Category Archives: Neuroscience

Neuroscience

Connectivity of Language Areas Unique in the Human Brain – Neuroscience News

Summary: Researchers shed new light on how the human brain evolved to be language-ready. Compared to the brains of chimps, the patterns of connections of language areas in the human brain expanded more than was previously thought.

Source: Radboud University

Neuroscientists have gained new insight into how our brain evolved into a language-ready brain. Compared to chimpanzee brains, the pattern of connections of language areas in our brain has expanded more than previously thought.

The researchers at Radboud University and University of Oxford publish their findings in PNAS on July 4.

At first glance, the brains of humans and chimpanzees look very much alike. The perplexing difference between them and us is that we humans communicate using language, whereas non-human primates do not, says co-first author Joanna Sierpowska.

Understanding what in the brain could have enabled this unique ability has inspired researchers for years. However, up to now, their attention was mainly drawn towards a particular nerve tract connecting frontal and temporal lobes calledarcuate fasciculus,which besides showing significant differences between species, is well-known to be involved in language function.

We wanted to shift our focus towards the connectivity of two cortical areas located in the temporal lobe, which are equally important for our ability to use language, says Sierpowska.

To study the differences between the human and chimpanzee brain, the researchers used scans of 50 human brains and 29 chimpanzee brains scanned in a similar way as humans, but under well-controlled anesthesia and as part of their routine veterinary check-ups.

More specifically, they used a technique called diffusion-weighted imaging (DWI), which images white matter, the nerve pathways that connect brain areas.

Using these images, they explored the connectivity of two language-related brain hubs (the anterior and posterior middle areas of the temporal lobe), comparing them between the species.

In humans, both of these areas are considered crucial for learning, using and understanding language and harbor numerous white matter pathways, says Sierpowska.

It is also known that damage to these brain areas has detrimental consequences for language function. However, until now, the question of whether their pattern of connections is unique to humans remained unanswered.

The researchers found that while the connectivity of the posterior middle temporal areas in chimpanzees is confined mainly to the temporal lobe, in humans a new connection towards the frontal and parietal lobes emerged using the arcuate fasciculus as an anatomical avenue. In fact, changes to both human language areas include a suite of expansions to connectivity within the temporal lobes.

The results of our study imply that the arcuate fasciculus surely is not the only driver of evolutionary changes preparing the brain for a full-fledged language capacity, says co-author Vitoria Piai.

Our findings are purely anatomical, so it is hard to say anything about brain function in this context, says Piai.

But the fact that this pattern of connections is so unique for us humans suggests that it may be a crucial aspect of brain organization enabling our distinctive language abilities.

Author: Harriette KoopSource: Radboud UniversityContact: Harriette Koop Radboud UniversityImage: The image is in the public domain

Original Research: The findings will appear in PNAS

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Neuroscience

Birmingham Student’s Essay about Grandmother Takes Third in National Alzheimer’s Awareness Contest – Oakland County Times

Birmingham Students Essay about Grandmother Takes Third in National Alzheimers Awareness Contest

(AFA, July 6, 2022)

Birmingham, MI The Alzheimers Foundation of America (AFA) named Jonathan Marx, of Birmingham, MI, the third-place winner of its national 2022 Alzheimers Awareness Scholarship Essay Contest and awarded him a $2,500 college scholarship.Jonathan was chosen from nearly 1,800 entries nationwide for his essay about his paternal grandmothers battle with Alzheimers, which inspired him to study the brain and neuroscience.

Jonathans heartwarming essay about his grandmother and the impact that she had on his life is a prime example of how Alzheimers disease affects people of all ages, said Charles J. Fuschillo, Jr., AFAs President and CEO.It also served as an example of how a loved one can influence and inspire someone to make a difference in the lives of others and the community around them. It is truly inspiring. We congratulate Jonathan on being chosen as a winner in this competition and thank him for sharing his story.

Jonathans essay focuses on his paternal grandmother, Mame Paulette, who is living with Alzheimers disease in France, and his relationship with her. He describes childhood memories of playing with her at her home and nearby park and breaking through the language barrier by connecting through music and laughter.

When she was diagnosed with Alzheimers six years ago, it inspired Jonathan. In his freshman year, he discovered the Brain Bee, a neuroscience competition. He started learning about the brain and took a specific interest in the subject of music in the brain, based on the experiences he had with his grandmother.

Music is important to me, and it plays a central role in my heritage and culture. Even now, when my grandmother might not recognize my face, she recognizes the tunes of her past, opera songs, and the hits of yesterday, Jonathan wrote. Paulette often enjoys such attempts at bringing her past to life again, and during such moments, I feel as though we can still connectI would never have felt the same drive to learn more about music and its effect without her influence.

Throughout his time in high school, Jonathan continued to pursue his passion for neuroscience, joining the International Youth Neuroscience Association (IYNA) and learning about topics such as neuroethics, Deep Brain Stimulation (DBS), and Closed-Loop DBS. Jonathan, who recently graduated from the International Academy Okma, will continue studying neuroscience at the University of Michigan this fall.

Jonathan wrote, In my struggle to cope with not just Alzheimers but other neurological disorders and diseases, I have found peace in knowledge. I still attempt, and will continue, to try and connect with my grandmother. If it had not been for my familial connections to neurological disorders and diseases, I would not be in the same spot I find myself in today. I implore everyone with the desire to know about how something affects others to go ahead and research it.

AFAs annual Alzheimers Awareness Scholarship Essay Contest asks high school seniors to describe how Alzheimers disease has impacted their lives, what they have learned about themselves, their families, and their community in the face of this disease, and what their plans are for bringing awareness to the disease in the future. This year, AFA awarded almost $90,000 in college scholarships to 117 students from across the country.

For more information about AFAs Alzheimers Awareness Scholarship Essay Contest, call AFA at 866-232-8484 or visit http://www.alzfdn.org.

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Birmingham Student's Essay about Grandmother Takes Third in National Alzheimer's Awareness Contest - Oakland County Times

Neuroscience

Important Factors for Regulating the Body’s Immune Response – Neuroscience News

Summary: Researchers identified differences in isoforms that control Treg cells and how that affects the bodys immune system response.

Source: Indiana University

Researchers atIndiana University School of Medicineare learning more about how special regulatory T cells can impact the immune systems response and how those cells could be manipulated for potential treatments for food allergies and autoimmune diseases.

Ina study recently published inScience Immunology,researchers focused on regulatory T cells, or Treg cells, that regulate immune responses in the body and keep the immune system in order while fighting pathogens.

In some cases, the immune system becomes overly responsive, leading to autoimmune diseases, such as Type 1 diabetes or lupus, food allergies or other issues. Researchers were able to identify the differences in isoforms that control Treg cells and how that affects the bodys immune function.

There is a particular gene that controls this regulatory group of T cells, which controls immune response, saidBaohua Zhou, PhD, lead author of the study and associate professor of pediatrics forIU School of Medicine Department of Pediatrics.

Treg cells can help maintain the right balance to help the immune system not respond too strongly or too weakly.

The human gene FOXP3 produces two major isoforms through alternative splicinga longer isoform and a shorter isoform.

The two isoforms are naturally expressed in humans, but their differences in controlling regulatory T cell phenotype and functionality has been unclear. In this study, researchers showed patients expressing only the shorter isoform fail to maintain self-tolerance and develop issues like immunodeficiency, polyendocrinopathy and enteropathy X-linked (IPEX) syndrome.

They uncovered different functions of the FOXP3 isoforms to regulate Treg cells and immune homeostasis.

Now that we know the different functions of the isoforms, we hope to study how to change them, which could lead to new treatments for autoimmune diseases and allergies, Zhou said.

We could also potentially manipulate them to keep the body from responding improperly to diseases like cancer. If T reg cells are suppressing the antitumor response, can we change that?

Author: Christina GriffithsSource: Indiana UniversityContact: Christina Griffiths Indiana UniversityImage: The image is in the public domain

Original Research: Closed access.FOXP3 exon 2 controls Treg stability and autoimmunity by Baohua Zhou et al. Science Immunology

Abstract

FOXP3 exon 2 controls Treg stability and autoimmunity

Differing from the mouseFoxp3gene that encodes only one protein product, humanFOXP3encodes two major isoforms through alternative splicinga longer isoform (FOXP3 FL) containing all the coding exons and a shorter isoform lacking the amino acids encoded by exon 2 (FOXP3 E2).

The two isoforms are naturally expressed in humans, yet their differences in controlling regulatory T cell phenotype and functionality remain unclear.

In this study, we show that patients expressing only the shorter isoform fail to maintain self-tolerance and develop immunodeficiency, polyendocrinopathy, and enteropathy X-linked (IPEX) syndrome.

Mice withFoxp3exon 2 deletion have excessive follicular helper T (TFH) and germinal center B (GC B) cell responses, and develop systemic autoimmune disease with anti-dsDNA and antinuclear autoantibody production, as well as immune complex glomerulonephritis. Despite having normal suppressive function in in vitro assays, regulatory T cells expressing FOXP3 E2 are unstable and sufficient to induce autoimmunity when transferred intoTcrb-deficient mice.

Mechanistically, the FOXP3 E2 isoform allows increased expression of selected cytokines, but decreased expression of a set of positive regulators ofFoxp3without altered binding to these gene loci.

These findings uncover indispensable functions of the FOXP3 exon 2 region, highlighting a role in regulating a transcriptional program that maintains Tregstability and immune homeostasis.

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Important Factors for Regulating the Body's Immune Response - Neuroscience News

Neuroscience

Protecting the Brain From Dementia-Inducing Abnormal Protein Aggregates – Neuroscience News

Summary: Researchers reveal the critical role the p62 gene plays in the selective autophagy of tau oligomers.

Source: National Institutes for Quantum Science and Technology

In order to maintain cellular homeostasis (i.e., a state of equilibrium), cells undergo selective autophagy or self-degradation of unwanted proteins. Autophagy receptors control this process, by mediating the selection of a target protein that is then cleared.

Tau proteinswhich otherwise play an important role in stabilizing and maintaining the internal organization of neurons in the brainabnormally accumulate inside neurons in conditions like dementia and Alzheimers disease.

This build-up of hyper-phosphorylated tau proteins (or tau oligomers) causes the formation of neurofibrillary tangles (NFTs) and eventual cell death of neurons in the brains of people with dementia, contributing to the diseases progressive neurodegenerative symptoms.

Now, while tau proteins can be degraded by selective autophagy, the exact mechanism of how this occurs remains a mystery.

In a recent breakthrough, however, a study done by scientists at the National Institutes for Quantum Science and Technology in Japan proved the critical role played by a certain genethe p62 genein the selective autophagy of tau oligomers. The team included researcher Maiko Ono, and group leader Naruhiko Saharaboth from the Department of Functional Brain Imaging at the National Institutes for Quantum Science and Technology in Japan.

Their paper, published inAging Cell, was made available online on 5 June 2022.

Previous studies have reported that the abnormal accumulation of thetau proteinsmay be selectively suppressed by autophagy pathways, through the p62 receptor protein (which is a selective autophagy receptor protein).

Says Maiko Ono, This proteins ubiquitin-binding ability helps in the identification of toxic protein aggregates (like tau oligomers), which can then be degraded by cellular processes and organelles.

This studys novelty, however, lay in the demonstration of p62s neuroprotective role in a living model, which had never been done before. So, how did the researchers achieve this? They used mouse models of dementia. The p62 gene had been deleted (or knocked out) in one group of these mice, so they did not express p62 receptor proteins.

On studying the brains of these mice using immunostaining and comparative biochemical analyses, an interesting picture was revealed. Neurotoxic tau protein aggregates were found in the hippocampusthe area of the brain associated with memoryand brainstemthe center that coordinates the bodys breathing, heartbeat, blood pressure, and other voluntary processesof p62 knockout (KO) mice.

When we consider this along with the symptoms of dementia, which includememory loss, confusion, and mood changes, these findings make a lot of sense.

MRI scans revealed that the hippocampus of p62 KO mice was degenerated (atrophied) and inflamed. A postmortem assessment of their brains revealed a greater loss of neurons in their hippocampus.

Further immunofluorescent studies showed that the abnormal tau species aggregates can cause cytotoxicity leading to inflammation and cell death of neurons in p62 KO mice. Oligomeric tau, specifically, accumulated more in the brains of p62 KO mice.

Overall, the findings of this study prove that by eliminating and, hence, preventing the aggregation of oligomeric tau species in the brain, p62 played a neuroprotective role in models of dementia.

At a time when researchers across the word are trying to develop drugs for dementia and other related neurodegenerative disorders, the findings of this study will be of great importance in providing evidence for the accurate targeting of tau oligomers.

Theglobal populationof aging humans is increasing each year; hence, the need to develop methods to slow down the onset and progression of various neurodegenerative diseases is also expanding.

This study provides a positive step towards addressing that need.

Author: Press OfficeSource: National Institutes for Quantum Science and TechnologyContact: Press Office National Institutes for Quantum Science and TechnologyImage: The image is credited to National Institutes for Quantum Science and Technology

Original Research: Open access.Central role for p62/SQSTM1 in the elimination of toxic tau species in a mouse model of tauopathy by Maiko Ono et al. Aging Cell

Abstract

Central role for p62/SQSTM1 in the elimination of toxic tau species in a mouse model of tauopathy

Intracellular accumulation of filamentous tau aggregates with progressive neuronal loss is a common characteristic of tauopathies. Although the neurodegenerative mechanism of tau-associated pathology remains unclear, molecular elements capable of degrading and/or sequestering neurotoxic tau species may suppress neurodegenerative progression.

Here, we provide evidence that p62/SQSTM1, a ubiquitinated cargo receptor for selective autophagy, acts protectively against neuronal death and neuroinflammation provoked by abnormal tau accumulation.

P301S mutant tau transgenic mice (line PS19) exhibited accumulation of neurofibrillary tangles with localization of p62mostly in the brainstem, but neuronal loss with few neurofibrillary tangles in the hippocampus.

In the hippocampus of PS19mice, the p62level was lower compared to the brainstem, and punctate accumulation of phosphorylated tau unaccompanied by co-localization of p62 was observed. In PS19mice deficient in p62 (PS19/p62-KO), increased accumulation of phosphorylated tau, acceleration of neuronal loss, and exacerbation of neuroinflammation were observed in the hippocampus as compared with PS19mice. In addition, increase of abnormal tau and neuroinflammation were observed in the brainstem of PS19/p62-KO.

Immunostaining and dot-blot analysis with an antibody selectively recognizing tau dimers and higher-order oligomers revealed that oligomeric tau species in PS19/p62-KO mice were significantly accumulated as compared to PS19mice, suggesting the requirement of p62 to eliminate disease-related oligomeric tau species.

Our findings indicated that p62 exerts neuroprotection against tau pathologies by eliminating neurotoxic tau species, suggesting that the manipulative p62 and selective autophagy may provide an intrinsic therapy for the treatment of tauopathy.

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Protecting the Brain From Dementia-Inducing Abnormal Protein Aggregates - Neuroscience News

Neuroscience

Gekko partners with CloudArmy on neuroscience – Research Live

UK Customer experience marketing agency Gekko has partnered with behavioural insight firm CloudArmy on a neuroscience research service for brands.

The partnership will see both companies work on a number of neuroscience techniques to help examine unconscious and conscious reactions to test a range of attributes, including brand recognition, responses to brand assets and brand perception.

CloudArmy runs a global online methodology that tests measure responses using smartphones to test stimuli and rapid responses and lexical decision making.

A trial of the partnership with 200 respondents will be used to help Gekko advise brands on in-store displays and messaging.

Daniel Todaro (pictured), managing director at Gekko, said: We are delighted to announce this pioneering service, combining our expertise in retail customer journeys and experiences with CloudArmys neuroscience insights.

Neuroscience is the new frontier of understanding human behaviour and this technology truly enables brands to uncover the truth about what customers really think about your brand, as opposed to what they might say.

Thom Noble, president at CloudArmy, said: We are thrilled to be partnering with Dan and his talented team to collaborate on deeper-level evaluation and optimisation of strategy and design.

We believe the blending of science-based approaches helps augment the creativity of interventions to deliver more compelling and powerful experiences and behavioural nudges.

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Gekko partners with CloudArmy on neuroscience - Research Live

Neuroscience

‘Cognitive Immobility’ When You’re Mentally Trapped in a Place From Your Past – Neuroscience News

Summary: Cognitive immobility is a form of mental entrapment that leads to conscious or unconscious efforts to recreate past instances in familiar locations.

Source: The Conversation

If you have moved from one country to another, you may have left something behind be it a relationship, a home, a feeling of safety or a sense of belonging. Because of this, you will continually reconstruct mental simulations of scenes, smells, sounds and sights from those places sometimes causing stressful feelings and anxiety.

This describes what I have dubbed cognitive immobility, outlined in my newresearch article, published in Culture & Psychology.

The study used autoethnography, a research method in which the author is also the topic of investigation. The research was partly based on my feelings, thoughts and experiences while living in the UK and Germany, far from my ancestral home in Igbo land, Africa.

Cognitive immobility is a stressful mental entrapment that leads to a conscious or unconscious effort to recreate past incidents in one or more locations that one lived in or visited in the past. By doing so, we are hoping to retrieve what is missing or left behind.

When people cannot remain in locations because of conditions beyond their control, such as a war or family or work commitments, their bodies may physically move to a new world, while their minds are left behind trapped in the previous location.

Thus, these people might be described as being cognitively immobilised. During this time, such individuals may seek consolation through the reconstruction of events or physical movement to the locations that they migrated or departed from.

This may be related to homesickness, but it is actually different. Homesickness is a feeling of longing for a previous home, whereas cognitive immobility is a cognitive mechanic that works on our attention and memory to mentally trap us in a place whether it is a previous home or just a place weve visited.

Ourconscious memory(made up of semantic and episodic memories) allows us to remember not just what happened in the past, but also basic knowledge of things around us. Specifically,episodic memoryhelps us remember or reconstruct events we experienced or events that could have happened in the past but didnt.

Indeed, research shows that recalling memory is a process of imagination we often recreate past events in a waythat isnt necessarily accurate, but rather affected by our current beliefs and emotional state. This can make our past look even better than it was.

I believe the experience may be very common for people who migrate. In an unrelatedstudy on Syrian studentswho fled to Turkey, one of them stated: I am still in Syria. My soul is there. I always have memories of my dead cousins. This affects my getting used to here.

Those days will never come back. Another Syrian student said: I left my homeland, my nation, my relatives, everything in Syria. I was physically here, but spiritually there. Both students are clearly suffering from cognitive immobility.

Due to cognitive immobility, some people who have moved from their homes to new locations perpetually long to visit their old homes. But cognitive immobility still applies when they do visit their old home, they immediately long to return to their new homeland.

So, according to my research, a person who has migrated may have a homeless mind while experiencing a situation where no home is truly ahome; even the previous home the ancestral home has lost its distinguishing features and allure in the real world.

It is easy to see why. Ultimately,there is no place without self and no self without place. Therefore, who we are is greatly influenced by the places we live or go and where we desire to be in the present and future.

The implications are serious. For example, it could lead toproblems integrating into a new placeand making new friends potentially making us even more trapped in the past as we dont have an engaging present to distract us. Constantly being stuck in the past could also get in the way of thinking ahead. This can have knock on effects for our wellbeing we need to focus on the past and present as well as the future to feel good.

According to my research, there are three stages of cognitive immobility. The first entails becoming aware of the stress and anxiety caused by leaving the location where the mind is entrapped. During this stage, most migrants experience a lot of uncertainty, which hinders their efforts in many aspects of their lives, including resettling, acquiring new skills such as language and making new acquaintances.

The second stage involves deliberate efforts to reclaim the lost or abandoned object, creating more tension than the first stage. Here, the person might engage in activities such as travelling to their ancestral land, reconstructing their memories and reading about the lost location. Although physical visits to sites could alleviate the stress, this could be a temporary solution.

The last phase consists of deliberate efforts to retain values and seek goals that will alleviate the loss. This approach might consist of using artefacts to symbolise the lost home, such as art or images.

It has also beenarguedthat migrants could make new homes, but also represent their memories and aspirations for example by making friends with people who come from the same place, or have the same religion. This is in fact one way to ultimately reduce the anxiety.

For now, it is evident that cognitive immobility has no perfect cure. But psychology offers some solutions which may prove to be useful, although they are yet to be investigated in the context of cognitive immobility.

For example, there arepsychological interventionsthat can help us balance our mental focus on the past, present and future. To avoid being stuck in the past and become more present focused, we can write down something we are grateful for every day. And to become more future focused, we could imagine our best possible self five years from now it worked for many people during the COVID lockdowns.

Author: Olumba E. EzenwaSource: The ConversationContact: Olumba E. Ezenwa The ConversationImage: The image is in the public domain

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'Cognitive Immobility' When You're Mentally Trapped in a Place From Your Past - Neuroscience News

Neuroscience

Researchers Uncover New Pathway for Accumulation of Age-Promoting ‘Zombie Cells’ – Neuroscience News

Summary: Oxidative damage to telomeres can trigger cellular senescence. The findings could lead to the development of new therapeutics for healthy aging and to combat cancers.

Source: University of Pittsburgh

Senescent cells those that have lost the ability to divide accumulate with age and are key drivers of age-related diseases, such as cancer, dementia and cardiovascular disease.

In a new study, a team led byUniversity of PittsburghandUPMC Hillman Cancer Centerresearchers has uncovered a mechanism by which senescent, or zombie, cells develop.

Published today inNature Structural & Molecular Biology, the study shows for the first time that oxidative damage to telomeres the protective tips of chromosomes that act like plastic caps at the end of a shoelace can trigger cellular senescence. These findings could eventually point to new therapeutics that promote healthy aging or combat cancer.

Zombie cells are still alive, but they cant divide, so they dont help replenish tissues, said senior authorPatricia Opresko, Ph.D., professor of environmental and occupational health and of pharmacology and chemical biology at Pitt.

Although zombie cells dont function properly, theyre not couch potatoes they actively secrete chemicals that promote inflammation and damage neighboring cells. Our study helps answer two big questions: How do senescent cells accumulate with age, and how do telomeres contribute to that?

When a healthy human cell divides to form two identical cells, a small piece of DNA is shaved off each chromosomes tip, so that telomeres become gradually shorter with each division. However, it remains unclear whether over a persons lifetime, a cell may divide so often that its telomeres erode completely, prompting transition to a zombie-like state.

Researchers have known for decades that telomere shortening triggers senescence in lab-grown cells, but they could only hypothesize that DNA damage at telomeres could turn cells into zombies.

Until now, testing this hypothesis had not been possible because the tools used to damage DNA were non-specific, causing lesions across the whole chromosome.

Our new tool is like a molecular sniper, explained first author Ryan Barnes, Ph.D., a postdoctoral fellow inOpreskos lab. It creates oxidative damage exclusively at the telomeres.

To develop such marksman-like precision, the team used a special protein that binds exclusively to telomeres. This protein acts like a catchers mitt, grabbing hold of light-sensitive dye baseballs that the researchers tossed into the cell.

When activated with light, the dye produces DNA-damaging reactive oxygen molecules. Because the dye-catching protein binds only to telomeres, the tool creates DNA lesions specifically at chromosome tips.

Using human cells grown in a dish, the researchers found that damage at telomeres sent the cells into a zombie state after just four days much faster than the weeks or months of repeated cell divisions that it takes to induce senescence by telomere shortening in the lab.

We found a new mechanism for inducing senescent cells that is completely dependent on telomeres, explained Opresko, who also co-leads the Genome Stability Program at UPMC Hillman. These findings also solve the puzzle of why dysfunctional telomeres are not always shorter than functional ones.

Sunlight, alcohol, smoking, poor diet and other factors generate reactive oxygen molecules that damage DNA. Cells have repair pathways to patch up DNA lesions, but, according to Opresko, telomeres are exquisitely sensitive to oxidative damage. The researchers found that damage at telomeres disrupted DNA replication and induced stress signaling pathways that led to senescence.

Now that we understand this mechanism, we can start to test interventions to prevent senescence, said Barnes. For example, maybe there are ways to target antioxidants to the telomeres to protect them from oxidative damage.

The findings could also inform the development of new drugs called senolytics that home in on zombie cells and kill them.

By reducing the accumulation of zombie cells, which contribute to degenerative diseases, we might be able to promote healthspan the length of time that a person is healthy, he added.

Other authors who contributed to the study were Mariarosaria de Rosa, Ph.D., Sanjana A. Thosar, M.S., Ariana C. Detwiler, M.S., Vera Roginskaya, B.S., Bennett Van Houten, Ph.D., and Jacob Stewart-Ornstein, Ph.D., all of Pitt and UPMC, and Marcel P. Bruchez, Ph.D., Carnegie Mellon University.

Funding: This research was supported by the National Institutes of Health (F32AG067710-01, K99ES033771, R35ES030396, R01CA207342 and R01EB017268), the Glenn Foundation for Medical Research, the UPMC Hillman Cancer Center Cytometry Facility (P30CA047904) and the UPMC Hillman Cancer Center Postdoctoral Fellowship for Innovative Cancer Research.

Author: Asher JonesSource: University of PittsburghContact: Asher Jones University of PittsburghImage: The image is credited to Barnes et al., Nature Structural & Molecular Biology

Original Research: Open access.Telomeric 8-oxo-guanine drives rapid premature senescence in the absence of telomere shortening by Barnes et al. Nature Structural & Molecular Biology

Abstract

Telomeric 8-oxo-guanine drives rapid premature senescence in the absence of telomere shortening

Oxidative stress is a primary cause of cellular senescence and contributes to the etiology of numerous human diseases. Oxidative damage to telomeric DNA has been proposed to cause premature senescence by accelerating telomere shortening.

Here, we tested this model directly using a precision chemoptogenetic tool to produce the common lesion 8-oxo-guanine (8oxoG) exclusively at telomeres in human fibroblasts and epithelial cells. A single induction of telomeric 8oxoG is sufficient to trigger multiple hallmarks of p53-dependent senescence.

Telomeric 8oxoG activates ATM and ATR signaling, and enriches for markers of telomere dysfunction in replicating, but not quiescent cells. Acute 8oxoG production fails to shorten telomeres, but rather generates fragile sites and mitotic DNA synthesis at telomeres, indicative of impaired replication.

Based on our results, we propose that oxidative stress promotes rapid senescence by producing oxidative base lesions that drive replication-dependent telomere fragility and dysfunction in the absence of shortening and shelterin loss.

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Researchers Uncover New Pathway for Accumulation of Age-Promoting 'Zombie Cells' - Neuroscience News

Neuroscience

When ASD Occurs With Intellectual Disability, a Convergent Mechanism for Two Top-Ranking Risk Genes May Be the Cause – Neuroscience News

Summary: Mutations in the ASD/intellectual disability genes ADNP and POGZ result in abnormal activation and overexpression of immune response genes and genes for microglia. This results in abnormal brain synaptic function, characteristic of ASD and ID.

Source: University at Buffalo

University at Buffalo scientists have discovered a convergent mechanism that may be responsible for how two top-ranked genetic risk factors for autism spectrum disorder/intellectual disability (ASD/ID) lead to these neurodevelopmental disorders.

While ASD is distinct from ID, a significant proportionapproximately 31%of people with ASD also exhibit ID. Neither condition is well-understood at the molecular level.

Given the vast number of genes known to be involved in ASD/ID and the many potential mechanisms contributing to the disorders, it is exciting to find a shared process between two different genes at the molecular level that could be underlying thebehavioral changes, said Megan Conrow-Graham, Ph.D., first author and an MD/Ph.D. candidate in the Jacobs School of Medicine and Biomedical Sciences at UB.

Published today in the journalBrain, the paper focuses on ADNP and POGZ, the two top-ranked risk factor genes for ASD/ID. The research demonstrates that mutations in these genes result in abnormal activation and overexpression of immune response genes and genes for a type of immune cell in the brain called microglia.

Our finding opens the possibility of targeting microglia and immune genes for treating ASD/ID, but much remains to be studied, given the heterogeneity and complexity of these brain disorders, said Zhen Yan, Ph.D., senior author and SUNY Distinguished Professor in the Department of Physiology and Biophysics in the Jacobs School.

The UB scientists found that mutations in the two genes studied activate microglia and cause immune genes in the brain to be overexpressed. The hypothesized result is the abnormal function of synapses in the brain, a characteristic of ASD/ID.

The research involved studies on postmortem brain tissue from humans with ASD/ID, as well as studies on mice in which ADNP and POGZ were silenced through viral delivery of small interference RNA. These mice exhibited impaired cognitive task performance, such as spatial memory, object recognition memory and long-term memory.

Weakening a repressive function

Under normal conditions, cells in the central nervous system should not express large quantities of genes that activate the immune system, said Conrow-Graham.

ADNP and POGZ both work to repress these genes so that inflammatory pathways are not continuously activated, which could damage surrounding cells. When that repression is weakened, these immune and inflammatory genes are then able to be expressed in large quantities.

The upregulated genes in the mouseprefrontal cortexcaused by the deficiencies in ADNP or POGZ activated the pro-inflammatory response.

This is consistent with what we see in upregulated genes in the prefrontal cortex of humans with ASD/ID, said Conrow-Graham. The prefrontal cortex is the part of the brain responsible for executive function, such as cognition and emotional control.

The mutated genes also activate the glial cells in the brain called microglia, which serve as support cells for neurons and have an immune function in the brain; they comprise 10-15% of all brain cells.

Sensitive microglia

Microglia are very sensitive to pathological changes in the central nervous system and are the main form of active immune defense to maintain brain health, explained Yan. Aberrant activation of microglia, which we demonstrate occurs as a result of deficiency in ADNP or POGZ, could lead to the damage and loss of synapses and neurons.

The researchers are hopeful that future research will determine whether chronic neuroinflammation could be directly contributing to at least some cases of ASD/ID, in which targeting microglia or inflammatory signaling pathways could prove to be a useful treatment.

The researchers pointed out that the clinical presentation of both ASD and ID is incredibly varied. Significant variation also likely is present in the kinds of mechanisms responsible for the symptoms of ASD and/or ID.

We found that changes in two riskgeneslead to a convergent mechanism, likely involving immune activation, said Conrow-Graham. However, this probably isnt the case for all individuals with ASD/ID. When designingclinical trialsto evaluate treatment effectiveness, I think our research underscores the importance of considering the genetic factors involved in an individuals ASD/ID.

The research is the culmination of Conrow-Grahams Ph.D. work; she has now returned to complete the last two years of the MD degree in the Jacobs School. She described her experience pursuing both an MD and a Ph.D. as extremely complementary.

The immune system has a role

My training at each level was super helpful to supplement the other, she said. When I began my Ph.D., I had completed two years of MD training, so I was familiar with the basics of physiology, anatomy and pathology.

Because of this, I was able to bring a broader perspective to my neuroscience research, identifying how the immune system might be playing a role. Prior to this, our lab had not really investigated immunology-related pathways, so having that background insight was really beneficial.

She added that she learned so much from all of her colleagues in Yans lab, including faculty members, lab technicians and other students. I learned so many technical skills that I had never used before joining the lab, thanks to the dedication of lab co-workers for my training, she said.

Her experience at the lab bench working on the basic science underlying neuropsychiatric disorders will definitely influence her work as a clinician.

I plan to pursue a career as a child and adolescent psychiatrist, so I may be able to work directly with this patient population, she said.

Were learning now that better care may be able to be provided by taking a personalized medicine approach, taking into account genetics, psychosocial factors and others. Being able to take a very deep dive into the field of psychiatric genetics was a privilege that I hope will help me to provide the best care for patients.

Author: Ellen GoldbaumSource: University at BuffaloContact: Ellen Goldbaum University at BuffaloImage: The image is in the public domain

Original Research: Closed access.A convergent mechanism of high risk factors ADNP and POGZ in neurodevelopmental disorders by Megan Conrow-Graham et al. Brain

Abstract

A convergent mechanism of high risk factors ADNP and POGZ in neurodevelopmental disorders

ADNPandPOGZare two top-ranking risk factors for autism spectrum disorder and intellectual disability, but how they are linked to these neurodevelopmental disorders is largely unknown. BothADNPandPOGZare chromatin regulators, which could profoundly affect gene transcription and cellular function in the brain.

Using post-mortem tissue from patients with autism spectrum disorder, we found diminished expression ofADNPandPOGZin the prefrontal cortex, a region highly implicated in neurodevelopmental disorders.

To understand the functional role of these neurodevelopmental disorder risk factors, we used viral-based gene transfer to investigate howAdnporPogzdeficiency in mouse prefrontal cortex affects behavioural, transcriptomic and synaptic function. Mice with prefrontal cortex deficiency ofAdnporPogzexhibited specific impairment of cognitive task performance.

RNA-sequencing revealed thatAdnporPogzdeficiency induced prominent upregulation of overlapping genes enriched in neuroinflammation, similar to the elevation of pro-inflammatory genes in humans with neurodevelopmental disorders. Concomitantly,AdnporPogzdeficiency led to the significant increase of pro-phagocytic microglial activation in prefrontal cortex, as well as the significant decrease of glutamatergic transmission and postsynaptic protein expression.

These findings have uncovered the convergent functions of two top risk factors for autism spectrum disorder and intellectual disability in prefrontal cortex, providing a mechanism linking chromatin, transcriptional and synaptic dysregulation to cognitive deficits associated with neurodevelopmental disorders.

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When ASD Occurs With Intellectual Disability, a Convergent Mechanism for Two Top-Ranking Risk Genes May Be the Cause - Neuroscience News

Neuroscience

Cannes 2022 – The Neuroscience of Apple’s winners – AdNews

Shaun Seixas.

Dr. Shaun Seixas, Director of Research, Neuro-Insight

Apple had another successful outing at Cannes this year picking up multiple Lions across Film, Film Craft, Entertainment and Media categories. Two of its short form films, Detectives and Fumble are particularly noteworthy, because both the brand and product are woven seamlessly into the narrative.

How we did it

Neuro-Insight measured brain activity to see how over 100 typical viewers respond to the ad. The specific technology used by Neuro-Insight is founded in work originally developed for academic and neuroscience research and has been used to analyse the effectiveness of Cannes award winners for over eight years.

The technology allows us to simultaneously record viewers second-by-second changes in approach (like)/withdraw (dislike), emotional intensity, engagement and memory, whilst watching advertisements. Of these measures, Neuro-Insight predominantly focuses on Long-term Memory Encoding, given its strong and highly researched link to consumer behaviour. This measure reveals, second-by-second, what the brain is storing (or encoding) into conscious and subconscious long-term memory.

True Detective?

Apples aptly named Detectives spot plays on the police detective trope, with protagonist and background character waiting patiently during a stakeout. It is the early moments where the background character experiences an existential crisis about being out of focus while his foreground, in-focus partner, assures him that it is because the camera only focuses on the most important character. As the narrative plays out, the viewer is brought on a journey that plays on dramatic pauses and a big reveal, both of which are aimed to elicit a strong response in viewers.

To precisely identify the size and shape of this response we focussed on our Memory Encoding & Engagement measures to highlight the moments that strongly resonated with viewers. Memory Encoding is a strong predictor of future behaviour, contributes to creation and updating of memory structures, and is a prerequisite for mental availability. In contrast, Engagement refers to personal relevance the more relevant something is to you, the higher the levels of engagement you will experience.

Below is the times series analysis for Apples Detective spot. The red trace reflects memory encoding from the left hemisphere, which is primarily responsible for the encoding of the detail in experiences, such as text, dialogue or micro features. In contrast, the right hemisphere, reflected by the blue line, is concerned with the storing of global features, such as soundtracks, scenery, and facial expressions, as well as the emotional underpinnings of a particular experience.

We can see that the peaks of Memory Encoding & Engagement are aligned with pivotal moments in the narrative, from the early existential crisis to the threat of the big reveal, to final moments to when the background character briefly comes into focus. Whilst the actors performance, framing and screenplay each play a significant role in the strong response we see, the fact that this scene is reminiscent of many popular police procedural dramas also influences why many of these scenes were so strongly encoded and highly engaging.

Importantly, the product reveal section of the ad is also strongly encoded. Given the ubiquitous nature of the iPhone, the three camera eyes are easily recognisable and serve as another moment of branding before the Apple logo appears on screen.

A big fumble

While the pacing and tone of Detectives was slow and dramatic, Apples Fumble spot was its antithesis. Featuring a woman who is frantically trying to catch her iPhone as it fumbles from her grasp, the narrative is carried by exaggerated movements and slow motion via the rhythmic sounds of Nitin Sawhney.

Despite differences in executive when compared to Detectives, the broad shape of the memory encoding response to Fumble is similar. In particular, the ad starts strongly, with the initial fumble and soundtrack both contributing to early peak responses. This is followed by another peak in response, during the moment where we think the iPhone has been saved, only for it to be lost again. These strong responses contribute heavily to the peak responses that we observe when the main message is delivered and are sustained through to final branding.

Perhaps, the most unique feature of this spot was its ability to also connect with the viewer emotionally.

As we can see in the above graphs, the emotional response closely mirrors the different stages of the iPhone flight. The emotional response is positive during the early stages where we see the exaggerated attempt to catch the iPhone in combination with the soundtracks staccato. However, the emotional response switches to a strong level of withdraw when the phone is fumbled for the last time, and we see the pain in the protagonists face and as the phone slips away a feeling Im sure many of us have experienced. This pattern of response is indicative of anxiety, and given the current state of the iPhone, is unsurprising. Lastly, during the reveal where we see the phone is OK and a smile on our protagonists face, the emotional response switches back to positive. This response tells us the creative was successful in creating an emotional connection with the viewer; something which is quite difficult to do in a 30-second spot.

Great ads but

Youve probably heard that phrase Great ad.but who was it for? and may have even experienced it before. You see, our brain is constantly breaking up our daily experiences into smaller chunks, which form the basis for what is stored and remembered. In terms of advertising, the gaps in memory often occur as the doorway to memory is temporarily shut during final branding, a process known as Conceptual Closure. This phenomenon is highlighted in the recently published analysis of Samsungs award-winning Spider and the Window spot.

However, in the case of both Apple ads we see the opposite strong levels of memory encoding during the reveal, and importantly at final branding. Given the strong memory encoding response that we observe during the narratives of both ads, the resulting memory structures will be strongly linked to the Apple brand and further furnish the Apples brand room.

The Brand Room

The brand room is a helpful analogy for the neural networks that we create in response to brand messaging. Consider Apple as a room in the brain, which begins life bare and unacknowledged. Over time, and through repeated interactions with the brand, the room becomes furnished with opinions, colour, and memories of the brand and its associations.

Putting it all together

Apple has been consistently active during the pandemic with various campaigns that either spoke to the quality of video on the iPhone (Shot on iPhone series) or highlighted other iPhone features. These two ads which were part of those campaigns were highly effective from a neuroscience standpoint and undoubtedly contributed to Apples bottom line. In particular, Apple increased its hold on premium phone sales from 57% in Q1 2021 to 62% in Q1 of 2022. Given how well Apple campaigns have performed over the past year and consistently being in front of potential new customers, it comes as no surprise that the brand continues to grow at the expense of competitors.

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Cannes 2022 - The Neuroscience of Apple's winners - AdNews

Neuroscience

Neuroscience Program – Neuroscience Program

The Neuroscience Program prepares students through education, research, and professional development for successful careers in neuroscience or neuroscience-related fields.

The Neuroscience Program Ph.D.-granting graduate program began in 1998, and theundergraduate B.S.-granting program began in 2012. The interdisciplinary program is comprised of over 70 faculty members with appointments in 18 departments and 5 colleges, including the 3 medical schools.

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Neuroscience Program - Neuroscience Program