Sleep is vital to associating emotion with memory, study finds

Woman sleeping

When you slip into sleep, it's easy to imagine that your brain shuts down, but University of Michigan research suggests that groups of neurons activated during prior learning keep humming, tattooing memories into your brain.

U-M researchers have been studying how memories associated with a specific sensory event are formed and stored in mice. In a study conducted prior to the coronavirus pandemic and recently published in Nature Communications, the researchers examined how a fearful memory formed in relation to a specific visual stimulus.

They found that not only did the neurons activated by the visual stimulus keep more active during subsequent sleep, sleep is vital to their ability to connect the fear memory to the sensory event.

Previous research has shown that regions of the brain that are highly active during intensive learning tend to show more activity during subsequent sleep. But what was unclear was whether this "reactivation" of memories during sleep needs to occur in order to fully store the memory of newly learned material.

"Part of what we wanted to understand was whether there is communication between parts of the brain that are mediating the fear memory and the specific neurons mediating the sensory memory that the fear is being tied to. How do they talk together, and must they do so during sleep? We would really like to know what's facilitating that process of making a new association, like a particular set of neurons, or a particular stage of sleep," said Sara Aton, senior author of the study and a professor in the U-M Department of Molecular, Cellular and Developmental Biology. "But for the longest time, there was really no way to test this experimentally."

Now, researchers have the tools to genetically tag cells that are activated by an experience during a specific window of time. Focusing on a specific set of neurons in the primary visual cortex, Aton and the study's lead author, graduate student Brittany Clawson, created a visual memory test. They showed a group of mice a neutral image, and expressed genes in the visual cortex neurons activated by the image.

To verify that these neurons registered the neutral image, Aton and her team tested whether they could instigate the memory of the image stimulus by selectively activating the neurons without showing them the image. When they activated the neurons and paired that activation with a mild foot shock, they found that their subjects would subsequently be afraid of visual stimuli that looked similar to the image those cells encode. They found the reverse also to be true: after pairing the visual stimulus with a foot shock, their subjects would subsequently respond with fear to reactivating the neurons.

"Basically, the precept of the visual stimulus and the precept of this completely artificial activation of the neurons generated the same response," Aton said.

The researchers found that when they disrupted sleep after they showed the subjects an image and had given them a mild foot shock, there was no fear associated with the visual stimulus. Those with unmanipulated sleep learned to fear the specific visual stimulus that had been paired with the foot shock.

"We found that these mice actually became afraid of every visual stimulus we showed them," Aton said. "From the time they go to the chamber where the visual stimuli are presented, they seem to know there's a reason to feel fear, but they don't know what specifically they're afraid of."

This likely shows that, in order for them to make an accurate fear association with a visual stimulus, they have to have sleep-associated reactivation of the neurons encoding that stimulus in the sensory cortex, according to Aton. This allows a memory specific to that visual cue to be generated.The researchers think that at the same time, that sensory cortical area must communicate with other brain structures, to marry the sensory aspect of the memory to the emotional aspect.

 

'Where did I park my car?' Brain stimulation improves mental time travel

Man trying to remember

You might remember you ate cereal for breakfast but forget the color of the bowl. Or recall watching your partner put the milk away but can't remember on which shelf.

A new Northwestern Medicine study improved memory of complex, realistic events similar to these by applying transcranial magnetic stimulation (TMS) to the brain network responsible for memory. The authors then had participants watch videos of realistic activities to measure how memory works during everyday tasks. The findings prove it is possible to measure and manipulate realistic types of memory.

"On a day-to-day basis we must remember complex events that involve many elements, such as different locations, people and objects," said lead author Melissa Hebscher, a postdoctoral fellow at Northwestern University Feinberg School of Medicine. "We were able to show that memory for complex, realistic events can be improved in a safe and non-invasive way using brain stimulation."

The study was conducted on healthy young adults in a controlled laboratory setting. These methods, however, also could eventually be used to improve memory in individuals with memory disorders due to brain damage or neurological disorders, Hebscher said.

The study will be published Feb. 4 in the journal Current Biology.

A new approach to studying memory: Incorporating video

The study authors used TMS with the goal of altering brain activity and memory for realistic events. Immediately following stimulation, subjects performed a memory task while having their brains scanned using functional magnetic resonance imaging (fMRI).

Instead of showing study participants pictures or lists of words -- typical practices in laboratory tests that analyze memory -- participants in this study watched videos of everyday activities such as such as someone folding laundry or taking out the garbage.

"Our study used video clips that more closely replicate how memory works on a day-to-day basis," Hebscher said.

Following stimulation, study participants more accurately answered questions about the content of the video clips, such as identifying the shirt color an actor was wearing or the presence of a tree in the background.

Additionally, the study found that brain stimulation led to higher quality reinstatement of memories in the brain. Reinstatement is when the brain replays or relives an original event, Hebscher said. Following stimulation, a person's brain activity while watching a video more closely resembled their brain activity when remembering that same video.

"This is why remembering can sometimes feel like 'mental time travel,'" Hebscher said. "Our findings show that stimulation enhances this 'mental time travel' in the brain and improves memory accuracy. These findings have implications for the development of safe and effective ways to improve real-world memory."

 

How a single gene alteration may have separated modern humans from predecessors

 

DNA illustration

As a professor of pediatrics and cellular and molecular medicine at University of California San Diego School of Medicine, Alysson R. Muotri, PhD, has long studied how the brain develops and what goes wrong in neurological disorders. For almost as long, he has also been curious about the evolution of the human brain -- what changed that makes us so different from preceding Neanderthals and Denisovans, our closest evolutionary relatives, now extinct?

Evolutionary studies rely heavily on two tools -- genetics and fossil analysis -- to explore how a species changes over time. But neither approach can reveal much about brain development and function because brains do not fossilize, Muotri said. There is no physical record to study.

So Muotri decided to try stem cells, a tool not often applied in evolutionary reconstructions. Stem cells, the self-renewing precursors of other cell types, can be used to build brain organoids -- "mini brains" in a laboratory dish. Muotri and colleagues have pioneered the use of stem cells to compare humans to other primates, such as chimpanzees and bonobos, but until now a comparison with extinct species was not thought possible.

In a study published February 11, 2021 in Science, Muotri's team catalogued the differences between the genomes of diverse modern human populations and the Neanderthals and Denisovans, who lived during the Pleistocene Epoch, approximately 2.6 million to 11,700 years ago. Mimicking an alteration they found in one gene, the researchers used stem cells to engineer "Neanderthal-ized" brain organoids.

"It's fascinating to see that a single base-pair alteration in human DNA can change how the brain is wired," said Muotri, senior author of the study and director of the UC San Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative Medicine. "We don't know exactly how and when in our evolutionary history that change occurred. But it seems to be significant, and could help explain some of our modern capabilities in social behavior, language, adaptation, creativity and use of technology."

The team initially found 61 genes that differed between modern humans and our extinct relatives. One of these altered genes -- NOVA1 -- caught Muotri's attention because it's a master gene regulator, influencing many other genes during early brain development. The researchers used CRISPR gene editing to engineer modern human stem cells with the Neanderthal-like mutation in NOVA1. Then they coaxed the stem cells into forming brain cells and ultimately Neanderthal-ized brain organoids.

Brain organoids are little clusters of brain cells formed by stem cells, but they aren't exactly brains (for one, they lack connections to other organ systems, such as blood vessels). Yet organoids are useful models for studying genetics, disease development and responses to infections and therapeutic drugs. Muotri's team has even optimized the brain organoid-building process to achieve organized electrical oscillatory waves similar to those produced by the human brain.

The Neanderthal-ized brain organoids looked very different than modern human brain organoids, even to the naked eye. They had a distinctly different shape. Peering deeper, the team found that modern and Neanderthal-ized brain organoids also differ in the way their cells proliferate and how their synapses -- the connections between neurons -- form. Even the proteins involved in synapses differed. And electrical impulses displayed higher activity at earlier stages, but didn't synchronize in networks in Neanderthal-ized brain organoids.

Much of Earth's nitrogen was locally sourced

Protoplanetary disk illustration

Where did Earth's nitrogen come from? Rice University scientists show one primordial source of the indispensable building block for life was close to home.

The isotopic signatures of nitrogen in iron meteorites reveal that Earth likely gathered its nitrogen not only from the region beyond Jupiter's orbit but also from the dust in the inner protoplanetary disk.

Nitrogen is a volatile element that, like carbon, hydrogen and oxygen, makes life on Earth possible. Knowing its source offers clues to not only how rocky planets formed in the inner part of our solar system but also the dynamics of far-flung protoplanetary disks.

The study by Rice graduate student and lead author Damanveer Grewal, Rice faculty member Rajdeep Dasgupta and geochemist Bernard Marty at the University of Lorraine, France, appears in Nature Astronomy.

Their work helps settle a prolonged debate over the origin of life-essential volatile elements in Earth and other rocky bodies in the solar system.

"Researchers have always thought that the inner part of the solar system, within Jupiter's orbit, was too hot for nitrogen and other volatile elements to condense as solids, meaning that volatile elements in the inner disk were in the gas phase," Grewal said.

Because the seeds of present-day rocky planets, also known as protoplanets, grew in the inner disk by accreting locally sourced dust, he said it appeared they did not contain nitrogen or other volatiles, necessitating their delivery from the outer solar system. An earlier study by the team suggested much of this volatile-rich material came to Earth via the collision that formed the moon.

But new evidence clearly shows only some of the planet's nitrogen came from beyond Jupiter.

In recent years, scientists have analyzed nonvolatile elements in meteorites, including iron meteorites that occasionally fall to Earth, to show dust in the inner and outer solar system had completely different isotopic compositions.

"This idea of separate reservoirs had only been developed for nonvolatile elements," Grewal said. "We wanted to see if this is true for volatile elements as well. If so, it can be used to determine which reservoir the volatiles in present-day rocky planets came from."

Iron meteorites are remnants of the cores of protoplanets that formed at the same time as the seeds of present-day rocky planets, becoming the wild card the authors used to test their hypothesis.

The researchers found a distinct nitrogen isotopic signature in the dust that bathed the inner protoplanets within about 300,000 years of the formation of the solar system. All iron meteorites from the inner disk contained a lower concentration of the nitrogen-15 isotope, while those from the outer disk were rich in nitrogen-15.

This suggests that within the first few million years, the protoplanetary disk divided into two reservoirs, the outer rich in the nitrogen-15 isotope and the inner rich in nitrogen-14.

New class of antibiotics active against a wide range of bacteria

Bacteria illustration

Wistar Institute scientists have discovered a new class of compounds that uniquely combine direct antibiotic killing of pan drug-resistant bacterial pathogens with a simultaneous rapid immune response for combatting antimicrobial resistance (AMR). These finding were published today in Nature.

The World Health Organization (WHO) has declared AMR as one of the top 10 global public health threats against humanity. It is estimated that by 2050, antibiotic-resistant infections could claim 10 million lives each year and impose a cumulative $100 trillion burden on the global economy. The list of bacteria that are becoming resistant to treatment with all available antibiotic options is growing and few new drugs are in the pipeline, creating a pressing need for new classes of antibiotics to prevent public health crises.

"We took a creative, double-pronged strategy to develop new molecules that can kill difficult-to-treat infections while enhancing the natural host immune response," said Farokh Dotiwala, M.B.B.S., Ph.D., assistant professor in the Vaccine & Immunotherapy Center and lead author of the effort to identify a new generation of antimicrobials named dual-acting immuno-antibiotics (DAIAs).

Existing antibiotics target essential bacterial functions, including nucleic acid and protein synthesis, building of the cell membrane, and metabolic pathways. However, bacteria can acquire drug resistance by mutating the bacterial target the antibiotic is directed against, inactivating the drugs or pumping them out.

"We reasoned that harnessing the immune system to simultaneously attack bacteria on two different fronts makes it hard for them to develop resistance," said Dotiwala.

He and colleagues focused on a metabolic pathway that is essential for most bacteria but absent in humans, making it an ideal target for antibiotic development. This pathway, called methyl-D-erythritol phosphate (MEP) or non-mevalonate pathway, is responsible for biosynthesis of isoprenoids -- molecules required for cell survival in most pathogenic bacteria. The lab targeted the IspH enzyme, an essential enzyme in isoprenoid biosynthesis, as a way to block this pathway and kill the microbes. Given the broad presence of IspH in the bacterial world, this approach may target a wide range of bacteria.

Researchers used computer modeling to screen several million commercially available compounds for their ability to bind with the enzyme, and selected the most potent ones that inhibited IspH function as starting points for drug discovery.