Tag Archives: #dopamine

Feel-good Hormone Dopamine Affects Passion And Autism (Neuroscience)

Dopamine is often called the “happy” or “feel-good” hormone. It can help explain both autistic behaviours and men’s need for passion in order to succeed.

Men – more often than women – need passion to succeed at things. At the same time, boys are diagnosed as being on the autism spectrum four times as often as girls.

Both statistics may be related to dopamine, one of our body’s neurotransmitters.

“This is fascinating. Research shows a more active dopamine system in most men” than in women, says Hermundur Sigmundsson, a professor at NTNU’s Department of Psychology.

He is behind a new study that addresses gender differences in key motivating factors for what it takes to become good at something. The study uses men’s and women’s differing activity in the dopamine system as an explanatory model.

An abstract illustration showing the chemical formula to dopamine and a man with a smiling brain
Among other things, dopamine can affect our feeling of happiness. Illustration: Shutterstock, NTB

Not just a “happy hormone”

“We looked at gender differences around passion, self-discipline and positive attitude,” Sigmundsson says.

Dopamine is a neurotransmitter that is released in the brain. It can contribute to a feeling of satisfaction.

The study refers to these qualities as passion, grit and mindset. The researchers also applied theories to possible links with dopamine levels.

Dopamine is linked to learning, attention and our ability to focus.

Dopamine is a neurotransmitter that is released in the brain. It can contribute to a feeling of satisfaction.

Men normally secrete more dopamine, which is often called the “happy hormone,” but it plays a far more complex role than that. The effects of dopamine are linked to learning, attention and our ability to focus.

Dopamine and passion

Previous studies on Icelandic students have shown that men are more dependent on passion in order to succeed at something. This study confirms the earlier findings. Men require more passion. In six out of eight test questions, men score higher on passion than women.

However, the association with dopamine levels has not been established previously.

“The fact that we’ve developed a test to measure passion for goal achievement means that we can now relate dopamine levels to passion and goal achievement,” says Sigmundsson.

An illustration showing the growth mindset
Positive attitude – or mindset – is the basis for a person’s success. Self-discipline – or grit – determines the strength and scope of the effort. Passion determines the direction, that is, what a person becomes good at. Illustration: Hermundur Sigmundsson, NTNU

Women, on the other hand, may have greater self-discipline – or grit – and be more conscientious, according to other studies. Their level of passion may not be as pronounced in general, but they still are able to do what it takes to be good.

The results for the women, however, are somewhat more ambiguous than men’s strong need to burn for something, and this study found no such gender difference.

Nor did the researchers find any difference between the sexes in terms of growth mindset.

Dopamine and autism

In the past, the dopamine system has been associated with many different conditions, such as ADHD, psychoses, manias and Parkinson’s disease. But it may also be related to a certain form of autistic behaviour.

Some individuals with autism may become very interested in certain topics, which can be a bit unusual, or even strange, for most people. People on the autism spectrum can focus intensely on these topics or pursuits, at least for a while. Dopamine may play a role.

“Other research in neuroscience has shown hyperactivity in the dopamine system in individuals with autism, and boys make up four out of five children on the autism spectrum. This, and dopamine’s relationship to passion, might be a mechanism that helps to explain this behaviour,” says Sigmundsson.

The research group tested 917 people aged 14 to 77, consisting of 502 women and 415 men. This is considered a major study in this context.

Sigmundsson collaborated with Stéfan Guðnason from the University of Akureyri and Sigurrós Jóhannsdóttir from the Icelandic State Diagnostic and Counselling Centre (SDCC).

Featured image: Dopamine can help explain why men depend on passion to succeed. But it may also explain a certain behaviour in boys on the autism spectrum. Photo: Shutterstock, NTB


ReferenceHermundur Sigmundsson, StéfanGuðnason, Sigurrós Jóhannsdóttir. Passion, grit and mindset: Exploring gender differences. Science Direct. Available online 3 June 2021. https://doi.org/10.1016/j.newideapsych.2021.100878


Provided by Norwegian SciTech

Novel Nano-encapsulation Approach For Efficient Dopamine Delivery in Parkinson’s Treatment (Neuroscience)

Parkinson’s disease (PD) is a common neurodegenerative disorder caused by the death of dopaminergic neurons in a part of the brain (known as substantia nigra pars compacta), which leads to a deficit of dopamine (DA), one of the main neurotransmitters active in the central nervous system. Symptomatic treatment focuses on increasing the concentration of dopamine into the brain.

However, dopamine is not directly administered, because it is unable to cross the so called blood-brain barrier, which prevents some of the substances circulating in the blood to penetrate into the nervous system. Thus, DA precursor levodopa (L-DOPA) -an amino-acid which participates in the synthesis of dopamine- is used, due to its better ability to cross such barrier. Nevertheless, long-term and intermittent administration of this drug is associated with important disabling complications, such as motor disorders and involuntary muscle movements.

In a paper recently published in ACS Nano, synthetic melanin-like nanoparticles are used to overcome these limitations. This research was coordinated by Dr Daniel Ruiz-Molina, leader of the ICN2 Nanostructured Functional Materials Group, and Dr Julia Lorenzo, leader of the Protein Engineering Group at the Institute of Biotehcnology and Biomedicine (IBB) of the Universitat Autònoma de Barcelona (UAB), and was developed in collaboration with the Neurodegenerative Diseases group of Vall d’Hebron Research Institute (VHIR), led by Prof. Miquel Vila.

The main objective of this work was to obtain a “nanoplatform” -which is a biocompatible nano-structure including the substance to be delivered- able to reach the brain through a noninvasive route and generate a slow and controlled release of dopamine. A tailor-made nanoscale coordination polymer (NCP), characterized by the reversible incorporation of DA as its principal component, was tested in vitro and in vivo in rats. Intranasal administration of these nanoparticles, called DA-NCPs, showed a relevant biocompatibility, non-toxicity and a fast and efficient distribution of dopamine in the central nervous system of the animals (avoiding the blood-brain barrier).

As reported by the researchers, the proposed method is effective in delivering dopamine to the brain and, thus, in reversing Parkinson’s symptoms. In addition, the synthetic methodology used is simple, cheap and exhibited a satisfactory yield (with a DA loading efficiency up to 60%).

These findings establish nanoscale coordination polymers as promising future candidates for efficient nasal delivery of drugs to the central nervous system, and thus for the symptomatic treatment of people affected by Parkinson’s and other neurodegenerative disorders. This type of nano-formulation and administration route may also pave the way to the development of other platforms able to deliver a wide range of drugs into the brain in a controlled manner, for the treatment of various brain diseases (such as brain tumours, Alzheimer’s, Epilepsy).

Featured image: Nanoencapsulation of dopamine © ICN2/IBB-UAB


Reference: Javier García-Pardo, Fernando Novio, Fabiana Nador, Ivana Cavaliere, Salvio Suárez-García, Silvia Lope-Piedrafita, Ana Paula Candiota, Jordi Romero-Gimenez, Beatriz Rodríguez-Galván, Jordi Bové, Miquel Vila, Julia Lorenzo, and Daniel Ruiz-Molina, “Bioinspired Theranostic Coordination Polymer Nanoparticles for Intranasal Dopamine Replacement in Parkinson’s Disease”, ACS Nano 2021, 15, 5, 8592–8609.
https://doi.org/10.1021/acsnano.1c00453


Provided by UAB

Impaired Dopamine Transporters Contribute to Parkinson’s Disease-like Symptoms (Neuroscience)

A rare mutation that causes a Parkinson’s disease-like disorder in young children interferes with dopamine transporters in the brain, suggesting that treatments targeting the transporters may be beneficial.

A rare mutation that causes Parkinson’s disease-like symptoms interrupts the flow of dopamine in the brain, suggests a study in fruit flies published today in eLife.

The findings provide more detailed insights about why young children with this mutation develop these symptoms. This new information, as well as previous evidence that therapies helping to improve dopamine balance in the brain can alleviate some symptoms in the flies, suggests that this could be a beneficial new treatment strategy.

Parkinson’s disease causes progressive degeneration of the brain that leads to impaired movement and coordination. Current treatments focus on replacing or increasing the levels of dopamine to help reduce movement-related symptoms. But these drugs can have side effects, do not resolve all symptoms, and often stop working over time.

“Although the exact cause of Parkinson’s disease remains unclear, studies of rare mutations that lead to the early onset of similar symptoms in some families have helped us learn more about possible causes, and suggested approaches for alleviating symptoms,” says first author Jenny Aguilar, a former graduate student at the Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, US.

To learn more, Aguilar and colleagues studied genetically modified fruit flies with a mutation that causes a Parkinson’s disease-like condition in young children, called dopamine transporter deficiency syndrome (DTDS).

They showed that the mutation impairs the function of a so-called ‘gate protein’ that ushers dopamine from the outside of the cell inside. The mutation causes the gate protein to become stuck facing the inside of the cell more frequently, meaning that dopamine builds up outside. This slows the ability of the flies to motor coordinate their take off. “Over time, this dopamine build-up may lead to the production of less dopamine, causing worsening movement problems and other symptoms,” Aguilar says.

The team next treated the flies with a malaria drug called chloroquine, which has been shown in animals to increase the number of other proteins by preventing them from being recycled. They found that the drug helped to alleviate some of the flies’ movement problems.

While chloroquine is a widely available drug, it has side effects that make it unlikely to serve as a treatment for Parkinson’s disease-like symptoms, except in rare circumstances. This work suggests that developing treatments to improve the function of the dopamine-transporting protein may relieve movement symptoms and also stop the progressive loss of dopamine production.

“Our study provides a blueprint for using fruit flies to learn more about how problems with dopamine-transporting proteins contribute to Parkinson’s-like symptoms,” concludes senior author Aurelio Galli, Professor at the Department of Surgery, University of Alabama at Birmingham, US. “This could pave the way for further research into new treatment approaches that focus on improving dopamine transport.”

Reference: Jenny I Aguilar et al., “Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia”, elife, 2021. DOI: 10.7554/eLife.68039

Brain Cells Decide on Their Own When to Release Pleasure Hormone (Neuroscience)

Study Findings Provide Insight into Why Dopamine Brain Cells Die in Parkinson’s Disease

In addition to smoothing out wrinkles, researchers have found that botulinum toxin—commonly known by its trade name, Botox®—can reveal the inner workings of the brain. A new study used it to show that feedback from individual nerve cells controls the release of dopamine, a chemical messenger involved in motivation, memory, and movement.

Such “self-regulation,” the researchers say, stands in contrast to the widely held view that the release of dopamine—known as the “feel good” hormone—by any cell relied on messages from nearby cells to recognize that it is releasing too much of the hormone.

Led by researchers at NYU Grossman School of Medicine, the new study showed that dopamine-releasing brain cells respond to their own signals to regulate the hormone’s output. Because the death of dopamine-releasing brain cells is a key factor in Parkinson’s disease, the new findings provide insight into why these cells die in the movement disorder, the researchers say.

“Our findings provide the first evidence that dopamine neurons regulate themselves in the brain,” says study lead author Takuya Hikima, PhD. “Now that we better understand how these cells behave when they are healthy, we can start to unravel why they break down in neurodegenerative disorders like Parkinson’s disease,” adds Dr. Hikima, an instructor in the Department of Neurosurgery at NYU Langone Health.

Dr. Hikima says their study was prompted by what the research team saw as flaws in the older way of thinking about how dopamine works. First, for one cell to control its neighbor with dopamine, a large number of synapses, or junctions where two cells meet and exchange messages, would be required. Yet researchers say there were not enough synapses to account for this. Second, many types of hormone-producing cells in the body use a streamlined system that self-regulates further release, so it seemed odd that dopamine neurons would use a more roundabout process.

For the study, published April 6 in the journal Cell Reports, the research team collected dopamine neurons from dozens of mice. They injected some of the brain cells with Botox®, a toxin that blocks nerve cells from sending chemical messages to neurons and other cells. The chemical’s nerve-blocking action accounts for its ability to relax muscles in migraine and wrinkle treatments.

By injecting Botox® into single neurons, says Dr. Hikima, the researchers hoped to show whether any signal to continue or stop dopamine release could only come from outside the “paralyzed” cell. If the neurons were in fact controlled by neighboring dopamine cells, then dopamine release would remain unaffected because the treated cells would still receive dopamine signals from the untreated cells nearby.

Instead, the findings revealed a 75 percent drop in dopamine outflow, suggesting that dopamine neurons largely rely on their own discharge to determine release rate of the hormone, according to the investigators.

“Since our Botox technique helped us solve the problem of how dopamine neurons regulate their communication, it should also enable us to uncover how other nerve cells interact with each other in the mammalian brain,” says study senior author Margaret E. Rice, PhD.

The research team next plans to explore other areas of dopamine neuron activity that remain poorly understood, such as the dependence of dopamine release on calcium from outside the brain cells, says Dr. Rice, a professor in the Departments of Neurosurgery and Neuroscience and Physiology at NYU Langone. The investigators also intend to examine how self-regulation of dopamine might contribute to cell death in Parkinson’s disease.

Funding for the study was provided by National Institutes of Health grants R01 DA038616 and R01AI093504 and by the Marlene and Paolo Fresco Institute for Parkinson’s Disease and Movement Disorders at NYU Langone.

In addition to Dr. Hikima and Dr. Rice, other NYU Langone researchers are Christian Lee, PhD; Paul Witkovsky, PhD; Julia Chesler, PhD; and Konstantin Ichtchenko, PhD.

Featured image credit: NAEBLYS/GETTY


Reference: Takuya Hikima, “Activity-dependent somatodendritic dopamine release in the substantia nigra autoinhibits the releasing neuron”, VOLUME 35, ISSUE 1, 2021. DOI: https://doi.org/10.1016/j.celrep.2021.108951


Provided by NYU Langone

Scientists Reveal How Dopamine and Its Activity Regulator Bind to Dopamine Receptor D1 (Neuroscience)

In a study published in Cell Research, Prof. H. Eric Xu from Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, collaborating with Prof. Bryan Roth from University of North Carolina Chapel Hill, Prof. ZHANG Yan from Zhejiang University, and the collaborators, reported the near-atomic structure of dopamine (DA) receptor D1 bound with DA, and revealed the high-resolution structure of D1R with its positive allosteric modulator LY3154207. 

DA is an important monoamine neurotransmitter involved in the regulation of various physiological functions of the central nervous system (CNS) and the peripheral nervous system (PNS). It conducts signal transformation through five DA receptors (DRs), namely, D1R, D2R, D3R, D4R and D5R. All the DRs belong to the G protein-coupled receptor (GPCR) superfamily.

Among DRs, D1R is most abundantly expressed in CNS. Dysfunction of D1R is associated with various neurological diseases such as Parkinson’s disease, schizophrenia, and drug addiction, making it an important drug target for developing efficient treatments of neuropsychiatric diseases. 

For a long time, as the endogenous ligand of D1R, the detail of how DA recognizes and activates D1R was poorly investigated. The cellular activities of D1R agonists, such as DA, can be regulated by D1R positive allosteric modulators (PAMs). However, the mechanisms remain unknown of how PAMs regulate D1R conformation and promote the cellular activity of D1R agonists.

To answer these questions, scientists determined the structures of D1R PAM LY3154207 bound D1R-Gs signaling complexes activated by either DA or a synthetic agonist SKF81297. They found that the overall interaction patterns of DA and SKF81297 with D1R are similar. The noticeable difference is that DA lacks an extended binding pocket (EBP) that interacts with D1R, which makes its affinity to D1R weaker than SKF81297. 

The structures clearly showed the binding pose of PAM LY3154207. LY3154207 molecule lies in the cleft between TM3 and TM4 and right above ICL2 with a boat conformation. Interestingly, the binding pose of LY3154207 in this study is different from that obtained by molecular dynamics simulation in previous studies, and the binding mode of LY3154207 in this study is also divergent from the recently reported structure of D1R binding to LY3154207.

By comparing the structures of D1R-SKF81297 in the presence or absence of LY3154207, scientists found that LY3154207 may help keeping D1R in its active state, thereby enhancing the activation efficiency of agonists.

“In this study, we present the clear view of human D1R bound to its endogenous agonist DA and allosteric modulator LY3154207 compound. The series of D1R structures, as we published in Cell last month, present a more complete landscape in understanding pharmacology of D1R, and provide multiple templates in designing more efficient and safer drugs treating CNS diseases,” one of the corresponding authors, Prof. H Eric. Xu said.

Featured image: Structures of DA or SKF81297 bound D1R-Gs complexes, both in presence of PAM. (Image by H. Eric Xu’s group)


Reference

Mechanism of dopamine binding and allosteric modulation of the human D1 dopamine receptor


Provided by Chinese Academy of Sciences

Researchers Discover How The Brain Learns From Subconscious Stimuli (Neuroscience)

Researchers uncovered for the first time what happens in animals’ brains when they learn from subconscious, visual stimuli. In time, this knowledge can lead to new treatments for a number of conditions. The study, a collaboration between KU Leuven, Massachusetts General Hospital, and Harvard was published in Neuron.

An experienced birdwatcher recognises many more details in a bird’s plumage than the ordinary person. Thanks to extensive training, he or she can identify specific features in the plumage. This learning process is not only dependent on conscious processes. Previous research has shown that when people are rewarded during the presentation of visual stimuli that are not consciously perceivable, they can still perceive these stimuli afterwards.

Although this is a known phenomenon, researchers were unsure as to how exactly this unconscious perceptual learning comes about. To find out, Professor Wim Vanduffel and colleagues studied the brains of two rhesus monkeys before and after they were exposed to subconscious visual stimuli.

Dopamine

The researchers activated part of the reward system at the base of the brain stem, the ventral tegmental area. This includes cells that produce dopamine, a molecule that is also released when you receive a reward. “Dopamine is a crucial messenger molecule of our motor and reward systems, and is extremely important for learning and enjoyment,” says Vanduffel. Activating the ventral tegmental area released dopamine, among other things. “By stimulating the brain area directly, we can causally link the activity in that area to perception or complex cognitive behaviour,” explains Vanduffel.

While the brain area was activated, the monkeys were shown virtually invisible images of human faces and bodies. Because the images were very blurry and the monkeys had to perform a very different and difficult task at the same time, they could not consciously perceive these images. The same process was followed during the control tests, but the brain was not stimulated.

When the monkeys received subconscious visual stimuli while the ventral tegmental area was stimulated, they knew details about those images afterwards. For example, they knew whether the bodies shown were turned to the left or to the right. This was not the case when there had been no brain stimulation.

“Thanks to this experiment, we can demonstrate for the first time a direct causal relationship between this brain region and, as a result, also the likely link between dopamine and the subconscious learning of complex visual stimuli.”

The parts in the darker colour regulate, among others, the production of dopamine. Disturbances in this region can lead to Parkinson’s disease and other conditions. | © Shutterstock

The researchers also made a brain scan of the animals before and after the test. “We can see the blood flow in the brain, which gives an indication of which neurons are active. The more blood flow, the more activity,” explains Vanduffel. The scans showed that the task caused activity in the visual cortex of the brain and in areas important for memory. “With this data, we can zoom in to find out what is happening exactly at a neuronal level in these brain areas, in future experiments.”

“Since Freud’s insights in the 20th century, the scientific community has been wondering how subconscious sensations can affect us. Thanks to the present awareness that there is a strong resemblance between humans and monkeys, and new and advanced technologies, we can finally map such processes physiologically.”

Parkinson’s disease

Disturbances in the dopaminergic system can lead to numerous psychiatric and motor disorders, such as depression, addiction and Parkinson’s disease. A better understanding of how this system works, in various forms of learning, is therefore crucial to developing targeted therapies for these conditions.

You have to know how a car’s engine works before you can fix a problem with it.

“Parkinson’s is a motor disorder and is caused by dopamine-producing neurons dying off. However, current dopamine treatments may produce side effects because they also trigger the entire reward system, which not only reduces motor symptoms but can also lead to addictive behaviour.” Fundamental research into the functioning of these brain areas will eventually lead to more targeted treatments with fewer side effects.

Plasticity

This insight is also useful in situations such as trauma, ageing or oncological problems where an increase in brain plasticity, i.e. the ability to change, could be very useful. “By stimulating areas of the brain that produce dopamine, we could, for example, enable people to regain their speech more quickly or improve their motor skills after an accident or illness. This could even be done through medication, although we are still a long way from that,” explains Vanduffel.

Insights about our brain and the conditions under which we and other primates visually shape our world are therefore crucial, because, as Vanduffel concludes: “you have to know how a car’s engine works before you can fix a problem with it.”

Featured image: The ventral tegmental area contains, among others, cells that produce dopamine. © Ku Leuven


More information

The study “Electrical stimulation of the macaque ventral tegmental area drives category-selective learning without attention” by Sjoerd R. Murris, John T. Arsenault, Rajani Raman, Rufin Vogels, and Wim Vanduffel was published in Neuron.


Provided by KU Leuven

‘Transient Forgetting’ Controlled by Dopamine Circuits, Scientists Find (Neuroscience)

Memory-retrieval block revealed; pauses thought without abolishing long-term memories.

In a landmark neurobiology study, scientists from Scripps Research have discovered a memory gating system that employs the neurotransmitter dopamine to direct transient forgetting, a temporary lapse of memory which spontaneously returns.

The study adds a new pin to scientists’ evolving map of how learning, memory and active forgetting work, says Scripps Research Neuroscience Professor Ron Davis, PhD.

“This is the first time a mechanism has been discovered for transient memory lapse,” Davis says. “There’s every reason to believe, because of conservation biology, that a similar mechanism exists in humans as well.”

The study, “Dopamine-based mechanism for transient forgetting,” appears Wednesday in the journal Nature.

Everyone has experienced transient forgetting. A name sits on the tip of our tongue, but resurfaces only after a meeting. We walk into a room and forget why we entered – until we leave. Annoying, to be sure. But does it represent a mental glitch, or is absentmindedness a feature of a normal brain? Was the elusive memory erased and somehow restored, or merely hidden for a time? Exactly how transient forgetting worked was unknown until now.

To derive an answer, Davis’ team worked in the common fruit fly, a model favored by neurobiologists for decades due to its relatively simple brain structure, ease of study and translatability to more complex animals.

The team put their flies through a series of training exercises, teaching them to associate an odor with an unpleasant foot shock. They then watched as several interfering stimuli, such as a blue light or a puff of air, distracted the flies so they forgot the odor’s negative association, temporarily. Interestingly, stronger stimulation led to longer lasting periods of forgetting.

Additional biochemical studies revealed a single pair of dopamine-releasing neurons in the flies, called PPL1-α2α’2, which directed the transient forgetting. Dopamine sent from other neurons didn’t have the same effect. The neurons activated dopamine receptors called DAMB on axons extending from neurons in the memory-processing center of the fruit fly brain, called its mushroom body.

Martin Sabandal is a graduate student in the lab of Neuroscientist Ron Davis, PhD, at Scripps Research in Jupiter, Florida.

Activation of the transient forgetting circuit did not erase the flies’ long-term memory recall, suggesting that transient forgetting doesn’t affect permanent, consolidated memory traces, or engrams, that are acquired over time, Davis says.

Intriguingly, they found the flies’ memory performance was restored after the transient forgetting period lifted, says the paper’s first author, John Martin Sabandal, a Scripps Research graduate student, who worked with staff scientist Jacob Berry, PhD, at the team’s lab in Jupiter, Florida.

“Could we perform better if certain memories are suppressed over others – could we learn or adapt to situations better? Nobody knows. Those are the type of questions that will be explored in the future,” Sabandal says. “We found, provisionally, there is a potential memory reserve that is just unable to be expressed at a particular moment.”

The mechanisms underlying long-term memory acquisition and consolidation have been thoroughly studied over the past 40 years, Davis says, but forgetting has been overlooked until recently. It’s proving to be a fascinating field. In 2012 Davis’ group found a mechanism directing permanent forgetting, finding it is an ongoing, active process, one apparently needed for healthy brain function.

“You can imagine that we have thousands of memories that occur every day in our lifetime, and the brain does not have the capability of remembering, or encoding, all of those memories. So there is a need to erase those memories that are irrelevant to our existence and our daily lives,” Davis says.

Taken together, it’s increasingly clear that much of what we think of as memory loss is not a result of broken connections or age-related decline, but an important feature, one necessary for survival, Davis says. Much more work lies ahead, he adds.

“We now know that there is a specific receptor in the memory center that receives the transient forgetting signal from dopamine. But we don’t yet know what happens downstream. What does that receptor do to the physiology of the neuron that temporarily blocks memory retrieval? That’s the major next goal, to understand how this block in retrieval occurs through the activation of this dopamine receptor,” Davis says. “We are just at the very beginning of understanding how the brain causes transient forgetting.”

The study, “Dopamine-based mechanism for transient forgetting,” was supported by the National Institutes of Health, grant 5R35NS098224 and F31MH123022.

Provided by Scripps

Potential Means of Improving Learning and Memory in People With Mental Illnesses (Psychiatry)

More than a dozen drugs are known to treat symptoms such as hallucinations, erratic behaviors, disordered thinking and emotional extremes associated with schizophrenia, bipolar disorder and other severe mental illnesses. But, drug treatments specifically able to target the learning, memory and concentration problems that may accompany such disorders remain elusive.

Average brain activity during a working memory task in a group of healthy subjects as measured by fMRI. The colors represent higher brain activity in the carriers of the G version of the GCPII enzyme, where brains are less efficient at performing the task, compared with those carriers with the A version of the enzyme. ©Bigos laboratory

In an effort to find such treatments, Johns Hopkins Medicine researchers report they have identified a genetic variation in the brain tissue of a subset of deceased people — some with typical mental health and some with schizophrenia or other psychoses — that may influence cognition and IQ. In the process, they unearthed biochemical details about how the gene operates.

Results of their work, described in the Dec. 1 issue of the American Journal of Psychiatry, could advance the development of drugs that target the enzyme made by this gene, and thus improve cognition in some people with serious mental illnesses or other conditions that cause reduced capacity in learning and memory.

Typical antipsychotic medications that treat schizophrenia symptoms regulate the brain chemical dopamine, a transmitter of nerve impulses associated with the ability to feel pleasure, think and plan, which malfunctions in patients with the disorder. However, previous genetic studies have also shown that another brain chemical signal transmitter, glutamate, a so-called “excitatory” chemical associated with learning and memory, plays a role as well. Another so-called neurotransmitter in this process, N-acetyl-aspartyl-glutamate (NAAG), specifically binds to a protein receptor found on brain cells that has been linked to schizophrenia, but how it impacts this disorder is unknown.

The research of clinical pharmacologist Kristin Bigos, Ph.D., assistant professor of medicine at the Johns Hopkins University School of Medicine, sought to explore more deeply the role of NAAG in cognitive impairment with the goal of eventually developing therapies for treating these learning, memory or concentration problems.

Using tissues gathered from a repository of brains from deceased donors belonging to the Lieber Institute for Brain Development, Bigos and her team measured and compared levels of certain genetic products in the brains of 175 people who had schizophrenia and the brains of 237 typical controls.

Bigos and her colleagues specifically looked at the gene that makes an enzyme known as glutamate carboxypeptidase II (GCPII), which breaks down NAAG into its component parts ? NAA and glutamate. In the brains of people with schizophrenia and in the typical controls, they found that carriers of this genetic variant (having one or two copies of the gene variation) had higher levels of the genetic product that makes the GCPII enzyme.

In the gene for the enzyme, the only difference in the versions was a single letter of the genetic code, either G or A (for the nucleotide bases guanine and adenine). If people had the version of the gene with one copy of G, then the tissue at the front of their brain ? the seat of cognition ? had 10.8% higher levels of the enzyme than those who had the version of the gene with A, and if people had two copies, they had 21% higher levels of the enzyme.

To see if this genetic variation in GCPII controlled the levels of NAAG in the brains of living people, the researchers measured levels of NAAG in the brain using magnetic resonance spectroscopy, which uses a combination of strong magnetic field and radio waves to measure the quantity of a chemical in a tissue or organ.

In this experiment, they focused on 65 people without psychosis and 57 patients diagnosed with recent onset of psychosis, meaning many of them were likely to eventually be diagnosed with schizophrenia, at the Johns Hopkins Schizophrenia Center. Participants averaged 24 years of age, and 59% were men. About 64% of participants identified as African American, and the remaining 36% were white.

The researchers found 20% lower levels of NAAG in the left centrum semiovale — a region of the brain found deep inside the upper left side of the head — in the white participants both with and without psychosis who had two copies of the G version of the enzyme compared with other white people who had the A version.

To see if having the G or A version of the gene plays a role in cognition, the researchers tested IQ and visual memory in the healthy participants and those with psychosis, both white and African American. They found that people with the most NAAG in their brain (in the top 25%) scored 10% higher on the visual memory test than those in the bottom 25%. They also found that people with two copies of the G version of the GCPII sequence scored 10 points lower on their IQ test on average than the people with the A version of the gene, which the researchers say is a meaningful difference in IQ.

Finally, they showed that healthy carriers of the G version of the GCPII sequence had less efficient brain activity during a working memory task, as measured by functional MRI, by at least 20% compared with those people with the A version of the gene.

“Our results suggest that higher levels of the NAAG are associated with better visual and working memory, and that may eventually lead us to develop therapies that specifically raise these levels in people with mental illness and other disorders related to poor memory to see if that can improve cognition,” says Bigos.

Additional authors on the study include Caroline Zink, Peter Barker, Akira Sawa, Min Wang, Andrew Jaffe, Joel Kleinman, Thomas Hyde, Kayla Carta and Marcus van Ginkel of Johns Hopkins Medicine, and Daniel Weinberger, Henry Quillian, William Ulrich, Qiang Chen, Greer Prettyman and Mellissa Giegerich of the Lieber Institute for Brain Development.

This work was supported by the Lieber Institute for Brain Development, the National Institutes of Mental Health (MH092443, MH094268, MH105660 and MH107730) and the National Institute on Drug Abuse (DA040127).

Some patient or volunteer recruitment costs were supported by the Mitsubishi Tanabe Pharma Corporation.

Provided by Johns Hopkins Medicine

Basketball on the brain: Neuroscientists use sports to study surprise (Neuroscience)

A team of neuroscientists tracked the brains and pupils of self-described basketball fans as they watched March Madness games to study how people process surprise, an unexpected change of circumstances that shifts an anticipated outcome.

The gasp of surprise. Fans leap to their feet. Shouts ring out.

The most exciting moments in sports are often linked to surprise, an unexpected change of circumstances that abruptly shifts the anticipated outcome of the game.

A team of Princeton neuroscientists tracked the brains and pupils of self-described basketball fans as they watched March Madness games to study how people process surprise, an unexpected change of circumstances that shifts an anticipated outcome. ©Victoria Ritvo, Princeton University

Princeton neuroscientist James Antony decided to capitalize on these moments to study how human brains process surprise.

“We’re trying to figure out how people update their understanding of things that are occurring in the real world, based on how events unfold over time — how they set up these contextually-based predictions, and what happens when those are confirmed or contradicted,” said Antony, a CV Starr Fellow in Neuroscience and the first author on a paper published today in the journal Neuron.

The researchers observed 20 self-identified basketball fans as they watched the last five minutes of nine games from the 2012 men’s NCAA March Madness tournament. While they watched the games, a specialized camera tracked their eye movements and functional MRI scans measured their neural activity. The scientists chose basketball because the frequent scoring provided more opportunities to observe how the brain responded to changes.

“This study has both theoretical significance, in terms of testing and refining models of how surprise affects the brain and behavior, and also popular science appeal,” said Ken Norman, the senior author on the paper, who is the Huo Professor in Computational and Theoretical Neuroscience and the chair of the Department of Psychology. “Sporting events like the NCAA tournament are both incredibly compelling and also hyper-quantifiable — you can assess, moment-by-moment, exactly how probable an outcome will be, given what happened in previous games — making them an ideal domain for studying how cognitive processes like memory, event understanding and emotional responses work in the real world. James’ paper is the first to unlock the potential of this approach.”

At surprising moments in the March Madness games — key turnovers, last-minute three-pointers — a typical participant would register rapid pupil dilation and shifts in the pattern of activity in high-level areas of the brain areas like the prefrontal cortex.

“There’s a lot of nuance — it’s not like ‘Surprise is surprise is surprise is surprise,'” Antony said. “Different kinds of surprises have different effects that we observed in different brain systems.”

One interesting result was that shifts in the pattern of activity in high-level brain areas only happened at moments that contradicted the watchers’ current beliefs about which team was more likely to win. “This fits with the idea that patterns in these areas reflect the story of the game, and that the chapters of this story are defined by which team has momentum,” Norman said.

The researchers received help from legendary basketball statistician Ken Pomeroy to create a “win-probability graph,” a tracker for which team was most likely to win at any given moment. Sport websites and sports announcers have long used win-probability graphs to quantify the likely impact of any given turnover or basket.

What the scientists realized was that avid sports fans have an intuitive version of that graph in their heads, Antony said.

“You can tell this by the way people react to things,” he said. “We’re measuring it in this somewhat confined setting here, but if you imagine two friends watching a championship game, and there’s a huge moment, one might get so excited that they tackle their friend over the couch. That doesn’t happen at a moment that isn’t eventful or only has a minimal impact on the overall outcome.”

“People really do have win-probability graphs in their heads,” Norman said. “When the win-probability graph shifts in either direction, that leads to better memory for that part of the game, and it seems to affect pupillary response in addition to memory. There’s an interesting association between those things.”

Historically, neuroscientists studying surprise have created very stripped-down experiments to build a particular expectation, then violate it.

“As a field, we’ve been eager to see whether the principles that we’ve come up with — based on these very simplified scenarios — apply in real life,” Norman said. “The challenge is that in real life, it’s hard to pinpoint the moment when the surprise occurs, or how big the surprise was. Sports let us precisely quantify surprise in a real-world setting, giving us the perfect opportunity to see whether these ideas about surprise generalize outside of the lab.”

References: “Behavioral, physiological, and neural signatures of surprise during naturalistic sports viewing,” by James W. Antony, Thomas H. Hartshorne, Ken Pomeroy, Todd M. Gureckis, Uri Hasson, Samuel D. McDougle and Kenneth A. Norman appears in the Jan. 20, 2021 issue of Neuron, published online Nov. 25 (DOI: 10.1016/j.neuron.2020.10.029). https://www.cell.com/neuron/fulltext/S0896-6273(20)30853-9?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627320308539%3Fshowall%3Dtrue

Provided by Princeton University