NS/ Lottery-loving rats reveal how the brain handles uncertainty
Neuroscience biweekly vol. 97, 25th October — 8th November
TL;DR
- Whether we decide to gamble our money or safely invest involves carefully calculating future risks. Studying how the brain weighs up this uncertainty has been a significant challenge. Animal research is needed to dig down into these mechanisms, but designing experiments that involve complicated economic decisions has hitherto required non-human primates as test subjects. With the use of these highly intelligent animals in research becoming more regulated, new ways of exploring the uncertain brain have been required. Now, a new study details an ingenious task that explores how rats weigh up complex economic decisions.
- A new study substantiates previous groundbreaking research that rumination (overthinking) can be reduced through an intervention called Rumination-focused Cognitive Behavioral Therapy (RF-CBT). In addition, fMRI technology allowed researchers to observe correlated shifts in the brain connectivity associated with overthinking.
- Scientists describe a new kind of neurochemical wave in the brain. Their research unveils the existence of traveling waves of the neurochemical acetylcholine in the striatum, a brain region responsible for motivating actions and habitual behaviors.
- Imperial researchers have discovered a hidden mechanism within hair follicles that allows us to feel touch.
- In a scientific first, researchers have established a close link between brain activity and a maturation process called cortical thinning.
- Hospital nurseries routinely place soft bands around the tiny wrists of newborns that hold important identifying information such as name, sex, mother, and birth date. Researchers at Rockefeller University are taking the same approach with newborn brain cells — but these neonates will keep their ID tags for life, so that scientists can track how they grow and mature, as a means for better understanding the brain’s aging process.
- Most people who have pulled an all-nighter are all too familiar with that ‘tired and wired’ feeling. Although the body is physically exhausted, the brain feels slap-happy, loopy, and almost giddy. Now, neurobiologists have uncovered what produces this punch-drunk effect. In a new study, researchers induced mild, acute sleep deprivation in mice and then examined their behaviors and brain activity. Not only did dopamine release increase during the acute sleep loss period but synaptic plasticity also was enhanced — literally rewiring the brain to maintain the bubbly mood for the next few days.
- New research found that daily strawberry consumption could help reduce the risk of dementia for certain middle-aged populations.
- Brain health in those over 50 deteriorated more rapidly during the pandemic, even if they didn’t have COVID-19, according to major new research linking the pandemic to sustained cognitive decline.
- In a mouse study designed to explore the impact of marijuana’s major psychoactive compound, THC, on teenage brains, researchers say they found changes to the structure of microglia, which are specialized brain immune cells, that may worsen a genetic predisposition to schizophrenia.
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The latest news and research
The rat frontal orienting field dynamically encodes value for economic decisions under risk
by Dubroqua S, Erlich JC. T, Bao C, Zhu X, Mōller-Mara J, Li J in Nature Neuroscience
Whether we decide to gamble our money or safely invest involves carefully calculating future risks. Studying how the brain weighs up this uncertainty has been a significant challenge. Animal research is needed to dig down into these mechanisms, but designing experiments that involve complicated economic decisions has hitherto required non-human primates as test subjects. With the use of these highly intelligent animals in research becoming more regulated, new ways of exploring the uncertain brain have been required. Now, a new study details an ingenious task that explores how rats weigh up complex economic decisions.
The study, led by Jeffrey Erlich, group leader at the Sainsbury Wellcome Centre, offered rats a choice between a small and guaranteed reward called a “surebet” and a lottery, which had a range of rewards with a fixed probability. Over a period of around a month, the team managed to teach the rats what the value of the lottery would be, based on a sound that was played to them.
As expected, the rats quickly learned that a sound indicating a very low or zero lottery reward should make them choose the surebet, while a sound indicating a high reward sent them scampering towards the lottery.
Erlich and team carefully monitored the rodents’ brains while they completed the task, studying their frontal and parietal lobes. In particular, they were focused on two brain areas called the frontal orienting field (FOF) and posterior parietal cortex (PPC). The FOF is the rodent equivalent of a primate brain structure called the frontal eye field.
“That part of the primate brain is really important for spatial attention, and planning and orienting movements,” says Erlich in an interview with Technology Networks.
In rodents, the FOF plays a central role in the behavioral task that Erlich’s team designed. The mice, upon hearing the sound cue, would have to move either left or right to get to the lottery or surebet.
“If you record from neurons in this brain area, you can predict which movement the animal will make at the time of the sound. It encodes upcoming movement,” explains Erlich. But that wasn’t the whole story.
“We could actually see the quality of the lottery in the activity,” explains Erlich.
When the FOF was silenced — an effect achieved using drugs and gene modifications — the rodents seemed to lose their appetite for risk. When a high-reward lottery was on offer, the rodents still picked it, but became more reticent to go after an intermediate-level lottery reward, preferring the safety of the surebet. They remained uninterested in a low lottery reward. Importantly, the researchers played the tone continuously until the rats made their choice, meaning that they were not required to use their working memory during the task. This enabled Erlich’s team to disentangle the effects of FOF silencing on decision-making from its impact on memory, which previous study designs had been unable to separate.
Silencing the PPC had a much smaller and more short-lived effect on risk tolerance — something that had previously been seen in primates. While the exact influence of the PPC remains mysterious, Erlich is animated about the possibilities that his team’s findings show:
“It’s confirming that there are these kinds of similarities across species. In the rodent, we can now actually do many more careful circuit experiments to try and understand why the effect is short-lived. Whereas in the monkey, it would be kind of hopeless to try to understand this short-lived effect.”
While Erlich reckons those further experiments will be taken up by other groups, his team hopes to further explore the neural basis of choice. The applications of this work are myriad — it could help us understand why people vote for poor political candidates or why they get tricked into buying overpriced TVs.
Rumination-Focused Cognitive Behavioral Therapy Reduces Rumination and Targeted Cross-network Connectivity in Youth With a History of Depression: Replication in a Preregistered Randomized Clinical Trial
by Scott A. Langenecker, Mindy Westlund Schreiner, Katie L. Bessette, Henrietta Roberts, Leah Thomas, Alina Dillahunt, Stephanie L. Pocius, Daniel A. Feldman, Dave Jago, Brian Farstead, Myah Pazdera, Erin Kaufman, Jennica A. Galloway, Patricia K. Kerig, Amanda Bakian, Robert C. Welsh, Rachel H. Jacobs, Sheila E. Crowell, Edward R. Watkins in Biological Psychiatry Global Open Science
A new study from The Ohio State University Wexner Medical Center and College of Medicine, University of Utah and University of Exeter (UK) substantiates previous groundbreaking research that rumination (overthinking) can be reduced through an intervention called Rumination-focused Cognitive Behavioral Therapy (RF-CBT). In addition, the use of fMRI technology allowed researchers to observe correlated shifts in the brain connectivity associated with overthinking.
“We know adolescent development is pivotal. Their brains are maturing, and habits are forming. Interventions like RF-CBT can be game-changers, steering them towards a mentally healthy adulthood. We were particularly excited that the treatment seemed developmentally appropriate and was acceptable and accessible via telehealth during the early pandemic,” said corresponding author Scott Langenecker, PhD, vice chair of research in the Department of Psychiatry and Behavioral Health at Ohio State, who started this project while at the University of Utah.
RF-CBT is a promising approach pioneered by Ed Watkins, PhD, professor of experimental and applied Clinical Psychology at the University of Exeter. It has been shown to be effective among adults with recurrent depression.
“We wanted to see if we could adapt it for a younger population to prevent the ongoing burden of depressive relapse,” said Rachel Jacobs, PhD, adjunct assistant professor of psychiatry and behavioral sciences at Northwestern University who conducted the pilot study in 2016.
“As a clinician, I continued to observe that standard CBT tools such as cognitive restructuring didn’t give young people the tools to break out of the painful mental loops that contribute to experiencing depression again. If we could find a way to do that, maybe we could help young people stay well as they transition to adulthood, which has become even more important since we’ve observed the mental health impact of COVID-19,” Jacobs said.
In the just published trial, 76 teenagers, ages 14–17, with a history of depression were randomly assigned to 10–14 sessions of RF-CBT, while controls were allowed and encouraged to receive any standard treatment. Teens reported ruminating significantly less if they received RF-CBT. Even more intriguing, fMRI illustrated shifts in brain connectivity, marking a change at the neural level.
Specifically, there was a reduction in the connection between the left posterior cingulate cortex and two other regions; the right inferior frontal gyrus and right inferior temporal gyrus. These zones, involved in self-referential thinking and emotional stimuli processing, respectively, suggest RF-CBT can enhance the brain’s ability to shift out of the rumination habit. Notably, this work is a pre-registered replication; it demonstrates the same brain and clinical effects in the Utah sample in 2023 that was first reported in the Chicago sample in 2016.
“For the first time, this paper shows that the version of rumination-focused CBT we have developed at the University of Exeter leads to changes in connectivity in brain regions in adolescents with a history of depression relative to treatment as usual. This is exciting, as it suggests the CBT either helps patients to gain more effortless control over rumination or makes it less habitual. We urgently need new ways to reduce rumination in this group in order to improve the mental health of our young people,” Watkins said.
Next, the researchers will focus on demonstrating the efficacy of RF-CBT in a larger sample with an active treatment control, including continued work at Ohio State, Nationwide Children’s Hospital, University of Exeter, University of Utah and the Utah Center for Evidence Based Treatment. Future directions include bolstering access to teens in clinical settings and enhancing the ways we can learn about how this treatment helps youth with similar conditions.
“Our paper suggests a science-backed method to break the rumination cycle and reinforces the idea that it’s never too late or too early to foster healthier mental habits. Our research team thanks the youths and families who participated in this study for their commitment and dedication to reducing the burden of depression through science and treatment, particularly during the challenges of a global pandemic,” Langenecker said.
Acetylcholine waves and dopamine release in the striatum
by Lior Matityahu, Naomi Gilin, Gideon A. Sarpong, Yara Atamna, Lior Tiroshi, Nicolas X. Tritsch, Jeffery R. Wickens, Joshua A. Goldberg in Nature Communications,
In a new study, a group of researchers, led by Dr. Joshua Goldberg from the Hebrew University, describe a new kind of neurochemical wave in the brain. Their research, published in Nature Communications, unveils the existence of traveling waves of the neurochemical acetylcholine in the striatum, a region of the brain responsible for motivating actions and habitual behaviors.
The motivation to execute an action is widely thought to depend on the release of another neurochemical, dopamine, in the striatum. Recent research has shown that dopamine is released in wave-like patterns within the striatum. The team led by Goldberg discovered that acetylcholine is also released in the striatum in wave-like patterns. It has long been thought that in order for the striatum to function properly a balance needs to be maintained between dopamine and acetylcholine release in the striatum and that the disruption of this balance leads to movement disorders such as Parkinson’s disease. The new study proposes a mathematical mechanism by which simultaneous waves of acetylcholine and dopamine arise, which may represent how this balance is realized.
The research was conducted using state-of-the-art genetic tools and advanced imaging techniques, allowing the team to visualize the acetylcholine waves in awake, behaving animals. Additionally, imaging techniques were employed to observe the interaction between acetylcholine and dopamine in vitro. Through a rigorous mathematical analysis, using reaction-diffusion activator-inhibitor models and computer simulations, the team proposed a model that explains the formation of both acetylcholine (the activator) and dopamine (the inhibitor) traveling waves.
Key Highlights of the Study:
- The first description of acetylcholine waves: in the striatum of healthy behaving animals.
- Local Dopamine Release is Triggered by individual non-dopamine neurons: The study demonstrated that electrical activation of a single acetylcholine-releasing neuron in the striatum is sufficient to induce local dopamine release in its proximity.
- A novel model for how the two neurochemical waves arise simultaneously: The study proposes a novel mathematical model based on the known interaction between acetylcholine and dopamine in the striatum, that can give rise to the simultaneous generation of these waves.
- Finally, the study provides strong testable predictions about the relationship between these two wave phenomena and the neural mechanism for their formation. The study also proposes that dopamine and acetylcholine axons (which are the very long appendages of the dopamine and acetylcholine neurons) interact directly and locally in the striatum, which is not how neurons are traditionally thought to interact.
Mechanical stimulation of human hair follicle outer root sheath cultures activates adjacent sensory neurons
by Julià Agramunt, Brenna Parke, Sergio Mena, Victor Ubels, Francisco Jimenez, Greg Williams, Anna DY Rhodes, Summik Limbu, Melissa Hexter, Leigh Knight, Parastoo Hashemi, Andriy S. Kozlov, Claire A. Higgins in Science Advances
Imperial researchers have discovered a hidden mechanism within hair follicles that allows us to feel touch.
Previously, touch was thought to be detected only by nerve endings present within the skin and surrounding hair follicles. This new research from Imperial College London has found that cells within hair follicles — the structures that surround the hair fibre — are also able to detect the sensation in cell cultures.
The researchers also found that these hair follicle cells release the neurotransmitters histamine and serotonin in response to touch — findings that might help us in future to understand histamine’s role in inflammatory skin diseases like eczema.
Lead author of the paper Dr Claire Higgins, from Imperial’s Department of Bioengineering, said: “This is a surprising finding as we don’t yet know why hair follicle cells have this role in processing light touch. Since the follicle contains many sensory nerve endings, we now want to determine if the hair follicle is activating specific types of sensory nerves for an unknown but unique mechanism.”
We feel touch using several mechanisms: sensory nerve endings in the skin detect touch and send signals to the brain; richly innervated hair follicles detect the movement of hair fibres; and sensory nerves known as C-LTMRs, that are only found in hairy skin, process emotional, or ‘feel-good’ touch.
Now, researchers may have uncovered a new process in hair follicles. To carry out the study, the researchers analyzed single cell RNA sequencing data of human skin and hair follicles and found that hair follicle cells contained a higher percentage of touch-sensitive receptors than equivalent cells in the skin.
They established co-cultures of human hair follicle cells and sensory nerves, then mechanically stimulated the hair follicle cells, finding that this led to activation of the adjacent sensory nerves.
They then decided to investigate how the hair follicle cells signalled to the sensory nerves. They adapted a technique known as fast scan cyclic voltammetry to analyze cells in culture and found that the hair follicle cells were releasing the neurotransmitters serotonin and histamine in response to touch.
When they blocked the receptor for these neurotransmitters on the sensory neurons, the neurons no longer responded to the hair follicle cell stimulation. Similarly, when they blocked synaptic vesicle production by hair follicle cells, they were no longer able to signal to the sensory nerves.
They therefore concluded that in response to touch, hair follicle cells release that activate nearby sensory neurons.
The researchers also conducted the same experiments with cells from the skin instead of the hair follicle. The cells responded to light touch by releasing histamine, but they didn’t release serotonin.
Dr Higgins said: “This is interesting as histamine in the skin contributes to inflammatory skin conditions such as eczema, and it has always been presumed that immune cells release all the histamine. Our work uncovers a new role for skin cells in the release of histamine, with potential applications for eczema research.”
The researchers note that the research was performed in cell cultures, and will need to be replicated in living organisms to confirm the findings. The researchers also want to determine if the hair follicle is activating specific types of sensory nerves. Since C-LTMRs are only present within hairy skin, they are interested to see if the hair follicle has a unique mechanism to signal to these nerves that we have yet to uncover.
Hemispheric asymmetry in cortical thinning reflects intrinsic organization of the neurotransmitter systems and homotopic functional connectivity
by Liao Z, Banaschewski T, Bokde ALW, et al. in Proc Natl Acad Sci
In a scientific first, researchers led by Université de Montréal neuroscientist Tomas Paus and postdoctoral fellow Zhijie Liao have established a close link between brain activity and a maturation process called cortical thinning.
Like all parts of the human body, the brain’s hemispheres are not perfectly symmetrical. Using magnetic resonance imaging data from the brains of 532 teenagers, the study shows for the first time that this asymmetry changes with age, and that each region of the cortex and each hemisphere thins at a different rate.
The right hemisphere thins faster than the left, with a few exceptions. But even within each hemisphere, thinning occurs at different rates from one region of the brain to another.
“So the differences in thickness between the two hemispheres are not the same at age 14 as they are at age 22,” explained Paus. “By early adulthood, however, the asymmetry between the two hemispheres has largely stabilized.”
Probing the roots of this process and asymmetry, the study also found that the rate of thinning reflects the density of neurotransmitter receptors, the substances that enable communication between brain cells. The more neurotransmitter receptors there are in a given area, the faster that area thins.
As well, the corresponding areas in the right and left hemispheres thin at a more similar rate the more they communicate with each other and act in concert, the researchers found.
“There’s a correlation, but it seems that the more you use a region of the brain, the faster it matures,” said Paus. “It’s possible that the organization of the neurotransmitter system is genetic, but the way we use our brains also has an impact.”
For certain psychopathologies where an abnormal asymmetry has been identified, this may enable people to modify the structure by changing their brain’s activity and function.
“If these results are confirmed, it means that we could, for example, give personalized exercises to stimulate brain maturation right down to the structural level,” said Paus, a medical professor and researcher at the UdeM-affiliated CHU Sainte-Justine Research Centre.
“Just as we can prescribe exercises to strengthen underused muscles, we could help stimulate less active parts of the brain,” he said.
Tracking cell-type-specific temporal dynamics in human and mouse brains
by Ziyu Lu, Melissa Zhang, Jasper Lee, Andras Sziraki, Sonya Anderson, Zehao Zhang, Zihan Xu, Weirong Jiang, Shaoyu Ge, Peter T. Nelson, Wei Zhou, Junyue Cao in Cell
Hospital nurseries routinely place soft bands around the tiny wrists of newborns that hold important identifying information such as name, sex, mother, and birth date. Researchers at Rockefeller University are taking the same approach with newborn brain cells — but these neonates will keep their ID tags for life, so that scientists can track how they grow and mature, as a means for better understanding the brain’s aging process.
As described in a new paper in Cell, the new method developed by Rockefeller geneticist Junyue Cao and his colleagues is called TrackerSci (pronounced “sky”). This low-cost, high-throughput approach has already revealed that while newborn cells continue to be produced through life, the kinds of cells being produced greatly vary at different ages. This groundbreaking work, led by co-first authors Ziyu Lu and Melissa Zhang from Cao’s lab, promises to influence not only the study of the brain but also broader aspects of aging and disease across the human body.
“The cell is the basic functional unit of our body, so changes to the cell essentially underlie virtually every disease and the aging process,” says Cao, head of the Laboratory of Single-Cell Genomics and Population Dynamics. “If we can systematically characterize the different cells and their dynamics using this novel technique, we may get a panoramic view of the mechanisms of many diseases and the enigma of aging.”
New cells are continuously produced in the adult mammalian brain, a critical process associated with memory, learning, and stress. They develop from progenitor cells — descendants of adult stem cells that differentiate into specialized cell types.
How this process unfolds, however, has been largely unknown, both because of technological limitations and cell rarity. Finding progenitor cells in the brain is a needle-in-haystack endeavor; in mammals, they account for a mere .5 percent of all brain cells. That number drops to .1 percent in later stages of life — a downward shift due to cellular instability, a core characteristic of disease and aging.
Cao studies how tissues and organs maintain stable populations of cells — a hallmark of health — so he and his team wanted to investigate how different cellular populations develop, and whether these varied neuronal cells decline in the same way or forge different paths. Tracking their cellular lifespans from birth to maturity would reveal not just differences, but also when they appeared.
His lab specializes optimizing methods for single-cell sequencing, an increasingly popular approach to analysis that homes in on the genetic expression and molecular dynamics of individual cells. Cao’s group uses combinatorial indexing, a sophisticated yet cost-effective technique that allows for the simultaneous analysis of millions of cells. This method uniquely tags cellular molecules with distinct barcodes that correlate to each cell’s unique molecular assembly. With TrackerSci, Cao and his colleagues have fine-tuned this technique even further. This enhancement enables the meticulous labeling and tracking of the dynamics of rare progenitor cells in mammalian organs.
“It’s like an ID card and GPS tracker combined,” Cao says.
For the current study, the researchers analyzed more than 10,000 newborn progenitor cells from across entire mouse brains spanning three ages (young, mature, and elderly) with a synthetic molecule known as 5-ethynyl-2-deoxyuridine (EdU). As these newborn cells differentiated, proliferated, and dispersed, EdU continued to label their DNA, functioning like a GPS tracker. This innovative technique allowed the researchers to analyze tens of thousands of gene expressions and the chromatin landscapes of these newborn cells as they grew into families of cell types with different molecular functions.
“We were able to quantify cellular proliferation and differentiation rates of many cell types across the entire brain in a single experiment, which wasn’t possible using conventional approaches,” Cao says. “Those only capture static information — the current molecular state of a cell at a single moment. But TrackerSci captures dynamic information over time. It’s like other methods take snapshots, and we shoot a film.”
Some clear — and surprising — characters emerged from these movies. Most strikingly, there were radical shifts in the type of cells generated, depending on the age of the mouse.
For example, the number of progenitors that become neurons, the essential communicative cells of the brain, are higher in young brains. The same is the case for a range of glial cells, which create a stable environment for neurons by ensheathing them, providing nutrients, and defending against pathogens — all important for a young, still-developing organ.
The opposite is true in the elderly brain. Progenitor cells rarely become either neurons or glial cells; in fact, virtually every type of brain cell plummets. Most lost are dentate gyrus neuroblasts, which are essential for creating neurons in the hippocampus, a region linked to memory and diseases like Alzheimer’s. In comparison to the adult brain, the number of these cells drops by 16-fold in the elderly brain.
Instead, immune cells and microglia, a kind of macrophage, proliferate in the aging brain. But rather than protect the brain, they convert into an inflammatory cellular state specific to aging — and these cells are produced at a higher rate. In short, the aging brain creates more of the cells that create more problems for the aging brain.
Cao says TrackerSci could be used to track the regenerative capacity of many organs.
“We’re not a brain lab,” he notes. “We also tested the protocol for profiling progenitor cells in the lung, colon, pancreas, and many different organs.”
Other organs have far higher proportions of progenitor cells than brains do; newborn progenitors account for more than 20 percent of the cells in the colon, for instance. A few years ago, Cao demonstrated the potential for analyzing cell population dynamics in human fetal development by creating a cellular atlas using a similar combinatorial indexing method.
TrackerSci is one of several single-sequencing techniques to recently emerge from Cao’s lab. Another, called PerturbSci-Kinetics, developed by graduate student Zihan Xu, decodes the genome-wide regulatory network that underlies RNA temporal dynamics by coupling scalable single-cell genomics with high-throughput genetic perturbations, or manipulations that can influence gene function. The method was recently described in a paper in Nature Biotechnology.
Dopamine pathways mediating affective state transitions after sleep loss
by Mingzheng Wu, Xin Zhang, Sihan Feng, Sara N. Freda, Pushpa Kumari, Vasin Dumrongprechachan, Yevgenia Kozorovitskiy in Neuron
Most people who have pulled an all-nighter are all too familiar with that “tired and wired” feeling. Although the body is physically exhausted, the brain feels slap-happy, loopy and almost giddy.
Now, Northwestern University neurobiologists are the first to uncover what produces this punch-drunk effect. In a new study, researchers induced mild, acute sleep deprivation in mice and then examined their behaviors and brain activity. Not only did dopamine release increase during the acute sleep loss period, but synaptic plasticity also was enhanced — literally rewiring the brain to maintain the bubbly mood for the next few days.
These new findings could help researchers better understand how mood states transition naturally. It also could lead to a more complete understanding of how fast-acting antidepressants (like ketamine) work and help researchers identify previously unknown targets for new antidepressant medications.
Northwestern postdoctoral fellow Mingzheng Wu is the paper’s first author, and Professor Yevgenia Kozorovitskiy is the corresponding author.
“Chronic sleep loss is well studied, and it’s uniformly detrimental effects are widely documented,” Kozorovitskiy said. “But brief sleep loss — like the equivalent of a student pulling an all-nighter before an exam — is less understood. We found that sleep loss induces a potent antidepressant effect and rewires the brain. This is an important reminder of how our casual activities, such as a sleepless night, can fundamentally alter the brain in as little as a few hours.”
An expert in neuroplasticity, Kozorovitskiy is an associate professor of neurobiology and the Irving M. Klotz Professor at Northwestern’s Weinberg College of Arts and Sciences.
Scientists long have known that acute perturbations in sleep are associated with altered mental states and behaviors. Alterations of sleep and circadian rhythms in patients, for example, can trigger mania or occasionally reverse depressive episodes.
“Interestingly, changes in mood state after acute sleep loss feel so real, even in healthy subjects, as experienced by myself and many others,” Wu said. “But the exact mechanisms in the brain that lead to these effects have remained poorly understood.”
To explore these mechanisms, Kozorovitskiy and her team developed a new experiment to induce acute sleep loss in mice that did not have genetic predispositions related to human mood disorders. The experimental setup needed to be gentle enough to avoid causing substantial stress for the animals but just uncomfortable enough to prevent the animals from falling asleep. After a sleepless night, the animals’ behavior shifted to become more aggressive, hyperactive and hypersexual, compared to controls that experienced a typical night’s sleep.
Using optical and genetically encoded tools, the researchers measured the activity of dopamine neurons, which are responsible for the brain’s reward response. And they found activity was higher in animals during the brief sleep loss period.
“We were curious which specific regions of the brain were responsible for the behavioral changes,” Kozorovitskiy said. “We wanted to know if it was a large, broadcast signal that affected the entire brain or if it was something more specialized.”
Kozorovitskiy and her team examined four regions of the brain responsible for dopamine release: the prefrontal cortex, nucleus accumbens, hypothalamus and dorsal striatum. After monitoring these areas for dopamine release following acute sleep loss, the researchers discovered that three of the four areas (the prefrontal cortex, nucleus accumbens and hypothalamus) were involved.
But the team wanted to narrow down the results even further, so they systematically silenced the dopamine reactions. The antidepressant effect disappeared only when researchers silenced the dopamine response in the medial prefrontal cortex. By contrast, the nucleus accumbens and hypothalamus appeared to be most involved in the hyperactivity behaviors but were less connected to the antidepressant effect.
“The antidepressant effect persisted except when we silenced dopamine inputs in the prefrontal cortex,” Kozorovitskiy said. “That means the prefrontal cortex is a clinically relevant area when searching for therapeutic targets. But it also reinforces the idea that has been building in the field recently: Dopamine neurons play very important but very different roles in the brain. They are not just this monolithic population that simply predicts rewards.”
While most of the behaviors (such as hyperactivity and increased sexuality) disappeared within a few hours following acute sleep loss, the antidepressant effect lingered for a few days. This suggested that synaptic plasticity in the prefrontal cortex might be enhanced.
When Kozorovitskiy and her team examined individual neurons, they discovered just that. The neurons in the prefrontal cortex formed tiny protrusions called dendritic spines, highly plastic features that change in response to brain activity. When the researchers used a genetically encoded tool to disassemble the synapses, it reversed the antidepressant effect.
While researchers do not fully understand why sleep loss causes this effect in the brain, Kozorovitskiy suspects evolution is at play.
“It’s clear that acute sleep deprivation is somehow activating to an organism,” Kozorovitskiy said. “You can imagine certain situations where there is a predator or some sort of danger where you need a combination of relatively high function with an ability to delay sleep. I think this could be something that we’re seeing here. If you are losing sleep routinely, then different chronic effects set in that will be uniformly detrimental. But in a transient way, you can imagine situations where it’s beneficial to be intensely alert for a period of time.”
Kozorovitskiy also cautions people not to start pulling all-nighters in order to brighten a blue mood.
“The antidepressant effect is transient, and we know the importance of a good night’s sleep,” she said. “I would say you are better off hitting the gym or going for a nice walk. This new knowledge is more important when it comes to matching a person with the right antidepressant.”
Early Intervention in Cognitive Aging with Strawberry Supplementation
by Robert Krikorian, Marcelle D. Shidler, Suzanne S. Summer in Nutrients
New research from the University of Cincinnati found that daily strawberry consumption could help reduce the risk of dementia for certain middle-aged populations.
In 2022, UC’s Robert Krikorian, PhD, and his team published research that found adding blueberries to the daily diets of certain middle-aged populations may lower the chances of developing late-life dementia. He said the current research into strawberries is an extension of the blueberry research.
“Both strawberries and blueberries contain antioxidants called anthocyanins, which have been implicated in a variety of berry health benefits such as metabolic and cognitive enhancements,” said Krikorian, professor emeritus in the UC College of Medicine’s Department of Psychiatry and Behavioral Neuroscience. “There is epidemiological data suggesting that people who consume strawberries or blueberries regularly have a slower rate of cognitive decline with aging.”
In addition to containing anthocyanins, Krikorian said strawberries contain additional micronutrients called ellagitannins and ellagic acid that have been associated with health benefits.
About 50% of individuals in the U.S. develop insulin resistance, commonly referred to as prediabetes, around middle age, which has been shown to be a factor in chronic diseases. Krikorian said the metabolic and cardiovascular benefits of strawberry consumption have been studied previously, but there were relatively few studies on its cognitive effects.
“This study assessed whether strawberry consumption might improve cognitive performance and metabolic health in this population and, if so, whether there might be an association between cognitive enhancement and reduced metabolic disturbance,” he said.
A total of 30 overweight patients between 50–65 years old with complaints of mild cognitive decline were enrolled and completed the study. Krikorian said this population has an increased risk for late-life dementia and other common conditions.
Over a period of 12 weeks, the participants were asked to abstain from berry fruit consumption of any kind except for a daily packet of supplement powder to be mixed with water and consumed with breakfast. Half of the participants received powders that contained the equivalent of one cup of whole strawberries (the standard serving size), while the other half received a placebo.
The participants were given tests that measured certain cognitive abilities like long-term memory. The researchers also tracked their mood, intensity of depressive symptoms and metabolic data over the course of the study.
Those in the strawberry powder group had diminished memory interference, which is consistent with an overall improvement in executive ability.
“Reduced memory interference refers to less confusion of semantically related terms on a word-list learning test,” Krikorian said. “This phenomenon generally is thought to reflect better executive control in terms of resisting intrusion of non-target words during the memory testing.”
The strawberry-treated participants also had a significant reduction of depressive symptoms, which Krikorian said can be understood as a result from “enhanced executive ability that would provide better emotional control and coping and perhaps better problem-solving.”
Other strawberry studies have found improvement in metabolic measures including lower insulin, but there was no effect found on the patients’ metabolic health in this study.
“Those studies generally used higher dosages of strawberry powder than in our research, and this could have been a factor,” Krikorian said.
While more research is needed, Krikorian said the strawberry treatment may have improved cognitive function by reducing inflammation in the brain.
“Executive abilities begin to decline in midlife and excess abdominal fat, as in insulin resistance and obesity, will tend to increase inflammation, including in the brain,” he said. “So, one might consider that our middle-aged, overweight, prediabetic sample had higher levels of inflammation that contributed to at least mild impairment of executive abilities. Accordingly, the beneficial effects we observed might be related to moderation of inflammation in the strawberry group.”
Moving forward, Krikorian said future research trials should include larger samples of participants and differing dosages of strawberry supplementation.
Cognitive decline in older adults in the UK during and after the COVID-19 pandemic: a longitudinal analysis of PROTECT study data
by Anne Corbett, Gareth Williams, Byron Creese, Adam Hampshire, Vincent Hayman, Abbie Palmer, Akos Filakovzsky, Kathryn Mills, Jeffrey Cummings, Dag Aarsland, Zunera Khan, Clive Ballard in The Lancet Healthy Longevity
Brain health in over 50s deteriorated more rapidly during the pandemic, even if they didn’t have COVID-19, according to major new research linking the pandemic to sustained cognitive decline.
Researchers looked at results from computerized brain function tests from more than 3,000 participants of the online PROTECT study, who were aged between 50 and 90 and based in the UK. The remote study, led by teams at the University of Exeter and the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, tested participants’ short-term memory and ability to complete complex tasks.
Through analyzing the results from this big dataset, researchers found that cognitive decline quickened significantly in the first year of the pandemic, when they found a 50 percent change to the rate of decline across the study group. This figure was higher in those who already had mild cognitive decline before the pandemic, according to the research published in The Lancet Healthy Longevity.
This continued into the second year of the pandemic, suggesting an impact beyond the initial 12-month period of lockdowns. The researchers believe this sustained impact to be particularly relevant to ongoing public health and health policy.
The cognitive decline seems to have been exacerbated by a number of factors during the pandemic, including an increase in loneliness and depression, a decrease in exercise and higher alcohol consumption. Previous research has found that physical activity, treating existing depression, getting back into the community and reconnecting with people, are all important ways to reduce dementia risk and maintain brain health.
Anne Corbett, Professor of Dementia Research and PROTECT Study Lead at the University of Exeter, said: “Our findings suggest that lockdowns and other restrictions we experienced during the pandemic have had a real lasting impact on brain health in people aged 50 or over, even after the lockdowns ended. This raises the important question of whether people are at a potentially higher risk of cognitive decline which can lead to dementia. It is now more important than ever to make sure we are supporting people with early cognitive decline, especially because there are things they can do to reduce their risk of dementia later on. So if you are concerned about your memory the best thing to do is to make an appointment with your GP and get an assessment.
“Our findings also highlight the need for policy-makers to consider the wider health impacts of restrictions like lockdowns when planning for a future pandemic response.”
Professor Dar Aarsland, Professor of Old Age Psychiatry at King’s IoPPN, said:
“This study adds to the knowledge of the long-standing health-consequences of COVID-19, in particular for vulnerable people such as older people with mild memory problems. We know a great deal of the risks for further decline, and now can add COVID-19 to this list. On the positive note, there is evidence that life-style changes and improved health management can positively influence mental functioning. The current study underlines the importance of careful monitoring of people at risk during major events such as the pandemic.”
Microglial cannabinoid receptor type 1 mediates social memory deficits in mice produced by adolescent THC exposure and 16p11.2 duplication
by Yuto Hasegawa, Juhyun Kim, Gianluca Ursini, Yan Jouroukhin, Xiaolei Zhu, Yu Miyahara, Feiyi Xiong, Samskruthi Madireddy, Mizuho Obayashi, Beat Lutz, Akira Sawa, Solange P. Brown, Mikhail V. Pletnikov, Atsushi Kamiya in Nature Communications
In a mouse study designed to explore the impact of marijuana’s major psychoactive compound, THC, on teenage brains, Johns Hopkins Medicine researchers say they found changes to the structure of microglia, which are specialized brain immune cells, that may worsen a genetic predisposition to schizophrenia. The findings, published Nature Communications, add to growing evidence of risk to brain development in adolescents who smoke or eat marijuana products.
“Recreational and medical marijuana use is rapidly expanding in the United States and abroad, and teens are especially vulnerable to long-term negative effects of THC,” says Atsushi Kamiya, M.D., Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “We know THC is psychoactive, and its concentration in marijuana plants has increased four times in the last 20 years, posing a particular danger for adolescents who are genetically predisposed to psychoactive disorders including schizophrenia.”
Microglial cells are a specialized subset of immune cells called brain-resident macrophages that are found in the central nervous system. They play a direct role in neuron-to-neuron communication, immune response and healthy brain development. In adolescence, microglial cells play a critical role in brain maturation related to social and cognitive function by synapse pruning and secreting of chemical transmitters. Structural changes that interfere with them, the Johns Hopkins investigators suspected, may alter the brain’s wiring and messaging system in the still developing brains of teens.
To test their idea, researchers used genetically engineered mice with a mutation that mimics a genetic risk for psychiatric disorders in humans, along with normal mice as a comparison group. The mice carrying the mutation show changes to the brain with or without THC, specifically to the areas responsible for emotion, learning and memory.
During mouse adolescence, animals from both the genetically altered and normal groups were treated either with daily single injections of THC or with benign saline solution. After 30 days of injections, the mice were given three weeks of rest before behavioral tests were performed to assess their psychosocial development. The tests included those involving odor sensing, object recognition, social interaction and memory. The researchers also used fluorescent staining to measure the number and morphology of microglial cells in the animals’ brains.
Results showed that mice exposed to THC had increased microglial apoptosis (programmed cell death), and the reduction in the number of microglia in mice with the genetic mutation and THC was 33% higher than in the normal mice with THC. Microglial reduction was particularly present in the brain’s prefrontal cortex, which is responsible in both mice and people for memory, social behavior, decision making and other executive functions.
Because microglia are involved in brain neuronal maturation, a decrease in healthy ones may result in higher instances of abnormal cell signaling and communication, the researchers say. The genetically altered mice given THC in the study scored 40% lower on social memory than their counterparts given saline.
“This kind of study is critical right now because marijuana is becoming more mainstream, and we are just beginning to understand how it affects the brain immune cells,” says Yuto Hasegawa, Ph.D., research associate of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and the study’s leading author.
Kamiya cautions that study results from genetically engineered mice cannot be applied directly to what happens in a human brain. But “studies in animals suggest there may be long lasting and negative effects of marijuana use during adolescence,” Kamiya says.
“More research is needed, but we strongly advise caution in marijuana use by teenagers,” Kamiya adds.
Researchers say the next step for these studies is to pinpoint exactly how microglial abnormality affects neuron function at the molecular level. From a clinical perspective, they hope to use these findings to explore how marijuana exposure contributes to schizophrenia and other psychiatric disorders.
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