Brain Ponderings podcast with Dr. Mark Mattson

The structure of neuronal networks is remarkably complex and dynamic. Professor Shelley Halpain has been at the forefront of research aimed at understanding how the brain's "neuroarchitecture" is established during development and changes in response to synaptic activity (neuroplasticity). Here she talks about the 'cytoskeleton' of neurons which consists of dynamic protein polymers of actin (microfilaments) and tubulin (microtubules), and how the polymerization state of these cytoskeletal proteins is controlled by the excitatory neurotransmitter glutamate and the calcium ion (Ca2+). Working with her students and collaborators Professor Halpain has elucidated roles for proteins that control actin or tubulin polymerization in the formation and adaptive modification of neuronal circuits. Such structural modifications play fundamental roles in the enduring changes in neuronal circuits involved in learning and memory. Interestingly, one of these proteins (INF2) mediates a process called 'actinification' which functions as an adaptive stress response that can prevent the death of neurons in conditions such as stroke and epileptic seizures. LINKS: Professor Halpain's Labpage: https://biology.ucsd.edu/research/faculty/shalpain Review article on Neuron Navigators: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9877351/pdf/fnmol-15-1099554.pdf Actinification and neuroprotection: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9558009/pdf/41467_2022_Article_33268.pdf Navigator control of growth cone internalization of neurotrophin receptors: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9561856/pdf/mbc-33-ar64.pdf Regulation of actin microfilaments by glutamate: https://www.jneurosci.org/content/jneuro/18/23/9835.full.pdf

Not only are obesity, insulin resistance, and chronic stress bad for peripheral organ systems but they can also wreak havoc on neuronal networks in the brain. Here Professor Larry Reagan talks about research showing that insulin acts directly on neurons in the brain and thereby plays important roles in synaptic plasticity and learning and memory. Neurons become unresponsive to insulin in obesity and diabetes and this neuronal insulin resistance may contribute to neuronal circuit dysfunction and damage in Alzheimer's disease. Elevated levels of the adrenal stress hormone cortisol also contributes to the adverse effects of insulin resistance and diabetes on the brain. Regular exercise, healthy dietary and sleep habits, and avoidance of chronic stress can prevent and reverse insulin resistance and excessive production of cortisol. LINKS: Professor Reagan's lab page: https://sc.edu/study/colleges_schools/medicine/about_the_school/faculty-staff/reagan_larry.php Review articles on brain insulin and leptin resistance: file:///Users/markmattson/Downloads/nrn4019%20(1).pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8642294/pdf/nihms-1756570.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988909/pdf/nihms927597.pdf Original research articles: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613975/pdf/db150596.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252121/pdf/main.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774048/pdf/nihms285696.pdf

Marten Scheffer is a Dutch mathematician and ecologist who has made major contributions to modeling of complex systems. While he is best known for his work on catastrophic shifts in ecosystems and climate, he has more recently been applying dynamical systems theory to major brain-based problems of individual brains (e.g., belief traps and mental illness) and societies (e.g., inequality and fragility of democracies). Here I talk with Marten about features of dynamical systems – tipping points, basins of attraction, resilience…) and how systems modeling can be used to understand, evaluate, and intervene in detrimental ways of thinking and interacting with others. Links: Catastrophic shifts in ecosystems: file:///Users/markmattson/Downloads/35098000.pdf Early warning signals: file:///Users/markmattson/Downloads/nature08227%20(1).pdf Belief traps: file:///Users/markmattson/Downloads/pnas.2203149119%20(1).pdf Cognitive distortions: file:///Users/markmattson/Downloads/pnas.2102061118.pdf Shifts in rationality in language: file:///Users/markmattson/Downloads/pnas.2107848118.pdf

Despite many advances in neuroscience the fundamental question of how brains make computations is as yet unanswered. Progress has been hindered by the inabilities to monitor activities of large numbers of neurons during natural behaviors and to determine the structures and synaptic connections of all neurons involved in circuits mediating computations. Recent progress towards overcoming these hurdles has come from studies of Zebrafish in Professor Rainer Friedrich's laboratory at the Friedrich Miescher Institute in Basel Switzerland. Here Rainer talks about Zebrafish brain development, structure, and function. and how technological advances in genetics, brain imaging, dense reconstruction of neuronal connectivity, and virtual reality are being used to elucidate fundamental mechanisms by which neuronal circuits make computations. Links: Rainer Friedrich's lab page: https://www.fmi.ch/research-groups/groupleader.html?group=119 Virtual reality: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100911/pdf/EMS85577.pdf Review article on Zebrafish behaviors: https://www-annualreviews-org.proxy1.library.jhu.edu/doi/pdf/10.1146/annurev-neuro-071714-033857 Odor coding: https://www.cell.com/action/showPdf?pii=S0960-9822%2817%2931452-5 Synaptic balance: https://www.cell.com/action/showPdf?pii=S0896-6273%2818%2930786-4 Dense circuit reconstruction: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100684/pdf/sdata2016100.pdf

Olfaction, the most primitive of our senses, enables our brains to perceive thousands of different airborne chemicals. But it is not known how the outside olfactory world is coded in neuronal networks in the brain nor how those codes are evaluated in ways that result in behavioral responses to specific odors. Professor Bob Datta's laboratory at Harvard is developing and using cutting-edge technologies to answer these questions. Here he talks about the different types of neurons and their spatial and function organization in the olfactory system, and how emerging 3D imaging and unsupervised machine learning technologies are enabling quantitative analysis of spontaneous and odor-evoked behaviors of animals in natural environments. Links: Datta Lab webpage: http://datta.hms.harvard.edu/ Review article: https://www-annualreviews-org.proxy1.library.jhu.edu/doi/pdf/10.1146/annurev-neuro-102119-103452 Recent publications from the Datta Lab: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9892006/pdf/41586_2022_Article_5611.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8758202/pdf/nihms-1757925.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606807/pdf/nihms-1619406.pdf

In 2011 and 2014 Tony Wyss-Coray and his lab members published high-profile papers in which they used a procedure called parabiosis and blood transfusions to show that blood plasma from young animals can rejuvenate the brains of old mice and vice-versa. Moreover, they found that young plasma restores cognitive function in a mouse model of Alzheimer's disease. Since then many other labs have confirmed this remarkable phenomena and Wyss-Coray and others have been working to identify the 'rejuvenating factor' or factors in young plasma. A recent preliminary clinical trial in which patients with Alzheimer's were infused with plasma from young people generated promising results. Here I talk with Tony about this exciting area of research. Links: Professor Wyss-Coray lab page: http://web.stanford.edu/group/twclab/cgi-bin/ Key publications: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170097/pdf/nihms313001.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224436/pdf/nihms632757.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586222/pdf/nihms901457.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9387403/pdf/nihms-1827565.pdf

The environment and experiences of caregivers can affect the development of social skills in the infants they care for in ways that can result in enduring changes in behavior patterns. In this episode neuroscientist Maya Opendak at Johns Hopkins University talks about her research using experimental models of deprivation and adversity which is shedding light on the brain circuits altered by deprivation and maternal stress and the cellular and molecular mechanisms underlying those alterations. Such fundamental information will be required to fully understand and therefore work towards optimization of the early life environments of infants and their caregivers. Links: Dr. Opendak's lab webpage: https://www.opendaklab.com/ Review article on animal models of early life adversity: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9385963/pdf/fnbeh-16-918862.pdf Nature Communications 2020 – Adverse caregiving in infancy blunts neural processing of the mother: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048726/pdf/41467_2020_Article_14801.pdf Nature 2021 – rodents can acquire maternal behavior by social transmission. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387235/pdf/41586_2021_Article_3814.pdf Neuron 2021 – Bidirectional control of infant rat social behavior via dopaminergic innervation of the basolateral amygdala: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8988217/pdf/nihms-1745418.pdf

Professor Cynthia Moss has been studying the neurobiology of bat echolocation for more than three decades. Psychologist Daniel Kish became blind during the first year of his life and learned use echolocation to guide himself as he walks or rides a bike. Daniel is the founder of World Access For Blind and has devoted his life to enabling people with blindness excel in all aspects of life. In this episode Dr. Moss and Daniel talk about all things echolocation from bats hunting insects to people living in our communities. Links to information on Professor Moss's research: https://pbs.jhu.edu/directory/cynthia-moss/ https://www.youtube.com/watch?v=ay37PSIukwA https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9306857/pdf/HIPO-32-298.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682551/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896882/pdf/elife-29053.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115611/pdf/fncel-12-00270.pdf Links to information on Daniel Kish and his work: https://visioneers.org/daniel-kish/ https://www.youtube.com/watch?v=uH0aihGWB8U https://waftb.net/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578488/pdf/pcbi.1005670.pdf

Jean Lud Cadet is a neurologist and neuroscientist at the National Institute on Drug Abuse whose research is revealing why some people become addicted to methamphetamine while others do not, and how methamphetamine can damage and kill neurons resulting in long-lasting or even permanent impairments of learning and memory. His recent findings suggest that methamphetamine can cause enduring alterations in gene expression in neurons by mechanisms involving epigenetic mechanisms. This research is providing insight into new approaches for identifying people at high risk for addiction and treating those who are already addicted. Links: Jean Lud Cadet webpage: https://irp.nida.nih.gov/staff-members/jean-lud-cadet/ Jean Lud Cadet on Wikepedia: https://en.wikipedia.org/wiki/Jean_Lud_Cadet METH epigenetics: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535492/pdf/genes-12-01614.pdf METH addiction and potassium channels: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865894/pdf/ijms-22-01249.pdf

Approximately 30% of people who are infected with COVID will experience long-lasting symptoms of impaired brain function including reduced ability to concentrate, impaired memory, confusion, depression and chronic fatigue. These problems often last for many months beyond the time at which the SARS-CoV2 virus is no longer detectable in their nasal passages or blood. In this podcast Professor Daniel Martins-de-Souza talks about research from his laboratory and those of his collaborators published in the Proceedings of the National Academy of Sciences which provides evidence that SARS-CoV2 enters the brain where it infects astrocytes, a type of glial cell that normally plays important roles in brain energy metabolism, the regulation of cerebral blood flow, and the production and removal of several neurotransmitters. Their research reveals several approaches for the prevention and treatment of "neuroCOVID" including those that may prevent entry of the virus into astrocytes and those that may protect neurons against adverse effects of astrocyte infection. Links Professor Martins-de-Souza's research gate: https://www.researchgate.net/profile/Daniel-Martins-De-Souza-2 PNAS article: Morphological, cellular, and molecular basis of brain infection in COVID-19 patients. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436354/pdf/pnas.202200960.pdf Review article on Long NeuroCOVID: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9537254/pdf/main.pdf