchers believe that the function of the lateral horn in fruit flies can be compared to that of the amygdala − two almond-shaped nuclei − in the brain of vertebrates. In humans, the amygdala plays a primary role in the emotional evaluation of situations and the assessment of risks. If the amygdala is damaged, humans fail to show fear or aggression. However, lesions in the amygdala also prevent vital flight or defense reactions from being triggered. The scientists hypothesize that damage to the lateral horn may have similar effects on fruit flies. However, this assumption is so far speculative because the lateral horn could not be selectively inactivated.

In their study, the Max Planck researchers identified the lateral horn as the processing center for odor information that triggers innate odor-guided behavior. Good and bad odors are spatially decoded in different regions of the lateral horn. Further experiments will be needed to find out how this spatial map is finally transformed into the insect's decision to act. The scientists are currently in the process of identifying higher-order neurons in the lateral horn to complete the olfactory circuitry from the periphery up to the brain centers where the decision is taking place that leads to purposive odor-guided behavior. [AO/SS]

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Opioid abuse initiates specific protein interactions in neurons in brain’s reward system 02-5

Opioid abuse initiates specific protein interactions in neurons in brain’s reward system

Identifying the specific pathways that promote opioid addiction, pain relief, and tolerance are crucial for developing more effective and less dangerous analgesics, as well as developing new treatments for addiction. Now, new research from the Icahn School of Medicine at Mount Sinai reveals that opiate use alters the activity of a specific protein needed for the normal functioning of the brain’s reward center.

Investigators were able to block the protein, as well as increase its expression in the mouse nucleus accumbens, a key component of the brain’s reward center. It altered the actions of opioids like morphine dramatically. The preclinical study, published online Feb. 24 in the journal Neuropsychopharmacology, is the first to show that opioid use changes activity of the protein RGS9-2 and alters both the threshold for pain relief and affects opioid tolerance.

“We were able to block addiction-related behaviors, but increasing the activity of the protein also lowered the pain relief response to morphine, and mice developed morphine tolerance much more quickly,” said the study’s senior researcher, Venetia Zachariou, PhD, Associate Professor, Fishberg Department of Neuroscience, Friedman Brain Institute, Department of Pharmacology and Systems Therapeutics, at the Icahn School of Medicine at Mount Sinai.

Dr. Zachariou explained that because the brain’s reward center has such a strong impact on analgesic responses, non-opioid medications should be used for the treatment of severe chronic pain conditions. Pain specialists have several alternatives for the treatment of chronic pain. For patients that are already addicted to opioids, “an alternative pain medication could offer more analgesic relief without the adverse effects of opioids.” Additionally, with this research in hand, the research team points out that targeting this molecule may eventually lead to a novel treatment for addiction.”

In the study, investigators used a novel technique known as optogenetics, which allows the activation of specific neurons via blue light in real time, to determine the exact cell types of the brain reward center responsible for the reduced analgesic response.

“In our earlier work, by inactivating RGS9-2, we saw a tenfold increase in sensitivity to the rewarding actions of morphine, severe morphine dependence, a better analgesic response, and delayed development of tolerance,” said the study’s senior author. While opiate analgesics act in several brain regions to alleviate pain, their actions in the brain reward center may also affect analgesia. The nucleus accumbens may also affect the development of morphine tolerance, via mechanism that are distinct from those described in other regions of the brain.

Eric Nestler, MD, PhD, Nash Family Professor of Neuroscience, Icahn School of Medicine at Mount Sinai, praised the research. “These discoveries provide important new information about the role of the brain reward pathway in the analgesic responses to opiates”.

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New ideas change your brain cells 02-25

New ideas change your brain cells

A new University of British Columbia study identifies an important molecular change that occurs in the brain when we learn and remember.

Published this month in Nature Neuroscience, the research shows that learning stimulates our brain cells in a manner that causes a small fatty acid to attach to delta-catenin, a protein in the brain. This biochemical modification is essential in producing the changes in brain cell connectivity associated with learning, the study finds.

In animal models, the scientists found almost twice the amount of modified delta-catenin in the brain after learning about new environments. While delta-catenin has previously been linked to learning, this study is the first to describe the protein’s role in the molecular mechanism behind memory formation.

“More work is needed, but this discovery gives us a much better understanding of the tools our brains use to learn and remember, and provides insight into how these processes become disrupted in neurological diseases,” says co-author Shernaz Bamji, an associate professor in UBC’s Life Sciences Institute.

It may also provide an explanation for some mental disabilities, the researchers say. People born without the gene have a severe form of mental retardation called Cri-du-chat syndrome, a rare genetic disorder named for the high-pitched cat-like cry of affected infants. Disruption of the delta-catenin gene has also been observed in some patients with schizophrenia.

“Brain activity can change both the structure of this protein, as well as its function,” says Stefano Brigidi, first author of the article and a PhD candidate Bamji’s laboratory. “When we introduced a mutation that blocked the biochemical modification that occurs in healthy subjects, we abolished the structural changes in brain’s cells that are known to be important for memory formation.”

Background

According to the researchers, more work is needed to fully establish the importance of delta-catenin in building the brain connectivity behind learning and memory. Disruptions to these nerve cell connections are also believed to cause neurodegenerative diseases such as Alzheimer’s and Huntington disease. Understanding the biochemical processes that are important for maintaining these connections may help address the abnormalities in nerve cells that occur in these disease states.

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Stanford researchers develop tool for reading the minds of mice 02-20

Stanford researchers develop tool for reading the minds of mice

Stanford scientists have developed a system for observing real-time brain activity in a live mouse. The device could prove useful in studying new treatments for neurodegenerative diseases, such as Alzheimer's.

BY BJORN CAREY

Courtesy of Mark Schnitzer

As the mouse explores the arena, neurons in its brain flash green when it recognizes a familiar spot.

If you want to read a mouse's mind, it takes some fluorescent protein and a tiny microscope implanted in the rodent's head.

Stanford scientists have demonstrated a technique for observing hundreds of neurons firing in the brain of a live mouse, in real time, and have linked that activity to long-term information storage. The unprecedented work could provide a useful tool for studying new therapies for neurodegenerative diseases such as Alzheimer's.

The researchers first used a gene therapy approach to cause the mouse's neurons to express a green fluorescent protein that was engineered to be sensitive to the presence of calcium ions. When a neuron fires, the cell naturally floods with calcium ions. Calcium stimulates the protein, causing the entire cell to fluoresce bright green.

A tiny microscope implanted just above the mouse's hippocampus – a part of the brain that is critical for spatial and episodic memory – captures the light of roughly 700 neurons. The microscope is connected to a camera chip, which sends a digital version of the image to a computer screen.

The computer then displays near real-time video of the mouse's brain activity as a mouse runs around a small enclosure, which the researchers call an arena.

The neuronal firings look like tiny green fireworks, randomly bursting against a black background, but the scientists have deciphered clear patterns in the chaos.

"We can literally figure out where the mouse is in the arena by looking at these lights," said Mark Schnitzer  , an associate professor of biology and of applied physics and the senior author on the paper, recently published   in the journal Nature Neuroscience.

When a mouse is scratching at the wall in a certain area of the arena, a specific neuron will fire and flash green. When the mouse scampers to a different area, the light from the first neuron fades and a new cell sparks up.

"The hippocampus is very sensitive to where the animal is in its environment, and different cells respond to different parts of the arena," Schnitzer said. "Imagine walking around your office. Some of the neurons in your hippocampus light up when you're near your desk, and others fire when you're near your chair. This is how your brain makes a representative map of a space."

The group has found that a mouse's neurons fire in the same patterns even when a month has passed between experiments. "The ability to come back and observe the same cells is very important for studying progressive brain diseases," Schnitzer said.

For example, if a particular neuron in a test mouse stops functioning, as a result of normal neuronal death or a neurodegenerative disease, researchers could apply an experimental therapeutic agent and then expose the mouse to the same stimuli to see if the neuron's function returns.

Although the technology can't be used on humans, mouse models are a common starting point for new therapies for human  believes the system could be a very useful tool in evaluating pre-clinical research.

The work was published Feb. 10 in the online edition of Nature Neuroscience. The researchers have formed a company to manufacture and sell the device.

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