← Brain Science with Ginger Campbell, MD: Neuroscience for Everyone
Brain Science with Ginger Campbell, MD: Neuroscience for Everyone
BS 214 Seventeenth Annual Review Episode
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This episode is brought to you by Progressive Insurance. Do you ever think about switching insurance companies to see if you could save some cash? Progressive makes it easy to see if you could save when you bundle your home and auto policies. Try it@progressive.com Progressive Casualty Insurance Company and affiliates. Potential savings will vary. Not available in all states.
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Welcome to Brain Science, the podcast that explores how recent discoveries in neuroscience are helping unravel the mystery of how our brain makes us human. This is episode 214 and I'm your host Dr. Ginger Campbell. This episode is scheduled for release on December 15, 2023, which is the 17th anniversary of episode one of the Brain Science Podcast on December 15, 2006. I want to start by thanking you for listening, whether you are new or have been with me from the beginning. If you are new to the show, this episode might be a little overwhelming, but it will give you a sense of the breadth of topics that we explored this year. As always, you can send me feedback@brainsciencepodcastmail.com you can also find complete show notes and episode transcripts@brainsciencepodcast.com because this is likely to be a long episode, I will try to keep my announcements to a minimum, but please listen to the end for an important announcement about the future of brain science. Usually I do my year end review in chronological order, but this year I'm going to mix things up a bit. I'm going to start by reviewing last month's conversation with Kevin Mitchell about his new book, Free Agents How Evolution Gave Us Free Will. This conversation generated a lot of feedback, both positive and negative, which is not surprising given that Mitchell challenges the current mainstream position of many neuroscientists and philosophers who argue that free will is an illusion. Whatever your position on this important issue, I encourage you to read Mitchell's book. One reason I say this is because much of the detail and rigor of Mitchell's approach was lost, partly due to time constraints and partly due to the very nature of the interview format. For example, the book includes a discussion of why the evidence that has been used to support the opposing view that free will is an illusion has been challenged, and this is discussed in detail in his book with ample references. It's not hard to find books arguing for the position that free will is an illusion. One that's getting a lot of attention is Robert Cybulsky's new book, A Science of Life Without Free Will. When I talked with Mitchell several months ago, he was looking forward to publicly debating Czabolski and I am hoping links to this will be available by the time this review is posted. Some listeners objected to the relative simplicity of Mitchell's argument, but to me this is part of its appeal. The key ideas are straightforward From a scientific standpoint, evolution doesn't have a purpose or a goal. It just reflects the constant changing nature of the universe and the fact that some changes persist while others disappear. Free will implies the ability to make meaningful choices, and Mitchell argues that this ability evolved with the emergence of life. Even single celled life forms have agency because they make simple choices like going toward food and away from threats. They also have a purpose, which is to stay alive. From an evolutionary point of view, as life became more complex, so did the level of agency or free will that organisms could enjoy. As far as we can tell, humans have an unprecedented ability to reflect on the consequences of our actions. One could argue that this also gives us an unprecedented level of responsibility. The second key element of Mitchell's argument attacks the assumption that everything is determined by low level physics, which is the claim that our universe is deterministic. To me, it is ironic that many consider determinism to be a highly scientific position rather than a philosophical one, but I guess this comes from the ongoing debate about the meaning of quantum mechanics. Quantum mechanics gives scientists the ability to make highly precise predictions about essentially probabilistic processes at the subatomic level. It's often joked that few people really understand quantum mechanics, but the reality is even those who do may disagree with what it really means. Thus, if one is inclined to a deterministic view, one can easily find a physicist to support that position. But I would also like to point out that Mitchell is not the only neuroscientist to consider the alternative approach. Michael Gazzaniga has also written extensively about the implications of indeterminacy to moral agents. My own knowledge of physics beyond the basics is limited to my extensive reading of books intended for general audiences. I've always found the standard interpretations of quantum mechanics unsatisfying, which is why I appreciate Carlo Rovelli's book Helgo Making Sense of the Quantum Revolution. Rovelli's relational interpretation of quantum mechanics resonates with much of what I have learned from neuroscience over the last 20 years. To me, it is not important that all physicists believe that the universe is indeterminate, because as long as it is a viable position, one cannot argue against free will on the basis of physics. The other main argument against free will is the assumption that we have overwhelming experimental evidence that our behavior is determined by unconscious processes in the brain. For example, labay's famous experiments where people were asked to move their fingers and to note when they felt the urge to move. This experiment showed a so called readiness potential in the EEG before they felt the urge to move. Since this experiment was first done, it has been analyzed and interpreted by countless scientists and philosophers, many of whom challenge the main conclusions. For one thing, the results are highly dependent on the experimental design. The issue is not whether there are unconscious processes going on in the brain, because clearly there are. The key question is whether these are what determine our actions, depriving us of conscious choice. Obviously, the answer to this question goes beyond any intellectual curiosity to key social concepts like personal responsibility. So it is important that you know that not everyone agrees that we are driven by unconscious forces beyond our control. Besides the discussion in Mitchell's book, I also recommend another new book, Open Searching for the Truth about the Unconscious Mind by Ben Newell and David Shanks. Newell and Shanks argue that the role of the unconscious in behavior has been highly exaggerated. I will come back to this later when I talk about my conversation with Luis Pessoa. Clearly, the question of free will is important, probably even more important than understanding how the brain generates consciousness. That's why I encourage you to read Kevin Mitchell's book Free How Evolution Gave Us Free Will. Now let's return to the beginning of the year, which started with two conversations with molecular biologist Guy Caldwell from the University of Alabama. Episode 204 was an encore episode featuring Dr. Caldwell's first appearance on Brain Science. Back in 2009, I actually heard Guy speak at a conference on Parkinson's disease, and I invited him. I invited him on Brain Science to talk about his work with the famous roundworm C. Elegans. Since I first talked with Dr. Caldwell, Molecular Biology has become increasingly important in neuroscience. That's why I asked him to come back on the show for episode 205. There's quite a bit of overlap between these two conversations, so I'm going to focus on the key ideas without discussing the episodes separately. According to Guy Caldwell first of all, what is molecular biology? According to Guy Caldwell, molecular biology is the study and analysis of the molecules that produce DNA, rna, and the proteins that are the components of the cell. In other words, molecular biology is the study of the molecules of life. Molecular biology should not be confused with genetic engineering, even though today many molecular biologists do genetic engineering when they manipulate the genes of whatever they are studying. Caldwell pointed out that the whole field of biotechnology has emerged from molecular biology he also says that he continues to believe that studying molecular biology is one of the finest backgrounds to launch into other fields of biology or medicine, because, as he said, in biology, everything is DNA. One of the key tools that molecular biology has developed is the use of green fluorescent protein to tag specific cells or proteins within a cell. When we first Talked back in 2009, Caldwell's mentor, Martin Chaffee, had just shared the 2008 Nobel Prize for this groundbreaking technique. Another tool that has emerged since we first talked is optogenetics. Molecular biologists can actually manipulate the genes of the cells they want to study so that they are essentially turned on or off by specific wavelengths of light. Talking with Dr. Caldwell also highlights the idea of a model organism. A model organism is a non human species that is used to model some aspect of human disease or physiology. The use of model organisms has become increasingly sophisticated as molecular biologists have learned to take advantage of the genes we share with other species. This is one reason why molecular biology has become an indispensable tool of 21st century neuroscience. Dr. Caldwell's work involves using C. Elegans as a model for studying Parkinson's disease, which involves loss of dopamine neurons in critical brain structures called the basal ganglia. C. Elegans has several unique features. First, every worm develops exactly the same way. This may be one reason why it was targeted as one of the first organisms to have its genome sequenced, and it was the first to have its entire wiring diagram determined. That project took about 10 years and required the tedious work of tracing neurons via photographs from electron microscopy. This was a landmark achievement that also illustrates that knowing the wiring diagram leaves many unanswered questions. Even when an organism's connections remain unchanged during its short life, C. Elegans makes a good model for Parkinson's disease because it's transparent and it only has eight dopamine neurons. Its transparency allows the dopamine neurons to be visualized using green fluorescent protein. C. Elegans shares about 50% of its genes with humans, which isn't much, all things considered, but it is thought that it has genetic homologs for 80 to 90% of the human genes associated with neurologic diseases. This means researchers can put human genes into C. Elegans and get important results. With these unique features in place, researchers can manipulate the genes and expose the worm to a wide variety of substances, including those that might be potential treatments. Experiments with C. Elegans have also uncovered genes that were not previously known to be involved in Parkinson's disease. Besides Talking about why C. Elegans is a great model for studying Parkinson's disease, we talked about how this approach can complement gene wide association studies and computational methods to determine which genetic changes are actually likely to be clinically relevant. Caldwell called this a predictive pre clinical model. And you may have also heard of the term personalized medicine or precision medicine. This refers to the idea that each of us could have our medical care tuned to our particular genetic makeup. This is still mostly a dream, but rapid progress is being made, especially in the area of cancer treatment. Let's review the key ideas from our conversations with Guy Caldwell. First, working with so called modeled organisms like C. Elegans and fruit flies contribute to key discoveries that that are an important part of making the dream of personalized medicine a reality. This is why understanding neuroscience requires approaching the subject at many levels, ranging from the molecular all the way up to the whole person. Another key idea is the importance of the fact that all life uses the same building blocks. This is what makes modern biology and modern neuroscience possible. These building blocks are what molecular biologists study. I think that Dr. Caldwell's story illustrates that if you're passionate about neuroscience, you can use your particular background to find a way to contribute. It also reminds us how important interdisciplinary approaches are to contemporary neuroscience. Next we have episode 206 with Paco Calvo of the Minimal Intelligence Lab at the University of Murcia and in Spain. Calvo is the author of the New Science of Plant Intelligence. He begins his book by describing an experiment in which a mimosa plant is anesthetized or put to sleep. This meant that the plant stopped responding to its environment and that the electrical activity that can usually be measured disappeared. He pointed out that even bacteria can be put to sleep by the same molecules. This is because the key signaling molecules appear nearly as old as life itself. Given this reminder of our ancient connection to plants, we considered the question of why we generally seem to be blind to the possibility of plant behavior. The most obvious reason is is that plants are living on a much slower time scale. Calvo alluded to the fact that we are wired to react to motion, but he forgot to mention a key point that he had in the book, which is that we don't generally see plants as potential threats since they rarely attack. Studying plant behavior obviously requires time lapsed photography, although it was actually pioneered by Darwin. And he tells us some of the innovative things that Darwin actually did to demonstrate plant behavior a long time ago. Anyway. Cava points out that considering the possibility of intelligent plant behavior challenges Deeply ingrained assumptions that humans are special. He said sapiens is all over the place. Sapiens has to do with the tree of life itself. Any form of life has got to be sapiens, otherwise it wouldn't be here. The most obvious argument against plant intelligence might be that they lack neurons. But as artificial or computer intelligence has become more and more a part of our daily lives, that seems less convincing. Cava pointed out that neurons are not required for information processing. He said the body itself is also about information processing. But action potentials or voltage spikes can actually be measured in plant cells because voltage spikes simply represent exchanges of charged ions across cell membranes. Of course, the plant time scale is again much slower and the voltages are much smaller. As I mentioned before, plants use the same molecules as animals. The molecules are called neurotransmitters in animals. Plants also have circadian rhythms based on melatonin. And this melatonin is the same molecule that we see in animals. Of course, the presence of these molecules should not be surprising given that they are present in fungi and even bacteria. Many of these molecules are transmitted by the so called vascular system of the plant. And as Dr. Calva pointed out, scientists tend to be blind to the the possibility that information is also being transmitted. So if we're going to claim that plants are intelligent, what would that mean? How do we conclude that an animal is intelligent? We look at their behavior. It is generally assumed that whatever behaviors plants do have is merely reflexive. In order for behavior to be intelligent, it has to be adaptive and flexible. It has to be influenced by past experience, not genetically determined. It has to be proactive, anticipatory and predictive. Cavell pointed out why this is important. If you're a slow moving plant, your actions have got to fit the conditions that are going to exist in the future. The easiest example of this would be predicting where the sun is going to be, which would be goal directed. This is probably the simplest example of intelligent behavior, because some species of plants can predict where the sun is going to be. And it's interesting to note that not all plants can do this, just the ones that are highly dependent on the amount of sunlight they receive. Calvo pointed out that domesticated plants are rather dumb. And this reminded me that scientists did not really appreciate how smart many animals were until they began to study them in wild environments where their intelligence was needed for survival. Finally, he mentioned the idea of embodied cognition. We need to realize that the body and the environment are equally important as the brain. In the case of plants, he mentioned the four embodied, embedded, extended, and inactive. Embodied cognition is actually one of my favorite topics. Recent episodes about embodied cognition include episode 193, 198, and episode 200. The evidence clearly favors the conclusion that plants demonstrate embodied cognition based on the simple definition that cognition implies choice over reflex. One topic that remains unresolved is the question of whether plants are capable of associative learning. This, of course, is a higher bar closer to the question of consciousness than intelligence. The New Science of Plant Intelligence by Paco also contains an extensive discussion of the contributions of Charles Darwin, a discussion of the electrical activity in plants, the role of various molecules that we think of as neurotransmitters, and a discussion of how plants communicate in the absence of neurons. When studied with sufficient rigor, it becomes clear that plants are intelligent. It seems a shame that this fascinating discovery has been virtually possible, buried in the controversy that swirls around the issue of plant consciousness. Rather than fueling that fire, I would like to see researchers focus on plant intelligence and what those discoveries can teach us. The New Science of Plant Intelligence by Paco Calvo does contain a detailed discussion of the controversial idea of plant consciousness. I encourage you to listen to episode 206 to hear my reflections on that topic. Next, I'm going to jump ahead slightly to episode 208 featuring Xander Van der Linden, author of why Misinformation Infects Our Minds and How to Build Immunity. This is an example of why I don't think psychology can be replaced by neuroscience. At the beginning of today's review, I alluded to some of the problems with psychology research, but in the end, most of us do want to know why we act the way we do, which is what psychologists are trying to understand. No doubt you have noticed the recent spread of misinformation and conspiracy theories. According to van der Linden's book Foolproof. The good news is that there really is something we can do about this problem, even though the techniques being used do seem to be becoming more and more sophisticated. The key principle is to build our awareness and our ability to recognize manipulative techniques. Studying conspiracies is a good place to start because this is where the principles are more easily recognized. Van der Linden uses the letters in the word conspire as a mnemonic. The first C is for contradictory thinking, O is for overriding suspicion, N is for nefarious intent, S is for something must be wrong, P is for persecuting victim, I is for immunity to evidence, and R is for reinterpreting randomness. Those who embrace conspiracy theories, tend to have similar psychological traits and often believe in multiple contradictory theories. I never used to take conspiracy theories seriously since it doesn't really matter if someone believes that the moon landing was a hoax. However, if they refused to be vaccinated despite the scientific evidence that vaccines are the best way to prevent serious infectious diseases, this can cost the lives of others. As a physician, I feel compelled to say that vaccines are one of the most important discoveries in medical history. When someone decides not to be vaccinated, their choice affects those around them, not just because herd immunity requires a high level of vaccination, but because there will always be those who can't be vaccinated or whose immune systems are too weak to respond properly. This is an issue of science and public health, not politics. Given the role that conspiracy theories have played in vaccine hesitancy, I wanted to have a better understanding of how they work. Dr. Benderlinden mentions the games his groups have developed. One of these games tasks the player with creating and spreading a conspiracy theory. In the book he describes this game and how it appears to generate at least a partial immunity against conspire tactics. Next, he moved to the basic techniques that are used to spread misinformation in general. In contrast to facts backed by evidence, misinformation is easily spread by being more novel, using more language, using emotional language, and being more provocative. A person might spread something because they say, oh, this would be interesting if it was true. Other techniques include false dichotomies, scapegoating, using emotions to polarize, and fake experts. He gave examples of all of these in the interview. Now I just gave you a relatively boring list that you're probably not really going to remember, so I suggest that you go to the website Inoculation Science where there are videos and there are three different games that you can try out. Next up, I'm going to review View two episodes featuring Luis Pessoa from the University of Maryland. We first talked back in early 2014 about his book the Cognitive Emotional From Interactions to Integrations. The key idea from this book is that seeing the brain as having separate systems of modules for emotion and cognition is obsolete because emotion and cognition are deeply intertwined at every level. The Cognitive Emotional Brain was written for students and working scientists, but I think these principles are important for everyone to understand. Our conversations focused on two parts of the brain, the amygdala and the pulvinar nucleus of the thalamus. The amygdala is in the medial temporal lobe near the hippocampus. To visualize the location of the amygdala. Just imagine pointing in from your ears. The thalamus is at the very top of the brain stem, and the pulvinar is its largest nucleus. The amygdala is more complex than you might imagine from its portrayal in mainstream media. It can be divided into as many as 12 parts. But we talked about the two main parts. The lateral amygdala, which is almost cortex like and highly connected to the cortical regions of the brain. The central or more medial amygdala, which is more primitive and connects to the brainstem, which controls autonomic functions. Autonomic functions like breathing and blood pressure. You've probably heard of the amygdala because of its connection to fear and other negative stimuli. But the amygdala is about much more than fear. It's involved in attentional functions such as arousal and vigilance, as well as value representation, which means it's involved in simple decision making. The key idea here is that cognition begins before you get to the cortex. Emotion and cognition can't be separated in terms of where they occur in the brain. Another key idea is the fact that the amygdala does respond to both positive and negative stimuli. Returning to my key idea that it's not just about fear. It's interesting to realize that the responses of the amygdala track perceptual responses. That means that the amygdala is influencing what we see and what we pay attention to. But it is also important to realize that the amygdala is not acting alone, but it is an important part of what you might think of as the brain's attentional network. We also talked about the pulvinar nucleus of the thalamus. And a nucleus is just a cluster of neurons. The thalamus is located at the very top of the brain stem, which is to say, at the base of the brain proper. It has long been thought to be the major relay station between the brain and the body. But Dr. Pessoa and his colleagues have challenged this view. He has specifically challenged what is called the standard hypothesis, which is that there is a so called load road by which sensory information goes rapidly from the periphery to the thalamus, through the thalamus, straight to the amygdala. The assumption being that this is faster and also essentially unconscious. The challenge to this is based on research that goes against all these basic elements. First, there is evidence the amygdala is more involved in attention and awareness than we thought. And second, it has been shown that the pathways involving the cortex are faster than was originally assumed, so that we don't need this low pathway from a speed standpoint. Finally, the anatomy just doesn't support the idea that the thalamus is a mere relay station. It has extensive connections to many parts of the cortex, including the various sensory areas and the frontal lobes, and these connections go in both directions. This evidence is incorporated into Pessoa's multiple waves model, which reflects that the amygdala receives information not just from the thalamus, but also from various parts of the cortex. The reason we focused on the pulvinar is that it's the largest thalamic nucleus and it processes visual information, and vision has been the most extensively studied. So what is the function of the pulvinar if it's not a relay station? First, it responds only to stimuli that are consciously perceived. Pessoas said that it helps amplify signals that are important to the organism. The fact that it has extensive connections to virtually the entire cortex is particularly relevant to this function. Pessoa also said that instead of thinking of the pulvinar and the rest of the thalamus, by implication as a passive relay, we should think of it as what he called a central hub of communication because it connects both the cortex and the brainstem, returning to the amygdala for a few minutes. In terms of its role in visual processing, the key idea to remember is that it has extensive connections in both directions to all the various visual areas of the brain, ranging from the primary visual cortex to the association areas. It has a key role in determining what we see and what we pay attention to. This brings me back to the most important idea of this episode, which is that the emotional and cognitive processes of the brain are deeply intertwined at every level. That's why this book is called the Cognitive Emotional Brain. There were a few important topics in the book that we didn't have time to discuss, such as what happens in the prefrontal cortex, where there is mounting evidence that cognitive and emotional processes are not segregated as has long been assumed. And also, we didn't talk about network theory, which I have explored several times with Olaf Spornes Poissoan. Sporns share the opinion that network theory is essential for understanding the complex functions of our brain, because no one section can carry out its function in isolation. So I replayed that 2014 interview with Louis Pessoa to prepare listeners both old and new, for his new book, the Entangled How Perception, Cognition and Emotion Are Woven Together. If you are a regular listener. You may not find this idea surprising, but Pessoa reminds us that the mainstream view of brain function remains largely modular and reductionistic. In fact, the two ideas are entangled in their own way. The evidence against this viewpoint began accumulating before I started this podcast in 2006, and I've talked with many guests about this evidence. One key discovery was the realization that individual neurons can participate in multiple networks and that even areas of the brain largely devoted to particular activities, such as sensory or motor functions, can contain neurons that do other things. Back when I first talked with Dr. Pessoa about his book the Cognitive Emotional Brain in 2014, I was surprised to learn that the amygdala is involved not just in emotion, but also decision making. But this actually makes sense if you consider the fact that animals without a cortex still have to make decisions, such as when to approach and when to flee. One outdated idea that just won't go away is the idea of the limbic system. As the emotional system of the brain addressed this eloquently in the Entangled Brain, but he told me that he was actually reluctant to mention this in the book for fear of helping perpetuate the problem. The main reason that the idea of the limbic system is outdated is the very fact that emotion is not tightly segregated in the brain. Sure, the amygdala is involved, as well as the anatomical locations that spawned the name limbic system. But as we have emphasized, emotion and cognition think decision making are deeply entangled at every level of the brain. Just try to remember that every part of the brain that is involved in emotion does other things as well. This is what it means to move from a modular, reductionist view of brain function to one that encompasses the emerging evidence. One challenge that Pessoa emphasized was the need for new tools and techniques that allow us to study the true complexity and dynamic nature of brain function. These techniques are being developed in other fields, which highlights the interdisciplinary nature of modern neuroscience. Pessoa emphasized that this also means there are opportunities for those from a wide variety of fields to contribute to neuroscience. In retrospect, Pessoa made one other observation worth there's been a trend toward discovering that processes that have been presumed to be unconscious actually involve some level of attention and awareness. Much depends on how experiments are designed and how things are measured. I think this is one reason why Pessoa emphasized the need for humility and appreciation for how little we really know about how the brain really works. The entangled brain, how perception and emotion are woven together, is Louis Pessoa's first book written for a general audience, but I highly recommend it to listeners of all backgrounds. Best of all, this is a great book to share with someone who's just getting interested in how the brain works. If you are new to brain science, the Entangled How Perception, Cognition and Emotion Are Woven Together by Luis Pessoa will give you an excellent overview.
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Episode 210 was my first review of neurotransmitters since episode 8 back in 2007. Unfortunately, this episode did not turn out to be as accessible to new listeners as I had intended. Even so, there are a few key ideas that are definitely worth knowing. Even though the key to signaling in the brain is the electrical spike known as an action potential, the end result of each spike is the release of a signaling molecule called a neurotransmitter, and neurons may be identified by what neurotransmitter they release. An example of this is the dopamine neurons we talked about with Guy Caldwell. This is also why the gap between neurons known as the synapse is so important. After the neurotransmitter is released, it crosses the synapse and interacts with the receptors on the so called postsynaptic neuron. This postsynaptic neuron integrates all the incoming signals. It might generate its own action potential, but if the incoming signals are inhibitory, it might be prevented from firing. The key idea to remember is that it's actually the receptors that determine what happens next. That is why a molecule like dopamine can have different actions not only in different parts of the brain, but also outside the brain where it helps regulate circulation and blood pressure. Calling dopamine the reward molecule completely distorts its complex role. Dopamine is one of several ancient signaling molecules that have been around since the emergence of single celled life. It was the increasing complexity of the receptors that allowed complex organisms and even brains to emerge. I will come back to this when we talk about my most recent interview with molecular biologist Seth Grant. Despite their complexity, there are only two basic types of receptors, ionotropic or ligand gated, and metabotropic G protein coupled. It's easy to remember which is which by remembering that the ionotropic receptors are actually ion channels that are opened and closed when the ligand, that is to say the neurotransmitter, interacts with a receptor protein in the cell membrane. Since this is a direct effect, it can occur fairly quickly on the order of a tenth of a millisecond. In contrast, the metabotropic G protein coupled receptors use one or more so called second messengers to kick off everything from indirectly opening and closing channels to changing gene expression. And while the actual synaptic transmission is only slowed down to about 0.5 to 3 milliseconds, the actual effects may occur much later, especially in the case of gene regulation. I send you back to this episode210 if you want to hear my discussion of specific neurotransmitters like glutamate and gaba. The most important principle is that each neurotransmitter has many complex functions that are determined by which receptors it binds to and where those receptors are located. It is inaccurate to describe any neurotransmitter by a single action. Again, don't think of dopamine as the reward molecule because although it is important in the reward circuits of the brain, it's not the only thing it does. It's really all about the receptors. In episode 211 we talked with molecular biologist Seth Grant. From the beginning, Brain Science has been a book focused show, so it is surprising that the guest who has appeared the most is molecular biologist seth Grant. Episode 211 was his sixth appearance. I'm about to do a review of this episode, which actually is the first review anyone will have heard, because when I was doing episode 211 around the time I was moving to, I think I recorded it just the intro outro after I came here to New Zealand and somehow I managed to leave out this actual episode review. So I apologize for that. Here it is now. It's always inspiring to talk with Seth Grant because not only is his work fascinating, but he's extremely good at making it accessible to everyone. In this episode we looked over 30 years of his career, which include helping to create the first transgenic mice back in 1992. The reason this is important is that humans and mice share many of the same genes, including most of the genes that code for the proteins of the nervous system. With transgenic mice, it's possible to introduce gene mutations that are known to be associated with problems in humans and explore not only how they affect behavior in mice, but also develop techniques to study what is happening at the level of the single synapse the most basic principle of genetics is that genes code for proteins and proteins are the machinery of life. So early on, Grant was interested in the proteomics of the synapse. He wanted to identify all the proteins in the synapse and he started at a time when only 10 had been identified and it was assumed that all synapses were identical. Grant made two surprising discoveries. One was that synapses actually contained thousands of proteins. And most surprising of all, many of the proteins that are critical to synapse function are present in single celled organisms like fungi. This means that the proteins came before the evolution of the nervous system. This was the discovery that blew me away when I first talked to him back in 2008. Grant also appreciated the discovery made by other scientists that the Cambrian explosion was probably triggered by two duplications of the entire genome, which provided the toolkit for the evolution of vertebrates. Back in episode 101 we talked about experiments that made direct use of this concept by creating knockout mice for the so called DLG genes that code for scaffolding proteins in the synapse. Not surprisingly, knocking out the most ancient form of this gene caused death, while knocking out the second oldest one caused severe learning and memory deficits. Knocking out either of the two newest genes had opposite and lesser but equally interesting effects. Over the last several years I've talked to Grant about his follow up experiments. In episode 137 he described a study that revealed gene expression of proteins in the brain follows a pattern that is like a calendar. I encourage you to listen to that episode for the details. In episode 150 he described the first synaptone of the mouse. The goal was to map protein diversity among post synaptic synapses throughout the brain. The map describes two of the main proteins, BSD95 and SAP102. But using just two proteins they identified 37 different types of synapses. Given that there are actually about 1,000 known proteins, the possibilities are literally endless. Most recently in episode 176, Grant described the distribution of PSD 95 changes throughout the lifespan. That brings us to his most recent paper, a brain atlas of synapse protein lifetime across the mouse lifespan. This is in Neuron and is freely available online. You will find a link in the show Notes the question addressed in this latest paper was how long do the individual proteins last? Grant's lab used an irreversible tagging technology that made it possible to see how long molecules of BSD 95 remain within a single synapse. Two key principles emerged. Some proteins are short lived hours to days, while others last weeks to months, possibly until death. Secondly, as the mice age, the number of long lived proteins increase and the turnover of the short lived proteins diminishes. The long lived proteins seem to be more prominent in areas involved in memory and higher cognitive functions. Finally, when they did the same experiment in animals with a mutation associated with autism and schizophrenia, the number of long lived proteins increased. What we've learned is that synapses are more complex than scientists ever imagined, and this has important clinical implications for understanding neurologic diseases and creating more effective treatments. Synapse complexity appears to have predated the evolution of the nervous system and brains. The distribution of the individual proteins in the synapse follows a predictable pattern both in mice and humans, and this includes the newest piece of the puzzle which was presented in the latest paper which showed that long lived proteins increase as the animal ages and more long lived proteins are also seen in the mouse model for autism and schizophrenia Whether you are a new or longtime listener, I encourage you to go back and enjoy episode 211 with Seth Grant. Now we come to episode 212, which was the third encore episode played this year with philosopher Thomas Metzinger, who I talked to in 2010 about his book the Ego the Science of the Mind and the Myth of the Self. I want to begin my review by thanking Thomas Metzinger for taking the time to talk with me. Since our original conversation back in 2010, I've talked to numerous philosophers and neuroscientists about consciousness, but Metzinger stands out for his original thinking. When we first talked, the key idea that stood out for me was his claim that any valid theory of consciousness should include an explanation of altered states. He emphasized that consciousness is a biological process and this includes the experience of selfhood. The ego tunnel is a metaphor for the fact that our conscious experience is internally generated by the brain and limited to a small portion of what's actually going on. Metzinger also touched on the question of the function of consciousness, but here he agrees with many others who assume that consciousness allows more flexible behavior. As I read through the original episode transcript, I developed a new appreciation for the depth of our conversation. Over the years I have become very interested in the role of embodiment, so that aspect of our discussion now stands out for me. For example, in describing virtual reality and out of body experiences, Metzinger emphasized the role of the body. He pointed out that during the typical out of body experience, one is usually body blind and how moving and how moving can rapidly end and how moving can rapidly end the out of body sensation during a virtual reality experiment. If you're interested in learning more about the recent experiments with virtual reality, I recommend episode 188 with neuroscientist Anil Seth. We talk about his book Being a New Science of Consciousness. I intentionally released this encore episode right before last month's discussion of Free will with Kevin Mitchell. I think it is important to realize that the scientific question of how brains generate consciousness has important consequences for how we see ourselves and our responsibility toward others. I also want to mention that Metzinger has a new book coming out in February 2024 entitled the Elephant and the the Experience of Pure Consciousness, philosophy, science and 500 plus experiential reports. I don't yet have a review copy of this, so I don't know much about Seemed fitting to end this review with a discussion of an episode about consciousness since this was the topic that began my exploration of neuroscience about 20 years ago. I want to conclude this 17th annual review episode by thanking you for listening and supporting my work, both financially and by sharing it with others. As many of you know, I moved from the United States to Auckland, New Zealand in August 2023. When this episode airs, I will have been here for about four months. I'm working full time as a physician at the Totara Hospice in South Auckland, so I haven't had much time to explore New Zealand. Therefore, I've made the difficult decision to stop producing brain science so that I can fully immerse myself in this new experience. Episodes of Brain Science will continue to remain available, including both free and premium content. Free content includes all episodes posted since December 2016, as well as all the year end episode summaries and encore episodes. The MyLipson Premium subscription gives you access to all episodes and transcripts going back to December 2006. About 10 years of content for $10 a month. Patreon supporters will also continue to have access to more recent transcripts. I want to thank everyone who has supported my work financially over the last few years. I know that some of you will need to cancel your subscriptions, but if you are able to continue, it will help me maintain the website and hosting that allows the show to reach new listeners. If you are a new listener, I recommend MyLipson Premium both for access to early episodes but also for transcripts. The first two years of content seem to be especially helpful to those who are new to neuroscience. If you'd like to learn more, please go to brainsciencepodcast.com premium I also want to encourage everyone to stay subscribed to the free Brain Science newsletter so that I'll be able to send you updates and let you know if I post any special episodes. If you aren't already subscribed, just text brain science, all one word to 55444. That's brain science. All one word to 55444. You'll get a free gift entitled five things you need to know about your brain. There's also a link in the show notes and@brainsciencepodcast.com one of the most rewarding things about producing Brain Science for the last 17 years has been getting to interact with listeners from around the world. I want to express my deepest gratitude to those of you who have shared this journey. I will continue to try to answer all listener emails@brainsciencepodcastmail.com I'm also still hoping to have some listener meetups in Australia and New Zealand, so please let me know if you're interested. Thanks again for listening and I wish you all the best. Brain Science is copyrighted to Virginia Campbell, MD. You may copy this episode to share it with others, but for any other uses or derivatives, please contact me at Brainsciencepodcast@gmail.com. the theme music for Brain Science is Mindfire, written and performed by Tony Katracchia. You can find his work at syncopationnow. Com.