Category Archives: Neuroscience

Urbanization Boosts Brain Size in Modern Dog Breeds – Neuroscience News

Summary: Modern dog breeds, which are genetically farther from wolves, have relatively larger brain sizes compared to ancient breeds. The increase in brain size is not related to the specific roles or life history characteristics of the breeds, indicating that its likely influenced by urbanization and a more complex social environment.

The study revealed that the further a dog breed is genetically distant from wolves, the larger its relative brain size becomes.

This study provides new insight into the rapid evolution and diversity within the dog species, possibly due to their adaptation to human environments and social complexity.

Key Facts:

Source: ELTE

Modern dog breeds that are genetically more distant from wolves have a relatively larger brain size compared to ancient breeds that are thousands of years old, according to the findings of Hungarian and Swedish researchers.

The increase in brain size cannot be attributed to the roles or life history characteristics of the breeds, suggesting that it is likely influenced by urbanization and a more complex social environment.

Even today, the known four hundred dog breeds have developed relatively quickly and exhibit great diversity, making them a treasure trove for researchers interested in rapid changes within a species.

Scientists have long been curious about the factors that affect brain size because the human brain is unusually large in comparison to body size.Comparing the various dog breeds can help answer some questions.

Is there a correlation between brain size and the specific tasks for which a breed was bred?

Are there differences, for example, between lap dogs and hunting dogs? Or is it more influenced by life expectancy and the challenges of offspring rearing?What we know for certain is thatthinking and cognitive processes require a lot of energy, and maintaining a larger brain is costly.

Lszl Zsolt Garamszegi,an evolutionary biologist at the Ecological Research Centre in Hungary, has been studying the evolution of brain size for a long time.

The brains of domesticated animals can be up to twenty percent smaller than those of their wild ancestors. The likely reason for this is that the lives of domesticated species are simpler compared to those of their wild counterparts. In the safe environment provided by humans, there is no need to fear predator attacks or hunt for food.

Therefore, there is no need to sustain the energetically costly large brain, and the freed-up energy can be directed towards other purposes, such as producing more offspring, which is important for domesticated animals, she said.

Niclas Kolm, at Stockholm University, focuses on brain evolution and the link between variation in brain morphology and behavior.

Different dog breeds live in varying levels of social complexity and perform complex tasks, which likely require a larger brain capacity.

Therefore, we hypothesize that the selective pressures on the brain can vary within the dog species, and we may find differences in brain size among breeds based on the tasks they perform or their genetic distance from wolves.

This is the first comprehensive study regarding the brain size of different dog breeds, and its preparation took several decades.

Tibor Csrg, a senior research fellow at the Department of Anatomy, Cell and Developmental Biology at Etvs Lornd University (ELTE), has been collecting skulls for decades. CT scans of the skulls were performed by Medicopus Nonprofit Ltd. in Kaposvr.

Based on the CT images, veterinarianKlmn Czeibertreconstructed the brains and determined their exact volume. This invaluable collection was complemented by the Canine Brain and Tissue Bank, operated by ELTE for the past seven years, which enabled the verification of brain volumes calculated from skull images using actual brains. In the end, data was gathered from 865 individuals representing 159 dog breeds, with 48 specimens representing wolves.

According to the results published in the journalEvolution,wolves have an average brain volume of 131 cm3, associated with an average body weight of 31 kg. In the case of dogs in a similar weight category, the brain volume is only about three-quarters of that, approximately 100 cm3.

This confirms that domestication has also led to a decrease in brain size in dogs. However, what surprised researchers is that the further a dog breed is genetically distant from wolves, the larger its relative brain size becomes.

Contrary to expectations, the original role of the breeds, average litter size, and life expectancy are independent of brain size.

The domestication of dogs began approximately twenty-five thousand years ago, but for ten thousand years, dogs and wolves did not differ in appearance. Many ancient breeds, such as sled dogs, still resemble wolves today.

However, the transition to settlement, agriculture, pastoralism, and the accumulation of wealth offered various tasks for dogs, requiring guard dogs, herding dogs, hunting dogs, and even lap dogs.

A significant portion of the distinct-looking breeds known today has only emerged since the industrial revolution, primarily in the last two centuries, as dog breeding has become a kind of hobby, saysEnik Kubinyi, a senior research fellow at the Department of Ethology at ELTE.

The results show that the breeding of modern dog breeds has been accompanied by an increase in brain size compared to ancient breeds. We couldnt explain this based on the tasks or life history characteristics of the breeds, so we can only speculate about the reasons.

Perhaps the more complex social environment, urbanization, and adaptation to more rules and expectations have caused this change, affecting all modern breeds.

These findings are supported by research indicating that ancient breeds known for their independence are less attentive to human cues and bark less, thus exhibiting differences in visual and acoustic communication compared to modern breeds.

Funding: The study was supported by the Hungarian Academy of Sciences via a grant to the Hungarian Academy of Sciences (grant no. PH1404/21) and National Brain Programme 3.0 (NAP2022-I-3/2022), and by the National Research, Development and Innovation Office (grant no. 2019-2.1.11-TT-2020-00109) and Swedish Research Council (grant no. 2021-04476).

Author: Sara BohmSource: ELTEContact: Sara Bohm ELTEImage: The image is credited to Neuroscience News

Original Research: Open access.Evolution of relative brain size in dogsno effects of selection for breed function, litter size, or longevity by Lszl Zsolt Garamszegi et al. Evolution

Abstract

Evolution of relative brain size in dogsno effects of selection for breed function, litter size, or longevity

Domestication is a well-known example of the relaxation of environmentally based cognitive selection that leads to reductions in brain size. However, little is known about how brain size evolves after domestication and whether subsequent directional/artificial selection can compensate for domestication effects.

The first animal to be domesticated was the dog, and recent directional breeding generated the extensive phenotypic variation among breeds we observe today.

Here we use a novel endocranial dataset based on high-resolution CT scans to estimate brain size in 159 dog breeds and analyze how relative brain size varies across breeds in relation to functional selection, longevity, and litter size. In our analyses, we controlled for potential confounding factors such as common descent, gene flow, body size, and skull shape.

We found that dogs have consistently smaller relative brain size than wolves supporting the domestication effect, but breeds that are more distantly related to wolves have relatively larger brains than breeds that are more closely related to wolves.

Neither functional category, skull shape, longevity, nor litter size was associated with relative brain size, which implies that selection for performing specific tasks, morphology, and life history does not necessarily influence brain size evolution in domesticated species.

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Urbanization Boosts Brain Size in Modern Dog Breeds - Neuroscience News

Eye-Opening Drug Discovery May Help Treat Age-Related Macular … – Neuroscience News

Summary: 350 million people worldwide are believed to suffer from blinding diseases including age-related macular degeneration and diabetic retinopathy.

Researchers have discovered small-molecule drugs that could be used to treat age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa. The drugs, called stress resilience-enhancing drugs (SREDs), slowed or halted the progression of retinopathies in animal models by inhibiting cyclic nucleotide phosphodiesterases.

Key Facts:

Source: UC Irvine

In a University of California, Irvine-led study, researchers have discovered small-molecule drugs with potential clinical utility in the treatment of age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinitis pigmentosa (RP).

The study, titled, Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition, was published in theProceedings of the National Academy of Sciences.

In this study, we introduce a new class of therapeutics called Stress Resilience-Enhancing Drugs (SREDs) for the treatment of neurodegenerative conditions, specifically the worlds leading causes of blindness in age-related and inheritedretinal diseases, said Krzysztof Palczewski, Ph.D., Donald Bren Professor of Ophthalmology at the UCI School of Medicine and corresponding author on the study.

Through selective, pharmacological inhibition of cyclic nucleotide phosphodiesterases, our prototypical SREDs slowed or halted the development and progression of retinopathies in a number of genetic and environmental animal models.

Today, approximately 350 million people worldwide suffer from debilitating vision loss caused by either AMD or DR, and a large majority of these cases (>90%) have only minimally effective or notreatment optionsavailable. These chronic, progressive retinal diseases, including retinitis pigmentosa, arise from genetic and environmental disruptions of cellular and tissue stability.

Such disruptions accumulate with repeated exposures to stress over time, leading to progressive visual impairment and, in many cases, legal blindness.

Despite decades of research, therapeutic options for the millions of patients suffering from these disorders remain severely limited, especially for treating earlier stages of disease when the opportunity to preserve the retinal structure and visual function is greatest.

To address this urgent, unmet medical need, the researchers in this study innovated a systems pharmacology platform that leverages state-of-the-art disease modeling and characterization to identify novel, mechanism-based therapies that mitigate disease at the root cause.

The SRED therapeutic intervention enhanced resilience to acute and chronic forms of stress in the degenerating retina, thus preserving tissue structure and function across multiple models of age-related or inherited retinal disease.

Taken together, these findings exemplify a systems pharmacology approach todrug discoveryand development, revealing a new class of therapeutics with potential clinical utility in the treatment or prevention of the most common causes of blindness.

SREDs represent a promising strategy for patients and clinicians to combat disease in earlier stages with superior efficacy over the current standard of care, augmenting the arsenal of ophthalmic medications presently available in anti-angiogenics, corticosteroids, and nonsteroidal anti-inflammatory drugs (NSAIDs), said lead author Jennings Luu, MD/Ph.D. Doctoral Fellow of Pharmacology in the Medical Scientist Training Program at Case Western Reserve University and Visiting Scholar at University of California, Irvine.

Ultimately, it is our expectation that SREDs will someday serve as a standard of care for human aging, effectively providing patients the means to diminish suffering from debilitating ailments for which there currently exist no viabletherapeutic options, thereby extending human lifespan and healthspan irrespective of disease etiology.

Predicated in part on the discoveries highlighted in this publication, Luu and Palczewski have co-founded a seed-stage startup pharmaceutical company,Hyperion Therapeutics, Inc., which aims to commercialize theintellectual propertyassociated with their recent discoveries and introduce to the market new therapeutic agents for the treatment or prevention of AMD, DR, RP, and other progressive, incurable blinding diseases.

The Company was recently awarded first place in the Morganthaler-Pavey Startup Competition hosted by the Veale Institute for Entrepreneurship and has additionally partnered with UCI Beall Applied Innovation in the Wayfinder Incubator Program; through this strategic alliance, Luu and Palczewski are serving as co-investigators on a newly awarded Proof of Product grant, which will support the advancement of their pipeline therapies toward clinical trials and eventual commercialization.

Author: Press OfficeSource: UC IrvineContact: Press Office UC IrvineImage: The image is credited to Neuroscience News

Original Research: Closed access.Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition by Jennings C. Luu et al. PNAS

Abstract

Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition

Chronic, progressive retinal diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa, arise from genetic and environmental perturbations of cellular and tissue homeostasis. These disruptions accumulate with repeated exposures to stress over time, leading to progressive visual impairment and, in many cases, legal blindness.

Despite decades of research, therapeutic options for the millions of patients suffering from these disorders remain severely limited, especially for treating earlier stages of pathogenesis when the opportunity to preserve the retinal structure and visual function is greatest.

To address this urgent, unmet medical need, we employed a systems pharmacology platform for therapeutic development. Through integrative single-cell transcriptomics, proteomics, and phosphoproteomics, we identified universal molecular mechanisms across distinct models of age-related and inherited retinal degenerations, characterized by impaired physiological resilience to stress.

Here, we report that selective, targeted pharmacological inhibition of cyclic nucleotide phosphodiesterases (PDEs), which serve as critical regulatory nodes that modulate intracellular second messenger signaling pathways, stabilized the transcriptome, proteome, and phosphoproteome through downstream activation of protective mechanisms coupled with synergistic inhibition of degenerative processes.

This therapeutic intervention enhanced resilience to acute and chronic forms of stress in the degenerating retina, thus preserving tissue structure and function across various models of age-related and inherited retinal disease.

Taken together, these findings exemplify a systems pharmacology approach to drug discovery and development, revealing a new class of therapeutics with potential clinical utility in the treatment or prevention of the most common causes of blindness.

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Eye-Opening Drug Discovery May Help Treat Age-Related Macular ... - Neuroscience News

New Antidepressant Reduces Stress and Depression With Low Side … – Neuroscience News

Summary: Scientists developed a potential anti-depressant drug that exhibits anti-stressing and anti-depressant effects with minimal side effects. The drug, KNT-127 quickly acts on the patient without inducing resistance.

Researchers found that KNT-127 administration during and after extreme psychological stress significantly improved social interaction and reduced inflammation in the hippocampus.

Key Facts:

Source: Tokyo University of Science

Depression due to psychological stress affects millions of people worldwide. However, most of the existing anti-depressant drugs are slow, prone to development of resistance, and have severe side effects, demanding the need for more effective treatment options.

Delta opioid receptors (DOPs) are known to play a key role in the development of depression and similar diseases. Previous studies have revealed that DOP agonists (substances that bind DOPs instead of the regular compound and cause the same effect) have improved efficacy and lower side effects than most existing anti-depressant drugs.

Recent studies have identified KNT-127 as a potent DOP agonist with significant anti-depressant activity, quick action, and minimal side effects. However, the underlying mechanism of action is not well understood.

To this end, Prof. Akiyoshi Saitoh, Mr. Toshinori Yoshioka, Jr. Associate Prof. Daisuke Yamada, and Prof. Eri Segi-Nishida, at the Tokyo University of Science, along with Prof.Hiroshi Nagase from the University of Tsukuba, set out to assess the therapeutic and preventive effects of KNT-127 in a mouse model with depression.

The findings of this study were published in the journalNeuropharmacology.

Explaining the motivation behind their study, Prof. Saitoh explains, We previously discovered that delta-opioid receptor (DOP) agonists may quick action and have a low risk of side effects compared to existing drugs. Thus, we have been working on their clinical development as a new treatment strategy for depression.

In this study, we attempted to elucidate the mechanism of antidepressant-like effects of KNT-127, a selective DOP agonist, in a mouse model of depression.

The hypothalamic-pituitary-adrenal axis, hippocampal neurogenesis, and neuroinflammation are regarded as the major factors in the processes leading to the development of depression. Thus, understanding the effect of KNT-127 on the above parameters was crucial towards decoding its underlying working principle.

To this end, Prof. Saitoh and team created the depression mouse model called chronic vicarious social defeat stress (cVSDS) mice, by exposing five-week-old male mice to extreme psychological stress for 10 minutes per day, repeated for 10 days. Next, KNT-127 was given to the mice both during (10 days) and after (28 days later) the stress period, to assess its efficacy.

They observed that prolonged administration of KNT-127 during (anti-stress effect) and after stress (anti-depressant effect) period, significantly improved social interaction and levels of serum corticosterone (a hormone secreted under stress in mice) in cVSDS mice.

Moreover, KNT-127 administration during stress, suppressed stress-induced newborn neuronal death in the hippocampus, rather than increasing neurogenesis, or the formation of new neurons.

In contrast, when administered after stress, KNT-127 did not affect newborn neuron survival rate at all. Furthermore, unlike conventional antidepressants, KNT-127 did not affect neurogenesis even under stress-free conditions.

Psychological stress increases the number of microglia and activated microglia in the brains of cVSDS mice. Interestingly, under both models of delivery, KNT-127 suppressed microglial activation and hence reduced inflammation in the hippocampus.

In a nutshell, during and post stress period, KNT-127 prevents neuronal inflammation and reduces newborn neuronal death without affecting neuron formation to exert anti-stress and anti-depressant-like effects, respectively.

However, further research is warranted for better insights regarding DOP agonists and the mechanism underlying their anti-depressant effects.

The anti-stress effect of KNT-127 may offer added benefits for patients during treatment. Prof. Saitoh elaborates, Patients with depression often have to face situations where they cannot avoid stressful environments, even during treatment. Therefore, we believe that the additional anti-stress effect during the treatment period has important clinical significance.

Prof. Saitoh concludes by sharing their vision for the future, We expect that the successful clinical development of DOP agonists will greatly broaden the options for the treatment of depression in the future.

Funding: This work was supported by the Cyclic Innovation for Clinical Empowerment as part of the Japan Agency for Medical Research and Development (AMED) [grant number 17pc0101018h0001].

Author: Hiroshi MatsudaSource: Tokyo University of ScienceContact: Hiroshi Matsuda Tokyo University of ScienceImage: The image is credited to Neuroscience News

Original Research: Open access.KNT-127, a selective delta opioid receptor agonist, shows beneficial effects in the hippocampal dentate gyrus of a chronic vicarious social defeat stress mouse model by Akiyoshi Saitoh et al. Neuropharmacology

Abstract

KNT-127, a selective delta opioid receptor agonist, shows beneficial effects in the hippocampal dentate gyrus of a chronic vicarious social defeat stress mouse model

Delta opioid receptors(DOPs) play an important role in depression and other mood disorders. However, little is known about the underlying physiological mechanisms.

The hypothalamicpituitaryadrenal axis, adult hippocampalneurogenesis, andneuroinflammationare regarded as key pathophysiological factors in depression.

In this study, we investigated the influence of DOP activation on those factors in a valid animal model of depression, chronic vicarious social defeat stress (cVSDS) mice. cVSDS mice (male C57BL/6J mice) were produced following a 10-day exposure to witness of social defeat stress, and each evaluation was performed more than 28 days after the stress period.

Repeated administrations to cVSDS mice with a selective DOP agonist, KNT-127, both during (10 days) and after (28 days) the stress period respectively improved their decreased social interactionbehaviorsand increased serumcorticosteronelevels. When administered during the stress period, KNT-127 suppressed decreases in the hippocampal newborn neuron survival rate in cVSDS mice.

Moreover, in both administration paradigms, KNT-127 reduced the number of Iba-1- and CD11b-positive cells in the subgranular zone and thegranule celllayer of the hippocampaldentate gyrus, indicating a suppression of cVSDS-induced microglial overactivation.

These results suggest that KNT-127 acts over the hypothalamicpituitaryadrenal axis and regulatesneurogenesisandneuroinflammationresulting in anti-stress effects, and the antidepressant-like effects of the DOP agonist are implicated in the suppression of the neuroinflammation.

This study presents a new finding on the effects of repeated DOP activations on the pathophysiological states of depression.

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New Antidepressant Reduces Stress and Depression With Low Side ... - Neuroscience News

Cannabis Use Disorder Linked to Increased Schizophrenia Risk in … – Neuroscience News

Summary: Young men who suffer from cannabis use disorder are more likely to develop schizophrenia, according to a new study.

The study analyzed health records data of over 6 million people in Denmark and discovered a strong association between cannabis use disorder and schizophrenia. 30% of cases of schizophrenia among men aged 21-30 may be prevented by treating cannabis use disorder.

Effective treatments for both conditions are available, making it imperative to expand prevention, screening, and treatment for people who experience mental illnesses associated with cannabis use.

Key Facts:

Source: NIH

Young men with cannabis (marijuana) use disorder have an increased risk of developing schizophrenia, according to a study led by researchers at the Mental Health Services in the Capital Region of Denmark and the National Institute on Drug Abuse (NIDA) at the National Institutes of Health.

The study, published inPsychological Medicine(link is external),analyzed detailed health records data spanning 5 decades and representing more than 6 million people in Denmark to estimate the fraction of schizophrenia cases that could be attributed to cannabis use disorder on the population level.

Researchers found strong evidence of an association between cannabis use disorder and schizophrenia among men and women, though the association was much stronger among young men. Using statistical models, the study authors estimated that as many as 30% of cases of schizophrenia among men aged 21-30 might have been prevented by averting cannabis use disorder.

Cannabis use disorderandschizophreniaare serious, but treatable, mental disorders that can profoundly impact peoples lives. People with cannabis use disorder areunable to stop using cannabis despite it causing negative consequences in their lives. Schizophrenia is a serious mental illness that affects how a person thinks, feels, and behaves.

People with schizophrenia may seem like they have lost touch with reality, and the symptoms of schizophrenia can make it difficult to participate in usual, everyday activities. However, effective treatments are available for both cannabis use disorder and schizophrenia.

The entanglement of substance use disorders and mental illnesses is a major public health issue, requiring urgent action and support for people who need it, said NIDA Director and study coauthor Nora Volkow, M.D.

As access to potent cannabis products continues to expand, it is crucial that we also expand prevention, screening, and treatment for people who may experience mental illnesses associated with cannabis use.

The findings from this study are one step in that direction and can help inform decisions that health care providers may make in caring for patients, as well as decisions that individuals may make about their own cannabis use.

Previous studies indicate that rates of daily or near daily cannabis use, cannabis use disorder, and new schizophrenia diagnoses are higher among men than women, and that early, frequent cannabis use is associated with an increased risk of developing schizophrenia.

However, few studies have examined differences in the relationship between cannabis use disorder and schizophrenia across different sex and age groups at the population level.

To address this research gap, investigators analyzed data from nationwide health registers in Denmark, which included health records data from more than 6.9 million people who were aged 16-49 at some point between 1972 and 2021.

Using these nationally representative longitudinal data, the researchers investigated how the associations between cannabis use disorder and schizophrenia varied by different sex and age groups, and how these differences changed over time.

Although there are many risk factors associated with schizophrenia, in this study, researchers sought to estimate the proportion of all schizophrenia cases that may be attributed to cannabis use disorder specifically, across sex and age groups at the population level.

The study team estimated that 15% of cases of schizophrenia among men aged 16-49 may have been avoided in 2021 by preventing cannabis use disorder, in contrast to 4% among women aged 16-49.

For young men aged 21-30, they estimated that the proportion of preventable cases of schizophrenia related to cannabis use disorder may be as high as 30%.

The authors emphasize that cannabis use disorder appears to be a major modifiable risk factor for schizophrenia at the population level, particularly among young men.

This study also adds toexisting evidencesuggesting that the proportion of new schizophrenia cases that may be attributed to cannabis use disorder has consistently increased over the past five decades.

The authors note that this increase is likely linked to the higher potency of cannabis and increasing prevalence of diagnosed cannabis use disorder over time.

Increases in the legalization of cannabis over the past few decades have made it one of the most frequently used psychoactive substances in the world, while also decreasing the publics perception of its harm.

This study adds to our growing understanding that cannabis use is not harmless, and that risks are not fixed at one point in time, said Carsten Hjorthj, Ph.D., lead author of the study and associate professor at the Mental Health Services in the Capital Region of Denmark and at the University of Copenhagen.

The authors note that further research is needed to examine potential differences in the potency and frequency of cannabis consumption between young men and women, and to examine the mechanisms underlying the higher vulnerability of young men to the effects of cannabis on schizophrenia.

The association of cannabis potency with cannabis use disorder andpsychosismay help inform public health guidelines; policies on cannabis sales and access; and efforts to effectively prevent, screen for, and treat cannabis use disorder and schizophrenia.

Author: NIDA Press OfficeSource: NIHContact: NIDA Press Office NIHImage: The image is credited to Neuroscience News

Original Research: Open access.Association between cannabis use disorder and schizophrenia stronger in young males than in females by Nora Volkow et al. Psychological Medicine

Abstract

Association between cannabis use disorder and schizophrenia stronger in young males than in females

Background

Previous research suggests an increase in schizophrenia population attributable risk fraction (PARF) for cannabis use disorder (CUD). However, sex and age variations in CUD and schizophrenia suggest the importance of examining differences in PARFs in sex and age subgroups.

Methods

We conducted a nationwide Danish register-based cohort study including all individuals aged 1649 at some point during 19722021. CUD and schizophrenia status was obtained from the registers. Hazard ratios (HR), incidence risk ratios (IRR), and PARFs were estimated. Joinpoint analyses were applied to sex-specific PARFs.

Results

We examined 6 907 859 individuals with 45 327 cases of incident schizophrenia during follow-up across 129 521 260 person-years. The overall adjusted HR (aHR) for CUD on schizophrenia was slightly higher among males (aHR = 2.42, 95% CI 2.332.52) than females (aHR = 2.02, 95% CI 1.892.17); however, among 1620-year-olds, the adjusted IRR (aIRR) for males was more than twice that for females (males: aIRR = 3.84, 95% CI 3.434.29; females: aIRR = 1.81, 95% CI 1.532.15). During 19722021, the annual average percentage change in PARFs for CUD in schizophrenia incidence was 4.8 among males (95% CI 4.35.3;p< 0.0001) and 3.2 among females (95% CI 2.53.8;p< 0.0001). In 2021, among males, PARF was 15%; among females, it was around 4%.

Conclusions

Young males might be particularly susceptible to the effects of cannabis on schizophrenia. At a population level, assuming causality, one-fifth of cases of schizophrenia among young males might be prevented by averting CUD. Results highlight the importance of early detection and treatment of CUD and policy decisions regarding cannabis use and access, particularly for 1625-year-olds.

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Cannabis Use Disorder Linked to Increased Schizophrenia Risk in ... - Neuroscience News

Shared Genetic Defects in ALS and FTD: New Insights Into … – Neuroscience News

Summary: Some patients with ALS/motor neuron disease (MND) and frontotemporal dementia (FTD) carry the same rare genetic defects that cause other neurodegenerative diseases. These defects, known as short tandem repeat expansions, are the cause of more than 20 neurodegenerative diseases including spinocerebellar ataxias and myotonic dystrophy.

The study suggests a shared risk factor and mechanism that cause nerves to die in different neurodegenerative diseases, which may lead to shared therapeutic strategies in the future.

Key Facts:

Source: Macquarie University

New research has discovered that some patients with ALS/motor neuron disease (MND) and frontotemporal dementia (FTD) carry the same rare genetic defects that cause other neurodegenerative diseases.

Researchers from the Macquarie University MND Research Centre and The Walter and Eliza Hall Institute of Medical Research have identified the defects in the genomes of some people with non-inherited, or sporadic, ALS and FTD.

ALS/MND results in the death of the neurons, or motor nerves, connecting the brain and spinal cord to the muscles. These are the cells that control our ability to move, breathe and swallow. The disease is progressive and eventually fatal.

FTD also causes the death of neurons in part of the brain, resulting in a range of progressive symptoms such as memory loss, unusual behavior, personality changes and communication problems. It is the same form of dementia with which actor Bruce Willis was recently diagnosed, and unlike older-onset dementia, it tends to affect people under 65.

The majority of cases in both diseases about 90 percent in the case of MND and 60-70 percent in FTD are sporadic, with the rest occurring in families.

These gene defects, known as short tandem repeat expansions, are the cause of more than 20 neurodegenerative diseases including spinocerebellar ataxias and myotonic dystrophy. This Australian study has been the most comprehensive assessment of these gene defects in ALS and FTD patients worldwide.

Macquarie University Postdoctoral Research Fellow Dr Lyndal Henden says the findings were a surprise.

We found almost 18 percent of sporadic ALS and FTD patients carried a DNA repeat expansion thought to be involved in other degenerative diseases, she says.

Finding this genetic connection between ALS and FTD offers a fresh opportunity to uncover common risk factors for neuron death, and it will have implications for understanding both diseases.

Macquarie University Associate Professor Kelly Williams directed the study, and says the team suspected there could be some overlap with other diseases, but not to such an extent.

This suggests shared risk factors among these diseases, shared mechanisms that cause nerves to die and perhaps shared therapeutic strategies in the future, she says.

While the causes of sporadic ALS and FTD remain unknown, this is an important step in a long-term effort to identify the risk factors for developing one of these diseases.

Work can now begin to understand how these shared repeat expansions contribute to neuron death.

Thestudy, published in the latest edition of the journalScience Advances, is the culmination of 10 years of research that could not have been possible without the cooperation of patients with ALS and FTD, who have donated biological samples for DNA at both Macquarie University and the University of Sydney.

Author: Georgia GowingSource: Macquarie UniversityContact: Georgia Gowing Macquarie UniversityImage: The image is credited to Neuroscience News

Original Research: Open access.Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia by Lyndal Henden et al. Science Advances

Abstract

Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia

Pathogenic short tandem repeat (STR) expansions cause over 20 neurodegenerative diseases. To determine the contribution of STRs in sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), we used ExpansionHunter, REviewer, and polymerase chain reaction validation to assess 21 neurodegenerative disease-associated STRs in whole-genome sequencing data from 608 patients with sporadic ALS, 68 patients with sporadic FTD, and 4703 matched controls.

We also propose a data-derived outlier detection method for defining allele thresholds in rare STRs. ExcludingC9orf72repeat expansions, 17.6% of clinically diagnosed ALS and FTD cases had at least one expanded STR allele reported to be pathogenic or intermediate for another neurodegenerative disease.

We identified and validated 162 disease-relevant STR expansions inC9orf72(ALS/FTD),ATXN1[spinal cerebellar ataxia type 1 (SCA1)],ATXN2(SCA2),ATXN8(SCA8),TBP(SCA17),HTT(Huntingtons disease),DMPK[myotonic dystrophy type 1 (DM1)],CNBP(DM2), andFMR1(fragile-X disorders).

Our findings suggest clinical and pathological pleiotropy of neurodegenerative disease genes and highlight their importance in ALS and FTD.

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Shared Genetic Defects in ALS and FTD: New Insights Into ... - Neuroscience News

Global Genomic Diversity: Unveiling the New Pangenome Reference – Neuroscience News

Summary: The Human Pangenome Reference Consortium has released a comprehensive collection of human genome sequences that captures remarkable diversity across global populations.

The new pangenome reference includes 94 distinct genome sequences from 47 individuals, with plans to increase this to 700 sequences from 350 people by mid-2024.

This expanded reference will better represent the genetic diversity of the human species and help reduce health disparities in genomic analyses. It also introduces over 100 million new DNA bases, and can more accurately identify larger genomic variants.

Key Facts:

Source: NIH

Researchers have released a new high-quality collection of reference human genome sequences that captures substantially more diversity from different human populations than what was previously available.

The work was led by the international Human Pangenome Reference Consortium, a group funded by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health.

The new pangenome reference includes genome sequences of 47 people, with the researchers pursuing the goal of increasing that number to 350 by mid-2024. With each person carrying a paired set of chromosomes, the current reference actually includes 94 distinct genome sequences, with a goal of reaching 700 distinct genome sequences by the completion of the project.

The work, appearing in the journalNature, is one of several papers published today by consortium members.

A genome is the set of DNA instructions that helps each living creature develop and function. Genome sequences differ slightly among individuals. In the case of humans, any two peoples genomes are, on average, more than 99% identical.

The small differences contribute to each persons uniqueness and can provide insights about their health, helping to diagnose disease, predict outcomes and guide medical treatments.

To understand these genomic differences, scientists create reference human genome sequences for use as a standard a digital amalgamation of human genome sequences that can be used as a comparison to align, assemble and study other human genome sequences.

The original reference human genome sequence is nearly 20 years old and has been regularly updated as technology advances and researchers fix errors and discover more regions of the human genome.

However, it is fundamentally limited in its representation of the diversity of the human species, as it consists of genomes from only about 20 people, and most of the reference sequence is from only one person.

Everyone has a unique genome, so using a single reference genome sequence for every person can lead to inequities in genomic analyses, said Adam Phillippy, Ph.D., senior investigator in the Computational and Statistical Genomics Branch within NHGRIs Intramural Research Program and a co-author of the main study.

For example, predicting a genetic disease might not work as well for someone whose genome is more different from the reference genome.

The current reference human genome sequence has gaps that reflect missing information, especially in areas that were repetitive and hard to read.

Recent technological advances such as long-read DNA sequencing, which reads longer stretches of the DNA at a time, helped researchers fill in those gaps to create thefirst complete human genome sequence.

This complete human genome sequence, released last year as part of the NIH-funded Telomere-to-Telomere (T2T) consortium, is incorporated into the current pangenome reference. In fact, many of the T2T researchers are also members of the Human Pangenome Reference Consortium.

Using advanced computational techniques to align the various genome sequences, the researchers constructed a new human pangenome reference with each assembly in the pangenome covering more than 99% of the expected sequence with more than 99% accuracy. It also builds upon the previous reference genome sequence, adding over 100 million new bases, or letters in DNA.

While the previous reference genome sequence was single and linear, the new pangenome represents many different versions of the human genome sequence at the same time. This gives researchers a wider range of options for using the pangenome in analyzing other human genome sequences.

By using the pangenome reference, we can more accurately identify larger genomic variants called structural variants, said Mobin Asri, a Ph.D. student at the University of California Santa Cruz and co-first author of the paper.

We are able to find variants that were not identified using previous methods that depend on linear reference sequences.

Structural variants can involve thousands of bases. Until now, researchers have been unable to identify the majority of structural variants that exist in each human genome using short-read sequencing due to the bias of using a single reference sequence.

The human pangenome reference will enable us to represent tens of thousands of novel genomic variants in regions of the genome that were previously inaccessible, said Wen-Wei Liao, a Ph.D. student at Yale University and co-first author of the paper.

With a pangenome reference, we can accelerate clinical research by improving our understanding of the link between genes and disease traits.

The total cost of supporting the work of the Human Pangenome Reference Consortium is projected to be about $40 million over five years, which includes efforts to create the human pangenome reference, improve DNA sequencing technology, operate a coordinating center, conduct outreach and create resources for the research community to use the pangenome reference.

Many of the individuals whose genomes were sequenced for constructing the new human pangenome reference were originally recruited as part of the1,000Genomes Project, a collaborative and international effort funded in part by NIH that aimed to improve the catalog of genomic variants in diverse populations.

Because the human pangenome reference is a work in progress, researchers from the international Human Pangenome Reference Consortium continue to add more genome sequences to increasingly improve the quality of the pangenome reference.

Basic researchers and clinicians who use genomics need access to a reference sequence that reflects the remarkable diversity of the human population. This will help make the reference useful for all people, thereby helping to reduce the chances of propagating health disparities, said Eric Green, M.D., Ph.D., NHGRI director.

Creating and enhancing a human pangenome reference aligns with NHGRIs goal of striving for global diversity in all aspects of genomics research, which is crucial to advance genomic knowledge and implement genomic medicine in an equitable way.

In line with this effort, the Human Pangenome Reference Consortium includes an embedded ethics group that is working to anticipate challenging issues and help guide informed consent, prioritize the study of different samples, explore possible regulatory issues pertaining to clinical adoption, and work with international and Indigenous communities to incorporate their genome sequences in these broader efforts.

Institutions involved in theHuman Pangenome Reference Consortium may be found on the projects main page.

Author: Sarah BatesSource: NIHContact: Sarah Bates NIHImage: The image is credited to Neuroscience News

Original Research: Open access.A draft human pangenome reference by Wen-Wei Liao et al. Nature

Abstract

A draft human pangenome reference

Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals.

These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels.

Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci.

We also add 119million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90million of the additional base pairs are derived from structural variation.

Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detectedper haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample.

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Global Genomic Diversity: Unveiling the New Pangenome Reference - Neuroscience News

Increased Long-Covid Risk for Those With Sleep Apnea – Neuroscience News

Summary: The risk of developing long COVID symptoms may be significantly increased in adults with sleep apnea, according to a new study.

This increased risk persisted even when controlling for other factors known to contribute to long COVID, such as obesity, hypertension, diabetes, and hospitalization at the time of initial COVID infection. Notably, the link between sleep apnea and long COVID was not observed in children when other risk factors were accounted for.

This research underlines the importance of early COVID treatment and symptom vigilance in sleep apnea patients.

Key Facts:

1 Adults with sleep apnea have a significantly increased risk of developing long COVID symptoms, according to a study by the National Institutes of Healths RECOVER Initiative and NYU Langone Health.

2 The increased risk for long COVID in adults with sleep apnea persisted even when accounting for factors such as obesity, hypertension, diabetes, and initial COVID hospitalization.

3 In contrast to the patterns seen in adults, the contribution of sleep apnea to the risk of long COVID was not significant in children when controlled for other risk factors.

Source: NYU Langone

Sleep apnea may significantly increase the risk for long COVID in adults, according to a study led by theNational Institutes of Healths RECOVER Initiativeand supported by NYU Langone Health as home to the efforts Clinical Science Core (CSC).

As ofApril 2023,more than 100 million Americans had been infected with the virus that causes COVID-19. As of April the U.S.Governments Household Pulse survey estimated that about 6 percent of U.S. adults are experiencingsymptoms associated with long COVID, including brain fog, fatigue, depression, and sleep problems.

Past studies have shown that patients with obstructive sleep apnea (OSA) tend to have more severe illness when initially infected with COVID-19. OSA affects about1 in 8adults but is often underdiagnosed.

To better understand links between sleep apnea and long-term COVID symptoms, the research team reviewed data across three RECOVER research networks of patients who had tested positive for COVID-19 between March 2020 and February 2022, according to their health records.

Two networks included adult patients the National Patient-Centered Clinical Research Network (PCORnet) with 330,000 patients and the National COVID Cohort Collaborative (N3C) with 1.7 million patients. The third patient cohort in the study analysis included the pediatric-focused network PEDSnet, made up of 102,000 children.

Published online on May 11 in the journalSleep,this study found that a prior diagnosis of sleep apnea in the PCORnet group came with a 12 percent increase in risk for long-term symptoms months after patients initial infections.

In the N3C patient group, in which patients had higher levels of other chronic conditions than those in PCORnet, sleep apnea came with a 75 percent increase in risk for long COVID compared to those without sleep apnea.

The observed increases in risk for long COVID in adults with sleep apnea remained significant even when the research team accounted for obesity, hypertension, diabetes, and hospitalization at the time of their initial COVID infection, all known to independently contribute to risk for long COVID.

The researchers hypothesize that the differences in the percentage increases in long COVID risk between the study groups may be further explained by variations indefinitionsof long COVID, study populations, and in analysis methods of patient records, across the large study.

In contrast to the patterns seen in adults, the contribution of sleep apnea to the risk of long COVID disappeared in children when the researchers controlled for other risk factors, including obesity.

A strength of the work is that the link between sleep apnea and long COVID persisted regardless of how the researchers in our study defined long COVID or gathered data,says senior study author Lorna Thorpe, PhD, MPH, Professor and Director of the Division of Epidemiology at NYU Langone Health.

She is also co-lead of efforts to understand long COVID using electronic health record networks for the RECOVER CSC at NYU Langone.

This study is the first collaboration of this focus and scale to find that adults with sleep apnea are at greater risk for long COVID.

RECOVERResearching COVID to Enhance Recoveryis dedicated to understanding why some people develop long-term symptoms following a COVID infection, and how to detect, treat, and prevent long COVID. As the CSC, NYU Langone Health is charged with integrating research activities of clinical sites around the country.

Theres still so much to uncover about long COVID, but this study will inform clinical care by identifying patients that should be watched more closely, says corresponding author Hannah Mandel, a senior research scientist for the electronic health record studies arm of the RECOVER CSC at NYU Langone Health.

People with sleep apnea who get infected with COVID should seek early treatment, pay attention to their symptoms, and keep up with their vaccinations to lower the risk of infection in the first place.

Interestingly, in the N3C study group, long COVID risk was higher among women with sleep apnea compared to men with sleep apnea.

Investigators identified an 89% increased likelihood for having long COVID in women, compared to a 59% increased chance for men.

The reasons for this are not clear, butwomenwith diagnosed sleep apnea in their medical records may have more severe conditions than men, in part because women with sleep apnea tend to go undiagnosed with OSA for longer.

Funding: The study was funded by RECOVER (OT2HL161847) and received additional support from the National Center for Advancing Translational Sciences (UL1TR002494).

For more information on RECOVER, visithttps://recovercovid.org.

Author: Gregory WilliamsSource: NYU LangoneContact: Gregory Williams NYU LangoneImage: The image is credited to Neuroscience News

Original Research: Open access.Risk of post-acute sequelae of SARS-CoV-2 infection associated with pre-coronavirus disease obstructive sleep apnea diagnoses: an electronic health recordbased analysis from the researching coronavirus disease to enhance recovery initiative by Lorna Thorpe et al. SLEEP

Abstract

Risk of post-acute sequelae of SARS-CoV-2 infection associated with pre-coronavirus disease obstructive sleep apnea diagnoses: an electronic health recordbased analysis from the researching coronavirus disease to enhance recovery initiative

Study Objectives

Obstructive sleep apnea (OSA) has been associated with more severe acute coronavirus disease-2019 (COVID-19) outcomes. We assessed OSA as a potential risk factor for Post-Acute Sequelae of SARS-CoV-2 (PASC).

Methods

We assessed the impact of preexisting OSA on the risk for probable PASC in adults and children using electronic health record data from multiple research networks. Three research networks within the REsearching COVID to Enhance Recovery initiative (PCORnet Adult, PCORnet Pediatric, and the National COVID Cohort Collaborative [N3C]) employed a harmonized analytic approach to examine the risk of probable PASC in COVID-19-positive patients with and without a diagnosis of OSA prior to pandemic onset. Unadjusted odds ratios (ORs) were calculated as well as ORs adjusted for age group, sex, race/ethnicity, hospitalization status, obesity, and preexisting comorbidities.

Results

Across networks, the unadjusted OR for probable PASC associated with a preexisting OSA diagnosis in adults and children ranged from 1.41 to 3.93. Adjusted analyses found an attenuated association that remained significant among adults only. Multiple sensitivity analyses with expanded inclusion criteria and covariates yielded results consistent with the primary analysis.

Conclusions

Adults with preexisting OSA were found to have significantly elevated odds of probable PASC. This finding was consistent across data sources, approaches for identifying COVID-19-positive patients, and definitions of PASC. Patients with OSA may be at elevated risk for PASC after SARS-CoV-2 infection and should be monitored for post-acute sequelae.

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Increased Long-Covid Risk for Those With Sleep Apnea - Neuroscience News

Depression Symptoms in Older People on the Decline – Neuroscience News

Summary: A recent study reveals that todays 75- and 80-year-olds experience fewer depressive symptoms and greater life satisfaction than their counterparts from the 1990s. The improvement in mental well-being is attributed to better-perceived health and higher education among the aging population. The research further supports the notion that older individuals today have better physical and cognitive functioning than those born earlier.

Key Facts:

Source: University of Jyvskyl

Depressive symptoms have decreased among older people and they are more satisfied with their lives so far than people at the same age three decades ago.

This was observed in a study conducted at the Gerontology Research Center at the Faculty of Sport and Health Sciences, University of Jyvskyl (Finland).

The study examined differences in depressive symptoms and life satisfaction between current 75- and 80-year-olds and same-aged people who lived in the 1990s.

The results showed that 75- and 80-year-old men and women today experience fewer depressive symptoms than those who were 75 and 80 years old in the 1990s. The differences were partly explained by the better-perceived health and higher education of those born later.

In our previous comparisons, we found that older people today have significantly better physical and cognitive functioning at the same age compared to those born earlier, says ProfessorTaina Rantanenfrom the Faculty of Sport and Health Sciences.

These new results complement these positive findings in terms of mental well-being.

Today, 75- and 80-year-olds are more satisfied with their lives to date. However, 80-year-old men who lived in the 1990s were even more satisfied with their current lives than 80-year-old men today.

These men born in 1910 had lived through difficult times, which may explain their satisfaction with their current lives in the 1990s when many things were better than before, says postdoctoral researcherTiia Keklinen.

Individuals adapt to their situation and living conditions. Both in the 1990s and today, the majority of older adults reported being satisfied with their current lives.

The study was conducted at the Faculty of Sport and Health Sciences and Gerontology Research Center at University of Jyvskyl, Finland.

The first cohort consisted of 617 individuals born in 1910 and 1914 who participated in the Evergreen study in 19891990. The second cohort consisted of 794 individuals born in 19381939 and 19421943 who participated in the AGNES study in 20172018. In both cohorts, the participants were assessed at the age of 75 or 80 years.

Funding: The study was funded by the Academy of Finland and the European Research Council.

Author: Tiia KeklinenSource: University of JyvskylContact: Tiia Keklinen University of JyvskylImage: The image is credited to Neuroscience News

Original Research: Open access.Cohort Differences in Depressive Symptoms and Life Satisfaction in 75- and 80-Year-Olds: A Comparison of Two Cohorts 28 Years Apart by Keklinen, T et al. Journal of Aging and Health

Abstract

Cohort Differences in Depressive Symptoms and Life Satisfaction in 75- and 80-Year-Olds: A Comparison of Two Cohorts 28 Years Apart

To examine birth cohort differences in depressive symptoms and life satisfaction in older men and women and the mechanisms underpinning the possible cohort differences.

Two independent cohorts of Finnish men and women aged 75 and 80 were assessed in 19891990 (n= 617) and 20172018 (n= 794). They reported their depressive symptoms (CES-D), current life satisfaction, and evaluation of life until now.

The later-born cohort reported fewer depressive symptoms (8.6 7.1 vs. 13.9 8.3) and the differences were similar for the subdomains of depressive symptoms. The later-born cohort was more often mostly satisfied with life until now (90 vs. 70%) but not with the current life than the earlier-born cohort. Better self-rated health and education of the later-born cohort partly explain the cohort differences.

Older people in Finland report fewer depressive symptoms and they are more satisfied with their past life compared to their counterparts assessed 28years ago.

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Depression Symptoms in Older People on the Decline - Neuroscience News

Menthol Inhalation May Boost Cognitive Ability in Alzheimer’s – Neuroscience News

Summary: Menthol inhalation can improve cognitive abilities in animal models of Alzheimers disease, researchers report.

Short, repeated exposure to menthol can modulate the immune system and prevent cognitive decline commonly seen in Alzheimers.

Researchers found that the smell of menthol reduced the level of interleukin-1-beta (IL-1b), a protein crucial to the inflammatory response. By inhibiting this protein with a specific drug, cognitive abilities were also improved in the mice models.

This research suggests the possibility of therapies based on stimulating the olfactory system to counteract Alzheimers and other central nervous system diseases.

Key Facts:

Source: Universidad de Navarra

Researchers fromCima University of Navarra(Spain) have shown in animal models ofAlzheimers diseasethat inhaling menthol improves cognitive ability.

This study discovered that repeated short exposures to this substance can modulate the immune system and prevent the cognitive deterioration typical of this neurodegenerative disease.

When analyzing its mechanism of action, they observed that when smelling this aroma, the level ofinterleukin-1-beta (IL-1b), a critical protein mediating the inflammatory response, was reduced.

Furthermore, by inhibiting this protein with a drug approved for the treatment of some autoimmune diseases, they were also able to improve cognitive ability in these diseased mice.

This research highlights the potential of odors and immune modulators as therapeutic agents. Furthermore, it opens the door to developing therapies based on stimulating and training the olfactory system to prevent or alleviate the effects of Alzheimers and other diseases of the central nervous system.

Frontiers in Immunologypublished the results of this study in its latest issue.

The functional balance of the brain depends on complex interactions between various types of nerve cells, immune cells, and neural stem cells. In this complex web of interactions, several studies have addressed the immunomodulatory and neurological effects of odorants.

Other previous works have also shown a correlation between the loss of the sense of smell and the appearance of the first symptoms of Alzheimers disease.

We have focused on the olfactory systems role in the immune and central nervous systems, and we have confirmed that menthol is an immunostimulatory odor in animal models.

But, surprisingly, we observed that short exposures to this substance for six months prevented cognitive decline in the mice with Alzheimers and, what is most interesting, also improved the cognitive ability of healthy young mice, says DrJuan Jos Lasarte.

Another result noted by the researchers is that blocking the activity of T regulatory cells, one type of immune cells with immunosuppressive activity, also improved the cognitive ability of mice with Alzheimers disease and also caused a clear benefit in the cognitive ability of healthy young mice, explains Dr.Ana Garca-Osta.

Both menthol exposure and Treg cell blockade caused a decrease in IL-1b, a protein that could be behind the cognitive decline observed in these models. In addition, the specific blockade of this protein with a drug used in treating some autoimmune diseases also improved the cognitive capacity of healthy mice and mice with Alzheimers.

This study is an important step toward understanding the connection between the immune system, the central nervous system and smell, as the results suggest that odors and immune modulators may play an important role in the prevention and treatment of Alzheimers. and other diseases related to the central nervous system, points out Dr.Noelia Casares.

Funding: The Government of Navarra and the Ministry of Economy and Competitiveness financed this work. It is part of the Instituto de Investigacin Santiaria de Navarra (IdiSNA). It is also part of the INNOLFACT project, a multicenter consortium coordinated by Dr Enrique Santamara, a Navarrabiomed researcher.

This consortium aims to study the olfactory function in aging and develop new immunomodulatory therapies to slow down the development of neurodegenerative diseases.

Author: Miriam SalcedoSource: Universidad de NavarraContact: Miriam Salcedo Universidad de NavarraImage: The image is credited to Neuroscience News

Original Research: Open access.Improvement of cognitive function in wild-type and Alzheimers disease mouse models by the immunomodulatory properties of menthol inhalation or by depletion of T regulatory cells by Casares Noelia et al. Frontiers in Immunology

Abstract

Improvement of cognitive function in wild-type and Alzheimers disease mouse models by the immunomodulatory properties of menthol inhalation or by depletion of T regulatory cells

A complex network of interactions exists between the olfactory, immune and central nervous systems. In this work we intend to investigate this connection through the use of an immunostimulatory odorant like menthol, analyzing its impact on the immune system and the cognitive capacity in healthy and Alzheimers Disease Mouse Models.

We first found that repeated short exposures to menthol odor enhanced the immune response against ovalbumin immunization. Menthol inhalation also improved the cognitive capacity of immunocompetent mice but not in immunodeficient NSG mice, which exhibited very poor fear-conditioning.

This improvement was associated with a downregulation of IL-1 and IL-6 mRNA in the brains prefrontal cortex, and it was impaired by anosmia induction with methimazole.

Exposure to menthol for 6 months (1 week per month) prevented the cognitive impairment observed in the APP/PS1 mouse model of Alzheimer. Besides, this improvement was also observed by the depletion or inhibition of T regulatory cells.

Treg depletion also improved the cognitive capacity of the APPNL-G-F/NL-G-FAlzheimers mouse model. In all cases, the improvement in learning capacity was associated with a downregulation of IL-1 mRNA. Blockade of the IL-1 receptor with anakinra resulted in a significant increase in cognitive capacity in healthy mice as well as in the APP/PS1 model of Alzheimers disease.

These data suggest an association between the immunomodulatory capacity of smells and their impact on the cognitive functions of the animals, highlighting the potential of odors and immune modulators as therapeutic agents for CNS-related diseases.

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Menthol Inhalation May Boost Cognitive Ability in Alzheimer's - Neuroscience News

High-Resolution Image of the Human Retina Reveals Stunning Details – Neuroscience News

Summary: Researchers developed a new imaging technique to visualize several dozen proteins in a thin tissue section at high resolution using fluorescence microscopy.

The technique enabled researchers to map the development of human retinal organoids at high temporal and spatial resolution, providing insights into how healthy tissue forms and developing a time series that describes the entire 39-week development of retinal organoids.

The researchers aim to apply this approach to other tissue types, such as the human brain and various tumor tissues, creating an atlas that provides information on the development of human organoids and tissues.

Key Facts:

Source: ETH Zurich

What cell types are found in which human tissue, and where? Which genes are active in the individual cells, and which proteins are found there?

Answers to these questions and more are to be provided by a specialized atlas in particular how the different tissues form during embryonic development and what causes diseases.

In creating this atlas, researchers aim to map not only tissue directly isolated from humans, but also structures called organoids. These are three-dimensional clumps of tissue that are cultivated in the laboratory and develop in a way similar to human organs, but on a small scale.

The advantage of organoids is that we can intervene in their development and test active substances on them, which allows us to learn more about healthy tissue as well as diseases, explains Barbara Treutlein, Professor of Quantitative Developmental Biology at the Department of Biosystems Science and Engineering at ETH Zurich in Basel.

To help produce such an atlas, Treutlein, together with researchers from the Universities of Zurich and Basel, has now developed an approach to gather and compile a great deal of information about organoids and their development. The research team applied this approach to the organoids of the human retina, which they derived from stem cells.

Many proteins visible simultaneously

At the heart of the methods the scientists used for their approach was the 4i technology: iterative indirect immunofluorescence imaging. This new imaging technique can visualize several dozen proteins in a thin tissue section at high resolution using fluorescence microscopy.

The 4i technology was developed a few years ago by Lucas Pelkmans, a professor at the University of Zurich and coauthor of the study that has just been published in the scientific journalNature Biotechnology.

It is in this study that the researchers applied this method to organoids for the first time.

Typically, researchers use fluorescence microscopy to highlight three proteins in a tissue, each with a different fluorescent dye.

For technical reasons, it is not possible to stain more than five proteins at a time. In 4i technology, three dyes are used, but these are washed from the tissue sample after measurements have been taken, and three new proteins are stained. This step was performed 18 times, by a robot, and the process took a total of 18 days.

Lastly, a computer merges the individual images into a single microscopy image on which 53 different proteins are visible. They provide information on the function of the individual cell types that make up the retina; for example, rods, cones, and ganglion cells.

The researchers have supplemented this visual information of retinal proteins with information on which genes are read in the individual cells.

High spatial and temporal resolution

The scientists performed all these analyses on organoids that were of different ages and thus at different stages of development. In this way, they were able to create a time series of images and genetic information that describes the entire 39-week development of retinal organoids.

We can use this time series to show how the organoid tissue slowly builds up, where which cell types proliferate and when, and where the synapses are located. The processes are comparable to those of retinal formation during embryonic development, says Gray Camp, a professor at the University of Basel and a senior author of this study.

The researchers published their image information and more findings on retinal development on a publicly accessible website:EyeSee4is.

Further tissue types planned

So far, the scientists have been studying how a healthy retina develops, but in the future, they hope to deliberately disrupt development in retinal organoids with drugs or genetic modifications.

This will give us new insights into diseases such as retinitis pigmentosa, a hereditary condition that causes the retinas light-sensitive receptors to gradually degenerate and ultimately leads to blindness, Camp says.

The researchers want to find out when this process begins and how it can be stopped.

Treutlein and her colleagues are also working on applying the new detailed mapping approach to other tissue types, such as different sections of the human brain and to various tumour tissues. Step by step, this will create an atlas that provides information on the development of human organoids and tissues.

Author: Press OfficeSource: ETH ZurichContact: Press Office ETH ZurichImage: The image is credited to Wahle et al. Nature Biotechnology 2023

Original Research: Open access.Multimodal spatiotemporal phenotyping of human retinal organoid development by Barbara Treutlein et al. Nature Biotechnology

Abstract

Multimodal spatiotemporal phenotyping of human retinal organoid development

Organoids generated from human pluripotent stem cells provide experimental systems to study development and disease, but quantitative measurements across different spatial scales and molecular modalities are lacking.

In this study, we generated multiplexed protein maps over a retinal organoid time course and primary adult human retinal tissue.

We developed a toolkit to visualize progenitor and neuron location, the spatial arrangements of extracellular and subcellular components and global patterning in each organoid and primary tissue. In addition, we generated a single-cell transcriptome and chromatin accessibility timecourse dataset and inferred a gene regulatory network underlying organoid development.

We integrated genomic data with spatially segmented nuclei into a multimodal atlas to explore organoid patterning and retinal ganglion cell (RGC) spatial neighborhoods, highlighting pathways involved in RGC cell death and showing that mosaic genetic perturbations in retinal organoids provide insight into cell fate regulation.

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High-Resolution Image of the Human Retina Reveals Stunning Details - Neuroscience News