For the first time, scientists in the Center for Interdisciplinary Research in Biology (CNRS/INSERM/Collège de France) have produced direct evidence that the long-term storage of memories involves a dialogue between two brain structures, the hippocampus and cortex, during sleep; by enhancing this dialogue, they succeeded in triggering the consolidation of memories that would otherwise have been forgotten. This work was published in Nature Neuroscience on 16 May 2016.

Since the 1950s, the principal theories on memory have posited that such traces are initially formed in the hippocampus and then gradually transferred to the cortex for long-term storage. Although supported by numerous experimental studies, this hypothesis had never yet been directly verified.

In order to prove it, the scientists first recorded the activity of the hippocampus and cortex during sleep. They found a correlation between the oscillations observed in these two structures: when the hippocampus emitted sharp wave-ripples, the cortex in turn emitted delta waves and spindles like a series of questions and answers. To establish a link with memory, the scientists then trained rats to memorize the position of two identical objects in a room. During testing the next day, one of the objects had been moved and the rodents had to determine which one. Those that had spent 20 minutes in the room on the first day passed the test, while those that had only been there for three minutes failed. This difference was also reflected in the hippocampal-cortical coupling during sleep just after the initial exploration: coupling was more visible in rats that passed the test the next day. It was then necessary to prove that this was indeed the cause of memorization.

The scientists then developed a system for real-time detection of hippocampal sharp wave-ripples and immediate triggering of cortical delta waves and spindles, or in other words to generate coupling between these two structures on demand. They applied this system in rats that had been trained for just three minutes the first day, and were therefore not expected to remember the position of the objects the next day: these rodents passed the test perfectly. By contrast, if a variable delay was introduced between the hippocampal and cortical waves, the effect disappeared.

To better understand the mechanisms at play, the scientists also recorded cortical activity during learning, sleep and the test. They observed that selected neurons changed their activity in the context of coupling during sleep, and that the next day the cortex responded to the task by becoming more active in the vicinity of the object that had been moved.

By demonstrating the mechanisms underlying long-term memorization, this work may shed new light on certain memory disorders in humans. It might thus be possible to envisage overcoming certain memory deficits if they result from the same mechanism as that studied here. However, the ethical issues related to these techniques will need to be addressed and methods will have to be refined to enable selective action on the memories that need to be enhanced, before any clinical application can be envisaged. The team is now set to elucidate the dialogue between the hippocampus and cortex, notably when several memories need to be remembered, or not.

Children’s brains are far more engaged by their mother’s voice than by voices of women they do not know, a new study from the Stanford University School of Medicine has found.

Brain regions that respond more strongly to the mother’s voice extend beyond auditory areas to include those involved in emotion and reward processing, social functions, detection of what is personally relevant and face recognition.

The study, which is the first to evaluate brain scans of children listening to their mothers’ voices, published online May 16 in the Proceedings of the National Academy of Sciences. The strength of connections between the brain regions activated by the voice of a child’s own mother predicted that child’s social communication abilities, the study also found.

“Many of our social, language and emotional processes are learned by listening to our mom’s voice,” said lead author Daniel Abrams, PhD, instructor in psychiatry and behavioral sciences. “But surprisingly little is known about how the brain organizes itself around this very important sound source. We didn’t realize that a mother’s voice would have such quick access to so many different brain systems.”

Preference for mom’s voice

Decades of research have shown that children prefer their mother’s voices: In one classic study, 1-day-old babies sucked harder on a pacifier when they heard the sound of their mom’s voice, as opposed to the voices of other women. However, the mechanism behind this preference had never been defined.

“Nobody had really looked at the brain circuits that might be engaged,” senior author Vinod Menon, PhD, professor of psychiatry and behavioral sciences, said. “We wanted to know: Is it just auditory and voice-selective areas that respond differently, or is it more broad in terms of engagement, emotional reactivity and detection of salient stimuli?”

The study examined 24 children ages 7 to 12. All had IQs of at least 80, none had any developmental disorders, and all were being raised by their biological mothers. Parents answered a standard questionnaire about their child’s ability to interact and relate with others. And before the brain scans, each child’s mother was recorded saying three nonsense words.

“In this age range, where most children have good language skills, we didn’t want to use words that had meaning because that would have engaged a whole different set of circuitry in the brain,” said Menon, who is the Rachael L. and Walter F. Nichols, MD, Professor.

Two mothers whose children were not being studied, and who had never met any of the children in the study, were also recorded saying the three nonsense words. These recordings were used as controls.

MRI scanning

The children’s brains were scanned via magnetic resonance imaging while they listened to short clips of the nonsense-word recordings, some produced by their own mother and some by the control mothers. Even from very short clips, less than a second long, the children could identify their own mothers’ voices with greater than 97 percent accuracy.

The brain regions that were more engaged by the voices of the children’s own mothers than by the control voices included auditory regions, such as the primary auditory cortex; regions of the brain that handle emotions, such as the amygdala; brain regions that detect and assign value to rewarding stimuli, such as the mesolimbic reward pathway and medial prefrontal cortex; regions that process information about the self, including the default mode network; and areas involved in perceiving and processing the sight of faces.

“The extent of the regions that were engaged was really quite surprising,” Menon said.

“We know that hearing mother’s voice can be an important source of emotional comfort to children,” Abrams added. “Here, we’re showing the biological circuitry underlying that.”

Children whose brains showed a stronger degree of connection between all these regions when hearing their mom’s voice also had the strongest social communication ability, suggesting that increased brain connectivity between the regions is a neural fingerprint for greater social communication abilities in children.

‘An important new template’

“This is an important new template for investigating social communication deficits in children with disorders such as autism,” Menon said. His team plans to conduct similar studies in children with autism, and is also in the process of investigating how adolescents respond to their mother’s voice to see whether the brain responses change as people mature into adulthood.

“Voice is one of the most important social communication cues,” Menon said. “It’s exciting to see that the echo of one’s mother’s voice lives on in so many brain systems.”

Call-and-response circuit tells neurons when to grow synapses

Brain cells called astrocytes play a key role in helping neurons develop and function properly, but there’s still a lot scientists don’t understand about how astrocytes perform these important jobs. Now, a team of scientists led by Associate Professor Nicola Allen has found one way that neurons and astrocytes work together to form healthy connections called synapses. This insight into normal astrocyte function could help scientists better understand disorders linked to problems with neuronal development, including autism spectrum disorders. The study was published in the journal eLife.

“We know that astrocytes could play a role in neurodevelopmental disorders, so we wanted to ask: How are they playing a role in typical development?” says Allen, a member of the Molecular Neurobiology Laboratory. “In order to better understand the disorders, we first have to understand what happens normally.”

Synapses form critical connections between neurons, allowing neurons to send signals and information throughout the body. Astrocyte cells play a role in synapse development by giving neurons directions, such as telling them when to start growing a synapse, when to stop, when to prune it back, and when to stabilize the connection.

Allen and her team took a closer look at how this process plays out in the visual cortex of the mouse brain. They sequenced the RNA of astrocytes at different stages of brain development to assess gene activity and compared it with neuronal synapse development. They found that astrocyte signaling was directly related to each stage of neuronal development. The researchers then wanted to know how the astrocytes knew to make these signals at the right time.

First, the researchers looked at what happened to the astrocytes when they changed the neurons’ activity. To do this, they stopped neurons from releasing a neurotransmitter called glutamate that can signal to astrocytes, and this stopped the astrocytes from showing the typical developmental changes. Next, the scientists stopped the astrocytes from responding to neurotransmitters, and found this stopped the astrocytes from expressing the right signals. With both these manipulations, the development of synapses was also disrupted, in line with the changes observed in the astrocytes.

Collectively, the findings suggest that astrocytes are responding to neurotransmitters produced by neurons to control the timing of when astrocytes produce signals to instruct neuronal development, according to Allen.

“It makes sense that you have this constant feedback going on between the neuron and the astrocyte,” says Allen. “They are sending signals to each other: ‘Am I in the right place?’ ‘Yes, you are.’ ‘I’ve made a connection now—do I keep it?’ ‘Yes, you do.’ And they keep going back and forth.”

Next, Allen and her team are studying whether these signals can be manipulated—for example, to stimulate neurons to repair synapses or form new ones in disorders of aging, such as Alzheimer’s disease.

(Image caption: Astrocytes (green) and neurons (magenta) closely interact in the developing cortex and signal to each other to ensure correct development. Credit: Salk Institute)

Mammalian motivation circuits: Maybe they’re born with it

Are we born to fear punishment or crave rewards? Or do those capacities evolve with experience? Cold Spring Harbor Laboratory (CSHL) Professor Bo Li and his lab found that mice have pre-programmed circuits that process “positive” and “negative” stimuli. These neurons are found in the mouse’s amygdala, a section of the brain that deals with learning rewards and punishments. The researchers’ findings may be useful for studying neurological and psychiatric disorders in humans.

Previously, Li and his colleagues discovered that the amygdala is the hub for both fear- and reward-based learning. Xian Zhang, a postdoc in Li’s lab, wanted to find out the exact circuitry that takes in positive or negative stimuli that trigger either pleasure or fear.

In an experiment similar to how Pavlov’s dog was taught to associate a bell sound with food, Li and Zhang trained mice to connect certain sounds with either a reward (a refreshing drink of water) or a punishment (an annoying puff of air to the whiskers). Then, in collaboration with CSHL Adjunct Professor Z. Josh Huang, they developed a method to mark and observe different neurons in the mouse amygdala. They discovered two distinct types of neurons: one that was activated when the mouse heard the reward sound, and one that was activated when it heard the punishment sound. Both neuron populations exist throughout the entire amygdala. Li explains:

“They’re spatially intermingled. When you start to image them, you know that some of the neurons respond only to good things, some of the neurons respond only to bad things, just like the pepper and the salt mixed together, and they do different jobs.”

The researchers were surprised to discover that some amygdala cells are hardwired to process motivation stimuli, even without training. A puff of air or sip of water triggered the same neurons in both untrained and trained mice.

Zhang thinks their findings may be relevant to human psychiatric disorders like depression. He says:

“If you have an imbalanced bit in different neural circuits, you probably have a deficit of your motivation, like you lost your interest in pursuing rewards, or you lost your interest in avoiding punishment. I think this finding is important to know for the future, to help people with depression or other mental disorders.”

In mouse models of depression, animals lack the motivation to seek rewards or avoid punishments. Li and Zhang hope that this study, published in Nature Neuroscience, will help researchers understand how motivation works or goes wrong in mammalian brains.

(Image caption: Cold Spring Harbor Laboratory Professor Bo Li and his postdoc Xian Zhang uncovered distinct hardwired circuits in this structure responsible for processing “positive” and “negative” stimuli that lead to reward or punishment for a mouse. In this image of a mouse amygdala, the green neurons and their connections process positive stimuli that lead the animal to seek rewards, while the red neurons and their connections process negative stimuli that lead the animal to avoid punishment. Credit: Xian Zhang/Li lab)

Treating Severe Depression with On-Demand Brain Stimulation

UCSF Health physicians have successfully treated a patient with severe depression by tapping into the specific brain circuit involved in depressive brain patterns and resetting them using the equivalent of a pacemaker for the brain.

The study, which appears in Nature Medicine, represents a landmark success in the years-long effort to apply advances in neuroscience to the treatment of psychiatric disorders.

“This study points the way to a new paradigm that is desperately needed in psychiatry,” said Andrew Krystal, PhD, professor of psychiatry and member of the UCSF Weill Institute for Neurosciences. “We’ve developed a precision-medicine approach that has successfully managed our patient’s treatment-resistant depression by identifying and modulating the circuit in her brain that’s uniquely associated with her symptoms.”

Previous clinical trials have shown limited success for treating depression with traditional deep brain stimulation (DBS), in part because most devices can only deliver constant electrical stimulation, usually only in one area of the brain. A major challenge for the field is that depression may involve different brain areas in different people.

What made this proof-of-principle trial successful was the discovery of a neural biomarker – a specific pattern of brain activity that indicates the onset of symptoms – and the team’s ability to customize a new DBS device to respond only when it recognizes that pattern. The device then stimulates a different area of the brain circuit, creating on-demand, immediate therapy that is unique to both the patient’s brain and the neural circuit causing her illness.

This customized approach alleviated the patient’s depression symptoms almost immediately, Krystal said, in contrast to the four- to eight-week delay of standard treatment models and has lasted over the 15 months she has had the implanted device. For patients with long-term, treatment-resistant depression, that result could be transformative.

“I was at the end of the line,” said the patient, who asked to be known by her first name, Sarah. “I was severely depressed. I could not see myself continuing if this was all I’d be able to do, if I could never move beyond this. It was not a life worth living.”

Applying Proven Advances in Neuroscience to Mental Health

The path to this project at UC San Francisco began with a large, multicenter effort sponsored under President Obama’s BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative in 2014.

Through that initiative, UCSF neurosurgeon Edward Chang, MD, and colleagues conducted studies to understand depression and anxiety in patients undergoing surgical treatment for epilepsy, for whom mood disorders are also common. The research team discovered patterns of electrical brain activity that correlated with mood statesandidentified new brain regions that could be stimulated to relieve depressed mood. 

With results from the previous research as a guide, Chang, Krystal, and first author Katherine Scangos, MD, PhD, all members of the Weill Institute, developed a strategy relying on two steps that had never been used in psychiatric research: mapping a patient’s depression circuit and characterizing her neural biomarker.

“This new study puts nearly all the critical findings of our previous research together into one complete treatment aimed at alleviating depression,” said Chang, who is co-senior author with Krystal on the paper and the Joan and Sanford Weill Chair of Neurological Surgery.

The team evaluated the new approach in June 2020 under an FDA investigational device exemption, when Chang implanted a responsive neurostimulation device that he has successfully used in treating epilepsy.

“We were able to deliver this customized treatment to a patient with depression, and it alleviated her symptoms,” said Scangos. “We haven’t been able to do this the kind of personalized therapy previously in psychiatry.”

To personalize the therapy, Chang put one of the device’s electrode leads in the brain area where the team had found the biomarker and the other lead in the region of Sarah’s depression circuit where stimulation best relieved her mood symptoms. The first lead constantly monitored activity; when it detected the biomarker, the device signaled the other lead to deliver a tiny (1mA) dose of electricity for 6 seconds, which caused the neural activity to change.

“The effectiveness of this therapy showed that not only did we identify the correct brain circuit and biomarker, but we were able to replicate it at an entirely different, later phase in the trial using the implanted device,” said Scangos. “This success in itself is an incredible advancement in our knowledge of the brain function that underlies mental illness.”

Translating Neural Circuits into New Insights

For Sarah, the past year has offered an opportunity for real progress after years of failed therapies.

“In the early few months, the lessening of the depression was so abrupt, and I wasn’t sure if it would last,” she said. “But it has lasted. And I’ve come to realize that the device really augments the therapy and self-care I’ve learned while being a patient here at UCSF.”

The combination has given her perspective on emotional triggers and irrational thoughts on which she used to obsess. “Now,” she said, “those thoughts still come up, but it’s just…poof…the cycle stops.”

While the approach appears promising, the team cautions that this is just the first patient in the first trial.

“There’s still a lot of work to do,” said Scangos, who has enrolled two other patients in the trial and hopes to add nine more. “We need to look at how these circuits vary across patients and repeat this work multiple times. And we need to see whether an individual’s biomarker or brain circuit changes over time as the treatment continues.”

FDA approval for this treatment is still far down the road, but the study points toward new paths for treating severe depression. Krystal said that understanding the brain circuits underlying depression is likely to guide future non-invasive treatments that can modulate those circuits.

Added Scangos, “The idea that we can treat symptoms in the moment, as they arise, is a whole new way of addressing the most difficult-to-treat cases of depression.”