Brain Ponderings podcast with Mark Mattson

Anxiety disorders are all too common in children and adolescents and their incidence has increased considerably during the past decade. Social interactions (positive or negative) in the home, schools, and the digital world have a major influence on a child’s risk for anxiety and major depression. In this episode I talk with Dr. Danny Pine at the National Institute of Mental Health who has devoted his career to the problem of mental health problems in children. His research has advanced an understanding of the complex factors that determine whether or not a child develops an anxiety disorder, the brain circuits involved, and the behavioral and pharmacological interventions that can provide effective treatments.  LINKS  Dr. Pine’s NIH webpage: https://www.nimh.nih.gov/research/research-conducted-at-nimh/research-areas/clinics-and-labs/edb/sdan Articles https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9248771/pdf/nihms-1797515.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490291/pdf/nihms-1734583.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9931491/pdf/nihms-1858084.pdf    

Cells in all organ systems experience the same ‘hallmarks of aging’ which include the accumulation of oxidatively damaged proteins, DNA, membranes and mitochondria, impaired DNA repair and autophagy, senescence, and inflammation. In this episode Professor Ron DePinho of the MD Anderson Cancer Center in Houston talks about his remarkable career during which he and his trainees established fundamental mechanisms that control cell proliferation and differentiation in normal development and how alterations in these mechanisms result in aging and cancers. He then describes how the telomerase protein influences hallmarks of aging by controlling gene expression, and how age-related reductions in telomerase levels contribute to normal aging and the pathogenesis of Alzheimer’s disease. Ron and his colleagues have recently identified a chemical called TAC that can increase telomerase levels in cells. Treatment of old mice with TAC rejuvenates multiple organ systems, and can restore neuroplasticity and cognition in mouse models of Alzheimer’s disease.  LINKS: DePinho laboratory web page: https://www.mdanderson.org/research/departments-labs-institutes/labs/depinho-laboratory.html Related Articles: https://www.cell.com/action/showPdf?pii=S0092-8674%2820%2931750-5 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733214/pdf/nihms487161.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759755/pdf/nihms-1761822.pdf https://pubmed.ncbi.nlm.nih.gov/38908367/

All cells including neurons in the brain release tiny (~ 100 nanometers in diameter) bubble-like vesicles that contain various molecules produced by the cell. These extracellular vesicles (EVs) are thought to have a variety of functions including sending molecular messages between cells and removing molecular garbage from the cells. Some EVs released from cells throughout the body and brain make their way into the bloodstream. Dimitrios Kapogiannis at the National Institute on Aging Biomedical Research Center in Baltimore, developed a technology for isolating EVs produced by neurons from the blood. By measuring amounts of abnormal Tau protein in neuronal EVs from patients with Alzheimer’s disease (AD) and controls, and in longitudinal studies of people in the years preceding their cognitive impairment,  he showed that his test can identify people who will very likely become symptomatic.  It turns out that neuronal EVs have insulin receptors in their membrane and Dimitrios provided evidence that neuronal EVs from AD patients exhibit insulin resistance. Because intermittent fasting can increase the sensitivity of cells to insulin and is effective in countering the disease process in AD mouse models, Dimitrios performed a clinical trials of intermittent fasting in older individuals with insulin resistance and found that it improved their performance on several memory tests. More recently he headed a clinical trial of a ketone ester in patients in older people at risk for AD. This episode is all about EVs – where they come from, the kinds of molecules they contain, their normal functions, and changes in EVs in Alzheimer’s disease (AD) and other brain disorders that can be used for diagnosis and in clinical trials.   LINKS  Dr. Kapogiannis’ NIA webpage: https://www.nia.nih.gov/about/staff/kapogiannis-dimitrios Review articles on EVs: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439289/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9985115/pdf/nihms-1878107.pdf  Key publications: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314222/?report=printable https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632160/?report=printable https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146429/pdf/cells-10-00993.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10060702/pdf/awac258.pdf

While upon casual inspection the left and right sides of the human brain seem symmetrical. But it turns out there are left – right differences in both the structure and functionality of neuronal networks in many brain regions. One well-known example of a brain asymmetry is that regions involved in language comprehension and speech which are located in the left hemisphere. Another example concerns handedness for which neural circuits are more robust on the contralateral side of the brain. In this episode I talk with professor Sebastian Oklenburg about his research on lateralized brain functions including their evolutionary and developmental origins, their adaptive value, their roles in cognition and emotion, and how they are impacted in certain brain disorders.  LINKS Professor Ocklenburg’s blog on Psychology Today: https://www.psychologytoday.com/us/blog/the-asymmetric-brain Brain lateralization – evolutionary perspective: https://journals.physiology.org/doi/epdf/10.1152/physrev.00006.2019  Brain asymmetries and neurological disorders: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8712556/pdf/fnsys-15-733898.pdf Building an asymmetric brain: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524718/pdf/fpsyg-10-00982.pdf

The ‘exposome’ is a term used to describe all of the environmental exposures encountered by an individual throughout their life and how these exposures affect their health and contribute to (or protect against) aging and disease. The exposures may be physical (e.g., temperature), chemical (e.g., toxic chemicals), biological (e.g., viruses), or social (psychological trauma).  In this episode I talk with University of Michigan professor of neurology Eva Feldman, about research aimed at identifying environmental factors that promote, cause, or protect against  neurological disorders. Exposome research is of vital practical importance because environmental factors and aging are responsible for the most common neurological disorders.   LINKS Dr. Feldman’s webpage https://medicine.umich.edu/dept/mneuronet/about/eva-l-feldman-md-phd Exposome review articles https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26897 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10643494/pdf/11357_2023_Article_913.pdf https://www.annualreviews.org/docserver/fulltext/pharmtox/63/1/annurev-pharmtox-051922-113350.pdf?expires=1722005819&id=id&accname=guest&checksum=97B61448008EE60ABAA4CA80EFF3D878

It turns out that regardless of which organ they affect tumors contain a web of axons coursing throughout them. Recent research has shown that interactions between the neurons and the cancer cells influence the proliferation of the cancer cells within the tumor as well as metastasis (the spread of cancer cells to other organs). In this episode I talk with University of Newcastle Professor Hubert Hondermarck about his research on interactions between neurons and cancer cells, and the roles of neurotrophic factors and neurotransmitters in facilitating tumor growth. Knowledge gained from this research is leading to new pharmacological approaches to treating cancers. LINKS Professor Hondermarck’s webpage: https://www.newcastle.edu.au/profile/hubert-hondermarck Review “The Neural Addiction of Cancers”: https://www.proquest.com/docview/2806715386/fulltextPDF/7785F348C7744E4PQ/9?accountid=11752&sourcetype=Scholarly%20Journals

Plants sense their environment and respond in ways consistent with advanced decision-making capabilities. The cellular mechanisms that control the behaviors of plants are similar to those of animals and include electrically excitable cells capable of transmitting information via calcium waves and volatile messengers such as nitric oxide throughout roots, shoots, and leaves. Molecular genetic studies have shown that plants have receptors for the neurotransmitters glutamate and GABA, and that these neurotransmitters control many plant behaviors. Individual plants communicate with other plants, insects, fungi, and bacteria via the stimulus-dependent production and release of a myriad of chemicals. In this episode I talk with Bonn University Professor Frantisek Baluska about the behavioral repertoire of plants, the underlying cellular mechanisms, and the rationale and value of considering plants as sentient and intelligent organisms.  LINKS  Individuality and Sociality of Plants: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934911/pdf/rstb.2019.0760.pdf  Anesthetics and Plant Consciousness: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907011/pdf/709_2020_Article_1594.pdf  Predictive Coding Model of Plant Behavior: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5047902/pdf/fpsyg-07-01505.pdf  Plants Behaviors and Climate Change: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054678/pdf/EMBR-21-e50109.pdf

Cells have evolved elaborate molecular systems that control cell growth and division in ways that enable optimal function and resilience of all organ systems including the brain.  Cells that have the potential to become cancerous are eliminated by a process called apoptosis. Cells may also acquire a senescent state in which they no longer divide and function normally, but survive and produce potentially damaging proteins such as pro-inflammatory cytokines and proteases. Senescent cells accumulate during normal aging and more so in chronic diseases, but until recently it was not known whether such senescent cells cause or accelerate aging and disease processes . Mayo Clinic Professor Darren Baker who is an expert on the molecular control of cell division and cancers recently used genetic engineering technologies to generate mice in which senescent cells can be selectively eliminated. By studying these mice he and his team have provided convincing evidence that senescent cells contribute to the aging process and are involved in the disease processes that occur in Alzheimer’s disease (AD). There is evidence that several types of glial cells in the brain undergo senescence and removal of these cells can slow disease progression. I talk with Dr. Baker about his research on cell senescence, key issues that remain unresolved, and drugs that target senescent cells – “senotherapeutics” as potential treatments for AD and other neurodegenerative disorders. Dr. Baker’s Mayo Clinic Profile page: https://www.mayo.edu/research/faculty/baker-darren-j-ph-d-m-s/bio-00027985 Review article on senescence and brain aging: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873891/pdf/jci-128-95145.pdf Introduction to special journal issue on senescence: https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/febs.16735 Review article on senotherapeutics: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9599677/pdf/nihms-1842277.pdf Targeted removal of senescent cells and senotherapeutics in animal models of AD: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206507/pdf/nihms-1505435.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10939718/pdf/nihms-1968907.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605052/pdf/nihms-1031989.pdf

Two interrelated features of the brains of humans and other social animals is that they develop attractions for kin and other members of their local community (tribalism) and perceive strangers as potential threats (xenophobia). Historically, tribalism and xenophobia are of fundamental importance in unnecessary suffering and death from isolated domestic incidents to major wars. It is therefore important to understand both the psychology and neuroscience of tribalism and xenophobia. Pascal Molenberghs is a social neuroscientist who has studied the neural networks that mediate the cognitive processing and decision-making involved in xenophobic beliefs and actions. Here I talk with him about the far-reaching implications of this research for a wide range of issues including religions, politics, and dehumanization.  LINKS: The neuroscience of intergroup threat and violence: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9620594/pdf/main.pdf The neuroscience of in-group bias: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174241/pdf/fpsyg-09-01868.pdf Empathy: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644680/pdf/fnhum-07-00176.pdf

The ability of the human brain to store and recall information, and particularly its ability to create new information, is remarkable. The research of Harvard University professor Daniel Schacter as revealed the fallibilities of memory which he categorizes into ‘the seven sins’: transience, absent-mindedness, blocking, persistence, misattribution, suggestibility, and bias. These are normal, are influenced by emotions, can have adaptive value, and may be exaggerated or absent in pathological conditions. The digital technologies that most of us use every day, often for hours at a time, present new challenges for our memory system. In this episode I talk with professor Schacter about his career in memory research, how memory fallibilities play out in our daily lives, how digital technologies impact our memory, and how some our memory fallibilities – particularly suggestibility and bias – can be hijacked by digital media companies and political operatives.    LINKS: Schacter Memory Lab: https://sites.harvard.edu/schacter-memory/ Book: “The Seven Sins of Memory”: https://www.amazon.com/Seven-Sins-Memory-Revised-Remembers/dp/0358325684/ref=asc_df_0358325684/?tag=hyprod-20&linkCode=df0&hvadid=693388554878&hvpos=&hvnetw=g&hvrand=1921889579114062764&hvpone=&hvptwo=&hvqmt=&hvdev=c&hvdvcmdl=&hvlocint=&hvlocphy=9051570&hvtargid=pla-1184742256946&psc=1&mcid=760a3293f66030f780a64df60d06431f&gad_source=1 Review article on memory fallibilities: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285452/pdf/nihms-1664500.pdf Review article on media, technology and the sins of memory: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373035/