Posts Tagged ‘optogenetics’

by Ruth Williams

By activating a particular pattern of nerve endings in the brain’s olfactory bulb, researchers can make mice smell a non-existent odor, according to a paper published June 18 in Science. Manipulating these activity patterns reveals which aspects are important for odor recognition.

“This study is a beautiful example of the use of synthetic stimuli . . . to probe the workings of the brain in a way that is just not possible currently with natural stimuli,” neuroscientist Venkatesh Murthy of Harvard University who was not involved with the study writes in an email to The Scientist.

A fundamental goal of neuroscience is to understand how a stimulus—a sight, sound, taste, touch, or smell—is interpreted, or perceived, by the brain. While a large number of studies have shown the various ways in which such stimuli activate brain cells, very little is understood about what these activations actually contribute to perception.

In the case of smell, for example, it is well-known that odorous molecules traveling up the nose bind to receptors on cells that then transmit signals along their axons to bundles of nerve endings—glomeruli—in a brain area called the olfactory bulb. A single molecule can cause a whole array of different glomeruli to fire in quick succession, explains neurobiologist Kevin Franks of Duke University who also did not participate in the research. And because these activity patterns “have many different spatial and temporal features,” he says, “it is difficult to know which of those features is actually most relevant [for perception].”

To find out, neuroscientist Dmitry Rinberg of New York University and colleagues bypassed the nose entirely. “The clever part of their approach is to gain direct control of these neurons with light, rather than by sending odors up the animal’s nose,” Caltech neurobiologist Markus Meister, who was not involved in the work, writes in an email to The Scientist.

The team used mice genetically engineered to produce light-sensitive ion channels in their olfactory bulb cells. They then used precisely focused lasers to activate a specific pattern of glomeruli in the region of the bulb closest to the top of the animal’s head, through a surgically implanted window in the skull. The mice were trained to associate this activation pattern with a reward—water, delivered via a lick-tube. The same mice did not associate random activation patterns with the reward, suggesting they had learned to distinguish the reward-associated pattern, or synthetic smell, from others.

Although the activation patterns were not based on any particular odors, they were designed to be as life-like as possible. For example, the glomeruli were activated one after the other within the space of 300 milliseconds from the time at which the mouse sniffed—detected by a sensor. “But, I’ll be honest with you, I have no idea if it stinks [or] it is pleasant” for the mouse, Rinberg says.

Once the mice were thoroughly trained, the team made methodical alterations to the activity pattern—changing the order in which the glomeruli were activated, switching out individual activation sites for alternatives, and changing the timing of the activation relative to the sniff. They tried “hundreds of different combinations,” Rinberg says. He likened it to altering the notes in a tune. “If you change the notes, or the timing of the notes, does the song remain the same?” he asks. That is, would the mice still be able to recognize the induced scent?

From these experiments, a general picture emerged: alterations to the earliest-activated regions caused the most significant impairment to the animal’s ability to recognize the scent. “What they showed is that, even though an odor will [induce] a very complex pattern of activity, really it is just the earliest inputs, the first few glomeruli that are activated that are really important for perception,” says Franks.

Rinberg says he thinks these early glomeruli most likely represent the receptors to which an odorant binds most strongly.

With these insights into the importance of glomeruli firing times for scent recognition, “the obvious next question,” says Franks, is to go deeper into the brain to where the olfactory bulb neurons project and ask, “ How does the cortex make sense of this?”

E. Chong et al., “Manipulating synthetic optogenetic odors reveals the coding logic of olfactory perception,” Science, 368:eaba2357, 2020.

https://www.the-scientist.com/news-opinion/researchers-make-mice-smell-odors-that-arent-really-there-67643?utm_campaign=TS_DAILY%20NEWSLETTER_2020&utm_medium=email&_hsmi=89854591&_hsenc=p2ANqtz–BMhsu532UL56qwtB0yErPYlgoFTIZWsNouvTV9pnT1ikTw6CvyIPyun3rPGdciV29we7ugRVWYc1uuBDh5CN_F-0FzA&utm_content=89854591&utm_source=hs_email

While it’s known that the brain is responsible for instructing our fat stores to break down and release energy as we need it, scientists haven’t yet been able to pin down exactly how this process plays out. Leptin, a hormone produced by our fat cells, travels to the brain to regulate appetite, metabolism and energy, but it hasn’t been clear what communication was coming back the other way. New research has now uncovered this missing link for the first time, revealing a set of nerves that connect with fat tissue to stimulate the process in a development that could lead to new types of anti-obesity treatments.

The leptin hormone was identified around 20 years ago as a regulator of the body’s metabolism. Low levels of the hormone serve to boost one’s appetite and slow metabolism, while conversely, high leptin levels dull the appetite and facilitate better fat breakdown. Using a combination of techniques, a research team led by Ana Domingos from Portugal’s Instituto Gulbenkian de Ciência were able to shed light on how leptin behaves when sending signals back to the fat by finding the nerves that meet with white fat tissue to prompt its breakdown.

“We dissected these nerve fibers from mouse fat, and using molecular markers identified these as sympathetic neurons,” explains Domingos. “When we used an ultra sensitive imaging technique, on the intact white fat tissue of a living mouse, we observed that fat cells can be encapsulated by these sympathetic neural terminals.”

But to determine the extent of these neurons’ role in obesity, the team carried out further research on mice. The rodents were genetically engineered so that these neurons could be switched on and off through optogenetics, where brain cells are made to behave differently by exposing them to light. Optogenetics is an emerging technique we have seen explored as a means of treating blindness and altering our pain threshold, among other things.

Domingos’ team found that flicking the switch on the neurons locally triggered the release of a neurotransmitter called norepinephrine, which in turn flooded the fat cells with signals that brought about fat breakdown. The team report that without these sympathetic neurons, leptin was not able to stimulate fat breakdown on its own. Therefore the findings suggest that these sympathetic neurons offer a potential target for obesity treatments other than leptin, which the brains of many obese people have a resistance to.

“This result provides new hopes for treating central leptin resistance, a condition in which the brains of obese people are insensitive to leptin,” says Domingos.

The team’s research was published in the journal Cell.

http://www.gizmag.com/neural-mechanism-fat-breakdown-anti-obesity-therapies/39601/

memory

All might not be lost. Researchers recently announced a discovery that could have significant implications later down the road for helping people with severe amnesia or Alzheimer’s disease.

The research tackles a highly debated topic of whether memory loss due to damaged brain cells means that memories cannot be stored anymore or if just accessing that memory is inhibited in some way.

Scientists from MIT found in new research that the latter is most likely the case, demonstrating how lost memories could be recovered using technology known as optogenetics, which a news release about the study described as when “proteins are added to neurons to allow them to be activated with light.”

“The majority of researchers have favored the storage theory, but we have shown in this paper that this majority theory is probably wrong,” Susumu Tonegawa, a professor in MIT’s biology department and director of the RIKEN-MIT Center at the Picower Institute for Learning and Memory, said in a statement. “Amnesia is a problem of retrieval impairment.”

First, the scientists demonstrated how “memory engram cells” — brain cells that trigger a memory upon experiencing a related sight or smell, for example — could be strengthened in mice.

The researchers then gave the mice anisomycin, which blocked protein synthesis in neurons, after they had formed a new memory. In doing so, the researchers prevented the engram cells from strengthening.

A day later, the scientists tried to trigger the memory in mice, but couldn’t see any activation that would indicate the mice were remembering it.

“So even though the engram cells are there, without protein synthesis those cell synapses are not strengthened, and the memory is lost,” Tonegawa explained of this part of the research.

The team first developed a clever technique to selectively label the neurons representing what is known as a memory engram – in other words, the brain cells involved in forming a specific memory. They did this by genetically engineering mice so they had extra genes in all their neurons. As a result, when neurons fire as a memory is formed, they produce red proteins visible under a microscope, allowing the researchers to tell which cells were part of the engram. They also inserted a gene that made the neurons fire when illuminated by blue light.

After the researchers induced amnesia, they used optogenetic tools on the mice and witnessed the animals experiencing full recollection.

“If you test memory recall with natural recall triggers in an anisomycin-treated animal, it will be amnesiac, you cannot induce memory recall. But if you go directly to the putative engram-bearing cells and activate them with light, you can restore the memory,” Tonegawa said.

With this discovery, the researchers wrote in the study published this week in the journal Science that they believe a “specific pattern of connectivity of engram cells may be crucial for memory information storage and that strengthened synapses in these cells critically contribute to the memory retrieval process.”

James Bisby, a neuroscientist at University College London, told New Scientist that it’s “not surprising that they could trigger the memories, but it is a cool way to do it.”

http://www.newscientist.com/article/dn27618-lost-memories-recovered-in-mice-with-a-flash-of-light.html

Thanks to Steven Weihing for bringing this to the It’s Interesting community.