​Summary: Mouse models of corticospinal injuries reveal adult neurons begin a natural regeneration process by reverting back to an embryonic state. The regeneration is sustained with the help of a gene more commonly associated with Huntington’s disease.  - Source: UCSD

​When adult brain cells are injured, they revert to an embryonic state, according to new findings published in the April 15, 2020 issue of Nature by researchers at University of California San Diego School of Medicine, with colleagues elsewhere. The scientists report that in their newly adopted immature state, the cells become capable of re-growing new connections that, under the right conditions, can help to restore lost function.
Repairing damage to the brain and spinal cord may be medical science’s most daunting challenge. Until relatively recently, it seemed an impossible task. The new study lays out a “transcriptional roadmap of regeneration in the adult brain.”
“Using the incredible tools of modern neuroscience, molecular genetics, virology and computational power, we were able for the first time to identify how the entire set of genes in an adult brain cell resets itself in order to regenerate. This gives us fundamental insight into how, at a transcriptional level, regeneration happens,” said senior author Mark Tuszynski, MD, PhD, professor of neuroscience and director of the Translational Neuroscience Institute at UC San Diego School of Medicine.
Using a mouse model, Tuszynski and colleagues discovered that after injury, mature neurons in adult brains revert back to an embryonic state. “Who would have thought,” said Tuszynski. “Only 20 years ago, we were thinking of the adult brain as static, terminally differentiated, fully established and immutable.”
But work by Fred “Rusty” Gage, PhD, president and a professor at the Salk Institute for Biological Studies and an adjunct professor at UC San Diego, and others found that new brain cells are continually produced in the hippocampus and subventricular zone, replenishing these brain regions throughout life.
“Our work further radicalizes this concept,” Tuszynski said. “The brain’s ability to repair or replace itself is not limited to just two areas. Instead, when an adult brain cell of the cortex is injured, it reverts (at a transcriptional level) to an embryonic cortical neuron. And in this reverted, far less mature state, it can now regrow axons if it is provided an environment to grow into. In my view, this is the most notable feature of the study and is downright shocking.”
To provide an “encouraging environment for regrowth,” Tuszynski and colleagues investigated how damaged neurons respond after a spinal cord injury. In recent years, researchers have significantly advanced the possibility of using grafted neural stem cells to spur spinal cord injury repairs and restore lost function, essentially by inducing neurons to extend axons through and across an injury site, reconnecting severed nerves.

Last year, for example, a multi-disciplinary team led by Kobi Koffler, PhD, assistant professor of neuroscience, Tuszynski, and Shaochen Chen, PhD, professor of nanoengineering and a faculty member in the Institute of Engineering in Medicine at UC San Diego, described using 3D printed implants to promote nerve cell growth in spinal cord injuries in rats, restoring connections and lost functions.
The latest study produced a second surprise: In promoting neuronal growth and repair, one of the essential genetic pathways involves the gene Huntingtin (HTT), which, when mutated, causes Huntington’s disease, a devastating disorder characterized by the progressive breakdown of nerve cells in the brain.
Tuszynski’s team found that the “regenerative transcriptome” — the collection of messenger RNA molecules used by corticospinal neurons — is sustained by the HTT gene. In mice genetically engineered to lack the HTT gene, spinal cord injuries showed significantly less neuronal sprouting and regeneration.
“While a lot of work has been done on trying to understand why Huntingtin mutations cause disease, far less is understood about the normal role of Huntingtin,” Tuszynski said. “Our work shows that Huntingtin is essential for promoting repair of brain neurons. Thus, mutations in this gene would be predicted to result in a loss of the adult neuron to repair itself. This, in turn, might result in the slow neuronal degeneration that results in Huntington’s disease.”
Co-authors include: Gunnar Poplawski, Erna Van Nierkerk, Neil Mehta, Philip Canete, Richard Lie, Jessica Meves and Binhai Zheng, all at UC San Diego; Riki Kawaguchi and Giovanni Coppola, UCLA; Paul Lu, UC San Diego and Veterans Administration Medical Center, San Diego; and Ioannis Dragatsis, University of Tennesee.

​ABOUT THIS ARTICLE​
Source:
UCSD
Media Contacts:
Scott LaFee – UCSD
Image Source:
The image is credited to UC San Diego Health Sciences.
Original Research: Closed access
“Injured adult neurons regress to an embryonic transcriptional growth state”. by Gunnar H. D. Poplawski, Riki Kawaguchi, Erna Van Niekerk, Paul Lu, Neil Mehta, Philip Canete, Richard Lie, Ioannis Dragatsis, Jessica M. Meves, Binhai Zheng, Giovanni Coppola & Mark H. Tuszynski.
Nature doi:10.1038/s41586-020-2200-5.
Abstract
Injured adult neurons regress to an embryonic transcriptional growth state
Grafts of spinal-cord-derived neural progenitor cells (NPCs) enable the robust regeneration of corticospinal axons and restore forelimb function after spinal cord injury1; however, the molecular mechanisms that underlie this regeneration are unknown. Here we perform translational profiling specifically of corticospinal tract (CST) motor neurons in mice, to identify their ‘regenerative transcriptome’ after spinal cord injury and NPC grafting. Notably, both injury alone and injury combined with NPC grafts elicit virtually identical early transcriptomic responses in host CST neurons. However, in mice with injury alone this regenerative transcriptome is downregulated after two weeks, whereas in NPC-grafted mice this transcriptome is sustained. The regenerative transcriptome represents a reversion to an embryonic transcriptional state of the CST neuron. The huntingtin gene (Htt) is a central hub in the regeneration transcriptome; deletion of Htt significantly attenuates regeneration, which shows that Htt has a key role in neural plasticity after injury.

​Nearly one in 25 American adults has serious mental illness, which means odds are someone in your life is coping with anxiety, depression, OCD, bipolar disorder or another debilitating condition. Still, shame about mental illness — likely a holdover from when people wrongly believed such conditions were character flaws or a mother’s fault — can make it hard to seek help or even know what to say to those who struggle. To shine a light on the daily realities of mental illness, Good Housekeeping and the National Alliance on Mental Illness (NAMI) surveyed more than 4,000 people, and found that over a third had a close friend or relative with mental illness. In our special package on how to support loved ones with mental illness, women who live with these widely misunderstood psychological issues share what it feels like, and how you can make a difference.

Going through a frightening or heart-wrenching experience — losing a loved one, being injured or assaulted, witnessing an act of violence, even living through a pandemic — triggers a range of emotions, from sadness to anger to fear. For most people, the intensity of those feelings fades over time. But for the 6 to 7% of Americans who will suffer from post-traumatic stress disorder at some point in their life, the feelings can linger for months or years, and can even get worse over time.
“I would have reenactments of the sexual abuse I experienced,” says Rachel, 34, from Danville, PA. “I would have the same physical feelings and shortness of breath that I had when it was happening, and at times I would even disassociate. It was almost as if my vision was coming from above me and I was watching myself go through it. There was this intense feeling that I was living in one reality that was physical and another reality that was emotional, but no one could see the second reality except me.”

​For some people, no matter how much they may want to leave the past in the past and move on with their lives, the flashbacks don't stop. “It plays in a constant loop in my head, like a movie. Even though I wish I wasn’t watching it, it pops on whenever it feels like it,” explains Melony, 38, from Baltimore. Simple, everyday interactions can trigger her PTSD, which stems from domestic abuse and assault. “Even a stranger getting too close to me makes me feel like I have to back away or run because they’re going to hurt me. It could be someone just looking at me — I get paranoid and feel like they’re trying to grab me.”
In addition to avoiding certain people and places, people with PTSD may feel like they’re constantly unsafe and on edge, which can affect their relationships. They may become detached emotionally as a protective mechanism, Dr. Weinstein says, adding that one of the most common symptoms is recurring nightmares and difficulty sleeping. It can sometimes be difficult for friends and family to understand why the person with PTSD continues to have trauma, even years after the event, which leads to further feelings of isolation. “Two people can experience the same events very differently, Dr. Weinstein says. “They can have a different interpretation and what happened may have a different impact on them.”

​When dealing with PTSD, support from loved ones is crucial. Here are ways you can be an ally to someone struggling:

• Don’t imply that there's a deadline for "getting over" it: Never say to a person with PTSD, But that happened so long ago, can’t you just move on? “This is not like breaking a bone, where it heals and you’re over it. The timeline is very variable,” says Dr. Weinstein. “For some people, it will naturally fade over time, but for other people it can continue to be very real and present in their daily life.”
• Listen without judgment: Instead of trying to explain away your friend’s fears or challenge their memory of the trauma, give them the freedom to be in charge their own narrative. “When you’re talking to someone who’s experienced emotional abuse, letting them be an expert on their life is so vital,” says Rachel, who explains that an abuser often convinces his victim that her feelings have no value and her words are unbelievable. Simply listening and asking "Can you tell me more about that?" is a powerful gift, she says.
• Ask about triggers and help make a plan: If your friend or family member knows that certain things can set off flashbacks or panic attacks (loud noises, news footage of war zones, or family gatherings, for example), ask in advance how you can help if they need it, and follow their lead.
• Don’t try to put a positive spin on the past: It can be really hard to hear about someone else’s trauma, so you may be tempted to say something like, “Well at least you weren’t permanently injured,” or “At least they finally arrested the guy.” Rachel says this happens quite often. “It makes me feel like I’m supposed to have thankfulness for what happened to me." Sitting with your friend while they talk about the most difficult parts of their story can help provide the sense of safety and trust they are trying to rebuild.

​The COVID-19 crisis has made life more challenging for everyone — especially those who are struggling with a mental illness. Visit NAMI’s COVID-19 Resource and Information Guide for additional advice. For more info on PTSD, visit the PTSD Alliance.

​by Scott Berinato  March 23, 2020 at Harvard Business Review - Click HERE for original link to article

​HBR Staff/d3sign/Getty Images

Some of the HBR edit staff met virtually the other day — a screen full of faces in a scene becoming more common everywhere. We talked about the content we’re commissioning in this harrowing time of a pandemic and how we can help people. But we also talked about how we were feeling. One colleague mentioned that what she felt was grief. Heads nodded in all the panes.
If we can name it, perhaps we can manage it. We turned to David Kessler for ideas on how to do that. Kessler is the world’s foremost expert on grief. He co-wrote with Elisabeth Kübler-Ross On Grief and Grieving: Finding the Meaning of Grief through the Five Stages of Loss. His new book adds another stage to the process, Finding Meaning: The Sixth Stage of Grief. Kessler also has worked for a decade in a three-hospital system in Los Angeles. He served on their biohazards team. His volunteer work includes being an LAPD Specialist Reserve for traumatic events as well as having served on the Red Cross’s disaster services team. He is the founder of www.grief.com, which has over 5 million visits yearly from 167 countries.  Kessler shared his thoughts on why it’s important to acknowledge the grief you may be feeling, how to manage it, and how he believes we will find meaning in it. The conversation is lightly edited for clarity.

HBR: People are feeling any number of things right now. Is it right to call some of what they’re feeling grief?
Kessler: Yes, and we’re feeling a number of different griefs. We feel the world has changed, and it has. We know this is temporary, but it doesn’t feel that way, and we realize things will be different. Just as going to the airport is forever different from how it was before 9/11, things will change and this is the point at which they changed. The loss of normalcy; the fear of economic toll; the loss of connection. This is hitting us and we’re grieving. Collectively. We are not used to this kind of collective grief in the air.

You said we’re feeling more than one kind of grief?
Yes, we’re also feeling anticipatory grief. Anticipatory grief is that feeling we get about what the future holds when we’re uncertain. Usually it centers on death. We feel it when someone gets a dire diagnosis or when we have the normal thought that we’ll lose a parent someday. Anticipatory grief is also more broadly imagined futures. There is a storm coming. There’s something bad out there. With a virus, this kind of grief is so confusing for people. Our primitive mind knows something bad is happening, but you can’t see it. This breaks our sense of safety. We’re feeling that loss of safety. I don’t think we’ve collectively lost our sense of general safety like this. Individually or as smaller groups, people have felt this. But all together, this is new. We are grieving on a micro and a macro level.

What can individuals do to manage all this grief?
Understanding the stages of grief is a start. But whenever I talk about the stages of grief, I have to remind people that the stages aren’t linear and may not happen in this order. It’s not a map but it provides some scaffolding for this unknown world. There’s denial, which we say a lot of early on: This virus won’t affect us. There’s anger: You’re making me stay home and taking away my activities. There’s bargaining: Okay, if I social distance for two weeks everything will be better, right? There’s sadness: I don’t know when this will end. And finally there’s acceptance. This is happening; I have to figure out how to proceed.
Acceptance, as you might imagine, is where the power lies. We find control in acceptance. I can wash my hands. I can keep a safe distance. I can learn how to work virtually.

When we’re feeling grief there’s that physical pain. And the racing mind. Are there techniques to deal with that to make it less intense?
Let’s go back to anticipatory grief. Unhealthy anticipatory grief is really anxiety, and that’s the feeling you’re talking about. Our mind begins to show us images. My parents getting sick. We see the worst scenarios. That’s our minds being protective. Our goal is not to ignore those images or to try to make them go away — your mind won’t let you do that and it can be painful to try and force it. The goal is to find balance in the things you’re thinking. If you feel the worst image taking shape, make yourself think of the best image. We all get a little sick and the world continues. Not everyone I love dies. Maybe no one does because we’re all taking the right steps. Neither scenario should be ignored but neither should dominate either.

Anticipatory grief is the mind going to the future and imagining the worst. To calm yourself, you want to come into the present. This will be familiar advice to anyone who has meditated or practiced mindfulness but people are always surprised at how prosaic this can be. You can name five things in the room. There’s a computer, a chair, a picture of the dog, an old rug, and a coffee mug. It’s that simple. Breathe. Realize that in the present moment, nothing you’ve anticipated has happened. In this moment, you’re okay. You have food. You are not sick. Use your senses and think about what they feel. The desk is hard. The blanket is soft. I can feel the breath coming into my nose. This really will work to dampen some of that pain.

You can also think about how to let go of what you can’t control. What your neighbor is doing is out of your control. What is in your control is staying six feet away from them and washing your hands. Focus on that.
Finally, it’s a good time to stock up on compassion. Everyone will have different levels of fear and grief and it manifests in different ways. A coworker got very snippy with me the other day and I thought, That’s not like this person; that’s how they’re dealing with this. I’m seeing their fear and anxiety. So be patient. Think about who someone usually is and not who they seem to be in this moment.

One particularly troubling aspect of this pandemic is the open-endedness of it.
This is a temporary state. It helps to say it. I worked for 10 years in the hospital system. I’ve been trained for situations like this. I’ve also studied the 1918 flu pandemic. The precautions we’re taking are the right ones. History tells us that. This is survivable. We will survive. This is a time to overprotect but not overreact.
And, I believe we will find meaning in it. I’ve been honored that Elisabeth Kübler-Ross’s family has given me permission to add a sixth stage to grief: Meaning. I had talked to Elisabeth quite a bit about what came after acceptance. I did not want to stop at acceptance when I experienced some personal grief. I wanted meaning in those darkest hours. And I do believe we find light in those times. Even now people are realizing they can connect through technology. They are not as remote as they thought. They are realizing they can use their phones for long conversations. They’re appreciating walks. I believe we will continue to find meaning now and when this is over.

What do you say to someone who’s read all this and is still feeling overwhelmed with grief?
Keep trying. There is something powerful about naming this as grief. It helps us feel what’s inside of us. So many have told me in the past week, “I’m telling my coworkers I’m having a hard time,” or “I cried last night.” When you name it, you feel it and it moves through you. Emotions need motion. It’s important we acknowledge what we go through. One unfortunate byproduct of the self-help movement is we’re the first generation to have feelings about our feelings. We tell ourselves things like, I feel sad, but I shouldn’t feel that; other people have it worse. We can — we should — stop at the first feeling. I feel sad. Let me go for five minutes to feel sad. Your work is to feel your sadness and fear and anger whether or not someone else is feeling something. Fighting it doesn’t help because your body is producing the feeling. If we allow the feelings to happen, they’ll happen in an orderly way, and it empowers us. Then we’re not victims.

In an orderly way?
Yes. Sometimes we try not to feel what we’re feeling because we have this image of a “gang of feelings.” If I feel sad and let that in, it’ll never go away. The gang of bad feelings will overrun me. The truth is a feeling that moves through us. We feel it and it goes and then we go to the next feeling. There’s no gang out to get us. It’s absurd to think we shouldn’t feel grief right now. Let yourself feel the grief and keep going.

Scott Berinato is a senior editor at Harvard Business Review and the author of Good Charts Workbook: Tips Tools, and Exercises for Making Better Data Visualizations and Good Charts: The HBR Guide to Making Smarter, More Persuasive Data Visualizations.