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Today Nayem, a PhD student, has returned to the South Bronx elementary school he attended as a kid to give current students the opportunities he didn’t have through the After School STEM Mentoring Program (ASMP).

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Please donate today to help more students work with STEM leaders from similar backgrounds and build the essential skills that can help safeguard our health and life on our planet.

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New Developments in Pain Research


Can we stop the pain? It may be the oldest question in medicine, and it remains one of the most important. But with chronic pain afflicting billions of people worldwide, and few effective treatments besides highly addictive opioids, researchers are still searching for better answers.

On May 3-4, the New York Academy of Sciences, in collaboration with Science Translational Medicine, convened the Advances in Pain conference. Across the meeting’s two keynote presentations, nine sessions of talks, and concluding panel discussion, leading experts in many branches of pain research discussed the field’s biggest challenges and latest developments.


  • Specific ion channels on neurons, such as Nav1.7, are critical components of pain sensing and potential drug targets for new analgesics.
  • Several novel laboratory models are revealing new details of nociception, or pain sensing.
  • Large databases of genetic and clinical records are helping researchers link specific genes with common pain conditions.
  • Neuroimaging and sleep studies may offer objective ways to measure the severity of chronic pain.
  • New mechanistic data are pointing researchers toward novel strategies for analgesic drug development.
  • A subset of gut epithelial cells is critical for sensing visceral pain.
  • The immune system links tightly to pain sensation, through multiple mechanisms scientists are now beginning to uncover.
  • Data mining reveals subsets of neurons with distinct responses to nerve injury, including chronic pain.
  • Understanding sex and ethnic differences in pain perception requires new strategies in experimental design and data analysis.
  • Besides neurons, Schwann cells can also carry pain signals.
  • Novel drug discovery platforms and trial designs can accelerate the development of new analgesics.

Part 1


David Bennett, MB, PhD
Oxford University, Nuffield Department of Clinical Neurosciences

Sarah E. Ross, PhD
University of Pittsburgh

Jing Wang, MD, PhD
NYU Langone Health

Tuning into the pain channel

A life free of pain may sound ideal, but as David Bennett explained in the meeting’s opening keynote presentation, individuals with defects in pain sensing often suffer tremendous difficulties. Describing one 26-year-old man with such a condition, Bennett explained that “he had pretty much fractured every long bone in his body, he is stunted because he’s destroyed all the growth plates … and had severe burns and mouth injuries.” The patient’s sister, who had the same condition, died of undiagnosed sepsis.

Genetic analysis revealed that the patient had a rare set of loss-of-function mutations in the gene for Nav1.7, a sodium ion channel expressed in nociceptors, or pain sensing neurons. Using a sophisticated cell culture system that mimics pain signaling through nociceptors, Bennett and his colleagues have characterized Nav1.7 in detail, and determined that it acts early in the pain signaling process, amplifying the electrical signal in the nociceptors to ensure that it’s relayed to the central nervous system.

Patients with gain-of-function mutations that make Nav1.7 overactive have the opposite problem: incurable chronic pain. Bennett’s team studied the Nav1.7 mutations in these patients, and discovered that the degree of the biochemical defect in a patient’s channel proteins correlates directly with the time of onset of their pain condition.

Based on his findings in patients with these rare, extreme pain disorders, Bennett hypothesized that Nav1.7 could also drive more common conditions. As rates of diabetes skyrocket globally, millions of people are developing diabetic neuropathy, which causes chronic pain only in a subset of patients. In an effort to determine what distinguishes painful from pain-free diabetic neuropathy, Bennett’s team looked at Nav1.7 gene sequences for patients with the condition.

“The rare variants in Nav1.7 seemed to cluster much more in the painful versus the painless diabetic neuropathy groups, so this is now acting as a risk factor, in the sense that these people did not experience [chronic] pain prior to developing diabetes,” Bennett says.

Some variants of Nav1.7 apparently predispose people to develop chronic pain, but the condition doesn’t manifest itself until a second event, such as diabetes, triggers it. A closer look at clinical testing results in these patients revealed that those with the rare variants were also more sensitive to certain stimuli, such as burning pain and pressure pain.

Nav1.7 isn’t the only ion channel involved in pain, though. The researchers have also identified strong associations between pain disorders and mutations in the related channel proteins Nav1.8 and Nav1.9, highlighting the diversity of channelopathies that can derail pain sensing. Indeed, an analysis of data from the UK Biobank, which has whole genome sequences and medical records for 100,000 Britons, revealed that voltage-gated sodium channels were the largest group of variants associated with neuropathic pain.

Based on his findings, Bennett advocates using both clinical testing data and gene sequencing to stratify patients according to which treatments are most likely to work for them. In particular, sodium channel blocking drugs appear to work much better in patients with variant channels predisposing them to pain.

Where does it hurt?

The meeting’s first regular session focused on efforts to dissect the central pain circuits in the nervous system. For Sarah Ross, the dissection is literal: she carefully removes a piece of a mouse spinal cord, along with the sensory nerves connected to a patch of skin from the animal’s hind paw, keeping all of the neuronal connections intact. Using luminescent probes, her team can then watch the activation of specific neurons in response to stimuli.

“We can see some neurons respond to heat, other neurons will respond to cool, other neurons will respond to mechanical stimuli,” said Ross.

Many neurons also respond to multiple stimuli, and mapping these responses reveals that distinct classes of neurons function as amplifiers, tuners, and integrators of pain signals.

Jing Wang studies what happens to pain signals in the cerebral cortex of the brain. Using optogenetics, which allows him to stimulate specific neurons in the brains of mice with light, he has identified subsets of neurons in the anterior cingulate cortex and prefrontal cortex that respond to pain.

In mice with experimentally induced chronic pain, low-intensity stimulation of the prefrontal cortex restores normal pain control. Wang’s lab is now studying ways to achieve similar responses with less invasive methods, including the drug ketamine and brain-machine interfaces.

“The cortex processes and regulates pain, but its normal endogenous function can be impaired by chronic pain, and [restoring cortical regulation] has the potential to transform pain treatment,” said Wang.

Part 2


Aarno Palotie, MD, PhD
Institute for Molecular Medicine, Finland

Luda Diatchenko, MD, PhD
McGill University

Irene Tracey, MA (Oxon), DPhil, FRCA, FMedSci
University of Oxford

Alban Latremoliere, MSc, PhD
Johns Hopkins University

The pains of the father

Aarno Palotie began the meeting’s session on the genetics of pain by discussing his results from large-scale studies on migraine. With the exception of some rare, strictly inherited forms of the condition, these sporadic, debilitating headaches usually stem from variations in numerous common genes. To identify those genes, Palotie and a large team of collaborators scrutinized genetic and medical data from hundreds of thousands of migraine sufferers.

The effort revealed over 100 gene loci linked to migraine, mostly in regulatory regions associated with genes expressed in cardiovascular tissue and the central nervous system. Tracking those variants in another large data set revealed a cumulative effect.

“We can see that those with a high polygenic risk score, meaning a high load of common variants, they seem to have an earlier onset of migraine,” said Palotie.

Using data from the 500,000 participants in the UK Biobank, Luda Diatchenko and her colleagues have performed a similar analysis to identify genetic variants linked to chronic pain. The investigators subdivided chronic pain patients based on the type of pain they experienced, such as back pain, hip pain, knee pain, and multi-site pain.

Analyzing gene sequences for these sub-groups showed that multi-site pain had the highest correlation with specific gene variants. The gene most strongly linked to multi-site pain encodes a receptor protein involved in guiding nerve axons in development.

“This is one example of how [genome-wide association studies] can show us a new mechanism which contributes to human chronic pain conditions,” said Diatchenko.

On a scale of one to ten

The meeting’s third session focused on one of the biggest challenges in studying pain: measuring it. Clinical studies attempt to quantify pain severity with patient questionnaires, while animal experiments rely on behavioral responses, but both methods are notoriously unreliable.

Ilene Tracey hopes to solve that problem with neuroimaging, linking specific patterns of neuronal activation to painful stimuli.

“We’ve got now quite a good array of tools that are reasonably well developed and robust, that allow you to look at … ways that patients will experience their pain,” said Tracey.

By combining functional magnetic resonance imaging with electroencephalography, video analysis, and other sensing methods, this approach could allow researchers to quantify patient responses to pain treatment more reliably than current, fundamentally qualitative methods. Using machine learning, Tracey’s team can now measure pain and also distinguish different categories of it, such as physical versus emotional pain.

Sleep disturbances might also provide a pain gauge.

“The vast majority of patients with chronic pain suffer from poor sleep quality,” said Alban Latremoliere, who has been studying this connection as a potential pain biomarker.

By tracking electroencephalography and other measurements in sleeping mice, he and his colleagues have found that nerve injury, which causes chronic neuropathic pain, also changes the animals’ sleep architecture. Compared to uninjured animals, those with injured nerves suffer multiple brief interruptions in the non-REM phase of their sleep. When the injury heals, the normal sleep architecture returns; Latremoliere now hopes to use these patterns to quantify neuropathic pain severity and treatment efficacy in humans.

Part 3


Greg Scherrer, PhD
University of North Carolina

Venetia Zachariou, PhD, MBBS, MMed, MS
Icahn School of Medicine at Mount Sinai

Rajesh Khanna, PhD
New York University

David J. Julius, PhD
University of California, San Francisco (UCSF)

The hurt blocker

As Greg Scherrer pointed out in the meeting’s fourth session, the real problem with pain isn’t that it exists, but that it’s unpleasant.

“If we were to understand how our brain collects this information from sensory neurons and the spinal cord to make pain unpleasant … maybe we’ll discover new ways to treat pain,” said Scherrer.

Indeed, a patient whose basolateral amygdala was removed to treat epilepsy could still sense painful stimuli, but didn’t label them as painful; the unpleasantness was gone. Examining mice with various alterations to the same brain region, Scherrer and his colleagues believe they have identified the amygdala cells responsible for connecting pain to unpleasantness. The investigators are now trying to identify receptors on those cells that would be good drug targets for new pain treatments.

Venetia Zachariou is also dissecting cellular signaling pathways to target in pain treatment, and her lab has uncovered several promising leads in recent years. When the COVID-19 pandemic derailed that work, though, the scientists quickly pivoted to apply their skills and techniques to study the new disease’s neuronal pathogenesis.

In a hamster model, they found that SARS-CoV-2, the virus that causes COVID-19, can acutely infect nerves in the dorsal root ganglia, which are also involved in pain sensing. Looking more closely at both the hamster model and a mouse model of SARS-CoV-2 infection, Zachariou has identified distinct changes in neurons’ gene expression patterns after virus infection, including a signature similar to that seen in models of neuropathic pain.

One of the most popular targets for researchers trying to develop new pain therapies is the sodium channel Nav1.7, a “pain amplifier” that several speakers at the meeting discussed. Rajesh Khanna is also interested in Nav1.7, but instead of targeting the protein directly, his team is trying to identify proteins that interact with it. That work led them to focus on collapsin response mediator protein 2 (Crmp2), which regulates Nav1.7 signaling.

Mice lacking Crmp2 are resistant to chronic pain, suggesting that drugs inhibiting its action would be good pain therapy candidates. After conducting extensive mechanistic studies, Khanna started a company to identify such inhibitors. So far, the company has optimized a lead compound that appears to stop chronic pain in animal models, without causing detectable side effects or tolerance.

You feel it in your gut

The meeting’s first day concluded with a keynote presentation by David Julius, who discussed his work on chronic visceral pain. This subtype of chronic pain, which can be caused by gut infection or non-infectious conditions such as inflammatory bowel disease, affects about 15% of the population. It’s three times more common in women than men, but nobody knows why.

“We’re interested in a particular aspect of visceral pain signaling, and that involves the interaction of sensory nerve fibers with the gut epithelium,” said Julius.

A subset of gut epithelial cells, called enterochromaffin cells, plays an outsize role in that interaction. Comprising only a fraction of a percentage of all gut epithelial cells, enterochromaffin cells make about 90% of the body’s serotonin, a potent neurotransmitter protein. They also fire electrical signals that could propagate to nearby neurons.

Julius wanted to analyze that process in live mice, but wasn’t happy with the standard mouse system for those types of experiments. That model involves putting irritants into a mouse’s gut to trigger a major inflammatory response, after which the animal remains hypersensitive to physical stimuli such as colon distention.

“Do we need to … put the mouse through all that, or can you have a model that’s simpler [and] does not require all the sequellae of an inflammatory episode?” asked Julius.

Instead, he and his colleagues first tried studying enterochromaffin cells in the context of cultured enteroids, pieces of intestinal epithelium that can mimic many aspects of gut biology in a petri dish. That system revealed that enterochromaffin cells respond to numerous compounds that fall into three general classes: ingested irritants, metabolites of common gut microbes, and endogenous regulatory hormones.

“So, we want to know how these cells integrate all this information, and what role this plays in maladaptive situations like [inflammatory bowel disease],” said Julius.

Based on those results, the researchers moved to a more complex system, an explanted piece of a mouse colon with its connecting nerves. Monitoring the electrical signals in the connected nerves reveals sensory signals from the explanted gut. In this setup, bathing the colon section with isovalerate, a bacterial metabolite that triggered a response from enterochromaffin cells in the enteroid experiment, makes it hypersensitive to subsequent physical or biochemical stimuli. This system also revealed different response patterns in guts from male and female mice.

Having demonstrated that isovalerate could induce gut hypersensitivity without the inflammatory response of harsher irritants, Julius’s team next tried looking at its effect in live mice. They used a small balloon in the colon, similar to an endoscope, as a stimulus, and monitored abdominal muscle contraction, a behavioral response to pain. Treating the mice with isovalerate increased the magnitude of subsequent pain responses potently in male mice, but less so in females, consistent with the explant results.

Subsequent experiments showed that enterochromaffin cells mediate these responses in live mice, apparently through both serotonin secretion and direct electrical signaling to neurons, and that these cells seem to respond differently in male and female mice.

Part 4


Isaac Chiu, PhD
Harvard Medical School

Camila Svensson, MS, PhD
Karolinska Institutet

Alexander J. Davies, PhD
Nuffield Department of Clinical Neurosciences

Dana Orange, MD
Rockefeller University

Shrinivasan Raghuraman, PhD
University of Utah

Jeffrey S. Mogil, PhD
McGill University

Frank Porreca, PhD
University of Arizona

Roger Fillingim, PhD
University of Florida

Is antibody hurt?

Infections commonly cause pain, which researchers had long assumed was just a byproduct of the body’s inflammatory response. However, as Isaac Chiu explained in the meeting’s session on neuroimmune and autoimmune mechanisms in pain, infecting pathogens can also interact directly with nociceptors, or pain-sensing neurons. In one set of mouse experiments, for example, Chiu’s team found that nociceptors in the intestine can detect infection with Salmonella enterica, triggering a response that decreases the number of M cells, the specialized intestinal epithelial cells S. enterica preferentially infects.

“These neurons actually regulate cell numbers, [which] not only shuts down the number of gates for pathogen entry, it also helps a protective microbe … attach better on the surface of the epithelium,” said Chiu.

Camila Svensson discussed a pain condition that has baffled researchers and clinicians for decades: fibromyalgia. Characterized by pain hypersensitivity in soft tissues, sometimes coupled with neuropathic pain, the condition has long eluded efforts to uncover its etiology and underlying mechanisms.

After serendipitously discovering evidence for autoantibodies in fibromyalgia patients, Svensson has now developed human tissue and mouse models to characterize these antibodies in more detail. Transferring antibodies from fibromyalgia patients into mice causes pain hypersensitivity in the animals, and patients with higher levels of antibodies that react with human dorsal root ganglia cells have more severe disease.

“This suggests that there is an autoimmunity in subpopulations of fibromyalgia patients,” said Svensson, adding that besides suggesting a mechanism for the disease, autoantibody levels could help stratify patients in clinical trials.

The body’s own immune response is also a key contributor to chronic neuropathic pain, especially through neuroinflammation. Alexander Davies presented his work on another component of neuropathic pain: the cytotoxic cellular response.

Cytotoxic cells normally detect cancerous or virally-infected cells and target them for destruction, but they can also target injured neurons. Dissecting this response in an extensive series of experiments in mice, Davies and his colleagues have found that a specific receptor on cytotoxic cells allows them to target nociceptors after nerve injury, leading to degeneration of the damaged axons and resolution of pain hypersensitivity.

“So, our data suggest that intact sensory networks are a source of ongoing neuropathic hypersensitivity, and that by targeting those, we can help to resolve that,” said Davies.

Short, sharp shocks

Dana Orange gave the first of two short “data blitz” presentations, providing an overview of her group’s work on rheumatoid arthritis pain. Though inflammation of joints is a hallmark of this form of arthritis, Orange noticed an odd discrepancy.

“Patients who really don’t have a lot of inflammation were reporting a lot of pain,” she said.

Through a combination of human gene expression and mouse studies, she’s found that nerve development may play a bigger role than inflammation in driving rheumatoid arthritis pain.

Shrinivasan Raghuraman described his approach to characterizing chronic pain mechanisms, using a rat model. By collecting thousands of data points from individual rat neurons under different conditions, his lab has identified 19 different subsets of neurons with distinct responses to nerve injury. Raghuraman hopes that correlating the cells’ electrical responses with their gene transcription profiles will identify the underlying mechanisms driving chronic pain, and how different candidate drugs can influence it.

Sex and race

In the session on sex and ethnic differences in pain, Jeffrey Mogil began by pointing out a critical flaw in traditional pain research methods. Despite ample evidence that women experience more pain than men, “80 percent of preclinical studies use male rats or male mice only,” said Mogil.

That skew overlooks important differences in the biology of pain in males and females, though. In a mouse model of chronic neuropathic pain, for example, Mogil’s lab has linked chronic pain to premature shortening of chromosome ends, or telomeres – but only in male mice. Besides studying both sexes instead of just one, Mogil argued that researchers need to extend their animal studies to monitor chronic pain for longer time periods, to account for age-related phenomena such as telomere shortening.

Frank Porreca also looks at sex differences in pain, but focuses on the role of stress. Clinical data clearly show that stress exacerbates functional pain syndromes such as inflammatory bowel disease, migraine, and fibromyalgia, all of which are more prevalent in women than men.

To study such syndromes, Porreca’s team developed a mouse model in which they restrain the animals for a short time to induce stress, then treat them with a compound that causes headaches. These stress-primed mice develop allodynia, interpreting normally non-painful stimuli as painful, while controls that only got the headache-inducing compound didn’t.

While both male and female mice exhibited the same response, Porreca found that it operates through different biochemical mechanisms in the two sexes, underscoring the importance of studying both in preclinical research.

Unlike sex, race and ethnicity lack clear biological definitions.

“It’s important to keep in mind that race and ethnicity are not causal factors, but rather proxies for these many psychosocial and biopsychosocial factors, largely driven by systemic societal and environmental exposures,” said Roger Fillingim.

At the same time, the groups that suffer disproportionately from racial and ethnic health disparities are often the least-studied. That’s certainly the case in pain research and treatment. Indeed, experiments suggest that Black patients may experience more pain than white ones, but health data show they’re less likely to be treated for pain in hospitals and clinics.

Summarizing a large body of additional evidence for similar skews in various minoritized groups, Fillingim advocated more holistic approaches to pain research across and within sub-populations.

Part 5


Alexander Chesler, PhD
National Center for Complementary and Integrative Health (NCCIH), NIH

Patrik Ernfors, PhD
Karolinska Institutet

Clifford Woolf, MD, PhD
Harvard Medical School

Bryan Roth, MD, PhD
University of North Carolina

Kelly Knopp, PhD
Eli Lilly

Get the sensation

The meeting’s penultimate session focused on how sensory signals such as pain propagate toward the central nervous system. Alexander Chesler started the session with a discussion of his work on peripheral sensory neurons.

To study these cells, Chesler and his colleagues initially developed an elegant system that allowed them to probe the responses of individual mouse cells in the trigenimal ganglion, a nerve cluster that receives sensory signals. That revealed a specific subset of neurons that responded only to a painful stimulus, while other subsets responded to gentle touches. By extending the system with gene expression profiling, and correlating responses in the mouse with those in a human patient who lacks a receptor critical for mechanical sensation, the scientists are now tracing pain-sensing pathways in unprecedented detail.

Neurons aren’t the only cells carrying pain signals, though, as Patrik Ernfors has discovered. In tracing sensory circuits, he and his colleagues discovered that Schwann cells, support cells closely associated with peripheral neurons, are also stem cells that form a sensory organ under the skin.

Using genetically modified mouse models that allowed them to selectively activate these Schwann cells, Ernfors and his colleagues discovered that both the Schwann cells and their associated neurons can initiate acute pain sensations. Further work revealed that the Schwann cells also appear to become sensitized during the development of arthritis.

“We believe that we have found the mechanosensory skin organ that is associated with [mechanical pain sensation],” said Ernfors, adding that these cells could contribute to allodynia in arthritis.

Something for the pain

Clifford Woolf began the meeting’s final session, on finding new ways to treat pain, with a summary of his team’s novel approach to drug discovery. Currently, most pharmaceutical companies focus on finding compounds that can target specific cellular molecules known to be involved in pain, then trying to develop them into drugs.

In 2010, Woolf advocated an alternative strategy, screening drugs to find those that inhibit stem cell-derived pain-sensing neurons, without worrying about their mechanisms of action.

“However, the question was how to execute on this,” he said.

After extensive effort, his team can now derive the correct neuron types from patients’ cells. Screening libraries of compounds against these cells has yielded several promising hits, which inhibit pain signaling in nociceptors without affecting other cell types.

Others hope to broaden the scope of target-based drug screening, which has focused on a large and diverse class of cell surface proteins called G-protein coupled receptors, or GPCRs.

“But … when we mapped the drugs onto the phylogeny of all the [GPCRs] in the genome, only a few targets actually came out as being targets of approved drugs,” said Bryan Roth, adding that “there are many, many other potential targets for treating pain and other serious conditions.”

To test those targets, Roth’s team developed an assay that allows them to test drugs against a library encompassing 90% of GPCRs encoded in the human genome. That has revealed several new targets, which the researchers are now testing with more specific screens, ultimately hoping to develop safer opioids.

Kelly Knopp began the meeting’s final talk with the grim statistics of chronic pain: affecting about one fourth of the global population, the direct and indirect costs of this condition add up to more than a trillion dollars.

“[Meanwhile,] the probability of technical success for pain [drugs] is worse than any other therapeutic area,” said Knopp.

To address that, she and her colleagues have focused on establishing standardized protocols for phase 2 proof-of-concept trials of pain treatments. Their approach uses sophisticated statistical techniques and uniform trial designs to enable testing of many more drug candidates, without exceeding available funding and medical trial capacity.

After the presentations, a panel of speakers from the meeting discussed several of the field’s biggest challenges. Chief among them are the immense burden of opioid addiction, and the difficulty of shifting real-world clinical treatment toward less addictive but possibly less effective therapies for chronic pain. Despite the difficulties, many researchers in the field remain optimistic.

As Ilene Tracey said in her presentation, “We’re often quite doom and gloom in the pain field, [but] we’ve actually got a lot of different tools at our disposal, [and] we should be more confident about where the field has got to and where it can go quite rapidly.”

New Developments in Human Healthspan and Longevity


Although advances made in health and safety have more than doubled life expectancy throughout much of the world since 1900, it hasn’t been without consequence. Disease, disability, and frailty have all impacted the quality of life associated with these later years. This unfortunate reality was recently illuminated by the COVID-19 pandemic, which severely affected this population, likely due to physiological changes and preexisting conditions. Fortunately, a primary goal of geroscience researchers is to attenuate age-related health issues so that older people not only enjoy an improved quality of life, but also maintain the resilience to survive severe diseases and infections.

While it’s irrefutable that we cannot avoid aging, it’s no longer within the realm of science fiction for us to temper and even reverse the aging process. On May 19, 2021, the New York Academy of Sciences hosted a virtual symposium that brought together geroscience experts spanning various disciplines, including genetics, endocrinology, gerontology, clinical psychology, and more. Speakers discussed targeting the key hallmarks of aging, developing biomarkers for geriatric therapies, and translating findings that extend healthspan and lifespan to the clinic.

Symposium Highlights

  • The Target Aging with Metformin study uses the FDA approved anti-diabetic metformin, which targets the hallmarks of aging, to investigate the prevention of age-related diseases.
  • Precluding the age-associated decline of chaperon-mediated autophagy restrains the aggregating effects of Alzheimer’s disease and extends lifespan in murine models.
  • Lower IGF-1 levels in older adults are associated with decreased cognitive impairment, age-related diseases, and mortality.
  • Epigenetic clocks can be applied to study biological aging differences, with accelerated epigenetic aging correlating with the prevalence and incidence of morbidity and mortality.
  • The metabolome is a powerful locus of opportunity to bridge the gap between genotype and age.
  • Alternative splicing is upregulated in response to declining mitochondrial function and increasing age.
  • Senescent cells upregulate pro-survival pathways, and their elimination alleviates diverse age-related conditions.
  • The mitochondrial-derived peptides humanin and MOTS-c are associated with increased longevity in animal models and humans.


Nir Barzilai, MD
Albert Einstein College of Medicine

Ana Maria Cuervo, MD, PhD
Albert Einstein College of Medicine

Sofiya Milman, MD
Albert Einstein College of Medicine

Morgan Levine, PhD
Yale School of Medicine

Daniel Promislow, PhD
University of Washington

Luigi Ferrucci, MD, PhD
National Institute on Aging, National Institutes of Health

James Kirkland, MD, PhD
Mayo Clinic

Pinchas Cohen, MD
USC Leonard Davis School of Gerontology

Targetable Aging Processes


Nir Barzilai, MD
Albert Einstein College of Medicine

Ana Maria Cuervo, MD, PhD
Albert Einstein College of Medicine

Keynote: Age Later: Translational Geroscience

Aging is the strongest risk factor for all age-related diseases, with diverse maladies accumulating during the later years of life. Hence, to abate or avert the relevant disorders, it’s critical to target the central driver—aging itself. Physician Nir Barzilai, the founding director of the Institute for Aging Research, investigates the genetics of longevity by studying centenarians and their offspring, interrogating the hypothesis that these individuals have genes that prolong aging and protect against age-related diseases.

Using Slow Off-Rate Modified Aptamer, Barzilai’s team assessed 5,000 proteins in a population of 1,000 individuals between the ages of 65-95, a period during which aging accelerates. Results demonstrated a significant change in the level of hundreds of proteins as a function of age. Among the top hits were proteins from collagen breakdown of tissue and cellular products, highlighting the pivotal role this process plays in aging, and suggesting that deterring disintegration may be a universal biomarker for geroprotection.

Metformin, a long-standing FDA approved anti-diabetic, targets the complement of aging indications.

A predominant challenge to translating advances made in geroscience from animal models to humans is the FDA, which currently doesn’t consider aging a disease indication or preventable condition. Barzilai and others are utilizing metformin, an FDA-approved anti-diabetic, to refute this contention. Various groups have shown that metformin has substantial effects on human healthspan, including delaying type-2 diabetes mellitus (T2DM). In this patient subset, metformin also impedes cardiovascular disease, cognitive decline, and Alzheimer’s and is associated with decreased cancer incidence, with population effects approaching 30% in all cases.

Barzilai’s team designed the Target Aging with Metformin, or TAME, study to investigate whether or not there’s a shift in the timeline of disease occurrence between a cohort receiving metformin versus a control cohort. Various biomarkers of aging and age-related diseases will be used to provide convergent evidence of broad, age-related effects, while also establishing a resource for innovation and discovery of emergent biomarkers.

“The most important thing for us is to develop biomarkers that will change when we use a gerotherapuetic,” Barzilai asserted, as this will expedite therapeutic prospects.

Targeting Selective Autophagy in Aging and Age-related Diseases

Physician-scientist Ana Maria Cuervo’s research seeks to understand the molecular basis of autophagy dysfunction with age and the contribution of defects in this cellular pathway to diseases such as neurodegeneration, metabolic disorders, and cancer. Autophagy belongs to the proteostasis network, which regulates protein content and quality control.

Chaperon-mediated autophagy (CMA) is a subset of the mammalian autophagy program that directly targets proteins to the lysosome for degradation. CMA has been shown to decrease with age in human and animal models. Cuervo’s lab developed a fluorescent murine reporter construct to visualize CMA and track the kinetics of its activity in different organs.

Blocking this pathway in neurons resulted in the aggregation of proteins like α-synuclein (α-syn), tau, and others that are causal in Alzheimer’s Disease (AD). Additionally, CMA reporter mice crossed with a mouse model of AD revealed that CMA activity dramatically decreases in the neurons of AD mice.

Leveraging these findings, Cuervo’s group generated a mouse model to restore CMA activity conditionally. Mice with preserved CMA exhibited an extended median and maximal lifespan compared to controls. Evaluation of the proteostasis network in mice with and without CMA restoration revealed major changes in the proteome. Mice in which CMA was preserved more closely resembled younger animals than their age-matched controls.

“By acting in one of these pathways, we can have an impact in the other hallmarks of aging… because of this interconnection among [them],” Cuervo emphasized.

A compound to selectively activate CMA was developed and tested in an AD model, with results illustrating a reduction in tau pathology and microglial activation in the presence of this agent.

Further Readings


Ismail K, Nussbaum L, Sebastiani P, et al.

Compression of Morbidity Is Observed Across Cohorts with Exceptional Longevity.

J Am Geriatr Soc. 2016 Aug;64(8):1583-91.

Sathyan S, Ayers E, Gao T, et al.

Plasma proteomic profile of age, health span, and all-cause mortality in older adults.

Aging Cell. 2020 Nov;19(11):e13250.

Lehallier B, Gate D, Schaum N, et al.

Undulating changes in human plasma proteome profiles across the lifespan. 

Nat Med. 2019 Dec;25(12):1843-1850.

Kulkarni AS, Gubbi S, Barzilai N.

Benefits of Metformin in Attenuating the Hallmarks of Aging.

Cell Metab. 2020 Jul 7;32(1):15-30.

Zhang ZD, Milman S, Lin JR, et al.

Genetics of extreme human longevity to guide drug discovery for healthy ageing.

Nat Metab. 2020 Aug;2(8):663-672.


Kaushik S, Cuervo AM.

Proteostasis and aging.

Nat Med. 2015 Dec;21(12):1406-1415.

Bourdenx M, Martín-Segura A, Scrivo A, et al.

Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome.

Cell. 2021 May 13;184(10):2696-2714.e25.

Kaushik S, Cuervo AM.

The coming of age chaperone-mediated autophagy.

Nat Rev Mol Cell Biol. 2018 Jun;19(6):365-381.

Dong S, Aguirre-Hernandez C, Scrivo A, et al. 

Monitoring spatiotemporal changes in chaperone-mediated autophagy in vivo. 

Nat Commun. 2020 Jan 31;11(1):645.

Dong S, Wang Q, Kao Y-R, et al.

Chaperone-mediated autophagy sustains haematopoietic stem-cell function.

Nature. 2021 Mar;591(7848):117-123.

Biomarkers for Therapies


Sofiya Milman, MD
Albert Einstein College of Medicine

Morgan Levine, PhD
Yale School of Medicine

Translational Geroscience: Role of IGF-1 in Human Healthspan and Lifespan

Physician Sofiya Milman conducts translational research to uncover the genomic mechanisms regulating the endocrine and metabolic pathways involved in age-related conditions like diabetes, cardiovascular disorders, and Alzheimer’s.

“The goal of geroscience is really to extend healthspan, and not necessarily lifespan,” Milman opened. “What we’re really trying to do is to compress the period of morbidity.”

To discover the biological pathways that allow humans to live long, healthy lives, Milman’s team focused on IGF-1: a reduction of this factor has been consistently shown to extend healthspan and lifespan in models. IGF-1 levels peak during the teenage years before gradually declining. If the reduction of IGF-1 protects from aging, Milman reasoned that lower IGF-1 levels would delay aging and prevent age-related diseases.

Examining a cohort of centenarians expressing lower levels of IGF-1 revealed a 50% reduction in cognitive impairment compared to higher IGF-1 level controls. Genetic studies demonstrated that centenarians were enriched for rare mutations in the IGF-1 receptor that diminished signaling. Additionally, individuals 65+ with low IGF-1 had less cognitive impairment, and delayed onset of cognitive impairment, multi-morbidities, and mortality.

Milman’s team also addressed the link between IGF-1 and age. Younger individuals with lower levels of IGF-1 were at an increased risk for mortality and age-related diseases compared to older individuals, while higher levels of IGF-1 in older adults were associated with increased risk. This suggests that the IGF-1 network aligns with the concept of antagonistic pleiotropy, wherein a factor that’s beneficial to individuals when they’re younger may become harmful when they’re older. It’s advantageous to maintain functionality of proteostasis and resilience as an individual gets older, but IFG-1 inhibits programs involved in these processes.

“So from this, we think it would be wise to maintain IGF-1 levels in youth, but to reduce them with aging,” Milman concluded.

Epigenetic Biomarker of Aging for Lifespan and Healthspan

Biological age is defined by changes or alterations in a living system that renders it more vulnerable to failure and is behind the age-related increase in susceptibility to chronic diseases. Unlike chronological age, it is very difficult to measure because it’s unobservable.

Morgan Levine integrates theories and methods from statistical genetics, computational biology, and mathematical demography to develop biomarkers of aging for humans and animal models. Among this work are efforts to establish systems-level outcome measures of aging to facilitate evaluation for gero-protective interventions.

“There’s some disagreement on how we actually quantify [biological age],” Levine started. “But I would argue that it’s really important to try and do so, because quantifying [this] will really help us in a number of endeavors in the field.”

Levin’s lab is particularly interested in epigenetic aging, as aging drastically remodels the DNA methylation landscape, with widespread increases and decreases as a function of age.

Senescent cells and cells with disrupted energy production show accelerated epigenetic aging.

Epigenetic clocks estimate DNA methylation across the genome and combine supervised machine-learning approaches to develop predictors of biological age.

“We think people who have a predicted [epigenetic] age that’s younger than their chronological age should be actually aging slower, whereas the opposite is true for people that have a genetic age that is predicted higher,” said Levine.

Applying these measures to diseased states yielded several pertinent findings. For example, individuals who have pathologically diagnosed Alzheimer’s post-mortem show accelerated epigenetic aging in their brain relative to their chronological age. Tissue differences were also captured, revealing that tissues seem to age asynchronously, with highly proliferative tissues and tumor cells having accelerated aging compared to slower aging brain tissue.

Levine’s group also evaluated cellular senescence and energy disruption, with results revealing that near senescent, HRAS oncogene induced senescent, and replicative stress senescent cells have an acceleration in epigenetic age compared to early parental control cells. Additionally, deletion of mitochondrial DNA accelerated epigenetic aging, while caloric restriction in mice stalled their epigenetic clocks.

Further Readings


Argente J, Chowen JA, Pérez-Jurado LA, et al.

One level up: abnormal proteolytic regulation of IGF activity plays a role in human pathophysiology.

EMBO Mol Med. 2017 Oct;9(10):1338-1345.

Gubbi S, Quipildor GF, Barzilai N, et al.

40 YEARS of IGF1: IGF1: the Jekyll and Hyde of the aging brain.

J Mol Endocrinol. 2018 Jul;61(1):T171-T185.


Hannum G, Guinney J, Zhao L, et al.

Genome-wide methylation profiles reveal quantitative views of human aging rates.

Mol Cell. 2013 Jan 24;49(2):359-367.

Levine M, McDevitt RA, Meer M, et al.

A rat epigenetic clock recapitulates phenotypic aging and co-localizes with heterochromatin.

Elife. 2020 Nov 12;9.

Horvath S.

DNA methylation age of human tissues and cell types.

Genome Biol. 2013;14(10):R115.

Levine ME, Lu AT, Quach A, et al.

An epigenetic biomarker of aging for lifespan and healthspan.

Aging. 2018 Apr 18;10(4):573-591.

Liu Z, Leung D, Thrush K et al.

Underlying features of epigenetic aging clocks in vivo and in vitro.

Aging Cell. 2020 Oct;19(10):e13229.

Omics for Therapies


Daniel Promislow
University of Washington

Luigi Ferrucci
National Institute on Aging, National Institutes of Health

Metabolomics in the Search for Biomarkers and Mechanisms of Aging

Daniel Promislow applies metabolomics and systems biology approaches to study aging, with a focus on understanding the evolutionary and molecular traits that shape fitness in the natural human population. Although genome-wide association studies have allowed researchers to identify thousands of polymorphisms associated with the complement of measurable traits, including aging, the disparities identified explain less than half of 1% of the phenotypic variations.

Many genes interacting with each other ultimately influence phenotypes, and the biological distance between the two is astronomical. To bridge this gap, researchers use endophenotypes—from the epigenome, transcriptome, proteome, metabolome, and microbiome—along with various omics approaches. Promislow’s lab focuses on the metabolome, which integrates information from the environment and genotype to ultimately affect aging.

Promislow’s team utilizes translational metabolomics in various insect and animal models to understand and translate aging patterns to human populations. Applying this approach to Drosophila demonstrated that the metabolome could predict stress resistance, completely separating groups of sensitive or resistant flies to a metabolic stressor by principal component analysis. These effects could not be recapitulated with a whole fly genome sequence dataset. Evaluating response to diet restriction (DR) also revealed changes in metabolite levels with age. Among nearly 200 different inbred strains, roughly 75% showed a benefit to DR.

“Interestingly, the effect of specific genetic variants on the lifespan response was very weak,” Promislow began. “But we did find genes that were associated with metabolites, which were associated with the lifespan response, reinforcing this idea…that the metabolite profile can be a kind of bridge between genotype and phenotype.”

Promislow’s group also demonstrated that the metabolome could serve as a biological clock, revealing that shorter-lived genotypes appeared to have a higher biological age than expected for their chronological age.

Translational Potential of the Biology of Aging

As individuals age, the incidence of chronic disease increase, and disease progression quickens. Physician-scientist Luigi Ferrucci aims to interrogate the causal pathways that lead to progressive physical and cognitive decline in aging.

Cellular damage is accumulated during a person’s life, eventually reaching a pathology threshold that becomes clinically relevant when the damage presents as a disorder. Conventionally, the disease is often only addressed once it reaches this stage. The problem with this approach is that the present disease is often a marker of a more profound and invasive disorder to come.

“[Instead], we need to measure the underlying force that determines the emergence of diseases and their consequences,” Ferrucci argued.

By interfering with the basic mechanisms of aging to curtail it, broader effects of abating multiple chronic disorders can be achieved.

Cellular damage is accumulated over the course of an individual’s lifetime, with disease presenting once the clinical threshold for a given disorder is reached.

The rate of biological aging can be defined by the ratio of cellular damage accumulation to repair capacity. If the rate of damage accretion is fast, but the repair capacity is high, there won’t be an accumulation of damage, and aging will be slowed. However, when damage outpaces repair, aging accelerates.

Repair pathways require energy to operate effectively, and mitochondrial function declines dramatically with age. Ferrucci’s team discovered that this decline is associated with an upregulation of alternative splicing of mitochondrial proteins. Delving deeper into this mechanism, they applied gene set enrichment analysis to 5,325 RNAs with at least one splice variant significantly altered in response to changing mitochondrial function, as measured by AMPK and aging.

Among the top hits were GLUT4, VEGFA, IRS2, mTOR, PI3K, ULK1, ACC1, NRF2, and PGC1-α. Of note, the splice A variant of the topmost hit, VEGFA, appeared to be geronic, while the B variant appeared to be anti-geronic, with the ratio of these variants declining with age. Thus, alternative splicing is a method by which the body copes with energy decline due to mitochondrial dysfunction.

Further Readings


Laye MJ, Tran V, Jones DP, et al.

The effects of age and dietary restriction on the tissue-specific metabolome of Drosophila.

Aging Cell. 2015 Oct;14(5):797-808.

Hoffman JM, Ross C, Tran V, et al.

The metabolome as a biomarker of mortality risk in the common marmoset.

Am J Primatol. 2019 Feb;81(2):e22944.

Nelson PG, Promislow DEL, Masel J.

Biomarkers for Aging Identified in Cross-sectional Studies Tend to Be Non-causative.

J Gerontol A Biol Sci Med Sci. 2020 Feb 14;75(3):466-472.


Fabbri E, An Y, Zoli M, et al.

Aging and the burden of multimorbidity: associations with inflammatory and anabolic hormonal biomarkers.

J Gerontol A Biol Sci Med Sci. 2015 Jan;70(1):63-70.

Choi S, Reiter DA, Shardell M, et al.

31P Magnetic Resonance Spectroscopy Assessment of Muscle Bioenergetics as a Predictor of Gait Speed in the Baltimore Longitudinal Study of Aging.

J Gerontol A Biol Sci Med Sci. 2016 Dec;71(12):1638-1645.

Translational Research for Healthspan and Lifespan


Pat Furlong, Panelist
Parent Project Muscular Distrophy

Roman J. Giger
University of Michigan School of Medicine

Senolytics: The Path to Translation

Physician-scientist James Kirkland studies the impact of cellular aging, specifically senescence, on age-related dysfunction and chronic diseases to develop methods for removing these cells and attenuating their deleterious effects. Senescent cells accumulate with aging and diseases, eliminating cells around them due to their senescence-associated secretory phenotype (SASP), which 30%-70% of senescent cells exhibit under most conditions.

Kirkland’s team applied a bioinformatics-based approach to analyze SASP proteomic databases, revealing that pro-survival networks are upregulated, with diverse senescent cells relying on different pathways. Several agents, termed senolytics, were identified that could target multiple nodes of these cascades.

“We’re moving away from the one drug, one target, one disease approach here,” said Kirkland,  “to try and use agents that have multiple targets, or combinations of agents, to go after networks, and to go after senescent cells by doing this, and thereby improve…multiple conditions.”

Dasatinib (D), a SRC kinase inhibitor, preferentially killed senescent preadipocytes, which relied on survival pathways that signal through this kinase. Quercetin (Q) eliminated senescent human umbilical endothelial cells (HUVECs), which partly act through the Bcl-2 family and others that this cell type is susceptible to.

In an in vivo experiment, combining Dasatinib with Quercetin (D+Q) cleared transplanted luciferase-expressing senescent preadipocytes from mice, explicitly targeting those cells with a SASP. A single dose of senolytics also alleviated radiation-induced gait disturbance in mice, with the effects persisting long-term. Bi-weekly dosing reduced physical dysfunction in older mice, as measured by parameters of maximal speed, including treadmill and hanging endurance, grip strength, and daily activity, with D+Q significantly increasing performance across the board.

Many conditions have now been shown to be alleviated by various senolytics in a range of mouse models, with D+Q delaying death from all causes, and increasing healthspan and median lifespan.

Keynote: Mitochondrial-derived Peptides (MDPs) and the Regulation of Aging Processes

The discovery of mitochondrial peptides (MDPs), encoded from small genes less than 100 codons in length, established the birth and advancement of the microprotein subfield. Physician Pinchas Cohen works to understand mitochondrial biology and characterize MDPs, exploiting findings to target aging. MDPs are secreted from cells and circulate within the body.

“Overall, they serve as protective factors, or hormones if you will, that act in the brain, the heart, the liver, the muscle, and other organs,” Cohen stated.

Among these MDPs, Cohen’s lab identified humanin, encoded from the 16S region of mtDNA, and MOTS-c, encoded from the 12S region.

Humanin has a strong protective effect on neurons and against atherosclerosis, mitigates the side effects of chemotherapy while enhancing its benefit, and is related to longevity in model organisms and humans. Cohen’s lab employs mitochondrial-wide association studies (MiWAS) to link the dysfunction of MDPs to disease. MiWAS identified a single-nucleotide polymorphism (SNPs) in the humanin gene (rs2854128) associated with reduced levels and cognitive decline in humans and mice. Supplementing humanin in mice carrying this SNP improved their cognition.

MOTS-c is a novel exercise mimetic that has potential utility in numerous age-related diseases. Mice on a high fat diet receiving MOTS-c had dramatically lower weight compared to controls. MOTS-c treatment also improved exercise tolerance and performance in middle-aged and old mice, with older mice displaying the most dramatic improvement.

MOTS-c levels are diminished in older mice, and supplementation of MOTS-c in this cohort increases both median and maximum lifespan compared to controls.

Cohen’s group also identified a link between a SNP in MOTS-c–K14Q–which nullifies MOTS-c activity and the risk of diabetes in males of the Asian population. Evaluating Japanese males from three cohorts revealed a 50% increase in the risk of diabetes for carriers, with almost double the risk seen exclusively in men who were sedentary. Like other MDPs, MOTS-c is reduced with age, and its administration to mice significantly extends lifespan.

“I think that everything we do in the aging field can be reduced to trying to simulate the beneficial effects of a healthy lifestyle, particularly diet…and exercise,” Cohen said. “We think that…mitochondria are the main source of action [here] by inducing the production of peptides such as MOTS-c, humanin, and others.”

Further Readings


Zhu Y, Tchkonia T, Pirtskhalava T, et al.

The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs.

Aging Cell. 2015 Aug;14(4):644-58.

Kirkland JL, Tchkonia T.

Senolytic drugs: from discovery to translation.

J Intern Med. 2020 Nov;288(5):518-536.

Ogrodnik M, Miwa S, Tchkonia T, et al.

Cellular senescence drives age-dependent hepatic steatosis.

Nat Commun. 2017 Jun 13;8:15691.

Xu M, Pirtskhalava T, Farr JN, et al.

Senolytics improve physical function and increase lifespan in old age.

Nat Med. 2018 Aug;24(8):1246-1256.

Justice JN, Nambiar AM, Tchkonia T, et al.

Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study.

EBioMedicine. 2019 Feb;40:554-563.


Mehta HH, Xiao J, Ramirez R, et al.

Metabolomic profile of diet-induced obesity mice in response to humanin and small humanin-like peptide 2 treatment.

Metabolomics. 2019 Jun 6;15(6):88.

Zempo H, Kim SJ, Fuku N, et al.

A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c.

Aging. 2021 Jan 19;13(2):1692-1717.

Yen K, Mehta HH, Kim SJ, et al.

The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan.

Aging. 2020 Jun 23;12(12):11185-11199.

Miller B, Kim SJ, Kumagai H, et al.

Peptides derived from small mitochondrial open reading frames: Genomic, biological, and therapeutic implications.

Exp Cell Res. 2020 Aug 15;393(2):112056.

Zempo H, Kim SJ, Fuku N, et al.

A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c.

Aging. 2021 Jan 19;13(2):1692-1717.

Psychedelics to Treat Depression and Psychiatric Disorders


Currently the FDA categorizes psychedelics such as LSD and psilocybin as Schedule I drugs, indicating that these substances have no medical value. Despite this classification, a resurgence of research in approved labs has demonstrated therapeutic benefits of psychedelics for treatment of psychiatric disorders.

Of note, a recent trial on the effects of MDMA-assisted therapy for post-traumatic stress disorder (PTSD) showed a reduction in the severity of patient symptoms compared with the placebo arm of the trial, providing hope for the future approval of MDMA for therapeutic use.  The exciting findings from this study as well as and investigations into other psychedelics are instigating a paradigm shift for treatment-resistant psychiatric conditions, along with increased public interest and efforts to legalize psychedelics for medicinal use.

The New York Academy of Sciences hosted a panel discussion bringing together leading scientists in the fields of pharmacology, neuroscience, and psychiatry to discuss how psychedelics work in the brain to produce therapeutic benefits for depression and other mood disorders.  The conversation commenced a description of the socio-political context of psychedelics research, spanning the rise of psychedelics research in the 1950s, restrictions in the 1960s, renewed interest in the 1990s, and present day clinical trials for patients with depression and various other mood disorders. 

The program continued by spotlighting the different types of classical and non-traditional psychedelics that are currently being investigated (e.g., psilocybin, MDMA, and ketamine) and how they work to produce therapeutic effects. Panelists concluded the conversation by sharing insights into the use of psychedelics in treatment settings, including explaining the process of facilitated treatment and the role of the therapist/guide during the psychedelic experience (including preparatory therapy, peak effects, and integration).

In this eBriefing, you will learn:

  • The socio-political history of psychedelic research for human health
  • The difference between classic and non-traditional psychedelics
  • The effects of psychedelics on the brain and targets
  • The role of the hallucinogenic experience
  • The role of psychological support during the psychedelic experience

Event Sponsors



Psychedelics for the Treatment of Depression and Psychiatric Disorders


John Krystal, MD
Yale School of Medicine


Roland Griffiths, PhD
Johns Hopkins University School of Medicine

David E. Nichols, PhD
Heffter Research Institute

Rachel Yehuda, PhD
Icahn School of Medicine at Mt. Sinai

John Krystal, MD
Yale School of Medicine

Dr. John Krystal is the Robert L. McNeil, Jr., Professor of Translational Research; Professor of Psychiatry, Neuroscience, and Psychology; and Chair of the Department of Psychiatry at the Yale University. He is also Chief of Psychiatry and Behavioral Health at Yale-New Haven Hospital.  He is a graduate of the University of Chicago, Yale University School of Medicine, and the Yale Psychiatry Residency Training Program.

Dr. Krystal has published extensively on the neurobiology and treatment of schizophrenia, alcoholism, PTSD, and depression. Notably, his laboratory discovered the rapid antidepressant effects of ketamine in humans. He is the Director of the NIAAA Center for the Translational Neuroscience of Alcoholism and the Clinical Neuroscience Division of the VA National Center for PTSD. Dr. Krystal is a member of the U.S. National Academy of Medicine and a Fellow of the American Association for the Advancement of Science. Currently, he is co-director of the Neuroscience Forum of the U.S. National Academies of Sciences, Engineering, and Medicine; and editor of Biological Psychiatry (IF=12.1).

He has chaired the NIMH Board of Scientific Counselors and served on the national advisory councils for both NIMH and NIAAA. Also, he is past president of the American College of Neuropsychopharmacology (ACNP) and International College of Neuropsychopharmacology (CINP).

Roland Griffiths, PhD
Johns Hopkins University School of Medicine

Roland Griffiths is Professor in the Departments of Psychiatry and Neurosciences and Director of the Center for Psychedelic and Consciousness Research at the Johns Hopkins University School of Medicine.  His principal research focus in both clinical and preclinical laboratories has been on the behavioral and subjective effects of mood-altering drugs and he is author of over 400 scientific publications.  He has conducted extensive research with sedative-hypnotics, caffeine, and novel mood-altering drugs.

About 20 years ago, he initiated a research program at Johns Hopkins investigating effects of the classic psychedelic substance psilocybin, the active component in “magic mushrooms.” Remarkably, many research participants rate their experience of psilocybin as among the most personally meaningful of their lives, and they attribute enduring positive changes in moods, attitudes and behavior months to years after the experience.  Completed and ongoing studies include those in healthy volunteers, in beginning and long-term meditators, and in religious leaders.

Therapeutic studies with psilocybin include treatment of psychological distress in cancer patients, major depressive disorder, nicotine addiction, anorexia nervosa, and various other psychiatric disorders. Related studies of brain imaging and drug interactions are examining pharmacological and neural mechanisms of action.  His research group has also conducted a series of survey studies characterizing various naturally-occurring and psychedelic-occasioned transformative experiences including mystical experiences, entity and God-encounter experiences, Near Death experiences, and experiences claimed to reduce depression, anxiety, and substance use disorders.

David E. Nichols, PhD
Heffter Research Institute

David E. Nichols previously held the Robert C. and Charlotte P. Anderson Distinguished Chair in Pharmacology and in addition was a Distinguished Professor of Medicinal Chemistry and Molecular Pharmacology at the Purdue University College of Pharmacy.  He was continuously funded by the NIH for nearly three decades and served on numerous government review panels.  His two principal research areas focused on drugs that affect serotonin and dopamine transmission in the CNS.

He began medicinal chemistry research on hallucinogens in 1969 and has been internationally recognized as a top expert on the medicinal chemistry of psychedelics (hallucinogens).  He has published more than 300 scientific articles, book chapters, and monographs.  In 1993 he founded the Heffter Research Institute, which has supported and funded clinical research with psilocybin and led the so-called “renaissance in psychedelic research.”

Rachel Yehuda, PhD
Icahn School of Medicine at Mt. Sinai

Rachel Yehuda, Ph.D. is the Director of the Center for the Study of Psychedelic Psychotherapy and Trauma, Vice Chair for Veterans Affairs for the Psychiatry Department and a Professor of Psychiatry and Neuroscience at the Icahn School of Medicine at Mount Sinai as well as the Director of Mental Health at the Bronx Veterans Affairs Medical Center and the Director of the Traumatic Stress Studies Division.

Throughout her career her research has focused on the study of the enduring effects of trauma exposure, particularly PTSD, as well as associations between biological and psychological measures. She has investigated novel treatment approaches for PTSD and the biological factors that may contribute to differing treatment outcomes for the purpose of developing personalized medicine strategies for treatment matching in PTSD. This work has resulted in an approved US patent for a PTSD blood test.

Recently, Dr. Yehuda’s laboratory has used advances in stem cell technology to examine PTSD gene expression networks in induced neurons.  The Center for Psychedelic Psychotherapy and Trauma integrates sophisticated brain imaging and molecular neuroscience in PTSD with clinical trials using MDMA assisted psychotherapy and other related medicines. She has authored more than 450 published papers, chapters, and books in the field of trauma and resilience, focusing on topics such as PTSD prevention and treatment, molecular biomarkers of stress vulnerability and resilience, and intergenerational effects of trauma and PTSD.

Further Readings

John Krystal

Abdallah CG and Krystal JH

Ketamine and Rapid Acting Antidepressants: Are We Ready to Cure, Rather Than Treat Depression?

Behavioral Brain Research. 2020 July 15;(30): 112628

Charney D and Duman R

A New Rapid-Acting Antidepressant

Cell. 2020 April 2;1(181): 7

Abdallah CG, Sanacora G, Charney DS, and Duman R

Ketamine: A Paradigm Shift for Depression Research and Treatment

Neuron. 2019 Mar 6;101(5):774-778

Roland Griffiths

Scharper J

Crash Course in the Nature of Mind

Johns Hopkins University Magazine. Fall 2017

Griffiths RG, Johnson MW, and Carducci MA, et al

Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial

Journal of Psychopharmacology. 2016 Dec; 30(12):1181-1197

David E. Nichols

Nichols DE

How Does One Go About Performing Research with Psychedelics?

Multidisciplinary Association for Psychedelic Studies Bulletin. Fall 1997

Nichols DE


Pharmacological Reviews. 2016 April;68(2):264-255

Nichols DE

Studies of the Relationship between Molecular Structure And Hallucinogenic Activity

Pharmacology, Biochemistry, and Behavior. 1986 Feb;2:335-340

Nichols DE

Psilocybin: From Ancient Magic to Modern Medicine

The Journal of Antibiotics. 2020 May 12;73:679-686

Nichols DE, Johnson MW, and Nichols CD

Psychedelics as Medicines: An Emerging New Paradigm

Clinical Pharmacology and Therapeutics. 2016 Nov 4;101(2):209-219

Rachel Yehuda

Vermetten E and Yehuda R

MDMA-assisted Psychotherapy for Posttraumatic Stress Disorder: A Promising Novel Approach to Treatment

Neuropsychopharmacology. 2020 Jan;45(1):231-232

Yehuda R

Mount Sinai: Five Things to Know About MDMA-Assisted Psychotherapy for PTSD

Multidisciplinary Association for Psychedelic Studies (MAPS) in the Media. 2020 Feb 20

Neuroplasticity, Neuroregeneration, and Brain Repair


Many promising strategies for promoting neuroregeneration have emerged in the past few years, but a further research push is needed for these ideas to be translated into therapies for neurodegenerative diseases.

On June 13–14, a symposium presented by Eli Lilly and Company and The New York Academy of Sciences brought together academic and industry researchers working on multiple neurodegenerative diseases as well as clinicians and government stakeholders to discuss cutting edge basic and clinical research on neuroregeneration and neurorestoration. Topics included neuronal plasticity, inflammation, glial cell function, autophagy, and mitochondrial function, as well as analysis of recent drug development failures and how to move forward from them.


Benedikt Berninger, PhD,
University Medical Center Johannes Gutenberg University
Mainz, Germany

Graham Collingridge, PhD,
University of Toronto

Ana Maria Cuervo, MD, PhD,
Albert Einstein College of Medicine

Valina Dawson, PhD,
Johns Hopkins School of Medicine

Roman Giger, PhD,
University of Michigan

Steven Goldman, MD, PhD,
University of Rochester Medical Center

Eric Karran, PhD,

Arthur Konnerth, PhD,
Technical University of Munich, Germany

Guo-li Ming, MD, PhD,
Johns Hopskins School of Medicine

David Rowitch, MD, PhD, ScD,
University of Cambridge and University of California, San Fransisco

Amar Sahay, PhD,
Massachusetts General Hospital

Reisa A. Sperling, MD, MMSc,
Brighman and Women’s Hospital

James Surmeier, PhD,
Northwestern University

Richard Tsien, DPhil,
New York University, Longone Medical Center

Jeffrey Macklis,
Harvard University

Mark Mattson,
National Institute of Aging

Clive Svendsen,
Cedars-Sinai Medical Center

Michael Sofroniew,
David Geffen School of Medicine, UCLA

Michael J. O’Neill,
Eli Lilly and Company

Presented By

Meeting Reports

Meeting Reports

Astrocytes in CNS Repair; Disease-Modifying Therapies in the Pipeline


Eric Karran

Michael V. Sofroniew
David Geffen School of Medicine, University of California, Los Angeles


  • Astrocyte scar formation is not detrimental to neuronal regeneration and repair after injury but is in fact critical to the healing process.
  • The clinical pipeline in Alzheimer’s disease is dominated by amyloid beta-targeting compounds, despite the fact that the approach has not been successful to date.

Astrocytes in CNS Repair

In his keynote talk, Michael V. Sofroniew of the University of California, Los Angeles, described 25 years of work on the overlooked and misunderstood role of astrocytes in the central nervous system (CNS).

These glial cells were discovered in the 19th century, and researchers widely believed that their activation after injury—which often results in scar formation around the lesion—detrimentally affects recovery. “But one has to ask, why would nature conserve this response to injury across all mammalian species if it were purely detrimental?” Sofroniew said.

Astrocytes can play fundamentally different roles in the CNS. In healthy tissue, they help synapses take up and release neurotransmitters and other factors, and help maintain neuronal energy balance and blood flow in surrounding tissue. Their activation in response to damage differs depending on whether recovery requires neurons to grow through lesioned tissue or through intact neural tissue.

Two different phenotypes of reactive astrocytes occur after injury.

Astrocytes responding to injury exist in different phenotypes:  a hypertrophic reactive form interacts with neural cells, and a scar-forming reactive form interacts with non-neuronal inflammatory and fibrotic cells. Researchers are just beginning to define the function of hypertrophic astrocytes, but Sofroniew and his colleagues hypothesize that they represent a beneficial gain of function—helping injured neurons make new synapses and reorganize damaged circuits. Much remains to be learned about this process, he said.

Ongoing research from Sofroniew’s lab suggests that scar-forming astrocytes have a different, also beneficial function: recruiting inflammatory cells into the tissue, regulating their activity, and restricting their spread outside the lesion. Inflammation is crucial for getting rid of damaged cells, but too much of it damages surrounding intact tissue.

When neural tissue is injured, astrocytes recruit cells to scavenge damaged tissue. Somehow, astrocytes sense where the border between damaged and healthy tissue should be and wall off the injury with scar tissue. Sofroniew and others have shown that disrupting scar formation causes neurons in surrounding tissue to die.

Entrenched dogma in the field, however, says that astrocyte scar formation prevents axon regeneration. Twenty years ago, Sofroniew’s lab first tested whether disrupting scar formation in mice would spur injured axons to spontaneously regenerate. Their results showed that it didn’t, but the findings went against current dogma so the team never published them. When a researcher interested in the question joined the lab recently, they began exploring the question again, using two mouse models with mutations that prevent scar format.

After a spinal cord injury, sensory axons stimulated with growth factors can regrow despite astrocyte scar formation.

They showed that axons in three different types of CNS tracts failed to regrow in the mutant mice. Both astrocytes in lesions, along with other, non-astrocyte cells, all produced a variety of molecules both promoting and inhibiting axonal growth, underscoring the multi-component nature of regeneration. And axons that received appropriate stimulatory molecules “grow happily across astrocyte scars,” he said. The group is now confirming the result in additional types of CNS tracts. Sofroniew concluded that astrocyte reactivity and scar formation are not forms of astrocyte dysfunction, but adaptive functions critical for CNS repair and regeneration after injury.

Disease-Modifying Drugs for Alzheimer’s Disease: An Industry Perspective

The 1990s were a rich decade of discovery in Alzheimer’s disease, said Eric Karran of the pharmaceutical company AbbVie. Researchers identified disease-causing autosomal dominant mutations in the amyloid precursor protein presenilin and in tau. The field began to uncover key mechanisms and targets, and many believed that the next decade would yield effective therapeutics. However, that has not transpired, and many uncertainties about Alzheimer’s disease drug development remain.

Researchers still puzzle over the relationship between tau pathology and amyloid beta deposition. And while evidence suggests that Apolipoprotein E (ApoE) is closely involved in amyloid beta pathology, the mechanistic details remain mysterious. Nonetheless, research on the autosomal dominant mutations has geared drug discovery toward the idea that amyloid deposition initiates the disease process. Yet it is not clear that amyloid beta is an effective target for people who already have symptoms of Alzheimer’s disease.

Three questions are critical for therapeutics targeting amyloid: at what stage of the disease is such a drug most likely to be effective, by how much should amyloid beta be lowered, or its clearance be facilitated, and what kind of clinical experiment will test the validity of the amyloid cascade hypothesis.

Karran made a distinction between onset and duration of the disease. Possibly, amyloid beta deposition initiates the disease, he said, but is not the factor that drives its progression. The amyloid cascade hypothesis has many permutations, making proving or disproving it particularly difficult. One clear sign of this is the multiple failed trials that targeted amyloid beta. Lilly’s solanezumab seemed to show a mild effect on cognitive decline, but the signal was too small for a phase 3 trial. One currently promising candidate is Biogen’s aducanumab, which showed time- and dose-dependent reduction of amyloid plaques in early-stage trials.

Tau binpathology correlates with disease progression, but amyloid does not.

A drug that intervenes with the onset and spread of tau pathology could potentially have therapeutic value relatively late in disease. Tau pathology is the most proximate marker for neuronal loss and cognitive impairment. Tau proteins are released by a currently unknown mechanism; how they are seeded and travel to distant neurons is also poorly understood. The process points to several points of interventions, such as anti-tau antibodies targeting seeds or fibrils. However, early efforts at tau therapeutics have failed.

Speaker Presentation

Further Readings

Michael Sofroniew

Anderson MA, Burda JE, Ren Y, Ao Y, O’Shea TM, Kawaguchi R, Coppola G, Khakh BS, Deming TJ, Sofroniew MV.

Astrocyte scar formation aids central nervous system axon regeneration.

Nature. 2016 Apr 14;532(7598):195-200. doi: 10.1038/nature17623. Epub 2016 Mar 30.

Burda JE, Sofroniew MV.

Reactive gliosis and the multicellular response to CNS damage and disease.

Neuron. 2014 Jan 22;81(2):229-48. doi:10.1016/j.neuron.2013.12.034. Review.

Khakh BS, Sofroniew MV.

Diversity of astrocyte functions and phenotypes in neural circuits.

Nat Neurosci. 2015 Jul;18(7):942-52. doi: 10.1038/nn.4043.

Sofroniew MV.

Astrocyte barriers to neurotoxic inflammation.

Nat Rev Neurosci. 2015 May;16(5):249-63. doi: 10.1038/nrn3898. Review. Erratum in: Nat Rev Neurosci.

Eric Karran

Braak H, Del Tredici K.

Alzheimer’s disease: pathogenesis and prevention.

Alzheimers Dement. 2012 May;8(3):227-33. doi: 10.1016/j.jalz.2012.01.011. Epub 2012 Mar 30.

Braak H, Thal DR, Ghebremedhin E, Del Tredici K.

Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years.

J Neuropathol Exp Neurol. 2011 Nov;70(11):960-9. doi: 10.1097/NEN.0b013e318232a379.

Gauthier S, Feldman HH, Schneider LS, Wilcock GK, Frisoni GB, et al.

Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer’s disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial.

Lancet. 2016 Dec 10;388(10062):2873-2884. doi: 10.1016/S0140-6736(16)31275-2.

Karran E, De Strooper B.

The amyloid cascade hypothesis: are we poised for success or failure?

J Neurochem. 2016 Oct;139 Suppl 2:237-252. doi: 10.1111/jnc.13632.

Dendritic Spines, Axons, and Synapses in Neuroplasticity


Richard Tsien
New York University Langone Medical Center

Roman J. Giger
University of Michigan School of Medicine

Jeffrey Macklis
Harvard University

James Surmeier
Feinberg School of Medicine, Northwestern University


  • Neuronal cell bodies regulate events at the synapse via the CamKII signaling pathway.
  • Imperfect adaptation to the gradual loss of dopaminergic neurons in the striatum drives Parkinson’s disease symptoms
  • Dectin1, a receptor expressed on the surface of macrophages, mediates a neuroregenerative immune response after injury.
  • Growth cones may contain autonomous machinery for building the neuronal circuitry of the brain.

Regulation of Synapses and Synaptic Strength

Understanding the neural circuitry underlying learning and memory requires understanding how neurophysiological events at the synapse are integrated with molecular events in the nucleus such as gene transcription and protein translation, said Richard Tsien of New York University. At the synapse, this process depends on the combined activation of glutamate receptors and so-called L-type calcium channels. Tsien’s lab discovered that such dual activation is coordinated by the mobilization of a molecule called CamKII—known to be a key player in learning and memory—around tiny protrusions from dendrites called dendritic spines.

Tsien and his colleagues then elucidated how the signal from this synaptic activity is conveyed to the nucleus. Two of the four known forms of CamKII do their jobs at the synapse, but a third form, called gamma CamKII, shuttles calcium and its binding partner calmodulin to the nucleus, where it initiates a signaling cascade that drives the transcription of genes involved in long-term potentiation, a key molecular mechanism underlying learning and memory. Mice mutated to lack gamma-CamKII showed reduced learning and memory and did not upregulate key genes after training in memory tasks.

Mice mutated to lack gamma-CamKII showed reduced learning and memory and did not upregulate key genes after training in memory tasks.

A mutation in gamma CamKII has been linked to intellectual disability in humans; studies on this human mutation revealed that it prevented the protein’s ability to shuttle calcium / calmodulin. Mutations in multiple proteins on this CamKII signaling pathway have been causally implicated in neuropsychiatric disorders such as autism, pointing to its importance in linking neuronal activity with nuclear processes.

Striatal Plasticity in Parkinson’s Disease

The core motor symptoms of Parkinson’s disease (PD) are caused by the loss of dopaminergic neurons in a brain region called the striatum. James Surmeier of Northwestern University described his lab’s research on how the two main pathways of the striatum—the direct (dSPN) and the indirect (iSPN) pathway—maintain homeostasis as the disease progresses.

Dopaminergic signaling in the striatum helps regulate goal-directed behaviors. The dSPN promotes desired actions, while the iSPN suppresses undesired actions, and the two must remain balanced for appropriate action selection to occur. Dopamine helps provide that balance. When its levels are high, it promotes long-term potentiation (LTP) of the dSPN (increasing choice of good actions) and long-term depression (LTD) of the iSPN (limiting opposition to them). When levels fall, the opposite occurs, quashing the selection of “bad” actions. Surmeier’s lab studies what drives LTP and LTD at these synapses by visualizing them. Only a subset of synapses is responsive to dopamine, they found.

Dopamine differentially affects the dSPN and iSPN via D1 and D2 receptors.

According to the standard model of Parkinson’s, loss of striatal neurons changes the excitability of the dSPN and iSPN, leading to suppression of motor activity. However, this model fails to account for how the system might compensate for its gradual deterioration. Such compensation may explain why the striatum must lose more than 60% of its dopaminergic cells before a person shows symptoms of the disease, Surmeier said. His work instead suggests that the dSPN and iSPN undergo a more graded but imperfect adaptation to the loss of dopaminergic innervation which distorts the information that these pathways receive, and which may cause deficits in goal-directed behavior before gross motor symptoms appear.

Immune-mediated Nervous System Regeneration

There is no spontaneous regeneration after nerve injury in the central nervous system. That is probably because extrinsic factors exist that block regeneration intrinsic factors that promote it are not activated, said Roman J. Giger of the University of Michigan School of Medicine. However, some types of inflammation can activate such regeneration factors.

His team found that an injection of zymosan (a mixture of proteins and carbohydrates prepared from the yeast cell wall) induced significant long-distance regeneration after optic nerve injury in mice, while the bacterial extract lipopolysaccharide did not. He and his colleagues found that this regenerative antifungal response is mediated primarily by a dectin-1, a receptor for a substance called beta glucan, which is expressed on the surface of macrophages and other immune cells, as well as by the immune recognition protein Toll-like receptor 2 (TLR2).

They also found this mechanism in spinal cord regeneration, as tested after a so-called conditioning injury to the sciatic nerve (which activates immune response genes) followed by a spinal cord lesion at the dorsal root ganglion. Wild type mice showed significant spinal cord axon regrowth after zymosan injection, while mice engineered to lack dectin-1 or TLR2 showed none.

Wild type mice showed significant spinal cord axon regrowth after zymosan injection, while mice engineered to lack dectin-1 or TLR2 showed none.

The researchers then tried to pinpoint which immune cell types produced dectin-1, and where it had to be localized to spur regeneration. They found that immune cells from the sciatic nerve—that is, the conditioning lesion—carried the signal. Although mice lacking dectin showed no regeneration, immune cells from the lesioned sciatic nerve of a wild type mouse transplanted into the dectin-1 knockout mouse could rescue this deficit.

Growth Cone Control over Circuit Development

Building the brain’s neuronal circuitry is enormously complex endeavor: neurons exist in a multitude of diverse subtypes, they project to precise sompatotopic targets, and some send projections to more than one specific location. Projections can be up to a meter in length – some 10,000 cell body diameters away. The system’s precision is astounding, said Jeffrey Macklis of Harvard University, and being able to rebuild circuits when they go awry is key to regeneration in the face of injury or disease.

Macklis described work showing that the transcriptional machinery that generates this complexity is present not just in the neuronal cell body, but also in growth cones located at the tips of projections as they extend. His lab has found that growth cones contain locally translated proteins, suggesting that these neuronal outposts might exert autonomous control over circuit development. “As a developmentalist, I view growth cones as little baby synapses,” Macklis said.

Immature axons transplanted in the developing mouse still project to their original, appropriate targets, suggesting a logic and subtype specificity to the process. Macklis’s lab came up with an approach to label and isolate growth cones from different neuronal subtypes. They found specific protein and RNA enriched at growth cones that was not present in the neuronal cell body, suggesting a localized projection machinery. Targeting this machinery could be an important strategy for promoting regeneration.

Speaker Presentations

Further Readings

Richard Tsien

Deisseroth K, Heist EK, Tsien RW.

Translocation of calmodulin to the nucleus supports CREB phosphorylation in hippocampal neurons.

Nature. 1998 Mar 12;392(6672):198-202.

Li B, Tadross MR, Tsien RW.

Sequential ionic and conformational signaling by calcium channels drives neuronal gene expression.

Science. 2016 Feb 19;351(6275):863-7. doi: 10.1126/science.aad3647.

Ma H, Groth RD, Cohen SM, Emery JF, Li B, Hoedt E, Zhang G, Neubert TA, Tsien  RW.

γCaMKII shuttles Ca2+/CaM to the nucleus to trigger CREB phosphorylation and gene expression.

Cell. 2014 Oct 9;159(2):281-94. doi: 10.1016/j.cell.2014.09.019.

James Surmeier

Gerfen CR, Surmeier DJ.

Modulation of striatal projection systems by dopamine.

Annu Rev Neurosci. 2011;34:441-66. doi: 10.1146/annurev-neuro-061010-113641. Review.

Surmeier DJ, Graves SM, Shen W.

Dopaminergic modulation of striatal networks in health and Parkinson’s disease.

Curr Opin Neurobiol. 2014 Dec;29:109-17. doi: 10.1016/j.conb.2014.07.008. Epub 2014 Jul 22.

Surmeier DJ, Obeso JA, Halliday GM.

Selective neuronal vulnerability in Parkinson disease.

Nat Rev Neurosci. 2017 Jan 20;18(2):101-113. doi:10.1038/nrn.2016.178. Review.

Thiele SL, Chen B, Lo C, Gertler TS, Warre R, Surmeier JD, Brotchie JM, Nash JE.

Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models.

Neurobiol Dis. 2014 Nov;71:334-44. doi: 10.1016/j.nbd.2014.08.006. Epub 2014 Aug 27.

Roman Giger

Baldwin KT, Carbajal KS, Segal BM, Giger RJ.

Neuroinflammation triggered by β-glucan/dectin-1 signaling enables CNS axon regeneration.

Proc Natl Acad Sci USA. 2015 Feb 24;112(8):2581-6. doi: 10.1073/pnas.1423221112. Epub 2015 Feb 9.

Jeffrey Macklis

Arlotta P, Molyneaux BJ, Chen J, Inoue J, Kominami R, Macklis JD.

Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo.

Neuron. 2005 Jan 20;45(2):207-21.

Cederquist GY, Azim E, Shnider SJ, Padmanabhan H, Macklis JD.

Lmo4 establishes rostral motor cortex projection neuron subtype diversity.

J Neurosci. 2013 Apr 10;33(15):6321-32. doi: 10.1523/JNEUROSCI.5140-12.2013.

Inflammation, Oxidative Stress, Mitochondrial Function, and Autophagy


Ana Maria Cuervo
Albert Einstein College of Medicine

Valina L. Dawson
Johns Hopkins University

Mark Mattson
National Institute of Aging


  • Fasting and exercise exert protective effects on the brain and improve the bioenergetics properties of neurons.
  • Activators of a selective autophagy process may help clear aggregating proteins implicated in neurodegenerative disease.
  • A key cluster of Parkinson’s disease proteins regulate mitochondrial biogenesis and function.

Bioenergetic Challenges Bolster Brain Resilience

Mark P. Mattson of the National Institute of Aging described how two bioenergetics challenges—food deprivation and exercise—affect brain health. The ability to function under conditions of food deprivation is the main driving force in brain evolution, he said: Fasting was frequent, and it drove humans to search for food. Aging is a major risk factor for dementia and stroke, but sedentary lifestyles contribute as well, by compromising cells’ ability to adapt to the molecular stresses of aging.

Increased exercise is known to boost brain levels of the neuroprotective factor BDNF, and early work in Mattson’s lab found that fasting has the same effect in mice. Also, in mice genetically engineered to be obese and diabetic, alternate day fasting and increased exercise on a running wheel increased the density of synaptic spines in their brain. Further work showed that fasting and exercise also increased the number of mitochondria—the cell’s energy-generating organelles—in cultured hippocampal neurons.

The brains of mice lacking Sirt3 experience more cell death (blue) upon excitotoxic treatment with glutamate, kainic acid, and NMDA.

More recently, Mattson’s lab found that exercise and intermittent fasting upregulate a mitochondrial protein called sirtuin 3 (sirt3), which goes on to block enzymes that protect the mitochondria against stress and protect cells against apoptosis. The group has also explored the effects of fasting in humans. Currently, the group is studying whether people at risk for cognitive impairment due to age or metabolic status benefit from fasting two days per week.

Malfunctioning Autophagy Pathways in Neurodegeneration

Autophagy is the process of degradation or recycling of materials inside the cell, and many facets of it are coming under scrutiny as causal factors in neurodegeneration. Ana Maria Cuervo of the Albert Einstein College of Medicine studies chaperone-mediated autophagy (CMA), in which individual proteins targeted with a degradation motif are recognized by a chaperone protein, carried to a receptor called LAMP-2A on the lysosome surface, and pulled inside for degradation. In order to study the role of CAM in neurodegeneration, Cuervo’s lab designed a fluorescent reporter system that can track the process in vivo, in the brain and other organs.

A fluorescent reporter technique developed by Cuervo lab allows researchers to observe chaperone-mediated autophagy in different tissues of a live mouse.

The CAM pathway is highly sensitive to aging; levels of the LAMP-2A receptor drop as animals age. Additionally, many proteins involved in neurodegenerative diseases have CMA degradation motifs. The mutant form of LRRK2, the protein most often mutated in familial cases of Parkinson’s, interferes with LAMP-2 receptor’s ability to form complexes as required for translocation into the lysosome; other neurodegeneration-related proteins, such as tau, showed a similar effect, which led to an aggregation of these proteins due to their inability to be broken down inside the lysosome. Human postmortem Alzheimer’s disease brains also appear to have a CMA deficit.

The lab has now developed a selective activator of the CAM pathway and is administering it to a mouse model of Alzheimer’s disease. The intervention ameliorates behavioral symptoms such as anxiety, depression, and visual memory in the animals, as well as cellular markers of the disease.

Mitochnodrial Mechanisms and Therapeutic Opportunities

Mitochondrial dysfunction was first observed in Parkinson’s disease some 40 years ago, but how it plays a role in the disease is unknown. Some genetic causes of PD have been identified, including mutations in Parkin and PINK1. Valina L. Dawson’s lab at Johns Hopkins University is investigating how three closely interacting proteins, Parkin, PINK1, and PARIS, regulate mitochondrial function and, in turn, the integrity of dopaminergic neurons, which malfunction in PD.

In 2011, Dawson’s lab identified PARIS, a protein that tamps down mitochondrial production by repressing another protein called PGC1-alpha. PARIS is ubiquitinated by Parkin to remove the brake on mitochondrial production. Mice genetically engineered to lack Parkin show age-dependent loss of dopaminergic neurons and serve as a model of PD. But if these mice also experience a knock-down in PARIS, the deficit is rescued. Loss and gain of function studies of these proteins in mice revealed a homeostasis between them that regulates mitochondrial biogenesis and function. Pink1 is also central; it must phosphorylate Parkin for this homeostasis to occur.

In human neuron lacking Parkin, knocking down PARIS restores mitochondrial deficits.

The relationships between these proteins also hold in human embryonic stem cells when these proteins are knocked down, and in induced pluripotent cells derived from Parkinson’s patients with mutations in these proteins. Based on these findings, Dawson’s team and collaborators are exploring whether PARIS inhibitors, Parkin activators, or other molecules affecting this protein network have therapeutic value in PD mice.

Speaker Presentations

Further Readings

Mark Mattson

Cheng A, Yang Y, Zhou Y, Maharana C, Lu D, Peng W, Liu Y, Wan R, Marosi K, Misiak M, Bohr VA, Mattson MP.

Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges.

Cell Metab. 2016 Jan 12;23(1):128-42. doi: 10.1016/j.cmet.2015.10.013. Epub 2015 Nov 19.

Mattson MP.

Energy intake and exercise as determinants of brain health and vulnerability to injury and disease.

Cell Metab. 2012 Dec 5;16(6):706-22. doi: 10.1016/j.cmet.2012.08.012. Epub 2012 Nov 15. Review.

Mattson MP, Longo VD, Harvie M.

Impact of intermittent fasting on health and disease processes.

Ageing Res Rev. 2016 Oct 31. pii: S1568-1637(16)30251-3. doi: 10.1016/j.arr.2016.10.005. [Epub ahead of print] Review.

Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson MP.

Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons.

Nat Neurosci. 2008 Mar;11(3):309-17. doi: 10.1038/nn2055. Epub 2008 Feb 17.

Ana Maria Cuervo

Anguiano J, Garner TP, Mahalingam M, Das BC, Gavathiotis E, Cuervo AM.

Chemical modulation of chaperone-mediated autophagy by retinoic acid derivatives.

Nat Chem Biol. 2013 Jun;9(6):374-82. doi: 10.1038/nchembio.1230. Epub 2013 Apr 14.

Wong E, Cuervo AM.

Autophagy gone awry in neurodegenerative diseases.

Nat Neurosci. 2010 Jul;13(7):805-11.

Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D.

Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy.

Science. 2004 Aug 27;305(5688):1292-5.

Koga H, Martinez-Vicente M, Arias E, Kaushik S, Sulzer D, Cuervo AM.

Constitutive upregulation of chaperone-mediated autophagy in Huntington’s disease.

J Neurosci. 2011 Dec 14;31(50):18492-505. doi: 10.1523/JNEUROSCI.3219-11.2011.

Orenstein SJ, Kuo SH, Tasset I, Arias E, Koga H, Fernandez-Carasa I, Cortes E,
Honig LS, Dauer W, Consiglio A, Raya A, Sulzer D, Cuervo AM.

Interplay of LRRK2 with chaperone-mediated autophagy.

Nat Neurosci. 2013 Apr;16(4):394-406. doi: 10.1038/nn.3350. Epub 2013 Mar 3.

Valina Dawson

Shin JH, Ko HS, Kang H, Lee Y, Lee YI, Pletinkova O, Troconso JC, Dawson VL, Dawson TM.

PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson’s disease.

Cell. 2011 Mar 4;144(5):689-702. doi: 10.1016/j.cell.2011.02.010.

Stevens DA, Lee Y, Kang HC, Lee BD, Lee YI, Bower A, Jiang H, Kang SU, Andrabi SA, Dawson VL, Shin JH, Dawson TM.

Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration.

Proc Natl Acad Sci USA. 2015 Sep 15;112(37):11696-701. doi: 10.1073/pnas.1500624112. Epub 2015 Aug 31.

Lee Y, Stevens DA, Kang SU, Jiang H, Lee YI, Ko HS, Scarffe LA, et al.

PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival.

Cell Rep. 2017 Jan 24;18(4):918-932. doi: 10.1016/j.celrep.2016.12.090.

Glial Function


Steven A. Goldman
University of Rochester Medical Center

David H. Rowitch
University of Cambridge

Clive Svendsen
Cedars-Sinai Medical Center


  • Glial cell dysfunction may causally contribute to schizophrenia and other neurological diseases.
  • Astrocytes engineered to produce GDNF are in clinical trials for treating amyotrophic lateral sclerosis.
  • Astrocytes are functionally and regionally heterogeneous, and their dysfunction may contribute to neurodegenerative disease.

Targeting Glial Cell Dysfunction in Neurological Disease

Glial cells make up a significant proportion of cells in the brain, yet their contribution to disease is poorly understood. Steven A. Goldman of the University of Rochester Medical Center studies glia’s role in brain diseases such as schizophrenia. His lab injects human glial progenitor cells into the brains of mutant mice that lack their own glia; the brains of the resultant chimeras become fully repopulated with human astrocytes and oligodendrocytes. This human glial chimera maintains the phenotypes of human glial cells, and mice with human glia show stronger long-term potentiation in the hippocampus and learn fear-conditioning and other behavioral and cognitive tasks more quickly than wildtype mice.

Astrocytes in mice populated by glial cells derived people with schizophrenia had different morphology than those derived from control subjects, with fewer and longer processes.

Goldman’s team created chimeric mice populated by glia derived from eight different people with juvenile onset schizophrenia, and compared them to mice with glial cells derived from control subjects. These glial precursor cells migrated abnormally and formed less myelin than precursors from control human subjects. Myelin-producing and glial differentiation genes, as well as genes associated with synaptic development and transmission, were downregulated. Astrocytes in the patient-derived chimeras also had irregular morphology. The animals exhibited impaired response to stimuli as well as anxiety and antisocial behavior. Genes related to glial cells might be potent therapeutic targets for schizophrenia and other diseases, like Huntington’s disease and frontotemporal dementia.

“We never thought of these as glial diseases, but fundamentally they might be,” Goldman said.

Stem-cell-derived Astrocytes for Treating Neurodegenerative Disease

Ninety percent of neurodegenerative diseases have no known genetic cause, and may be amenable to treatment with cell therapy, said Clive Svendsen of Cedars-Sinai Medical Center. While delivering neurons into diseased CNS is still evolving, astrocytes have great potential for immediate use, Svendsen said.

His lab developed a protocol for deriving astrocytes from human fetal tissue; these cells migrate to areas of damage when delivered to a rat brain. To give these cells more regenerative capacity, Svendsen and collaborators engineered the cells to release the growth factor GDNF. They initially tested this cell delivery therapy in a Parkinson’s disease model, but it has also been applied in stroke, and both Huntington’s and Alzheimer’s disease.

More recently they have begun to explore its use in amyotrophic lateral sclerosis (ALS), where life expectancy after diagnosis is a mere three years and no treatments exist. They first tested it in an ALS rat transgenic model in which astrocytes lacked the protein SOD1. When they transplanted the therapeutic astrocytes to the lumbar spine, the cells survived well and improved neuronal survival, but did not prevent paralysis. As they moved up the spinal cord, results improved; cell delivery into the brain’s motor cortex yielded improved motor function and survival in the animals.

GDNF-releasing astrocytes injected into the motor cortex spur motor neuron growth in a rat model of ALS.

Last October, Svendsen and his team launched an 18-person clinical trial of this approach. For safety reasons, the U.S. Food and Drug Administration required the researchers to start by delivering cells into the lumbar spine; patients will receive the therapy in one leg, with the other acting as a control. If the first few patients experience no adverse effects, delivery into the cervical spine and the cortex will also be attempted.

Functionally Heterogeneous Astrocytes in the Mammalian CNS

How neuron patterning generates a diversity of neuronal types throughout the central nervous system is well understood. But very little is known about heterogeneity in astrocytes, although they are the most abundant cells in the CNS, comprising about half of all brain cells, said David H. Rowitch of the University of Cambridge.

Early work in Rowitch’s lab identified an astrocyte-specific transcription factor that showed that astrocytes are allocated to specific regions of the brain during development. They then searched for postnatal astrocytes in the spinal cord that were regionally and functionally distinct by comparing gene expression in the dorsal and ventral part of the spinal cord. The gene Sema3a was most highly expressed in ventral astrocytes in mice, and when it was deleted, half the animal’s alpha motor neurons, which innervate fast-twitching muscle, died.

Mice lacking Kir4.1 have abnormal signaling in motor neurons, smaller muscle fibers, and decreased strength.

To investigate how neurons and astrocytes interact, the researchers examined a potassium channel called Kir4.1, which is preferentially expressed in the ventral brain and spinal cord. Loss of function mutations to the channel cause epilepsy, and the channel is strongly downregulated in astrocytes of people with ALS. Mice engineered to lack the channel in astrocytes have smaller alpha motor neurons and weaker muscle function. Transfecting the astrocytes of these mice with the channel reverses these deficits. The fact that astrocytes so strongly affect neuron function suggests that dysfunction in specific subsets of astrocyte may play a role in neurodegenerative diseases.

Speaker Presentations

Further Readings

Steven Goldman

Han X, Chen M, Wang F, Windrem M, Wang S, Shanz S, Xu Q, Oberheim NA, Bekar L,
Betstadt S, Silva AJ, Takano T, Goldman SA, Nedergaard M.

Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice.

Cell Stem Cell. 2013 Mar 7;12(3):342-53. doi: 10.1016/j.stem.2012.12.015.

Windrem MS, Schanz SJ, Guo M, Tian GF, Washco V, Stanwood N, Rasband M, Roy NS, Nedergaard M, Havton LA, Wang S, Goldman SA.

Neonatal chimerization with human glial progenitor cells can both remyelinate and rescue the otherwise lethally hypomyelinated shiverer mouse.

Cell Stem Cell. 2008 Jun 5;2(6):553-65. doi: 10.1016/j.stem.2008.03.020.

Osorio MJ, Goldman SA.

Glial progenitor cell-based treatment of the childhood leukodystrophies.

Exp Neurol. 2016 Sep;283(Pt B):476-88. doi: 10.1016/j.expneurol.2016.05.010. Epub 2016 May 8.

Wang S, Bates J, Li X, Schanz S, Chandler-Militello D, Levine C, Maherali N, Studer L, Hochedlinger K, Windrem M, Goldman SA.

Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination.

Cell Stem Cell. 2013 Feb 7;12(2):252-64. doi: 10.1016/j.stem.2012.12.002.

Windrem MS, Schanz SJ, Morrow C, Munir J, Chandler-Militello D, Wang S, Goldman SA.

A competitive advantage by neonatally engrafted human glial progenitors yields mice whose brains are chimeric for human glia.

J Neurosci. 2014 Nov 26;34(48):16153-61. doi: 10.1523/JNEUROSCI.1510-14.2014.

Clive Svendsen

Suzuki M, Svendsen CN.

Combining growth factor and stem cell therapy for amyotrophic lateral sclerosis.

Trends Neurosci. 2008 Apr;31(4):192-8. doi: 10.1016/j.tins.2008.01.006. Epub 2008 Mar 10.

Thomsen GM, Gowing G, Latter J, Chen M, Vit JP, Staggenborg K, Avalos P, Alkaslasi M, Ferraiuolo L, Likhite S, Kaspar BK, Svendsen CN.

Delayed disease onset and extended survival in the SOD1G93A rat model of amyotrophic lateral sclerosis after suppression of mutant SOD1 in the motor cortex.

J Neurosci. 2014 Nov 19;34(47):15587-600. doi: 10.1523/JNEUROSCI.2037-14.2014.

David Rowitch

Freeman MR, Rowitch DH.

Evolving concepts of gliogenesis: a look way back and ahead to the next 25 years.

Neuron. 2013 Oct 30;80(3):613-23. doi: 10.1016/j.neuron.2013.10.034. Review.

Molofsky AV, Kelley KW, Tsai HH, Redmond SA, Chang SM, Madireddy L, Chan JR, Baranzini SE, Ullian EM, Rowitch DH.

Astrocyte-encoded positional cues maintain sensorimotor circuit integrity.

Nature. 2014 May 8;509(7499):189-94. doi: 10.1038/nature13161.

Tsai HH, Li H, Fuentealba LC, Molofsky AV, Taveira-Marques R, Zhuang H, Tenney A, Murnen AT, Fancy SP, Merkle F, Kessaris N, Alvarez-Buylla A, Richardson WD, Rowitch DH.

Regional astrocyte allocation regulates CNS synaptogenesis and repair.

Science. 2012 Jul 20;337(6092):358-62. doi: 10.1126/science.1222381. Epub 2012 Jun 28.

Innovative Approaches to Promote Neuroregeneration


Graham Collingridge
University of Toronto

Guo-li Ming
University of Pennsylvania

Benedikit Berninger
Johannes Gutenberg University Mainz

Amar Sahay
BROAD Institute of Havard and MIT


  • Novel therapies targeting the synaptic plasticity pathways could address the dysregulation of long term depression underlying Alzheimer’s disease.
  • Brain organoids grown from human induced pluripotent stem cells recapitulate development and can model brain disease.  
  • Reprogramming pericyte cells into neuronal cells occurs via a distinct developmental program.
  • Promoting neurogenesis and re-engineering molecular connectivity in the hippocampus restored age-related memory decline in mice.

Is Alzheimer’s Disease Caused by Long Term Depression Gone Awry?

One key purpose of brains is to enable learning and memory—a process that relies on a balance between long term potentiation (LTP) and long term depression (LTD) to drive synaptic plasticity, said Graham Collingridge of the University of Toronto. Dysregulation of that balance causes Alzheimer’s disease, he said.

In 1983, Collingridge’s lab identified the role of the NMDA receptor in synaptic plasticity, finding that its activation could cause both LTP and LTD. In later work, they sought kinase inhibitors that could block LTP and LTD. One of the few ways to inhibit LTD was to block glycogen synthase kinase 3beta (GSK-3beta). This molecule is also known as tau kinase because it hyperphosphorylates the protein tau—a process implicated in Alzheimer’s disease pathogenesis. “I thought, well, that’s just not coincidence, is it,” Collingridge said.

Dysregulation of the pathway regulating LTD can cause the pathogenic features of Alzheimer’s disease.

Tau regulates microtubules in axons, but Collingridge’s lab found that it also exists in synapses, and is phosphorylated by GSK-3beta. In mice engineered to lack tau, LTD is absent but LTP is undisturbed. Work from other researchers had shown that amyloid beta, the protein that aggregates in Alzheimer’s disease, inhibits LTP and facilitates LTP. His group showed that GSK-3beta reverses this effect, and identified other parts of the signaling pathway linking amyloid beta, tau, GSK-3beta, and both LTP and LTD. Dysregulation in these components can generate amyloid beta plaques, tau tangles, and the neuroinflammation, synapse loss and memory loss that characterizes Alzheimer’s. Modulators of NMDA receptor activity may have therapeutic potential.

Modeling Human Brain Development and Disease with Human Induced Pluripotent Stem Cells

Guo-Li Ming of the University of Pennsylvania is developing 3-dimensional cell culture models of the developing brain—so-called organoids—using induced pluripotent stem cells. High school students working in her lab designed 3D-printed lids with shafts that insert into standard cell culture plates, to divide each individual well of the plate into a separate miniaturized spinning bioreactor. Because most brain organoid protocols produced highly heterogeneous tissue, she used these tiny bioreactors to create organoids containing almost exclusively forebrain tissue.

Using markers specific to different layers of the cerebral cortex, Ming’s lab could show that organoids roughly recapitulated the cortical architecture.

Cell labeling and gene expression studies showed that when grown for 100 days, these organoids recapitulated fetal forebrain development through the end of the second trimester. Progenitor cells generated neurons and glia whose migration pattern mirrored development, and the neurons received both excitatory and inhibitory input. The researchers used the organoids to study how Zika virus affects the developing brain. They found that the virus specifically targets neural progenitor cells, dose-dependently causing cell death and causing a collapse of tissue that resembles the microcephaly in infants affected by Zika. A screen of 6000 compounds yielded a neuroprotective compound called Emricasan that is positioned to enter clinical trials.

The group has now developed other brain-region specific organoids, modeling the midbrain and the hypothalamus. They plan to use these tools to study other neurodevelopmental disorders. Recent publications suggest the approach can also recapitulate features of neurodegenerative diseases, Ming said.

Engineering Neurogenesis via Lineage Reprogramming

For the past decade, Benedikit Berninger of Johannes Gutenberg University Mainz has been working on identifying cellular signals that can drive the reprogramming of astroglial cells from early postnatal mouse brain into neurons. More recently, to see if such reprogramming could be conducted in human cells, his lab began working with cells derived from adult human brains during epilepsy surgery. These cells turned out to be pericytes, and Berninger’s team identified a two transcription factors—Sox2 and Ascl1—that could reprogram them into functional neurons, which formed synapses and fired action potentials in culture.

To understand how the two transcription factors interact, the researchers investigated gene expression in the early stages—day 2 and day 7—in this two-week reprogramming process. A few genes were regulated by just one of the factors, but most were turned on only when both factors were present, suggesting that the two factors act synergistically. Ascl1 alone appears to target a different set of genes—ones associated with mesodermal cell fate (which generate pericytes), rather than neurogenesis-related genes activated when Ascl1 is co-expressed with Sox2. A similar difference was seen on a single cell level.

The researchers also observed two subpopulations in the starting population of pericytes—one of which was susceptible to reprogramming into neurons while the other was not. That may account for distinct competence in reprogramming in individual cells, Berninger said. For example, cells expressing the leptin receptor had a low level of reprogramming efficiency, indicating subtype differences in reprograming competence.

Three sets of genes are induced during reprogramming of pericytes to neurons—a set associated with pericytes, one associated with a progenitor-like stage, and one associated with neurons.

In the subset of cells that do reprogram successfully, a set of genes was induced transiently, then downregulated. These genes reflect a progenitor-like stage in the reprogramming process. These studies suggest that cells are not transforming directly from pericyte to neuron, but undergo a series of events reminiscent of an unfolding developmental program, Berninger said.

Rejuvenating and Re-engineering Aging Memory Circuits

The hippocampus plays a critical role in formation of episodic memories-that is, memories of what, when, and where. Essential to this capacity is the need to keep similar memories separate and retrieve past memories in a context appropriate manner. With age, the ability to keep similar memories separate and context-appropriate retrieval is potentially impaired, said Amar Sahay of Massachusetts General Hospital and Harvard Medical School. Within the hippocampus, the dentate gyrus-CA3 circuit performs operations such as pattern separation and pattern completion that support resolution of memory interference and retrieval. With age, neurogenesis in the hippocampus declines and CA3 neurons become hyper excitable in rodents, non-human primates and humans. Sahay’s lab investigates circuit mechanisms that may be harnessed to optimize hippocampal memory functions in adulthood and aging.

The DG-CA3 circuit in the hippocampus regulates episodic memory.

The hippocampus generates new neurons throughout life, and previous work has suggested that adult-born neurons integrate into the hippocampal circuitry by competing with existing mature neurons for inputs. Sahay and his colleagues identified a transcription factor called Klf9 that, when unregulated just in the mature neurons, biases competition dynamics in favor of integration of the adult-born neurons. This enhances neurogenesis in adult (3-month-old), middle-aged (12 months) and in aged (17-month-old) mice. Older rejuvenated animals (with enhanced adult hippocampal neurogenesis) had a memory advantage: they were better at discriminating between two similar contexts, one safe and one associated with a mild footshock.

In a complementary series of experiments, Sahay and his colleagues found age-related changes in connectivity between dentate granule neurons and inhibitory interneurons. They performed a screen and identified a factor with which they re-engineered connectivity between dentate granule neurons and inhibitory interneurons and augmented feed-forward inhibition onto CA3. By targeting this factor in the dentate gyrus of aged mice, the authors were able to reverse age-related alterations in dentate granule neuron-inhibitory interneuron connectivity and enhance memory precision.

Speaker Presentations

Further Readings

Graham Collingridge

Collingridge GL, Peineau S, Howland JG, Wang YT.

Long-term depression in the CNS.

Nat Rev Neurosci. 2010 Jul;11(7):459-73. doi: 10.1038/nrn2867. Review.

Jo J, Whitcomb DJ, Olsen KM, Kerrigan TL, Lo SC, Bru-Mercier G, Dickinson B, Scullion S, Sheng M, Collingridge G, Cho K.

Aβ(1-42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3β.

Nat Neurosci. 2011 May;14(5):545-7. doi: 10.1038/nn.2785. Epub 2011 Mar 27.

Kimura T, Whitcomb DJ, Jo J, Regan P, Piers T, Heo S, Brown C, Hashikawa T, Murayama M, Seok H, Sotiropoulos I, Kim E, Collingridge GL, Takashima A, Cho K.

Microtubule-associated protein tau is essential for long-term depression in the hippocampus.

Philos Trans R Soc Lond B Biol Sci.2013 Dec 2;369(1633):20130144. doi: 10.1098/rstb.2013.0144. Print 2014 Jan 5.

Peineau S, Taghibiglou C, Bradley C, Wong TP, Liu L, Lu J, Lo E, Wu D, Saule E, Bouschet T, Matthews P, Isaac JT, Bortolotto ZA, Wang YT, Collingridge GL.

LTP inhibits LTD in the hippocampus via regulation of GSK3beta.

Neuron. 2007 Mar 1;53(5):703-17.

Shipton OA, Leitz JR, Dworzak J, Acton CE, Tunbridge EM, Denk F, Dawson HN, Vitek MP, Wade-Martins R, Paulsen O, Vargas-Caballero M.

Tau protein is required for amyloid {beta}-induced impairment of hippocampal long-term potentiation.

J Neurosci. 2011 Feb 2;31(5):1688-92. doi: 10.1523/JNEUROSCI.2610-10.2011.

Guo-li Ming

Qian X, Nguyen HN, Song MM, Hadiono C, Ogden SC, Hammack C, Yao B, et al.

Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure.

Cell. 2016 May 19;165(5):1238-54. doi: 10.1016/j.cell.2016.04.032. Epub 2016 Apr 22.

Benedikit Berninger

Heinrich C, Blum R, Gascón S, Masserdotti G, Tripathi P, Sánchez R, Tiedt S, Schroeder T, Götz M, Berninger B.

Directing astroglia from the cerebral cortex into subtype specific functional neurons.

PLoS Biol. 2010 May 18;8(5):e1000373. doi: 10.1371/journal.pbio.1000373.

Karow M, Schichor C, Beckervordersandforth R, Berninger B.

Lineage-reprogramming of pericyte-derived cells of the adult human brain into induced neurons.

J Vis Exp. 2014 May 12;(87). doi: 10.3791/51433.

Karow M, Sánchez R, Schichor C, Masserdotti G, Ortega F, Heinrich C, Gascón S, Khan MA, Lie DC, Dellavalle A, Cossu G, Goldbrunner R, Götz M, Berninger B.

Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells.

Cell Stem Cell. 2012 Oct 5;11(4):471-6. doi: 10.1016/j.stem.2012.07.007.

Amar Sahay

McAvoy K, Besnard A, Sahay A.

Adult hippocampal neurogenesis and pattern separation in DG: a role for feedback inhibition in modulating sparseness to govern population-based coding.

Front Syst Neurosci. 2015 Aug 20;9:120. doi: 10.3389/fnsys.2015.00120.

McAvoy KM, Sahay A.

Targeting Adult Neurogenesis to Optimize Hippocampal Circuits in Aging.

Neurotherapeutics. 2017 Jul;14(3):630-645. doi: 10.1007/s13311-017-0539-6. Review.

McAvoy KM, Scobie KN, Berger S, Russo C, Guo N, Decharatanachart P, Vega-Ramirez H, Miake-Lye S, Whalen M, Nelson M, Bergami M, Bartsch D, Hen R, Berninger B, Sahay A.

Modulating Neuronal Competition Dynamics in the Dentate Gyrus to Rejuvenate Aging Memory Circuits.

Neuron. 2016 Sep 21;91(6):1356-73. doi: 10.1016/j.neuron.2016.08.009. Epub 2016 Sep 1.

Biomarkers, Hot Topics, and the Future of Therapeutics


Reisa Sperling
Brigham and Women’s Hospital

Johanna Jackson
Eli Lilly and Company

Eliška Zlámalová
University of Cambridge

Arthur Konnerth
Technical University of Munich

Milo Robert Smith
Icahn School of Medicine at Mount Sinai


  • Multimodal imaging is becoming advanced enough to identify people with early-stage disease, which will help determine the critical window for therapies in clinical trials.
  • Slow wave oscillations are disrupted in Alzheimer’s disease model mice due to a misregulation of excitatory and inhibitory synaptic activity.
  • Imaging pre- and post-synaptic structures over time can reveal how disease progression affects synapses.
  • Integrative bioinformatics can identify common pathways across neurodegenerative diseases and as well as drugs that can may act on those pathways.
  • An RNAi-based screen in Drosophila can reveal genes that shape the morphology of axonal ER.

Neuroimaging in Early Alzheimer’s Disease

Alzheimer’s disease evolves over a couple decades, but most research to date has examined the disease at a late stage—perhaps too late to intervene effectively, said Reisa Sperling of Brigham and Women’s Hospital. Multimodal imaging is becoming advanced enough to identify people with early-stage disease, which will help determine the critical window for therapies in clinical trials.

PET amyloid imaging detects amyloid pathology in humans in vivo. Some 30% of clinically normal individuals have high amyloid levels, accumulating data suggests that this increases the risk of cognitive decline over the next 15 years—particularly when combined with markers of neurodegeneration such as decreased hippocampal volume. Still, Sperling said, “I see that as a glass half full—we’ve got 15 years to intervene.”

Committing something to memory requires activation of a brain region called the medial temporal lobe, where tau accumulates in AD. It also requires disabling the so-called default mode network (DMN), a brain circuit active when the brain is not engaged in a particular task. Amyloid accumulation disrupts the DMN, and disruptions also emerge in other networks and the specificity with which they signal.

Tau levels are associated with cognitive decline.

It’s the combination of amyloid and tau that is important for cognitive decline. Because tau—though not amyloid—correlates clearly with cognitive decline, tau PET imaging, which emerged just a couple years ago, has the most promise as a neurodegenerative marker for clinical trials, Sperling said. Ultimately, trials should move toward primary prevention—identifying drugs that block disease onset before clinical symptoms emerge. The field also needs biomarkers that show a person’s response to therapy.

Circuitry Dysfunction in Alzheimer’s Disease Mouse Models

A lot is known about clinical symptoms, pathology, and molecular mechanisms involved in Alzheimer’s disease, but there is a big gap in understanding how neuronal circuits are affected, said Arthur Konnerthof the Technical University of Munich.

About ten years ago, Konnerth’s lab developed a method for measuring neuronal function at the single cell level in living mice using fluorescent calcium indicators. They used it to investigate neurons surrounding amyloid beta plaques in mice lacking functional amyloid precursor protein (APP), an Alzheimer’s disease model. They hypothesized that these neurons would show decreased activity, but to their surprise, they were hyperactive, while further-away cells were silent. The error signal sent by these hyperactive cells probably disturbs the circuit significantly, Konnerth said.

His team also explored the function of long-range circuits in Alzheimer’s disease model mice. They studied slow wave oscillations, a form of activity that is essential for slow wave sleep and for memory consolidation. These waves travels through the cortex and into the hippocampus in a coherent fashion. In Alzheimer’s disease mice, the coherence of this circuitry is highly disrupted. Enhancing inhibitory (GABAergic) neuron activity reversed the deficit.

Alzheimer’s disease model mice showed improved learning after restoration of slow wave activity.

Tweaking GABAergic activity in normal mice also affected this circuitry, pointing to a synaptic effect. Returning the circuitry to normal also improved a learning task, the Morris water maze, and individual animals’ behavioral performance could be predicted by the coherence of this slow wave oscillation. An fMRI study in humans conducted by another lab showed also showed a disruption in slow wave oscillation. Targeting the shift in excitation-inhibition that underlies slow wave disruption may ameliorate cognitive deficits in the disease, Konnerth said.

Hot Topics in Neuroregeneration

In three short talks, early career researchers described imaging, bioinformatics and candidate gene analyses for probing neurodegenerative diseases.

Johanna Jackson from Eli Lilly used two-photon imaging in two mouse models of Alzheimer’s disease to study how disease progression affects synapses. She and her colleagues tracked axonal boutons and dendritic spines—the presynaptic and postsynaptic points of contact—over time in the same brain region. In the J20 mouse, which develops amyloid plaques, dendritic spine number remained constant, but axonal boutons were lost and the turnover rate of both spines and boutons increased as amyloidopathy progressed. The Tg4510s mouse, which develops tauopathy, showed a different pattern: both spines and boutons were lost, and neurites sickened then disappeared over time. Switching off the transgene in these mice could partially prevent or delay these deficits.

Milo Robert Smith of the Icahn School of Medicine at Mt. Sinai used bioinformatics to probe plasticity mechanisms in neurodegenerative diseases and to identify common disease pathways and potential therapeutic drugs. First, his team conducted microarray experiments to capture gene expression signatures of plasticity in mice. They then matched these signatures to transcriptomics signatures of 436 diseases taken from publicly available databases. The 100-plus illnesses showing a significant association were enriched for neurodegenerative diseases, and inflammatory genes appeared highly implicated. Finally, the researchers matched disease transcriptional signatures to transcriptional signatures of drugs measured in cell lines, also from publicly available databases. Using this approach, they identified drug candidates for resting plasticity in Huntington’s disease.

A strategy for using integrative bioinformatics to identify drugs that target common mechanisms in neurodegenerative disease.

Human motor neuron axons can extend a meter in length, but dysfunction in trafficking such a distance underlies a neurodegenerative disease called hereditary spastic paraplegia (HSP), in which corticospinal motor neurons progressively degenerate. Eliška Zlámalová of the University of Cambridge is identifying candidate genes involved in long axon transport and HSP pathology. Three genes associated with HSP—reticulon, REEP1, and REEP2—produce proteins that localize to smooth endoplasmic reticulum (ER) in axons. When Zlámalová disabled all three in Dropsophila, ER fragmented in the middle of the axon and degenerated distally. To look for additional candidate genes, Zlámalová developed fluorescent markers for two other proteins, knocked own their genes in triple-mutant flies using RNA interference, and imaged ER morphology. She found a trend toward further ER fragmentation; a higher number of experiments may yield more conclusive results.

Further Readings

Reisa Sperling

Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Feldman HH, Frisoni GB, Hampel H, Jagust WJ, Johnson KA, Knopman DS, Petersen RC, Scheltens P, Sperling RA, Dubois B.

A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers.

Neurology. 2016 Aug 2;87(5):539-47. doi: 10.1212/WNL.0000000000002923. Epub 2016 Jul 1. Review.

Schultz AP, Chhatwal JP, Hedden T, Mormino EC, Hanseeuw BJ, Sepulcre J, Huijbers W, LaPoint M, Buckley RF, Johnson KA, Sperling RA.

Phases of Hyperconnectivity and Hypoconnectivity in the Default Mode and Salience Networks Track with Amyloid and Tau in Clinically Normal Individuals.

J Neurosci. 2017 Apr 19;37(16):4323-4331. doi: 10.1523/JNEUROSCI.3263-16.2017. Epub 2017 Mar 17.

Sperling R, Mormino E, Johnson K.

The evolution of preclinical Alzheimer’s disease: implications for prevention trials.

Neuron. 2014 Nov 5;84(3):608-22. doi: 10.1016/j.neuron.2014.10.038. Epub 2014 Nov 5. Review.

Sperling RA, Jack CR Jr, Aisen PS.

Testing the right target and right drug at the right stage.

Sci Transl Med. 2011 Nov 30;3(111):111cm33. doi: 10.1126/scitranslmed.3002609. Review.

Sperling RA, Laviolette PS, O’Keefe K, O’Brien J, Rentz DM, Pihlajamaki M, Marshall G, Hyman BT, Selkoe DJ, Hedden T, Buckner RL, Becker JA, Johnson KA.

Amyloid deposition is associated with impaired default network function in older persons without dementia.

Neuron. 2009 Jul 30;63(2):178-88. doi: 10.1016/j.neuron.2009.07.003.

Arthur Konnerth

Busche MA, Kekuš M, Adelsberger H, Noda T, Förstl H, Nelken I, Konnerth A.

Rescue of long-range circuit dysfunction in Alzheimer’s disease models.

Nat Neurosci. 2015 Nov;18(11):1623-30. doi: 10.1038/nn.4137. Epub 2015 Oct 12.

Busche MA, Konnerth A.

Neuronal hyperactivity — a key defect in Alzheimer’s disease?

Bioessays. 2015 Jun;37(6):624-32. doi: 10.1002/bies.201500004. Epub 2015 Mar 14.

Busche MA, Grienberger C, Keskin AD, Song B, Neumann U, Staufenbiel M, Förstl 
H, Konnerth A.

Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer’s models.

Nat Neurosci. 2015 Dec;18(12):1725-7. doi: 10.1038/nn.4163. Epub 2015 Nov 9.

Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold KH, Haass C, Staufenbiel M, Konnerth A, Garaschuk O.

Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease.

Science. 2008 Sep 19;321(5896):1686-9. doi: 10.1126/science.1162844.

Willem M, Tahirovic S, Busche MA, Ovsepian SV, Chafai M, et al.

η-Secretase processing of APP inhibits neuronal activity in the hippocampus.

Nature. 2015 Oct 15;526(7573):443-7. doi: 10.1038/nature14864. Epub 2015 Aug 31.

Johanna Jackson

Scheff SW, Price DA, Schmitt FA, Mufson EJ.

Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment.

Neurobiol Aging. 2006 Oct;27(10):1372-84. Epub 2005 Nov 9.

Milo Robert Smith

Smith MR, Burman P, Sadahiro M, Kidd BA, Dudley JT, Morishita H.

Integrative Analysis of Disease Signatures Shows Inflammation Disrupts Juvenile Experience-Dependent Cortical Plasticity.

eNeuro. 2017 Jan 18;3(6). pii: ENEURO.0240-16.2016. doi: 10.1523/ENEURO.0240-16.2016. eCollection 2016 Nov-Dec.

Eliška Zlámalová

Blackstone C.

Cellular pathways of hereditary spastic paraplegia.

Annu Rev Neurosci. 2012;35:25-47. doi: 10.1146/annurev-neuro-062111-150400. Epub 2012 Apr 20.

Gerondopoulos A, Bastos RN, Yoshimura S, Anderson R, Carpanini S, Aligianis I, Handley MT, Barr FA.

Rab18 and a Rab18 GEF complex are required for normal ER structure.

J Cell Biol. 2014 Jun 9;205(5):707-20. doi: 10.1083/jcb.201403026. Epub 2014 Jun 2.

Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, et al.

Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.

Science. 2014 Jan 31;343(6170):506-511. doi: 10.1126/science.1247363.

Panel Discussion: The Future of Research and Therapies in Neuroregeneration and Restoration


Michael J. O’Neill, Moderator
Eli Lilly and Company

Ana Maria Cuervo, Panelist
Albert Einstein College of Medicine

Mark P. Mattson, Panelist
National Institute of Aging

Clive Svendsen, Panelist
Cedars-Sinai Medical Center

Jeffrey Macklis, Panelist
Harvard University

Panel Discussion
The Future of Research & Therapies in Neuroregeneration & Restoration

The panelists began by summarizing what they consider the most exciting dimension in the field of regeneration. Jeffery Macklis said that since graduate school, he had puzzled over the fact that only certain cell types were vulnerable and selectively damaged in different neurodegenerative diseases. “I find that the most exciting question,” he said. “Until we get to neuron subtype specificity and the circuits involved, we could be looking at a lot of unrelated stuff.”

Ana Maria Cuervo notes that neurodegenerative diseases primarily occur in the elder population, yet researchers still don’t know enough about the physiology of aging to determine which dimensions of the disease are due to aging and which are not.

Mark P. Mattson agreed, noting that in Alzheimer’s disease, events upstream of amyloid including generic age-related events such as increased oxidative stress, can affect the disease. “We need to understand those if we want to intervene earlier,” he said. He also wondered whether mechanisms being targeted by drug development could also be activated by exercise or energy restriction. A related approach might be to induce mild intermittent bioenergetic stress on cell pharmacology.

“The thing that keeps me up at night in this field is biomarkers,” said Clive Svendsen. Molecules that change as the disease progresses are not necessarily causative; indeed, some of the stress responses observed in Alzheimer’s disease might be neuroprotective, and that holds for Huntigton’s disease, too, he explained.

An audience member raised the question of sex differences in neurodegenerative disease, noting that even when boys and girls reach the same cognitive milestones, they often arrive there through different routes. In response, Mattson described a study conducted by his group that compared responses to different diets in male versus female mice. At 40% calorie restriction, females shut down their estrus cycle, increased their physical activity, and lost most of their body fat. Males under the same circumstances remained fertile, and their activity levels did not change. That could be because from an evolutionary perspective, females would ostensibly want to avoid having babies when there is no food around, because they lack the energy to care for them, while males might want to inseminate as widely as possible before they starve to death.

Reisa Sperling noted that women respond more adversely to a smaller amount of amyloid beta. “Something about being female means that you are more vulnerable,” she noted. An audience member noted that although men have a higher risk of Parkinson’s disease, females deteriorate faster once diagnosed. Svendsen noted that these observations speak to broader issues in personalizing treatments for neurodegenerative diseases. Sporadic Alzheimer’s disease likely consists of more than one disease, for example. “We’re trying to subdivide ALS into 10 types,” he said.

Panel Discussion

Open Questions

  • How do hypertrophic astrocytes help require damaged neuronal circuits?
  • What is the best way of clinically testing the amyloid beta hypothesis?
  • Can the signaling mechanism linking neuronal activity at the synapse and gene transcription in the nucleus be therapeutically targeted?
  • How should Parkinson’s disease therapeutic efforts account for homeostatic plasticity in stratal neurons?
  • Why do different inflammatory responses have different effects on CNS regeneration? [Giger]
  • How can growth cone machinery be targeted to promote regeneration?
  • Can fasting and exercise mitigate against dementia and neurodegenerative damage in diseases like Alzheimer’s and Parkinson’s?
  • How do pathogenic proteins cause the breakdown of chaperone-mediated autophagy, and how does such authophagy contribute to the clearance of pathogenic proteins?
  • Will improvements in mitochondrial function obtained by targeting Parkin, PARIS or related proteins provide therapeutic benefits in Parkinson’s disease?
  • How does glial cell dysfunction cause neurological disease and can it be therapeutically targeted? [Goldman]
  • Can a cell therapy consisting of GDNF-releasing astrocytes stave off paralysis in ALS?
  • Are there neurodegenerative diseases besides ALS in which genes are maladaptively downregulated in astrocytes?
  • Will drugs that modulate NMDA activity prove beneficial for Alzheimer’s disease?
  • How well can organoids reflect the pathology of neurodegenerative diseases?
  • Can promoting reprogramming strategies that turn non-neuronal cells into neurons be used therapeutically?
  • Can memory be improved with the help of molecular strategies to rejuvenate hippocampal circuitry that degenerates with age?
  • Will candidates identified through integrative bioinformatics yield drugs that target common mechanisms in neurodegenerative disease?
  • How to determine the optimal window for efficacy of different prospective Alzheimer’s disease therapies?
  • Will reversing the disintegration of slow wave oscillations ameliorate cognitive impairment in Alzheimer’s disease?