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NT/ Injectable porous scaffolds promote better, quicker healing after spinal cord injuries

Neuroscience biweekly vol. 28, 5th March — 17th March

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Injectable, macroporous scaffolds for delivery of therapeutic genes to the injured spinal cord

by Arshia Ehsanipour, Mayilone Sathialingam, Laila M. Rad, Joseph de Rutte, Rebecca D. Bierman, Jesse Liang, Weikun Xiao, Dino Di Carlo, Stephanie K. Seidlits in APL Bioengineering

Spinal cord injuries can be life-changing and alter many important neurological functions. Unfortunately, clinicians have relatively few tools to help patients regain lost functions.

Researchers from UCLA have developed materials that can interface with an injured spinal cord and provide a scaffolding to facilitate healing. To do this, scaffolding materials need to mimic the natural spinal cord tissue, so they can be readily populated by native cells in the spinal cord, essentially filling in gaps left by injury.

“In this study, we demonstrate that incorporating a regular network of pores throughout these materials, where pores are sized similarly to normal cells, increases infiltration of cells from spinal cord tissue into the material implant and improves regeneration of nerves throughout the injured area,” said author Stephanie Seidlits.

The researchers show how the pores improve efficiency of gene therapies administered locally to the injured tissues, which can further promote tissue regeneration.

Since many spinal cord injuries result from a contusion, the biomaterial implants need to be injected in or near the injured area without causing damage to any surrounding spared tissue. A major technical challenge has been fabricating scaffold materials with cell-scale pore sizes that are also injectable.

In the researchers’ method, they injected beads of material through a small needle into the spinal cord, where the beads stick together to form a scaffold, where cells can crawl in the pore spaces between the beads. The researchers found inclusion of these larger cell-scale pores within biomaterial scaffolds improved cell infiltration, gene delivery, and tissue repair after spinal cord injury, compared to more conventional materials with nanoscale pores.

The researchers made the highly porous scaffolds using two different methods. One was simpler but created a more irregularly sized pore network. The second was more complicated but created a highly regular pore structure.

Even though both materials had the same average pore size and chemical composition, more regenerating nerves were found to infiltrate scaffolds with regularly shaped pores.

“These results inform how to maximize interfacing with the nervous system,” said Seidlits. “This has potential applications not only for developing new therapies for brain and spinal cord repair but also for brain-machine interfaces, prosthetics, and treatment of neurodegenerative diseases.”

Delivery of FLuc-encoding lentivirus to the injured spinal cord. Both pHA-MP and mHA-MP scaffolds exhibited significantly greater integrated bioluminescence intensity than NP-HA scaffolds [(a) and (b)] 2 weeks post-injection. There was no significant difference between pHA-MP and mHA-MP scaffolds. Bootstrap analysis with 10 000 iterations agreed with statistical testing (c )(*p < 0.05, Kruskal-Wallis test with Dunn’s multiple comparisons test, n = 5–6).

Long-lasting analgesia via targeted in situ repression of NaV1.7 in mice

by Ana M. Moreno, Fernando Alemán, Glaucilene F. Catroli, Matthew Hunt, Michael Hu, Amir Dailamy, Andrew Pla, Sarah A. Woller, Nathan Palmer, Udit Parekh, Daniella McDonald, Amanda J. Roberts, Vanessa Goodwill, Ian Dryden, Robert F. Hevner, Lauriane Delay, Gilson Gonçalves dos Santos, Tony L. Yaksh, Prashant Mali in Science Translational Medicine

A gene therapy for chronic pain could offer a safer, non-addictive alternative to opioids. Researchers at the University of California San Diego developed the new therapy, which works by temporarily repressing a gene involved in sensing pain. It increased pain tolerance in mice, lowered their sensitivity to pain and provided months of pain relief without causing numbness.

The gene therapy could be used to treat a broad range of chronic pain conditions, from lower back pain to rare neuropathic pain disorders — conditions for which opioid painkillers are the current standard of care.

“What we have right now does not work,” said first author Ana Moreno, a bioengineering alumna from the UC San Diego Jacobs School of Engineering. Opioids can make people more sensitive to pain over time, leading them to rely on increasingly higher doses. “There’s a desperate need for a treatment that’s effective, long-lasting and non-addictive.”

The idea for such a treatment emerged when Moreno was a Ph.D. student in UC San Diego bioengineering professor Prashant Mali’s lab. Mali had been investigating the possibility of applying CRISPR-based gene therapy approaches to rare as well as common human diseases. Moreno’s project focused on exploring potential therapeutic avenues. One day, she came across a paper about a genetic mutation that causes humans to feel no pain. This mutation inactivates a protein in pain-transmitting neurons in the spinal cord, called NaV1.7. In individuals lacking functional NaV1.7, sensations like touching something hot or sharp do not register as pain. On the other hand, a gene mutation that leads to overexpression of NaV1.7 causes individuals to feel more pain.

When Moreno read this, it clicked. “By targeting this gene, we could alter the pain phenotype,” she said. “What’s also cool is that this gene is only involved in pain. There aren’t any severe side effects observed with this mutation.”

Non-permanent gene therapy

Moreno had been working on gene repression using the CRISPR gene editing tool as part of her dissertation. Specifically, she was working with a version of CRISPR that uses what’s called “dead” Cas9, which lacks the ability to cut DNA. Instead, it sticks to a gene target and blocks its expression.

Moreno saw an opportunity to use this approach to repress the gene that codes for NaV1.7. She points out an appeal of this approach: “It’s not cutting out any genes, so there are no permanent changes to the genome. You wouldn’t want to permanently lose the ability to feel pain,” she said. “One of the biggest concerns with CRISPR gene editing is off-target effects. Once you cut DNA, that’s it. You can’t go back. With dead Cas9, we’re not doing something irreversible.”

Mali, who is a co-senior author of the study, says that this use of dead Cas9 opens the door to using gene therapy to target common diseases and chronic ailments.

“In some common diseases, the issue is that a gene is being misexpressed. You don’t want to completely shut it down,” he said. “But if you could turn down the dose of that gene, you could bring it to a level where it is not pathogenic. That is what we are doing here. We don’t completely take away the pain phenotype, we dampen it.”

Moreno and Mali co-founded the spinoff company Navega Therapeutics to work on translating this gene therapy approach, which they developed at UC San Diego, into the clinic. They teamed up with Tony Yaksh, an expert in pain systems and a professor of anesthesiology and pharmacology at UC San Diego School of Medicine. Yaksh is a scientific advisor to Navega and co-senior author of the study.

Early lab studies

The researchers engineered a CRISPR/dead Cas9 system to target and repress the gene that codes for NaV1.7. They administered spinal injections of their system to mice with inflammatory and chemotherapy-induced pain. These mice displayed higher pain thresholds than mice that did not receive the gene therapy; they were slower to withdraw a paw from painful stimuli (heat, cold or pressure) and spent less time licking or shaking it after being hurt.

The treatment was tested at various timepoints. It was still effective after 44 weeks in the mice with inflammatory pain and 15 weeks in those with chemotherapy-induced pain. The length of duration is still being tested, researchers said, and is expected to be long-lasting. Moreover, the treated mice did not lose sensitivity or display any changes in normal motor function.

To validate their results, the researchers performed the same tests using another gene editing tool called zinc finger proteins. It’s an older technique than CRISPR, but it does the same job. Here, the researchers designed zinc fingers that similarly bind to the gene target and block expression of NaV1.7. Spinal injections of the zinc fingers in mice produced the same results as the CRISPR-dead Cas9 system.

“We were excited that both approaches worked,” Mali said. “The beauty about zinc finger proteins is that they are built on the scaffold of a human protein. The CRISPR system is a foreign protein that comes from bacteria, so it could cause an immune response. That’s why we explored zinc fingers as well, so we have an option that might be more translatable to the clinic.”

The researchers say this solution could work for a large number of chronic pain conditions arising from increased expression of NaV1.7, including diabetic polyneuropathy, erythromelalgia, sciatica and osteoarthritis. It could also provide relief for patients undergoing chemotherapy.

And due to its non-permanent effects, this therapeutic platform could address a poorly met need for a large population of patients with long-lasting (weeks to months) but reversible pain conditions, Yaksh said.

“Think of the young athlete or wounded war fighter in which the pain may resolve with wound healing,” he said. “We would not want to permanently remove the ability to sense pain in these people, especially if they have a long life expectancy. This CRISPR/dead Cas9 approach offers this population an alternative therapeutic intervention — that’s a major step in the field of pain management.”

Schematic of the overall strategy used for in situ NaV1.7 repression using ZFP-KRAB and KRAB-dCas9 via the intrathecal route of administration (ROA). NaV1.7 is a DRG channel involved in the transduction of noxious stimuli into electric impulses at the peripheral terminals of DRG neurons. In situ repression of NaV1.7 via AAV-ZFP-KRAB and AAV-KRAB-dCas9 is achieved through intrathecal injection, leading to disruption of the pain signal before reaching the brain.

Functional genomic analyses highlight a shift in Gpr17 ‐regulated cellular processes in oligodendrocyte progenitor cells and underlying myelin dysregulation in the aged mouse cerebrum

by Andrea D. Rivera, Francesca Pieropan, Irene Chacon‐De‐La‐Rocha, Davide Lecca, Maria P. Abbracchio, Kasum Azim, Arthur M. Butt in Aging Cell

A new study led by the University of Portsmouth has identified that one of the major factors of age-related brain deterioration is the loss of a substance called myelin.

Myelin acts like the protective and insulating plastic casing around the electrical wires of the brain — called axons. Myelin is essential for superfast communication between nerve cells that lie behind the supercomputer power of the human brain.

The loss of myelin results in cognitive decline and is central to several neurodegenerative diseases, such as Multiple Sclerosis and Alzheimer’s disease. This new study found that the cells that drive myelin repair become less efficient as we age and identified a key gene that is most affected by ageing, which reduces the cells ability to replace lost myelin.

The study, is part of an international collaboration led by Professor Arthur Butt at the University of Portsmouth with Dr Kasum Azim at the University of Dusseldorf in Germany, together with Italian research groups of Professor Maria Pia Abbracchio in Milan and Dr Andrea Rivera in Padua.

Professor Butt said: “Everyone is familiar with the brain’s grey matter, but very few know about the white matter, which comprises of the insulated electrical wires that connect all the different parts of our brains.

A key feature of the ageing brain is the progressive loss of white matter and myelin, but the reasons behind these processes are largely unknown. The brain cells that produce myelin — called oligodendrocytes — need to be replaced throughout life by stem cells called oligodendrocyte precursors. If this fails, then there is a loss of myelin and white matter, resulting in devastating effects on brain function and cognitive decline. An exciting new finding of our study is that we have uncovered one of the reasons that this process is slowed down in the aging brain.”

Dr Rivera, lead author of the study while he was in University of Portsmouth and who is now a Fellow at the University of Padua, explained:

“By comparing the genome of a young mouse brain to that of a senile mouse, we identified which processes are affected by ageing. These very sophisticated analysis allowed us to unravel the reasons why the replenishment of oligodendrocytes and the myelin they produce is reduced in the aging brain.

We identified GPR17, the gene associated to these specific precursors, as the most affected gene in the ageing brain and that the loss of GPR17 is associated to a reduced ability of these precursors to actively work to replace the lost myelin.”

The work is still very much ongoing and has paved the way for new studies on how to induce the ‘rejuvenation’ of oligodendrocyte precursor cells to efficiently replenish lost white matter.

Dr Azim of the University of Dusseldorf said:

“This approach is promising for targeting myelin loss in the aging brain and demyelination diseases, including Multiple Sclerosis, Alzheimer’s disease and neuropsychiatric disorders. Indeed, we have only touched the tip of the iceberg and future investigation from our research groups aim to bring our findings into human translational settings.”

Dr Rivera performed the key experiments published in this study while at the University of Portsmouth and he has been awarded the MSCA Seal of Excellence @UniPD Fellowship to translate these findings and investigate this further in the human brain, in collaboration with Professors Raffele De Caro, Andrea Porzionato and Veronica Macchi at the Institute of Human Anatomy of the University of Padua.

Dr Emma Gray, Assistant Director of Research at the MS Society, said:

“MS can be relentless and painful, and there are sadly still no treatments to stop disability progression. We can see a future where no one has to worry about MS getting worse but, for that to happen, we need to find ways to repair damaged myelin. This research sheds light on why cells that drive myelin repair become less efficient as we age, and we’re really proud to have helped fund it. By improving our understanding of ageing brain stem cells, it gives us a new target to help slow the progression of MS, and could have important implications for future treatment.”

Transcriptomic characterisation of ageing‐induced genes in the brain. (a) QC of Datasets, analysis and dispersion plot of normalised mean gene counts. (b) MA plot illustrating the differential expression analysis and identified 1706 genes significantly altered between the two groups (FDR <0.01 or pADJ <0.01) using DEseq2 (V.1.4.2). (c )Heatmap of the most altered genes in the ageing cerebrum ranked by FDR values and colour intensity relative to log2 fold change. (d) Major ageing‐induced gene changes (threshold genes at FDR <0.05) represented by GO analysis revealing Extracellular Matrix (ECM) Organisation, Gliogenesis, Neurogenesis and Myelination among the most altered Biological Pathways. (e) Network analysis of predicted protein‐protein interaction performed with STRING (V.10.5) identified an alteration of the major processes and highlighting Cell Cycle (Red, FDR<0.0127), Cell Differentiation (Green, FDR<0.0307) and Inflammatory Response (Blue, FDR<0.0243, PPI Enrichment p‐Value <1.0e‐16)

Altered Neuronal Support and Inflammatory Response in Bipolar Disorder Patient-Derived Astrocytes

by Krishna C. Vadodaria et al. in Stem Cell Reports

Brain cells called astrocytes derived from the induced pluripotent stem cells of patients with bipolar disorder offer suboptimal support for neuronal activity. Researchers show that this malfunction can be traced to an inflammation-promoting molecule called interleukin-6 (IL-6), which is secreted by astrocytes. The results highlight the potential role of astrocyte-mediated inflammatory signaling in the psychiatric disease, although further investigation is needed.

“Our findings suggest that IL-6 may contribute to defects associated with bipolar disorder, opening new avenues for clinical intervention,” says co-senior study author Fred Gage of the Salk Institute for Biological Studies.

Approximately 1–3% of individuals suffer from bipolar disorder, which is characterized by recurrent mood states ranging from high energy and elation, known as mania, to low energy and depressive episodes. Several lines of evidence suggest a link between imbalanced inflammatory signaling and bipolar disorder. For example, these patients show signs of chronic inflammation and have a higher prevalence of inflammation-related conditions such as cardiovascular disease, diabetes, and metabolic syndrome. Moreover, they have higher concentrations of circulating pro-inflammatory cytokines such as IL-1? and IL-6, particularly during manic episodes.

“While mild inflammation can be beneficial for many neural processes, the overproduction of IL-6 may worsen the symptoms of bipolar disorder and may be an important therapeutic target,” says co-senior study author Maria Carolina Marchetto of the Salk Institute for Biological Studies and the University of California, San Diego and the University of California San Diego’s Department of Anthropology.

Astrocytes are known to participate in the inflammatory cascade within the brain. These cells are activated by IL-1? and other pro-inflammatory cytokines and in turn secrete cytokines that participate in the process of neuroinflammation. “Due to a growing understanding of the role of neuroinflammation in psychiatric disorders, we wondered whether altered inflammation-driven signaling in astrocytes was associated with bipolar disorder,” says co-senior study author Renata Santos of Salk and the Institute of Psychiatry and Neuroscience of Paris.

The researchers previously developed a method for rapidly generating inflammation-responsive astrocytes from human induced pluripotent stem cells (iPSCs). In the new study, they compared the inflammation signatures in iPSC-derived astrocytes generated from six patients with bipolar disorder and four healthy individuals.

The response of astrocytes from patients to pro-inflammatory cytokines revealed a unique transcriptional pattern, which was characterized by higher expression of the IL-6 gene. As a result, these cells secreted more IL-6, which negatively impacted the activity of co-cultured neurons. Exposure to the culture medium of the astrocytes was sufficient to decrease neuronal activity, and this effect was partially blocked by IL-6-inactivating antibody. Moreover, blood levels of IL-6 were higher in patients compared to healthy individuals.

“These results suggest that secreted factors from astrocytes play a role in regulating neuronal activity and that, in the case of bipolar disorder, IL-6 at least in part mediated the effects of inflammation-primed astrocytes on neuronal activity,” says first author Krishna Vadodaria of the Salk Institute for Biological Studies.

Moving forward, the researchers plan to further investigate the effect of IL-6 on neuronal activity. In the meantime, the findings should be interpreted with caution. The experiments may not mimic conditions of chronic inflammation associated with bipolar disorder, and the culture system did not include many cell types involved in potentially relevant immune responses. In addition, iPSC-derived astrocytes are relatively immature compared to those in the brains of bipolar patients, and there is a lack of reliable biomarkers for pinpointing exact developmental age.

“At this moment, direct extrapolation of the results to patients remains challenging,” Gage says. “Despite these limitations, our findings elucidate aspects of the understudied role of astrocytes in neuroinflammation in psychiatric disorders.”

Characterization and Validation of BD Patient iPSC-Derived Astrocytes through a Glial Precursor Intermediate

(A) Summary of an 8- to 10-week cell culture timeline to differentiate human astrocytes from iPSCs. Bright field images show cell types: patient fibroblast-derived iPSCs, GPCs, and 5-week-old astrocytes (scale bar, 300 μm).

(B) Representative images and quantification of GPCs immunostained with early glial fate markers: A2B5, Vimentin and NFIA. Scale bar, 50 μm.

(C ) Representative images and quantification of 4- to 5-week-old astrocytes immunostained with astrocytic markers: S100β, CD44, and GFAP. Scale bar, 50 μm. Data are expressed as mean ± SEM of percent of stained cells over total number detected by DAPI. Experiments in triplicate with n = 4 controls and n = 6 BD patients.

(D) Transcriptome of BD astrocytes shows inflammatory response to IL-1β: unsupervised hierarchical clustering of top expressed genes from whole transcriptome analysis (increased, red; decreased, blue) in vehicle and IL-1β-treated astrocytes from four control and five BD individuals (in duplicate).

(E) Normalized expression values for IL-6 in unstimulated (veh) BD versus control astrocytes.

(F) Venn diagram showing the number of upregulated genes in IL-1β treatment versus vehicle in controls (92) and BD (188), with 421 overlapping genes.

(G) List of significantly enriched GO terms for 188 uniquely upregulated genes in IL-1β-treated BD astrocytes.

Gene-expression correlates of the oscillatory signatures supporting human episodic memory encoding

by Stefano Berto, Miles R. Fontenot, Sarah Seger, Fatma Ayhan, Emre Caglayan, Ashwinikumar Kulkarni, Connor Douglas, Carol A. Tamminga, Bradley C. Lega, Genevieve Konopka in Nature Neuroscience

UT Southwestern scientists have identified key genes involved in brain waves that are pivotal for encoding memories. The findings, could eventually be used to develop novel therapies for people with memory loss disorders such as Alzheimer’s disease and other forms of dementia.

Making a memory involves groups of brain cells firing cooperatively at various frequencies, a phenomenon known as neural oscillations. However, explain study leaders Bradley C. Lega, M.D., associate professor of neurological surgery, neurology, and psychiatry, and Genevieve Konopka, Ph.D., associate professor of neuroscience, the genetic basis of this process is not clear.

“There’s a famous saying for 100 years in neuroscience: Neurons that fire together will wire together,” says Lega. “We know that cells involved in learning fire in groups and form new connections because of the influence of these oscillations. But how genes regulate this process in people is completely unknown.”

Lega and Konopka, both members of the Peter O’Donnell Jr. Brain Institute, collaborated on a previous study to explore this question, collecting data on neural oscillations from volunteers and using statistical methods to connect this information to data on gene activity collected from postmortem brains. Although these results identified a promising list of genes, Konopka says, there was a significant shortcoming in the research: The oscillation and genetic data came from different sets of individuals.

More recently, the duo capitalized on an unprecedented opportunity — performing a similar study on patients undergoing surgeries in which damaged parts of their brains were removed to help control their epilepsy.

The researchers worked with 16 volunteers from UT Southwestern’s Epilepsy Monitoring Unit, where epilepsy patients stay for several days before having surgery to remove the damaged parts of their brains that spark seizures. Electrodes implanted in these patients’ brains over this time not only help their surgeons precisely identify the focus of the seizure, Lega says, but can also provide valuable information on the brain’s inner workings.

While recording the electrical activity in the brains of 16 volunteers, the researchers had them do “free recall” tasks that involved reading a list of 12 words, doing a short math problem to distract them, and then recalling as many words as possible. As these patients were memorizing the word lists, their brain waves were recorded, creating a dataset that differed slightly from person to person.

About six weeks later, each volunteer underwent a temporal lobectomy — removal of the brain’s temporal lobe — to cure their seizures. This area frequently serves as an originator of epileptic seizures and is also important for memory formation. Within five minutes of the surgery, the damaged brain tissue was sent for processing to assess genetic activity.

Konopka’s team first performed whole RNA sequencing, a technique that identifies active genes, in temporal lobe samples that included all the brain’s cell types. Using statistical techniques that linked this activity to the patients’ neural oscillations during the free recall task, the researchers identified 300 genes that appeared to play a part in oscillatory activity. The researchers narrowed this number to a dozen “hub genes” that appeared to control separate gene networks.

Next, the researchers looked at the activity of these hub genes in separate cell types within the samples. Surprisingly, they found that several of these hubs weren’t active within nerve cells themselves but in a different population of cells known as glia. These cells provide support and protection for nerve cells, including manufacturing the fatty layer that insulates nerve cells so they can efficiently pass electrical signals.

Finally, the researchers used a technique called ATAC-seq, which identifies areas of DNA that are open for molecules called transcription factors to attach to and activate genes. Using this approach, they honed in on SMAD3, a gene that appears to serve as a master regulator to control activity of many of the hub genes and the genes they control in return.

Konopka and Lega note that several of the genes they identified as important in human neural oscillations have been linked to other disorders that can affect learning and memory, such as autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, and schizophrenia. With further research into these genes and the networks they operate within, it may eventually be possible to target select genes with pharmaceuticals to improve memory in individuals with these and other conditions, the researchers say.

“This gives us an entry point,” says Konopka, a Jon Heighten Scholar in Autism Research. “It’s something we can focus on to learn more about the underpinnings of human memory.”

Human hippocampal connectivity is stronger in olfaction than other sensory systems

by Guangyu Zhou, Jonas K. Olofsson, Mohamad Z. Koubeissi, Georgios Menelaou, Joshua Rosenow, Stephan U. Schuele, Pengfei Xu, Joel L. Voss, Gregory Lane, Christina Zelano in Progress in Neurobiology

A new Northwestern Medicine paper is the first to identify a neural basis for how the brain enables odors to so powerfully elicit those memories. The paper shows unique connectivity between the hippocampus — the seat of memory in the brain — and olfactory areas in humans.

This new research suggests a neurobiological basis for privileged access by olfaction to memory areas in the brain. The study compares connections between primary sensory areas — including visual, auditory, touch and smell — and the hippocampus. It found olfaction has the strongest connectivity. It’s like a superhighway from smell to the hippocampus.

“During evolution, humans experienced a profound expansion of the neocortex that re-organized access to memory networks,” said lead investigator Christina Zelano, assistant professor of neurology at Northwestern University Feinberg School of Medicine. “Vision, hearing and touch all re-routed in the brain as the neocortex expanded, connecting with the hippocampus through an intermediary — association cortex — rather than directly. Our data suggests olfaction did not undergo this re-routing, and instead retained direct access to the hippocampus.”

Epidemic loss of smell in COVID-19 makes research more urgent In COVID-19, smell loss has become epidemic, and understanding the way odors affect our brains — memories, cognition and more — is more important than ever, Zelano noted.

“There is an urgent need to better understand the olfactory system in order to better understand the reason for COVID-related smell loss, diagnose the severity of the loss and to develop treatments,” said first author Guangyu Zhou, research assistant professor of neurology at Northwestern. “Our study is an example of the basic research science that our understanding of smell, smell loss and future treatments is built on.”

Below is a Q & A with Zelano about the importance of the sense of smell, olfactory research and the link to COVID-19.

Why do smells evoke such vivid memories?

“This has been an enduring mystery of human experience. Nearly everyone has been transported by a whiff of an odor to another time and place, an experience that sights or sounds rarely evoke. Yet, we haven’t known why. The study found the offactory parts of the brain connect more strongly to the memory parts than other senses. This is a major piece of the puzzle, a striking finding in humans. We believe our results will help future research solve this mystery.’

How does smell research relate to COVID-19?

“The COVID-19 epidemic has brought a renewed focus and urgency to olfactory research. While our study doesn’t address COVID smell loss directly, it does speak to an important aspect of why olfaction is important to our lives: smells are a profound part of memory, and odors connect us to especially important memories in our lives, often connected to loved ones. The smell of fresh chopped parsley may evoke a grandmother’s cooking, or a whiff of a cigar may evoke a grandfather’s presence. Odors connect us to important memories that transport us back to the presence of those people.”

Loss of smell linked to depression and poor quality of life

“Loss of the sense of smell is underestimated in its impact. It has profound negative effects of quality of life, and many people underestimate that until they experience it. Smell loss is highly correlated with depression and poor quality of life.

Most people who lose their smell to COVID regain it, but the time frame varies widely, and some have had what appears to be permanent loss. Understanding smell loss, in turn, requires research into the basic neural operations of this under-studied sensory system.

Research like ours moves understanding of the olfactory parts of the brain forward, with the goal of providing the foundation for translational work on, ultimately, interventions.”

Recalling autobiographical self-efficacy episodes boosts reappraisal-effects on negative emotional memories

by Christina Paersch, Ava Schulz, Frank H. Wilhelm, Adam D. Brown, Birgit Kleim in Emotion

The unpredictable nature of life during the coronavirus pandemic is particularly challenging for many people. Not everyone can cope equally well with the uncertainty and loss of control. Research has shown that while a large segment of the population turns out to be resilient in times of stress and potentially traumatic events, others are less robust and develop stress-related illnesses. Events that some people experience as draining seem to be a source of motivation and creativity for others.

These differing degrees of resilience demonstrate that people recover from stressful events at different rates, with psychosocial factors such as positivity, optimism, the ability to self-regulate, social skills, problem-solving skills and social support playing a role. A team from the Department of Psychology and the University Hospital of Psychiatry Zurich teamed up with researchers from New York to investigate how people can strengthen their psychological resilience when facing adversity.

Importance of believing in your own power

“Self-efficacy is a key element of resilience,” explains Birgit Kleim, professor of psychology at UZH and director of the study. “By self-efficacy, I mean the belief that we have the ability to influence things to at least a small degree, even if some things are unchangeable.” A self-efficacious person is convinced that they can draw on their own powers to overcome difficult and challenging situations. It doesn’t matter whether this is actually the case, as Kleim explains: “Without believing in your own capabilities, you wouldn’t take on any challenges in the first place.” Self-efficacious people have stronger problem-solving abilities and a higher level of persistence. They also show changes in brain activation in regions linked to emotional regulation.

How might it be possible, then, to boost people’s self-efficacy so that they can harness its positive powers in the coronavirus era? For the resilience study, a team of researchers examined 75 people who were distressed by a negative emotional memory. Before recalling and reassessing this distressing memory, one group of subjects was instructed to vividly recall a positive event such as a beautiful experience in nature or a joyful encounter with others. The others were instructed to think of a time in which they felt they were particularly self-efficacious: situations such as having a successful conversation, passing a difficult exam or giving a presentation. In many cases, doing this exercise just once was already enough to achieve a positive effect.

Recalling autobiographical self-efficacy yields dramatic effects

“Recalling a specific instance of one’s own self-efficacy proved to have a far greater impact than recalling a positive event,” says Kleim. People who actively recalled their own self-efficacious behavior found it easier to reassess a negative situation and view it in a different light. They perceived the negative experience as less distressing than the subjects who were instructed to reflect on a positive memory unconnected to self-efficacy.

“Our study shows that recalling self-efficacious autobiographical events can be used as a tool both in everyday life and in clinical settings to boost personal resilience,” explains the research team. It may be possible to strategically use memories of overcoming past challenges as a way of coping with crisis situations. This also applies to the coronavirus crisis, where these memories can be used to shield against the negative impacts of the pandemic.

Impact of the KCNQ2/3 Channel Opener Ezogabine on Reward Circuit Activity and Clinical Symptoms in Depression: Results From a Randomized Controlled Trial

by Sara Costi, Laurel S. Morris, Katherine A. Kirkwood, Megan Hoch, Morgan Corniquel, Brittany Vo-Le, Tabish Iqbal, Nisha Chadha, Diego A. Pizzagalli, Alexis Whitton, Laura Bevilacqua, Manish K. Jha, Stefan Ursu, Alan C. Swann, Katherine A. Collins, Ramiro Salas, Emilia Bagiella, Michael K. Parides, Emily R. Stern, Dan V. Iosifescu, Ming-Hu Han, Sanjay J. Mathew, James W. Murrough in American Journal of Psychiatry

Researchers from the Icahn School of Medicine at Mount Sinai have identified a drug that works against depression by a completely different mechanism than existing treatments.

Their study showed that ezogabine (also known as retigabine), a drug that opens KCNQ2/3 type of potassium channels in the brain, is associated with significant improvements in depressive symptoms and anhedonia in patients with depression. Anhedonia is the reduced ability to experience pleasure or lack of reactivity to pleasurable stimuli; it is a core symptom of depression and associated with worse outcomes, poor response to antidepressant medication, and increased risk of suicide.

Ezogabine was approved by the U.S. Food and Drug Administration in 2011 as an anticonvulsant for epilepsy treatment but had not been previously studied in depression. The research results provide initial evidence in humans for the KCNQ2/3 channel as a new target for novel drug discovery for depression and anhedonia.

“Our study is the first randomized, placebo-controlled trial to show that a drug affecting this type of ion channel in the brain can improve depression and anhedonia in patients. Targeting this channel represents a completely different mechanism of action than any currently available antidepressant treatment,” says James Murrough, MD, PhD, Associate Professor of Psychiatry, and Neuroscience, Director of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai, and senior author of the paper.

The new drug target, the KCNQ2/3 channel, is a member of a large family of ion channels referred to as the KCNQ (or Kv7) family that act as important controllers of brain cell excitability and function in the central nervous system. These channels affect brain cell function by controlling the flow of the electrical charge across the cell membrane in the form of potassium (K+) ions. Researchers at Mount Sinai, including study co-author Ming-Hu Han, PhD, Professor of Pharmacological Sciences, and Neuroscience, had previously conducted a series of studies in mice showing that changes in the KCNQ2/3 potassium channel play an important role in determining if the animals show depression and anhedonic-like behavior following chronic stress in an experimental model of depression. In particular, mice that appear to be resistant to developing depression in the face of stress show an increase in KCNQ2/3 channels in the brain.

“We viewed enhanced functioning of the KCNQ channel as a potential molecular mechanism of resilience to stress and depression,” said Dr. Han, who also discovered that if he gave a drug that could increase the activity of this channel, such as ezogabine, to mice that had become depressed in the stress model, the mice no longer showed the depression and anhedonic behaviors; in other words, the drug acted as an antidepressant.

The current study was a two-site, double-blind, randomized, placebo-controlled proof of concept clinical trial designed as a preliminary test of the hypothesis that increasing KCNQ2/3 channel activity in the brain is a viable new approach for the treatment of depression. Forty-five adult patients diagnosed with a depressive disorder were assigned to a five-week treatment period with daily dosing of either ezogabine or matching placebo. All participants underwent clinical evaluations and functional magnetic resonance imaging (fMRI) during a reward task at baseline and at the end of the treatment period. Compared to patients treated with placebo, those treated with ezogabine showed a significant and large reduction in several key measures of depression severity, anhedonia, and overall illness severity. For example, significant improvements following treatment with ezogabine compared to placebo was observed using the Montgomery-Asberg Depression Rating Scale (MADRS), the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR), the Snaith-Hamilton Pleasure Scale (SHAPS), and the Temporal Experience of Pleasure Scale (TEPS)-Anticipatory Subscale. The ezogabine group showed also a trend towards an increase in response to reward anticipation in the brain compared to placebo although this effect did not reach statistical significance.

“The fundamental insight by Dr. Han’s group that a drug that essentially mimicked a mechanism of stress resilience in the brain could represent a whole new approach to the treatment of depression was very exciting to us,” said Dr. Murrough.

In collaboration with Dr. Han, Dr. Murrough carried out a series of studies in patients with depression to begin to test if the observations in mice could be translated to humans. An initial open-label (no placebo) study in patients with depression led by Dr. Murrough provided initial evidence that ezogabine could improve symptoms of depression and anhedonia in a manner that was associated with changes in brain function.

“I think it’s fair to say that most of us on the study team were quite surprised at the large size of the beneficial effect of ezogabine on clinical symptoms across multiple measures related to depression. We are greatly encouraged by these findings and the hope they offer for the prospect of developing novel, effective treatments for depression and related disorders. New treatments are urgently needed given that more than one-third of people suffering from depression are inadequately treated with currently approved therapeutics.”

KCNQ5 Potassium Channel Activation Underlies Vasodilation by Tea

by Kaitlyn E. Redford, Salomé Rognant, Thomas A. Jepps, Geoffrey W. Abbott in Cellular Physiology and Biochemistry

A new study from the University of California, Irvine shows that compounds in both green and black tea relax blood vessels by activating ion channel proteins in the blood vessel wall. The discovery helps explain the antihypertensive properties of tea and could lead to the design of new blood pressure-lowering medications.

The discovery was made by the laboratory of Geoffrey Abbott, PhD, a professor in the Department of Physiology and Biophysics at the UCI School of Medicine. Kaitlyn Redford, a graduate student in the Abbott Lab, was first author of the study titled, “KCNQ5 potassium channel activation underlies vasodilation by tea.”

Results from the research revealed that two catechin-type flavonoid compounds (epicatechin gallate and epigallocatechin-3-gallate) found in tea, each activate a specific type of ion channel protein named KCNQ5, which allows potassium ions to diffuse out of cells to reduce cellular excitability. As KCNQ5 is found in the smooth muscle that lines blood vessels, its activation by tea catechins was also predicted to relax blood vessels — a prediction confirmed by collaborators at the University of Copenhagen.

“We found by using computer modeling and mutagenesis studies that specific catechins bind to the foot of the voltage sensor, which is the part of KCNQ5 that allows the channel to open in response to cellular excitation. This binding allows the channel to open much more easily and earlier in the cellular excitation process,” explained Abbott.

Because as many as one third of the world’s adult population have hypertension, and this condition is considered to be the number one modifiable risk factor for global cardiovascular disease and premature mortality, new approaches to treating hypertension have enormous potential to improve global public health. Prior studies demonstrated that consumption of green or black tea can reduce blood pressure by a small but consistent amount, and catechins were previously found to contribute to this property. Identification of KCNQ5 as a novel target for the hypertensive properties of tea catechins may facilitate medicinal chemistry optimization for improved potency or efficacy.

In addition to its role in controlling vascular tone, KCNQ5 is expressed in various parts of the brain, where it regulates electrical activity and signaling between neurons. Pathogenic KCNQ5 gene variants exist that impair its channel function and in doing so cause epileptic encephalopathy, a developmental disorder that is severely debilitating and causes frequent seizures. Because catechins can cross the blood-brain barrier, discovery of their ability to activate KCNQ5 may suggest a future mechanism to fix broken KCNQ5 channels to ameliorate brain excitability disorders stemming from their dysfunction.

Tea has been produced and consumed for more than 4,000 years and upwards of 2 billion cups of tea are currently drunk each day worldwide, second only to water in terms of the volume consumed by people globally. The three commonly consumed caffeinated teas (green, oolong, and black) are all produced from the leaves of the evergreen species Camellia sinensis, the differences arising from different degrees of fermentation during tea production.

Black tea is commonly mixed with milk before it is consumed in countries including the United Kingdom and the United States. The researchers in the present study found that when black tea was directly applied to cells containing the KCNQ5 channel, the addition of milk prevented the beneficial KCNQ5-activating effects of tea. However, according to Abbott, “We don’t believe this means one needs to avoid milk when drinking tea to take advantage of the beneficial properties of tea. We are confident that the environment in the human stomach will separate the catechins from the proteins and other molecules in milk that would otherwise block catechins’ beneficial effects.”

This hypothesis is borne out by other studies showing antihypertensive benefits of tea regardless of milk co-consumption. The team also found, using mass spectrometry, that warming green tea to 35 degrees Celsius alters its chemical composition in a way that renders it more effective at activating KCNQ5.

“Regardless of whether tea is consumed iced or hot, this temperature is achieved after tea is drunk, as human body temperature is about 37 degrees Celsius,” explained Abbott. “Thus, simply by drinking tea we activate its beneficial, antihypertensive properties.”

Green tea extract inhibits KCNQ1/E1 channels. All error bars indicate SEM. A: Image of the tea producing plant, Camellia sinensis. B: Topological representation of a Kv channel showing two of the four α subunits that comprise a channel. PH, pore helix; VSD, voltage sensing domain. C: Schematic of heteromeric composition of KCNQ2/KCNQ3 (left) and KCNQ1/KCNE1 (right) channels. D: Voltage protocol used throughout the study (20 mV prepulse increments). E: Mean TEVC current traces for KCNQ1/E1 cRNA-injected Xenopus oocytes (10 ng/ 2 ng) as indicated, in the absence (Control) or presence of 1% green tea extract (GTE) (n = 5). Dashed line here and throughout indicates the zero-current level. F: Left, mean tail current; right, mean prepulse peak current verses prepulse voltages for traces as in E (n = 5). G: Scatter plot of unclamped membrane potential (EM) for cells as in E (n = 5). Statistical analyses by two-way ANOVA. H: Magnified mean tail currents from E (left, control; right, green tea extract). I: Mean TEVC current trace for KCNQ1 (left), with mean tail current magnified (right). J: Mean TEVC current traces for uninjected oocytes in the absence (Control) or presence of GTE. K: Left, mean tail current; right, mean tail current fold-change verses prepulse voltage for traces as in J (n = 5). L: Scatter plot of unclamped membrane potential (EM) for cells as in E (n = 5). Statistical analyses by two-way ANOVA. M: Mean TEVC currents from uninjected oocytes (J) subtracted from mean KCNQ1/E1 currents (E). N: Left, mean tail current; right, mean prepulse current verses prepulse voltage for traces as in M (n = 5).

Becoming the King in the North: identification with fictional characters is associated with greater self–other neural overlap

by Timothy W Broom, Robert S Chavez, Dylan D Wagner in Social Cognitive and Affective Neuroscience

If you count yourself among those who lose themselves in the lives of fictional characters, scientists now have a better idea of how that happens.

Researchers found that the more immersed people tend to get into “becoming” a fictional character, the more they use the same part of the brain to think about the character as they do to think about themselves.

“When they think about a favorite fictional character, it appears similar in one part of the brain as when they are thinking about themselves,” said Timothy Broom, lead author of the study and doctoral student in psychology at The Ohio State University.

The study involved scanning the brains of 19 self-described fans of the HBO series “Game of Thrones” while they thought about themselves, nine of their friends and nine characters from the series. (The characters were Bronn, Catelyn Stark, Cersei Lannister, Davos Seaworth, Jaime Lannister, Jon Snow, Petyr Baelish, Sandor Clegane and Ygritte.)

Participants reported which “Game of Thrones” character they felt closest to and liked the most.

“Game of Thrones” was a fantasy drama series lasting eight seasons and concerning political and military conflicts between ruling families on two fictional continents. It was ideal for this study, Broom said, because it attracted a devoted fan base and the large cast presented a variety of characters that people could become attached to.

One of the key findings involved participants in the study who scored highest on what is called “trait identification.” In a questionnaire they completed as part of the study, these participants agreed most strongly with statements like “I really get involved in the feelings of the characters in a novel.”

“People who are high in trait identification not only get absorbed into a story, they also are really absorbed into a particular character,” Broom said. “They report matching the thoughts of the character, they are thinking what the character is thinking, they are feeling what the character is feeling. They are inhabiting the role of that character.”

For the study, the participants’ brains were scanned in an fMRI machine while they evaluated themselves, friends and “Game of Thrones” characters. An fMRI indirectly measures activity in various parts of the brain through small changes in blood flow.

The researchers were particularly interested in what was happening in a part of the brain called the ventral medial prefrontal cortex (vMPFC), which shows increased activity when people think about themselves and, to a lesser extent, when thinking about close friends.

The process was simple. While in the fMRI, participants were shown a series of names — sometimes themselves, sometimes one of their nine friends, and other times one of the nine characters from “Game of Thrones.” Each name appeared above a trait, like lonely, sad, trustworthy or smart.

Participants simply said “yes” or “no” to whether the trait described the person while the researchers simultaneously measured activity in the vMPFC portion of their brains.

As expected, the vMPFC was most active when people were evaluating themselves, less active when they evaluated friends, and least active when they evaluated “Game of Thrones” characters.

But for those who were high in trait identification, the vMPFC was more active when they thought about the fictional characters than it was for participants who identified less with the characters. That brain area was especially active when they evaluated the character they felt closest to and liked the most.

The findings help explain how fiction can have such a big impact on some people, said Dylan Wanger, co-author of the study and assistant professor of psychology at Ohio State.

“For some people, fiction is a chance to take on new identities, to see worlds though others’ eyes and return from those experiences changed,” Wagner said.

“What previous studies have found is that when people experience stories as if they were one of the characters, a connection is made with that character, and the character becomes intwined with the self. In our study, we see evidence of that in their brains.”

(A) The nine Game of Thrones characters selected as targets in the study based on the high levels of variance in participants’ ratings of closeness. Below each character is a violin plot displaying the distribution across participants of the 0–100 ratings of similarity to self (blue), liking (orange) and closeness (green). The width of each plot reflects the density of responses within that range of the scale for each rating type. Vertical lines within each plot mark the lower extrema, mean and higher extrema for each rating type. (B) Examples of the trait-evaluation task completed while participants underwent functional magnetic resonance imaging. Target trials were randomly intermixed with jittered fixation. On each trial, participants made a yes–no judgment using a two-button button box as to whether the trait word presented below the dash accurately described the target presented above the dash. These judgments were made for 19 targets in total: the self, nine fictional characters and nine self-selected personally familiar friends and acquaintances. On target trials, the co-presented target and trait word appeared for 2000 ms followed by 500 ms of fixation.

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