NS/ Researchers demonstrate the brain’s adaptation to external stimulation for the first time
Neuroscience biweekly vol. 106, 13th March — 27th March
TL;DR
- For the first time, researchers at the University of Minnesota Twin Cities showed that non-invasive brain stimulation can change a specific brain mechanism that is directly related to human behavior. This is a major step forward in discovering new therapies to treat brain disorders such as schizophrenia, depression, Alzheimer’s disease, and Parkinson’s disease.
- The brain is an incredibly complex and active organ that uses electricity and chemicals to transmit and receive signals between its sub-regions. Researchers have explored various technologies to directly or indirectly measure these signals to learn more about the brain. Functional magnetic resonance imaging (fMRI), for example, allows them to detect brain activity via changes related to blood flow. A new study by the lab has confirmed their suspicions that fMRI interpretation is not as straightforward as it seems.
- Weill Cornell Medicine investigators discovered that unique bacteria colonize the gut shortly after birth and make the neurotransmitter serotonin to educate gut immune cells. This prevents allergic reactions to food and the bacteria themselves during early development.
- How do our brains snap to attention and orient us to the outside world — like when we’re sound asleep and the smoke alarm goes off? And when different choices confront us, how does our brain make decisions? Two groups of researchers at Boston Children’s explored these all-important brain operations.
- Hunger can drive a motivational state that leads an animal to a successful pursuit of a goal — foraging for and finding food. In a highly novel study, researchers describe how two major neuronal subpopulations in a part of the brain’s thalamus called the paraventricular nucleus participate in the dynamic regulation of goal pursuits. This research provides insight into the mechanisms by which the brain tracks motivational states to shape instrumental actions.
- Gait impairments often are prevalent in the early stages of cognitive decline. Researchers quantitatively compared straight walking and curved walking — a more natural yet complex activity — in healthy older adults and adults with mild cognitive impairment (MCI). A depth camera detected and tracked 25 joints of body movement and signals were processed to extract 50 gait markers. Intriguingly, curved walking illuminated notable disparities between the study groups. The non-invasive, low-cost, non-wearable and easy-setting depth camera system is a crucial step in enhancing patient care and intervention strategies.
- Researchers discovered a mechanism behind middle-age obesity in rat brains. They believe that a similar mechanism exists in humans as well. This discovery may lead to improvements in preventing obesity and metabolic syndrome.
- The stress-induced mechanisms that cause our brain to produce feelings of fear in the absence of threats — such as in PTSD — have been mostly a mystery. Now, neurobiologists have identified the changes in brain biochemistry and mapped the neural circuitry that causes generalized fear experiences.
- Researchers at the National Institutes of Health (NIH) have discovered that symptoms of attention-deficit/hyperactivity disorder (ADHD) are tied to atypical interactions between the brain’s frontal cortex and information-processing centers deep in the brain. The researchers examined more than 10,000 functional brain images of youth with ADHD and published their results in the American Journal of Psychiatry. The study was led by researchers at NIH’s National Institute of Mental Health (NIMH) and the National Human Genome Research Institute.
- Spending quality time with dogs reduces stress and increases the power of brain waves associated with relaxation and concentration, according to a study published in PLOS ONE by Onyoo Yoo from Konkuk University, South Korea, and colleagues.
- A new Apple patent suggests the company is developing technology that could integrate brainwave and biometric sensors into its Apple Vision Pro headset or future AR/VR devices, aiming to enhance mental and physical health.
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The latest news and research
Induced neural phase precession through exogenous electric fields
by Wischnewski M, Tran H, Zhao Z, et al. in Nature Communications
For the first time, researchers at the University of Minnesota Twin Cities showed that non-invasive brain stimulation can change a specific brain mechanism that is directly related to human behavior. This is a major step forward for discovering new therapies to treat brain disorders such as schizophrenia, depression, Alzheimer’s disease, and Parkinson’s disease.
Researchers used what is called “transcranial alternating current stimulation” to modulate brain activity. This technique is also known as neuromodulation. By applying a small electrical current to the brain, the timing of when brain cells are active is shifted. This modulation of neural timing is related to neuroplasticity, which is a change in the connections between brain cells that is needed for human behavior, learning, and cognition.
“Previous research showed that brain activity was time-locked to stimulation. What we found in this new study is that this relationship slowly changed and the brain adapted over time as we added in external stimulation,” said Alexander Opitz, University of Minnesota biomedical engineering associate professor. “This showed brain activity shifting in a way we didn’t expect.”
This result is called “neural phase precession.” This is when the brain activity gradually changes over time in relation to a repeating pattern, like an external event or in this case non-invasive stimulation. In this research, all three investigated methods (computational models, humans, and animals) showed that the external stimulation could shift brain activity over time.
“The timing of this repeating pattern has a direct impact on brain processes, for example, how we navigate space, learn, and remember,” Opitz said.
The discovery of this new technique shows how the brain adapts to external stimulation. This technique can increase or decrease brain activity, but is most powerful when it targets specific brain functions that affect behaviors. This way, long-term memory as well as learning can be improved. The long-term goal is to use this technique in the treatment of psychiatric and neurological disorders.
Opitz hopes that this discovery will help bring improved knowledge and technology to clinical applications, which could lead to more personalized therapies for schizophrenia, depression, Alzheimer’s disease, and Parkinson’s disease.
Distinct neurochemical influences on fMRI response polarity in the striatum
by Cerri DH, Albaugh DL, Walton LR, et al. in Nature Communications.
The brain is an incredibly complex and active organ that uses electricity and chemicals to transmit and receive signals between its sub-regions. Researchers have explored various technologies to directly or indirectly measure these signals to learn more about the brain. Functional magnetic resonance imaging (fMRI), for example, allows them to detect brain activity via changes related to blood flow. A new study by the lab has confirmed their suspicions that fMRI interpretation is not as straightforward as it seems.
Yen-Yu Ian Shih, PhD, professor of neurology and associate director of UNC’s Biomedical Research Imaging Center, and his fellow lab members have long been curious about how neurochemicals in the brain regulate and influence neural activity, blood flow, and subsequently, fMRI measurement in the brain.
“Neurochemical signaling to blood vessels is less frequently considered when interpreting fMRI data,” said Shih, who also leads the Center for Animal MRI. “In our study on rodent models, we showed that neurochemicals, aside from their well-known signaling actions to typical brain cells, also signal to blood vessels, and this could have significant contributions to fMRI measurements.”
Their findings, published in Nature Communications, stem from a $3.8-million grant from the National Institutes of Health and UNC’s investments in supporting the installation and upgrade of two 9.4-Tesla animal MRI systems and a 7-Tesla human MRI system at the Biomedical Research Imaging Center.
When activity in neurons increases in a specific brain region, blood flow and oxygen levels increase in the area, usually proportionate to the strength of neural activity. Researchers decided to use this phenomenon to their advantage and eventually developed fMRI techniques to detect these changes in the brain.
For years, this method has helped researchers better understand brain function and influenced their knowledge about human cognition and behavior. The new study from Shih’s lab, however, demonstrates that this well-established neuro-vascular relationship does not apply across the entire brain because cell types and neurochemicals vary across brain areas.
Shih’s team focused on the striatum, a region deep in the brain involved in cognition, motivation, reward, and sensorimotor function, to identify the ways in which certain neurochemicals and cell types in the brain region may be influencing fMRI signals.
For their study, Shih’s lab controlled neural activity in rodent brains using a light-based technique, while measuring electrical, optical, chemical, and vascular signals to help interpret fMRI data. The researchers then manipulated the brain’s chemical signaling by injecting different drugs into the brain and evaluated how the drugs influenced the fMRI responses.
They found that in some cases, neural activity in the striatum went up, but the blood vessels constricted, causing negative fMRI signals. This is related to internal opioid signaling in the striatum. Conversely, when another neurochemical, dopamine, predominated signaling in striatum, the fMRI signals were positive.
“We identified several instances where fMRI signals in the striatum can look quite different from expected,” said Shih. “It’s important to be mindful of underlying neurochemical signaling that can influence blood vessels or perivascular cells in parallel, potentially overshadowing the fMRI signal changes triggered by neural activity.”
Members of Shih’s lab, including first- and co-authors Dominic Cerri, PhD, and Lindsey Walton, PhD, travelled to the University of Sussex in the United Kingdom, where they were able to perform experiments and further demonstrate the opioid’s vascular effects.
They also collected human fMRI data at UNC’s 7-Tesla MRI system and collaborated with researchers at Stanford University to explore possible findings using transcranial magnetic stimulation, a procedure that uses magnetic fields to stimulate the human brain.
By better understanding fMRI signaling, basic science researchers and physician scientists will be able to provide more precise insights into neural activity changes in healthy brains, as well as in cases of neurological and neuropsychiatric disorders.
Gut bacteria–derived serotonin promotes immune tolerance in early life
by Sanidad KZ, Rager SL, Carrow HC, et al. in Science Immunology
Weill Cornell Medicine investigators discovered that unique bacteria colonize the gut shortly after birth and make the neurotransmitter serotonin to educate gut immune cells. This prevents allergic reactions to food and the bacteria themselves during early development.
The preclinical study, published in Science Immunology on Mar. 15, showed that bacteria abundant in the guts of newborns produce serotonin, which promotes the development of immune cells called T-regulatory cells or Tregs. These cells suppress inappropriate immune responses to help prevent autoimmune diseases and dangerous allergic reactions to harmless food items or beneficial gut microbes.
“The gut is now known as the second human brain as it makes over 90 percent of the neurotransmitters in the human body. While neurotransmitters such as serotonin are best known for their roles in brain health, receptors for neurotransmitters are located throughout the human body,” explained the study’s senior author, Dr. Melody Zeng, an assistant professor of immunology in the Gale and Ira Drukier Institute for Children’s Research and the Department of Pediatrics at Weill Cornell Medicine.
The researchers observed that the neonatal mouse gut had much higher levels of neurotransmitters, including serotonin, than the adult gut.
“So far, almost all studies of gut neurotransmitters were conducted in adult animals or human subjects, where a specific gut cell type called enterochromaffin cells produce neurotransmitters,” said Dr. Zeng. “However, we discovered that this isn’t the case in the newborn gut where most of the serotonin is made by bacteria that are more abundant in the neonatal gut.”
This was also confirmed in babies through a human infant stool biobank that the Zeng lab has established in collaboration with the Neonatal Intensive Care Unit in the NewYork-Presbyterian Alexandra Cohen Hospital for Women and Newborns. These samples were obtained with parental consent and deidentified.
The study results suggest that before the neonatal gut is mature enough to make its own neurotransmitters, unique gut bacteria may supply neurotransmitters that are needed for critical biological functions during early development.
“We found that gut bacteria in young mice not only directly produce serotonin but also decrease an enzyme called monoamine oxidase that normally breaks down serotonin, thus keeping gut serotonin levels high,” said the study’s lead author Dr. Katherine Sanidad, postdoctoral associate in pediatrics at Weill Cornell Medicine.
The high serotonin levels shift the balance of immune cells by increasing the number of Tregs, which helps prevent the immune system from overreacting and attacking gut bacteria or food antigens.
“The neonatal gut needs these serotonin-producing bacteria to keep the immune system in check,” Dr. Sanidad added.
Dr. Zeng noted that this work underscores the importance of having the right types of beneficial bacteria soon after birth. Babies in developed countries have better access to antibiotics, less exposure to diverse microbes in their clean environments and potentially unhealthy diets that may significantly impact the abundance of serotonin-producing bacteria in their intestines.
As a result, these babies may have fewer Tregs and develop immune reactions to their own gut bacteria, or allergies to food. This may be one reason food allergies have become increasingly common in children, particularly in developed countries.
“If educated properly, the immune system in babies would recognize that things like peanuts and eggs are okay, and it doesn’t have to attack them,” she said.
This may also have an impact on developing autoimmune diseases — when the immune system attacks the body’s own healthy cells — later in life.
The team next plans to look at bacteria in human infant stool samples to measure their production of serotonin, other neurotransmitters and molecules that may help train the immune system to prevent future immune-related diseases, such as allergies, infections and cancer.
“It’s essential to understand how the immune system is trained during early life, but this is understudied in newborns and children. Further studies of these developmental periods may hopefully lead us to mitigation approaches to reduce the risk of inflammatory diseases like food allergies and inflammatory bowel disease later in life,” Dr. Sanidad said.
Neural and behavioural state switching during hippocampal dentate spikes
by Farrell JS, Hwaun E, Dudok B, Soltesz I. in Nature
How do our brains snap to attention and orient us to the outside world — like when we’re sound asleep and the smoke alarm goes off? And when different choices confront us, how does our brain make decisions? Two groups of researchers at Boston Children’s explored these all-important brain operations.
The first study, published in Nature, explored how the brain is organized to guide our choices.
“We wanted to understand how neurons are connected to one another in brain areas important for decision-making,” says Wei-Chung Allen Lee, PhD, a researcher with the F.M. Kirby Neurobiology Center at Boston Children’s. Lee co-led the study with Christopher Harvey, PhD, at Harvard Medical School and Stefano Panzeri, PhD, at University Medical Center Hamburg-Eppendorf.
The researchers focused on the posterior parietal cortex, an “integrative hub” that processes information gathered by multiple senses. Studying mice, they recorded brain activity as the animals chose which path to take in a maze to get to a reward (after receiving a clue). Using powerful microscopes, Lee’s lab mapped the network of connections between the neurons involved in navigating to the reward.
“We’re looking for rules of connectivity — simple principles that provide a foundation for the brain’s computations as it makes decisions,” Lee says.
When a mouse chose to turn right, a specific set of excitatory “right turn” neurons fired, they found. These neurons activated a set of inhibitory neurons that curbed activity in “left-turn” neurons — solidifying the choice to turn right. When a mouse decided to turn left, the opposite scenario played out. The researchers now hope to confirm these findings in the human brain.
The second study, led by Jordan Farrell, PhD, focused on how brains that have been zoning out wake up and focus when a situation demands it.
“We have found a brain mechanism for breaking up periods of mind wandering and realigning the ‘cognitive map’ back to reality,” says Farrell, an investigator in the F.M. Kirby Neurobiology Center and Rosamund Stone Zander Translational Neuroscience Center.
During sleep or periods of daydreaming, our brains replay past events in a form of synchronized activity called the “sharp-wave ripple.” This enables us to consolidate our memories.
Analyzing data from a mouse model, Farrell and colleagues from the laboratory of Ivan Soltesz, PhD, at Stanford University began exploring another, little-known neuronal activity pattern: synchronized spikes of firing in the dentate gyrus, part of the hippocampus. These spikes, they found, occur when an “offline” brain is aroused. They may help us quickly process new information and orient ourselves to what’s happening in our environment — like when the teacher suddenly called on us while we were daydreaming in class.
But dentate spikes also seem to promote associative memory — in which a sensory stimulus (say, a series of piercing beeps) is stored as a memory, so that we come to associate the noise with a smoke alarm going off and the possible need to evacuate.
Sharp-wave ripples and dentate spikes may have complementary roles, Farrell says. “The brain is toggling through these two states.”
This new knowledge about dentate spikes could open windows into some neuropsychiatric disorders. Perhaps dentate spikes affect attention and arousal in people with ADHD or post-traumatic stress. Or maybe they are altered in Alzheimer’s, disrupting formation of new memories.
Farrell is most interested in epilepsy, which is marked by synchronized spikes of excessive neuron firing. He plans to investigate the role of dentate spikes by better understanding their basic mechanisms and then manipulating the neural networks that control dentate spikes in the brains of epileptic mice. He also hopes to extend the study to children with epilepsy, in collaboration with clinicians at Boston Children’s.
“In people with epilepsy, the synchronous activity during dentate spikes could tip the brain into a pathological state,” Farrell speculates. “The dentate spikes add an extra push to the system.”
Dissociable encoding of motivated behavior by parallel thalamo-striatal projections
by Sofia Beas, Isbah Khan, Claire Gao, Gabriel Loewinger, Emma Macdonald, Alison Bashford, Shakira Rodriguez-Gonzalez, Francisco Pereira, Mario A. Penzo in Current Biology
Hunger can drive a motivational state that leads an animal to a successful pursuit of a goal — foraging for and finding food.
In a highly novel study published in Current Biology, researchers at the University of Alabama at Birmingham and the National Institute of Mental Health, or NIMH, describe how two major neuronal subpopulations in a part of the brain’s thalamus called the paraventricular nucleus participate in the dynamic regulation of goal pursuits. This research provides insight into the mechanisms by which the brain tracks motivational states to shape instrumental actions.
For the study, mice first had to be trained in a foraging-like behavior, using a long, hallway-like enclosure that had a trigger zone at one end and a reward zone at the other end, more than 4 feet distant.
Mice learned to wait in a trigger zone for two seconds, until a beep triggered initiation of their foraging-like behavioral task. A mouse could then move forward at its own pace to the reward zone to receive a small gulp of strawberry-flavored Ensure. To terminate the trial, the mice needed to leave the reward zone and return to the trigger area, to wait for another beep. Mice learned quickly and were highly engaged, as shown by completing a large volume of trials during training.
The researchers then used optical photometry and the calcium sensor GCaMP to continuously monitor activity of two major neuronal subpopulations of the paraventricular nucleus, or PVT, during the reward approach from the trigger zone to the reward zone, and during the trial termination from the reward zone back to the trigger zone after a taste of strawberry-flavored food. The experiments involve inserting an optical fiber into the brain just about the PVT to measure calcium release, a signal of neural activity.
The two subpopulations in the paraventricular nucleus are identified by presence or absence of the dopamine D2 receptor, noted as either PVTD2(+) or PVTD2(-), respectively. Dopamine is a neurotransmitter that allows neurons to communicate with each other.
“We discovered that PVTD2(+) and PVTD2(-) neurons encode the execution and termination of goal-oriented actions, respectively,” said Sofia Beas, Ph.D., assistant professor in the UAB Department of Neurobiology and a co-corresponding author of the study. “Furthermore, activity in the PVTD2(+) neuronal population mirrored motivation parameters such as vigor and satiety.”
Specifically, the PVTD2(+) neurons showed increased activity during the reward approach and decreased activity during trial termination. Conversely, PVTD2(-) neurons showed decreased activity during the reward approach and increased activity during trial termination.
“This is novel because people didn’t know there was diversity within the PVT neurons,” Beas said. “Contrary to decades of belief that the PVT is homogeneous, we found that, even though they are the same types of cells (both release the same neurotransmitter, glutamate), PVTD2(+) and PVTD2(-) neurons are doing very different jobs. Additionally, the findings from our study are highly significant as they help interpret contradictory and confusing findings in the literature regarding PVT’s function.”
For a long time, the thalamic areas such as the PVT had been considered just a relay station in the brain. Researchers now realize, Beas says, that the PVT instead processes information, translating hypothalamic-derived needs states into motivational signals via projections of axons — including the PVTD2(+) and PVTD2(-) axons — to the nucleus accumbens, or NAc. The NAc has a critical role in the learning and execution of goal-oriented behaviors. An axon is a long cable-like extension from a neuron cell body that transfers the neuron’s signal to another neuron.
Researchers showed that these changes in neuron activity at the PVT were transmitted to the NAc by measuring neural activity with an optical fiber inserted where the terminals of the PVT axons reach the NAc neurons. The activity dynamics at the PVT-NAc terminals largely mirrored the activity dynamics the researchers saw at the PVT neurons — namely increased neuron activity signal of PVTD2(+) during reward approach and increased neuron activity of PVTD2(-) during trial termination.
“Collectively, our findings strongly suggest that motivation-related features and the encoding of goal-oriented actions of posterior PVTD2(+) and PVTD2(-) neurons are being relayed to the NAc through their respective terminals,” Beas said.
During each mouse recording session, the researchers recorded eight to 10 data samples per second, resulting in a very big dataset. In addition, these types of recordings are subject to many potential confounding variables. As such, the analysis of this data was another novel aspect of this study, through use of a new and robust statistical framework based on Functional Linear Mixed Modeling that both account for the variability of the recordings and can explore the relationships between the changes of photometry signals over time and various co-variates of the reward task, such as how quickly mice performed a trial, or how the hunger levels of the animals can influence the signal.
One example of how researchers correlated motivation with task performance was separating the trial times into “fast” groups, two to three seconds to the reward zone from the trigger zone, and “slow” groups, nine to 11 seconds to the reward zone.
“Our analyses showed that reward approach was associated with higher calcium signal ramps in PVTD2(+) neurons during fast compared to slow trials,” Beas said. “Moreover, we found a correlation between signal and both latency and velocity parameters. Importantly, no changes in posterior PVTD2(+) neuron activity were observed when mice were not engaged in the task, as in the cases where mice were roaming around the enclosure but not actively performing trials. Altogether, our findings suggest that posterior PVTD2(+) neuron activity increases during reward-seeking and is shaped by motivation.”
Deficits in motivation are associated with psychiatric conditions like substance abuse, binge eating and the inability to feel pleasure in depression. A deeper understanding of the neural basis of motivated behavior may reveal specific neuronal pathways involved in motivation and how they interact. This could lead to new therapeutic targets to restore healthy motivational processes in patients.
Curve Walking Reveals More Gait Impairments in Older Adults with Mild Cognitive Impairment than Straight Walking: A Kinect Camera-Based Study
by Mahmoud Seifallahi, James E. Galvin, Behnaz Ghoraani in Journal of Alzheimer’s Disease Reports
A first-of-its-kind study suggests that to detect subtle gait impairments in older adults that often are prevalent in the early stages of cognitive decline, “throw them a curve.”
Gait analysis, examining the way an individual stands and walks, is emerging as a valuable, non-invasive complement to cognitive assessments that aid in early diagnosis and management. In clinical settings, gait and balance tests typically focus on a straight walking path.
This new study ventures into a different realm — curved path walking — a more natural yet complex activity. Straight walking is a rhythmic and simpler activity, whereas walking on a curving path requires greater cognitive and motor skills such as a transition time to change directions and correct balance.
College of Engineering and Computer Science researchers at Florida Atlantic University are the first to quantitatively compare the performance of healthy older adults versus older adults with mild cognitive impairment (MCI) in straight and curve walking. MCI is the early stage of cognitive decline and people with MCI have a much higher risk of transitioning to Alzheimer’s disease (AD).
For the study, researchers used a depth camera, which can detect and track 25 joints of body movement, to record study participants’ gait while performing the two different walking tests (straight versus curve). Signals from the 25 body joints were processed to extract 50 gait markers for each test, and these markers were compared between the two groups using descriptive statistical analyses.
Results, published in the Journal of Alzheimer’s Disease Reports, showed curve walking resulted in greater challenges for the MCI group and outperformed straight walking in detecting MCI. Furthermore, several gait markers showed significant differences between healthy controls and MCI patients.
Findings showed that 31 out of 50 gait markers (62 percent) were greater for the MCI group than healthy control older adults when the walking tests changed from straight walking to curve walking, and 13 markers showed significant differences between the two study groups.
“Intriguingly, curved walking illuminated notable disparities between our study groups, even for these macro gait markers. The MCI group exhibited a markedly lower average step length and speed during curve walking, coupled with higher variability across most micro-gait markers,” said Behnaz Ghoraani, Ph.D., senior author, an associate professor, FAU Department of Electrical Engineering and Computer Science, co-director of the FAU Center for SMART Health, and a fellow, FAU Institute for Sensing and Embedded Network Systems Engineering (I-SENSE). “The MCI group showed diminished symmetry and regularity in both step and stride lengths for curved walking. They also required extended double support time in various areas, especially while changing directions, which resulted in reduced step speed.”
Study findings did not show any significant differences in age and gender distribution between the two groups. However, the two groups had significant differences in body mass index (BMI), years of education and Geriatric Depression Scale (GDS) scores. Participants with MCI had a higher BMI, lower levels of education and higher GDS scores than the healthy older adults.
“Mild cognitive impairment can be an early sign of Alzheimer’s disease and other types of dementia,” said Ghoraani. “Our comprehensive approach enhances the understanding of gait characteristics and suggests curved path walking may be more sensitive to detect mild cognitive dementia, which can complement cognitive assessments and aid in early diagnosis and management.”
AD typically manifests as a decline in cognitive function with a gradual decline in an individual’s ability to perform daily activities such as walking. Accurate and early clinical detection of AD remains a challenge. Typical clinical evaluations include a detailed history, comprehensive physical and neurological examination, cognitive testing, blood work and brain imaging. However, depending on the clinical setting, these methods can be time-consuming, costly and outside some clinicians’ comfort level.
The study fills this gap by using a novel system to record gait in older adults employing a non-invasive, low-cost, non-wearable and easy-setting depth camera, which is a crucial step in enhancing patient care and intervention strategies.
“These gait markers offer a promising potential as early indicators of cognitive impairment and lay the foundational groundwork for expansive research in this domain,” said Stella Batalama, Ph.D., dean, FAU College of Engineering and Computer Science. “Impacts from this study also extend to clinical practice by providing improved methods for screening and monitoring that can be easily replicated with minimal costs and time in the clinic setting.”
Age-related ciliopathy: Obesogenic shortening of melanocortin-4 receptor-bearing neuronal primary cilia
by Manami Oya, Yoshiki Miyasaka, Yoshiko Nakamura, Miyako Tanaka, Takayoshi Suganami, Tomoji Mashimo, Kazuhiro Nakamura in Cell Metabolism
Nagoya University researchers and their colleagues in Japan have found that middle-age obesity is caused by age-related changes in the shape of neurons in the hypothalamus, a region of the brain that controls metabolism and appetite.
A protein called melanocortin-4 receptor (MC4R) detects overnutrition and regulates metabolism and appetite to prevent obesity. According to their study in rats, MC4Rs were concentrated in primary cilia (antenna-like structures) that extend from a couple of groups of hypothalamic neurons. The study also showed that the primary cilia became shorter with age, which decreased MC4Rs accordingly, resulting in weight gain.
“We believe that a similar mechanism exists in humans as well,” said Professor Kazuhiro Nakamura of the Nagoya University Graduate School of Medicine, the lead author of the study. “We hope our finding will lead to a fundamental treatment for obesity.”
As we get older, we become more prone to being overweight and obesity. Obese people are more susceptible to diabetes, hyperlipidemia, and other chronic diseases. Previous studies have suggested that middle-age weight gain is caused by a decline in overall metabolism due to aging, but the mechanism was unclear.
A research team of the Nagoya University Graduate School of Medicine, in collaboration with researchers from Osaka University, the University of Tokyo, and the Nagoya University Research Institute of Environmental Medicine, conducted a study focusing on MC4Rs.
MC4Rs stimulate metabolism and suppress food intake in response to an overeating signal from melanocortin. Initially, the research team examined the distribution of MC4Rs in the rat brain by utilizing an antibody they had developed specifically to make MC4Rs visible. They found that MC4Rs are present exclusively in primary cilia of specific groups of hypothalamic neurons.
The team next investigated the length of the primary cilia that had MC4Rs (MC4R+ cilia) in the brains of 9-week-old (young) rats and 6-month-old (middle-age) rats. The team found that MC4R+ cilia in middle-aged rats were significantly shorter than those in young rats. Accordingly, the metabolism and the fat-burning capacity of middle-aged rats were much lower than those of young rats.
The team next analyzed MC4R+ cilia in rats under different dietary conditions. The results showed that MC4R+ cilia in rats on a normal diet gradually shortened with age. On the other hand, MC4R+ cilia in rats on a high-fat diet shortened at a faster pace, while those in rats on a restricted diet shortened at a slower pace.
Interestingly, the team also found that MC4R+ cilia that once disappeared with age were regenerated in rats raised under two months of dietary restriction.
In the study, the team also used genetic technologies to make MC4R+ cilia shorter in young rats. These rats showed increased food intake and decreased metabolism, leading to weight gain.
The team also administered a hormone called leptin to the brains of rats with artificially shortened MC4R+ cilia. Leptin is thought to help reduce food intake. Surprisingly, however, their appetite was not reduced, indicating that leptin could not exert anti-obesity effects.
“This phenomenon, called leptin resistance, is often observed in obese human patients as well. This is an obstacle to the treatment of obesity, but the cause has long been unknown,” explained Dr. Manami Oya, the first author of the study.
“In obese patients, adipose tissue secretes excessive leptin, which triggers the chronic action of melanocortin. Our study suggests that this may promote the age-related shortening of MC4R+ cilia and put animals into a downward spiral where melanocortin becomes ineffective, increasing the risk of obesity.”
The study concluded that the age-related shortening of MC4R+ cilia causes middle-age obesity and leptin resistance in rats. The researchers demonstrated that dietary restriction is one method to prevent and treat overweight and obesity.
Prof. Nakamura said, “Moderate eating habits could maintain MC4R+ cilia long enough to keep the brain’s anti-obesity system in good shape even as we age.”
Generalized fear after acute stress is caused by change in neuronal cotransmitter identity
by Hui-quan Li, Wuji Jiang, Li Ling, Marta Pratelli, Cong Chen, Vaidehi Gupta, Swetha K. Godavarthi, Nicholas C. Spitzer in Science
Our nervous systems are naturally wired to sense fear. Whether prompted by the eerie noises we hear alone in the dark or the approaching growl of a threatening animal, our fear response is a survival mechanism that tells us to remain alert and avoid dangerous situations.
But if fear arises in the absence of tangible threats, it can be harmful to our well-being. Those who have suffered episodes of severe or life-threatening stress can later experience intense feelings of fear, even during situations that lack a real threat. Experiencing this generalization of fear is psychologically damaging and can result in debilitating long-term mental health conditions such as post-traumatic stress disorder (PTSD).
The stress-induced mechanisms that cause our brain to produce feelings of fear in the absence of threats have been mostly a mystery. Now, neurobiologists at the University of California San Diego have identified the changes in brain biochemistry and mapped the neural circuitry that cause such a generalized fear experience. Their research, published in the journal Science, provides new insights into how fear responses could be prevented.
In their report, former UC San Diego Assistant Project Scientist Hui-quan Li, (now a senior scientist at Neurocrine Biosciences), Atkinson Family Distinguished Professor Nick Spitzer of the School of Biological Sciences and their colleagues describe the research behind their discovery of the neurotransmitters — the chemical messengers that allow the brain’s neurons to communicate with one another — at the root of stress-induced generalized fear.
Studying the brains of mice in an area known as the dorsal raphe (located in the brainstem), the researchers found that acute stress induced a switch in the chemical signals in the neurons, flipping from excitatory “glutamate” to inhibitory “GABA” neurotransmitters, which led to generalized fear responses.
“Our results provide important insights into the mechanisms involved in fear generalization,” said Spitzer, a member of UC San Diego’s Department of Neurobiology and Kavli Institute for Brain and Mind. “The benefit of understanding these processes at this level of molecular detail — what is going on and where it’s going on — allows an intervention that is specific to the mechanism that drives related disorders.”
Building upon this new finding of a stress-induced switch in neurotransmitters, considered a form of brain plasticity, the researchers then examined the postmortem human brains of individuals who had suffered from PTSD. A similar glutamate-to-GABA neurotransmitter switch was confirmed in their brains as well.
The researchers next found a way to stop the production of generalized fear. Prior to the experience of acute stress, they injected the dorsal raphe of the mice with an adeno-associated virus (AAV) to suppress the gene responsible for synthesis of GABA. This method prevented the mice from acquiring generalized fear.
Further, when mice were treated with the antidepressant fluoxetine (branded as Prozac) immediately after a stressful event, the transmitter switch and subsequent onset of generalized fear were prevented.
Not only did the researchers identify the location of the neurons that switched their transmitter, but they demonstrated the connections of these neurons to the central amygdala and lateral hypothalamus, brain regions that were previously linked to the generation of other fear responses.
“Now that we have a handle on the core of the mechanism by which stress-induced fear happens and the circuitry that implements this fear, interventions can be targeted and specific,” said Spitzer.
Subcortico-cortical dysconnectivity in ADHD: a voxel-wise mega-analysis across multiple cohorts
by Norman LJ, Sudre G, Price J, Shaw P in AJP
Researchers at the National Institutes of Health (NIH) have discovered that symptoms of attention-deficit/hyperactivity disorder (ADHD) are tied to atypical interactions between the brain’s frontal cortex and information processing centers deep in the brain. The researchers examined more than 10,000 functional brain images of youth with ADHD and published their results in the American Journal of Psychiatry. The study was led by researchers at NIH’s National Institute of Mental Health (NIMH) and National Human Genome Research Institute.
Luke Norman, Ph.D., a staff scientist in the NIMH Office of the Clinical Director, and colleagues analyzed brain images supplied by more than 8,000 youth with and without ADHD sourced from six different functional imaging datasets. Using these images, the researchers examined associations between functional brain connectivity and ADHD symptoms.
They found that youth with ADHD had heightened connectivity between structures deep in the brain involved in learning, movement, reward, and emotion (caudate, putamen, and nucleus accumbens seeds) and structures in the frontal area of the brain involved in attention and control of unwanted behaviors (superior temporal gyri, insula, inferior parietal lobe, and inferior frontal gyri).
While neuroscience researchers have long suspected that ADHD symptoms result from atypical interactions between the frontal cortex and these deep information-processing brain structures, studies testing this model have returned mixed findings, possibly due to the small nature of the studies, with only 100 or so subjects. Researchers suggest that the smaller studies may not have been able to reliably detect the brain interactions leading to the complex behaviors seen in ADHD.
The findings from this study help further our understanding of the brain processes contributing to ADHD symptoms — information that can help inform clinically relevant research and advancements.
Psychophysiological and emotional effects of human–Dog interactions by activity type: An electroencephalogram study
by Yoo O, Wu Y, Park SA, Han JS in PLOS ONE.
Spending quality time with dogs reduces stress and increases the power of brain waves associated with relaxation and concentration, according to a study published in the open-access journal PLOS ONE by Onyoo Yoo from Konkuk University, South Korea, and colleagues.
Animal-assisted interventions, like canine therapy, are widely used in hospitals, schools, and beyond to help reduce anxiety, relieve stress, and foster feelings of trust. Studies of the potential benefits of animal interactions often take a holistic approach, comparing people’s mood or hormone levels before and after spending time with a service animal. But this approach doesn’t differentiate between types of interactions, like grooming, feeding, or playing with an animal, limiting our understanding of how each specific interaction impacts a person’s health and well-being. To better understand how such animal-related activities affect mood, Yoo and colleagues recruited a small sample of 30 adult participants to each perform eight different activities with a well-trained dog, such as playing with a hand-held toy, giving her treats, and taking pictures with her. Participants wore electroencephalography (EEG) electrodes to record electrical activity from the brain while they interacted with the dog, and they recorded their subjective emotional state immediately following each activity.
The relative strength of alpha-band oscillations in the brain increased while participants played with and walked the dog, reflecting a state of relaxed wakefulness. When grooming, gently massaging, or playing with the dog, relative beta-band oscillation strength increased, a boost typically linked to heightened concentration. Participants also reported feeling significantly less fatigued, depressed, and stressed after all dog-related activities.
While not all participants had pets of their own, their fondness for animals likely motivated their willingness to participate in the experiment, potentially biasing the results. Nonetheless, the authors state that the unique relationships between specific activities and their physiological effects could serve as a reference for programming targeted animal-assisted interventions in the future.
The authors add: “This study provides valuable information for elucidating the therapeutic effects and underlying mechanisms of animal-assisted interventions.”
Apple patent points to brainwave sensors for headset
A new Apple patent suggests the company is developing technology that could integrate brainwave and biometric sensors into its Apple Vision Pro headset or future AR/VR devices, aiming to enhance mental and physical health. The patent outlines a brain-computer interface capable of monitoring various bodily systems, including heart, lungs, and brain activity, to support mental health, mindfulness, and physical training without directly reading thoughts.
The envisioned sensors could offer new insights into a user’s health and activity, akin to how the Apple Watch tracks physical metrics. Applications could range from aiding trauma therapy to assisting individuals with neurodivergent learning.
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