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This illustration shows a protein complex at work in brain signaling. Its structure, which contains joined protein complexes known as SNARE (shown in blue, red, and green) and synaptotagmin-1 (orange), is shown in the foreground. This complex is responsible for the calcium-triggered release of neurotransmitters from our brain’s nerve cells in a process called synaptic vesicle fusion. The background image shows electrical signals traveling through a neuron. (credit: SLAC National Accelerator Laboratory)

Stanford School of Medicine scientists have mapped the 3D atomic structure of a two-part protein complex that controls the release of signaling chemicals, called neurotransmitters, from brain cells in less than one-thousandth of a second.

The experiments were reported today (August 17) in the journal Nature. Performed at the Linac Coherent Light Source (LCLS) X-ray laser at the Department of Energy’s SLAC National Accelerator Laboratory, the experiments were built on decades of previous research at Stanford University, Stanford School of Medicine, and SLAC.

“This is a very important, exciting advance that may open up possibilities for targeting new drugs to control neurotransmitter release,” said Axel Brunger, the study’s principal investigator — a professor at Stanford School of Medicine and SLAC and a Howard Hughes Medical Institute investigator. “Many mental disorders, including depression, schizophrenia and anxiety, affect neurotransmitter systems.”

The two protein parts are known as neuronal SNAREs and synaptotagmin-1. “Both parts of this protein complex are essential,” Brunger said, “but until now it was unclear how its two pieces fit and work together.” Earlier X-ray studies, including experiments at SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL) nearly two decades ago, shed light on the structure of the SNARE complex, a helical protein bundle found in yeasts and mammals.

SNAREs play a key role in the brain’s chemical signaling by joining, or “fusing,” little packets of neurotransmitters to the outer edges of neurons, where they are released and then dock with chemical receptors in another neuron to trigger a response.

Explains rapid triggering of brain signaling

In this latest research, the scientists found that when the SNAREs and synaptotagmin-1 join up, they act as an amplifier for a slight increase in calcium concentration, triggering a gunshot-like release of neurotransmitters from one neuron to another. They also learned that the proteins join together before they arrive at a neuron’s membrane, which helps to explain how they trigger brain signaling so rapidly.

The team speculates that several of the joined protein complexes may group together and simultaneously interact with the same vesicle to efficiently trigger neurotransmitter release, an exciting area for further studies. “The structure of the SNARE-synaptotagmin-1 complex is a milestone that the field has awaited for a long time, and it sets the framework for a better understanding of the system,” said James Rothman, a professor at Yale University who discovered the SNARE proteins and shared the 2013 Nobel Prize in Physiology or Medicine.

Thomas C. Südhof, a professor at the Stanford School of Medicine and Howard Hughes Medical Institute investigator who shared that 2013 Nobel Prize with Rothman, discovered synaptotagmin-1 and showed that it plays an important role as a calcium sensor and calcium-dependent trigger for neurotransmitter release.

“The new structure has identified unanticipated interfaces between synaptotagmin-1 and the neuronal SNARE complex that change how we think about their interaction by revealing, in atomic detail, exactly where they bind together,” Südhof said. “This is a new concept that goes much beyond previous general models of how synaptotagmin-1 functions.”

Using crystals, robotics and X-rays to advance neuroscience

To study the joined protein structure, researchers in Brunger’s laboratory at the Stanford School of Medicine found a way to grow crystals of the complex. They used a robotic system developed at SSRL to study the crystals at SLAC’s LCLS, an X-ray laser that is one of the brightest sources of X-rays on the planet. The researchers combined and analyzed hundreds of X-ray images from about 150 protein crystals to reveal the atomic-scale details of the joined structure.

According to SSRL’s Aina Cohen, who oversaw the development of the highly automated platform used for the neuroscience experiment, “This experiment was the first to use this robotic platform at LCLS to determine a previously unsolved structure of a large, challenging multi-protein complex.” The study was also supported by X-ray experiments at SSRL and at Argonne National Laboratory’s Advanced Photon Source.

Brunger said future studies will explore other protein interactions relevant to neurotransmitter release. “What we studied is only a subset,” he said. “There are many other factors interacting with this system and we want to know what these look like.”

Other contributing scientists were from Lawrence Berkeley National Laboratory. The research was supported by the Howard Hughes Medical Institute, the National Institutes of Health (NIH), the DOE Office Science, and the SSRL Structural Molecular Biology Program, which is also supported by the DOE Office of Science and the NIH’s National Institute of General Medical Sciences.

Abstract of Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis

Synaptotagmin-1 and neuronal SNARE proteins have central roles in evoked synchronous neurotransmitter release; however, it is unknown how they cooperate to trigger synaptic vesicle fusion. Here we report atomic-resolution crystal structures of Ca²⁺- and Mg²⁺-bound complexes between synaptotagmin-1 and the neuronal SNARE complex, one of which was determined with diffraction data from an X-ray free-electron laser, leading to an atomic-resolution structure with accurate rotamer assignments for many side chains. The structures reveal several interfaces, including a large, specific, Ca²⁺-independent and conserved interface. Tests of this interface by mutagenesis suggest that it is essential for Ca²⁺-triggered neurotransmitter release in mouse hippocampal neuronal synapses and for Ca²⁺-triggered vesicle fusion in a reconstituted system. We propose that this interface forms before Ca²⁺ triggering, moves en bloc as Ca²⁺ influx promotes the interactions between synaptotagmin-1 and the plasma membrane, and consequently remodels the membrane to promote fusion, possibly in conjunction with other interfaces.

UW-Madison Campus Connection | Koko the Gorilla Coughs

Koko the gorilla has learned vocal and breathing behaviors that may change the perception that humans are the only primates with the capacity for speech.

In 2010, Marcus Perlman started research work at The Gorilla Foundation in California, where Koko has spent more than 40 years living immersed with humans — interacting for many hours each day with psychologist Penny Patterson and biologist Ron Cohn.

“I went there with the idea of studying Koko’s gestures, but as I got into watching videos of her, I saw her performing all these amazing vocal behaviors,” says Perlman, now a postdoctoral researcher at the University of Wisconsin-Madison.

“Decades ago, in the 1930s and ’40s, a couple of husband-and-wife teams of psychologists tried to raise chimpanzees as much as possible like human children and teach them to speak. Their efforts were deemed a total failure,” Perlman says. “Since then, there is an idea that apes are not able to voluntarily control their vocalizations or even their breathing.”

Instead, the thinking went, the calls apes make pop out almost reflexively in response to their environment — the appearance of a dangerous snake, for example. And the particular vocal repertoire of each ape species was thought to be fixed, unable to learn new vocal and breathing-related behaviors.

UW-Madison Campus Connection | Koko the gorilla blows her nose

These limits fit a theory on the evolution of language. “This idea says there’s nothing that apes can do that is remotely similar to speech,” Perlman says. “And, therefore, speech essentially evolved — completely new — along the human line since our last common ancestor with chimpanzees.”

Learned vocalization and breathing

However, in a study published online in July in the journal Animal Cognition, Perlman and collaborator Nathaniel Clark of the University of California, Santa Cruz, sifted 71 hours of video of Koko interacting with Patterson and Cohn and others, and found repeated examples of Koko performing nine different, voluntary behaviors that required control over her vocalization and breathing. These were learned behaviors, not part of the typical gorilla repertoire.

Among other things, Perlman and Clark watched Koko blow a raspberry (or blow into her hand) when she wanted a treat, blow her nose into a tissue, play wind instruments, huff moisture onto a pair of glasses before wiping them with a cloth and mimic phone conversations by chattering wordlessly into a telephone cradled between her ear and the crook of an elbow.

UW-Madison Campus Connection | Koko the gorilla plays an instrument

“She doesn’t produce a pretty, periodic sound when she performs these behaviors, like we do when we speak,” Perlman says. “But she can control her larynx enough to produce a controlled grunting sound.” Koko can also cough on command — impressive for a gorilla because it requires her to close off her larynx.

These behaviors are all learned, Perlman figures, and the result of living with humans since Koko was just six months old.

This suggests that some of the evolutionary groundwork for the human ability to speak was in place at least by the time of our last common ancestor with gorillas, estimated to be around 10 million years ago.

“Koko bridges a gap,” Perlman says. “She shows the potential under the right environmental conditions for apes to develop quite a bit of flexible control over their vocal tract. It’s not as fine as human control, but it is certainly control.”

Orangutans have also demonstrated some impressive vocal and breathing-related behavior, according to Perlman, indicating the whole great ape family may share the abilities Koko has learned to tap.

Abstract of Learned vocal and breathing behavior in an enculturated gorilla

We describe the repertoire of learned vocal and breathing-related behaviors (VBBs) performed by the enculturated gorilla Koko. We examined a large video corpus of Koko and observed 439 VBBs spread across 161 bouts. Our analysis shows that Koko exercises voluntary control over the performance of nine distinctive VBBs, which involve variable coordination of her breathing, larynx, and supralaryngeal articulators like the tongue and lips. Each of these behaviors is performed in the context of particular manual action routines and gestures. Based on these and other findings, we suggest that vocal learning and the ability to exercise volitional control over vocalization, particularly in a multimodal context, might have figured relatively early into the evolution of language, with some rudimentary capacity in place at the time of our last common ancestor with great apes.

The Parietal Memory Network, a newly discovered memory and learning network shows consistent patterns of activation and deactivation in three distinct regions of the parietal cortex in the brain’s left hemisphere — the precuneus, the mid-cingulate cortex and the dorsal angular gyrus (credit: Image adapted from Creative Commons original by Patrick J. Lynch, medical illustrator; C. Carl Jaffe, MD, cardiologist)

New research from Washington University in St. Louis has identified a novel learning and memory brain network, dubbed the Parietal Memory Network (PMN), that processes incoming information based on whether it’s something we’ve experienced previously or appears to be new and unknown — helping us recognize, for instance, whether a face is that of a familiar friend or a complete stranger.

The study pulls together evidence from multiple neuroimaging studies and methods to demonstrate the existence of this previously unknown and distinct functional brain network, one that appears to have broad involvement in human memory processing.

“When an individual sees a novel stimulus, this network shows a marked decrease in activity,” said Adrian Gilmore, first author of the study and a fifth-year psychology doctoral student at Washington University. When an individual sees a familiar stimulus, this network shows a marked increase in activity.”

The new memory and learning network shows consistent patterns of activation and deactivation in three distinct regions of the parietal cortex in the brain’s left hemisphere — the precuneus, the mid-cingulate cortex, and the dorsal angular gyrus.

Activity within the PMN during the processing of incoming information (encoding) can be used to predict how well that information will be stored in memory and later made available for successful retrieval.

Researchers identified interesting characteristics of the PMN by analyzing data from a range of previously published neuroimaging studies. Using converging bits of evidence from dozens of fMRI brain experiments, their study shows how activity in the PMN changes during the completion of specific mental tasks and how the regions interact during resting states when the brain is involved in no particular activity or mental challenge.

This study builds on research by Marcus Raichle, MD, the Alan A. and Edith L. Wolff Distinguished Professor of Medicine, and other neuroscience researchers at Washington University, which established the existence of another functional brain network that remains surprisingly active when the brain is not involved in a specific activity, a system known as the Default Mode Network.

Like the Default Mode Network, key regions of the PMN were shown to hum in a similar unison while the brain is in relative periods of rest. And while key regions of the PMN are located close to the Default Mode Network, the PMN appears to be its own distinct and separate functional network, preliminary findings suggest.

A broad role in learning and recall

Another characteristic that sets the PMN apart from other functional networks is that its activity patterns remains consistent regardless of the type of mental challenge it is processing.

Many regions of the cortex jump into action only during the processing of a very specific task, such as learning a list of words, but remain relatively inactive during very similar tasks, such as learning a group of faces, The PMN, on the other hand, exhibits activity across a wide range of mental tasks, with levels rising and falling based on how much a task’s novelty or familiarity captures our attention.

“It seems like the amount of change relies heavily on how much a given stimulus captures our attention,” Gilmore said. “If something really stands out as old or new, you see much larger changes in the network’s activity than if it doesn’t stand out as much.”

The consistency of these patterns across various types of processing tasks suggests that the PMN plays a broad role in many different learning and recall processes, the research team suggests.

“A really cool feature of the PMN is that it seems to show its response patterns regardless of what you’re doing,” Gilmore said. “The PMN doesn’t seem to care what it is that you’re trying to do. It deactivates when we encounter something new, and activates when we encounter something that we’ve seen before. This makes it a really promising target for future research in areas such as education or Alzheimer’s research, where we want to foster or improve memory performance broadly, rather than focusing on specific tasks.”

The study is forthcoming in the September issue of the journal Trends in Cognitive Sciences.

Abstract of A parietal memory network revealed by multiple MRI methods

The manner by which the human brain learns and recognizes stimuli is a matter of ongoing investigation. Through examination of meta-analyses of task-based functional MRI and resting state functional connectivity MRI, we identified a novel network strongly related to learning and memory. Activity within this network at encoding predicts subsequent item memory, and at retrieval differs for recognized and unrecognized items. The direction of activity flips as a function of recent history: from deactivation for novel stimuli to activation for stimuli that are familiar due to recent exposure. We term this network the ‘parietal memory network’ (PMN) to reflect its broad involvement in human memory processing. We provide a preliminary framework for understanding the key functional properties of the network.